Ultra-short-acting neuromuscular blocking agent, preparation method therefor, and use thereof

Abstract

The present invention relates to a biquaternary ammonium salt compound having an ultra-short-acting neuromuscular blocking function. In particular, the present invention relates to a compound represented by general formula (I-2), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of the stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof. The present invention also relates to a pharmaceutical composition containing the compound, a preparation method therefor, and the function and use thereof in neuromuscular blockade. Each substituent in the general formula (I-2) is as defined in the description.

Description

An ultra-short-acting neuromuscular blocking agent and its preparation method and use

[0001] This application claims priority to Chinese Patent Application No. 202411054280.4, filed on August 2, 2024, and No. 202411591598.6, filed on November 8, 2024, the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a bis-quaternary ammonium salt compound with ultra-short-acting neuromuscular blocking function. The present application also relates to the preparation method of the bis-quaternary ammonium salt compound, pharmaceutical composition, and its function and use in neuromuscular blocking. BACKGROUND

[0003] In modern anesthetic practice, neuromuscular blocking agents (NMBAs) are indispensable drugs, which are mainly used to block the transmission of excitation at the neuromuscular junction, causing muscle paralysis. These drugs are widely used to assist endotracheal intubation, mechanical ventilation, and maintain muscle relaxation during various surgical procedures. According to the mechanism of action, NMBAs can be divided into two categories: depolarizing and non-depolarizing. The typical representative of depolarizing NMBAs is succinylcholine, which inhibits neuromuscular transmission by continuously depolarizing motor endplates, and has the characteristics of rapid onset and short duration. Non-depolarizing NMBAs produce muscle relaxation effects by competing with nicotinic acetylcholine receptors, including the benzylisoquinoline class of succinylcholine and mivacurium, and the aminosteroid class of rocuronium, vecuronium, pipecuronium, and pancuronium.

[0004] In clinical practice, depolarizing neuromuscular blocking agents (NMBAs), such as succinylcholine, although have rapid onset, are accompanied by some serious side effects, including elevated serum potassium, muscle tremors, malignant hyperthermia, arrhythmia, and increased intraocular pressure, which limit their use in certain cases. In contrast, non-depolarizing NMBAs have fewer side effects, but most of them are intermediate or long-acting drugs, such as succinylcholine and rocuronium, which have a duration of action of 40 to 60 minutes, while pancuronium has an even longer duration of action of more than 60 minutes. These NMBAs are usually used for surgeries that require longer muscle relaxation times. From the perspective of clinical duration of action, NMBAs can be classified as ultra-short-acting (less than 10 minutes), short-acting (10 to 20 minutes), intermediate-acting (20 to 50 minutes), and long-acting (more than 50 minutes). The choice of ultra-short-acting NMBAs on the market is very limited, mainly succinylcholine. Since non-depolarizing NMBAs are mostly intermediate and long-acting, their application in emergency or short procedures is limited, highlighting the importance of more ultra-short-acting NMBAs in these clinical situations.

[0005] Therefore, this invention aims to provide a novel neuromuscular blocking agent that combines the rapid onset of action with the safety of non-depolarizing NMBAs to fill a gap in current clinical needs and reduce the risk of side effects associated with existing drugs. The development of this novel neuromuscular blocking agent will provide a safer and more effective drug option for a wide range of clinical applications. Summary of the Invention

[0006] This invention relates to a compound represented by formula (I),

[0007] Or its stereoisomers, pharmaceutically acceptable salts or cocrystals, pharmaceutically acceptable salts or cocrystals of its stereoisomers, its solvates, its prodrugs, its deuterated derivatives, or its metabolites, wherein,

[0008] Y is selected from

[0009] Y1 is selected from -C(R) Y1A )2-, and -N(R Y1B )-;

[0010] R 1A R 1B R 2A R 2B R 2C R YA R YB R Y1A 、or R B Each is independently selected from hydrogen, halogen, -C 1- 6-alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-6 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-6 alkyl), -S(C 3-7 cycloalkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1- 6-alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1- 6-alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Alkyl), 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl, and 5-14 membered heteroaryl; wherein each (R) 1A R 1B R 2A R 2B R 2C R YA R YB R Y1A 、or R B )Optionally selected by one or more halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, -NO2, oxo, -NH2, -NH(C) 1- 6-alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6-alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1- Substituents of 6-alkyl, 3-14-membered carbocyclic, 3-14-membered heterocyclic, 6-14-membered aryl and 5-14-membered heteroaryl groups;

[0011] Optional, (R) 1A and R 1B ), (R 2A and R 2B ), or (R 2B and R 2C Together with the C atoms respectively connected to it, they form an optional n S3 R S3 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-14 membered aryl rings or 5-14 membered heteroaryl rings;

[0012] Optional, 2 R YA Together with the C atoms respectively connected thereto, they form an optional n S4 R S4 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-14 membered aryl rings or 5-14 membered heteroaryl rings;

[0013] Optional, 2 R YB Together with the C atoms respectively connected thereto, they form an optional n S5 R S5 Substituted 3-14 membered carbocyclic rings, 3-14 membered heterocyclic rings, 6-14 membered aryl rings or 5-14 membered heteroaryl rings;

[0014] Optional, 2 RY1A together with the C atom to which they are attached form a 3-14 membered carbocyclyl ring, a 3-14 membered heterocyclyl ring, a 6-14 membered aryl ring, or a 5-14 membered heteroaryl ring, each of which is optionally substituted with n S6 R S6 substituted 3-14 membered carbocyclyl ring, and 3-14 membered heterocyclyl ring;

[0015] optionally, the fragment , together with the ring atom and its attached substituents, the C atom in (-C(R Y1A )2- and R Y1A ), or the N atom in (-N(R Y1B )- and R Y1B , form a 3-14 membered carbocyclyl ring, a 3-14 membered heterocyclyl ring, a 6-14 membered aryl ring, or a 5-14 membered heteroaryl ring, each of which is optionally substituted with n S7 R S7 substituted 3-14 membered carbocyclyl ring, and 3-14 membered heterocyclyl ring;

[0016] each R A , or R Y1B is, at each occurrence, independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CHO, -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, 3-14 membered carbocyclyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; wherein each R A , or R Y1B is optionally substituted with one or more selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -O-C 1-6 haloalkyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1- 6alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1- 6-alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 Substituents of alkyl, 3-14 membered carbocyclic, 3-14 membered heterocyclic, 6-14 membered aryl, and 5-14 membered heteroaryl groups;

[0017] Each R C Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Haloalkyl, -(C 0-6 alkylene)-(3-14-membered carbon cycloyl), -(C 0-6 alkylene)-(3-14 membered heterocyclic group), -(C 0-6 alkylene)-(6-14 aryl), -(C 0-6 (alkylene)-(5-14-membered heteroaryl); wherein each R C Optionally by n SC R SC Instead, the R SC Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6haloalkyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1- alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), 3-14 membered carbocyclyl, 3-14 membered heterocyclyl, 6-14 membered aryl, and 5-14 membered heteroaryl;

[0018] n SC is selected from 0, 1, 2, 3, 4, 5, and 6;

[0019] each n1, n2, n3, n4, or n5 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0020] each n6, n7, n8, or n9 is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0021] and n6 + n7 + n8 + n9≤ 6;

[0022] each (RS1 R S2 R S3 R S4 R S5 R S6 R S7 R S8 ) is independently selected at each occurrence from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C 1-6 haloalkoxy, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C1-6 alkyl)S(=O)2(C 1-6 alkyl), -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein each (R S1 , R S2 , R S3 , R S4 , R S5 , R S6 , R S7 , or R S8 is independently optionally substituted with one or more selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C 1-6 haloalkoxy, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 haloalkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1- 6alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1-6 alkyl), -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl;

[0023] each n S3 , n S4 , n S5 , n S6 , n S7 , or n S8 is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0024] each heterocyclyl independently comprises 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S at each occurrence;

[0025] each heteroaryl independently comprises 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S at each occurrence.

[0026] In some embodiments, the compound of Formula (I) is a compound of any one of Formula (I-1) to Formula (I-5):

[0027] Further preferred are compounds of any one of Formula (I-1-A) to Formula (I-5-A):

[0028] or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof;

[0029] wherein each R 1A , R 1B , R 2A , R 2BR 2C R A R B R C ,n1,n2,n3,n4,n5,n6,n7,n8,n9,n 10 n 11 n 12 n 13 n 14 n 15 n 16 n 17 n 18 m, X z- Y, Y1, R S1 R S2 R S6 R S7 R S8 n S6 n S7 and n S8 The definition is the same as that of formula (I).

[0030] In some embodiments, the compound represented by formula (I) is a compound represented by any one of formulas (II-1), (II-1A), (II-2), (II-2A), (II-3), and (II-3A):

[0031] Further preferred compounds are those represented by any one of the formulas (II-1-1), (II-1A-1), (II-2-1), (II-2A-1), (II-3-1), and (II-3A-1):

[0032] Or its stereoisomers, pharmaceutically acceptable salts or cocrystals, pharmaceutically acceptable salts or cocrystals of its stereoisomers, its solvates, its prodrugs, its deuterated derivatives, or its metabolites;

[0033] Among them, each R 1A R 1B R 2A R 2B R 2C R SC R A R B R C ,n1,n2,n3,n4,n5,n6,n7,n8,n9,n 10 n 11 m, X z- R S1 RS2 , R S6 , R S8 , n SC , n S6 , and n S8 are as defined for formula (I).

[0034] In some embodiments, the compound of formula (I) is a compound of any one of formula (III-1), formula (III-1A), (III-2), to formula (III-2A):

[0035] Further preferred are compounds of any one of formula (III-1-1), formula (III-1A-1), formula (III-2-1), and formula (III-2A-1):

[0036] or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof;

[0037] wherein each R 1A , R 1B , R 2A , R 2B , R 2C , R A , R B , R C , R SC , n1, n2, n3, n4, n5, n6, n7, n8, n9, n 10 , n 11 , m, z, R S1 , R S2 , R S6 , R S8 , n SC , n S6 , and n S8 are as defined for formula (I).

[0038] In another aspect, the present application relates to a compound as represented by Formula (I-2), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), the general structures of Formula (I-2), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2) are shown above; further preferably a compound as represented by Formula (I-2-A), Formula (II-1-1), Formula (II-2-1), Formula (III-1-1), Formula (III-2-1), the general structures of Formula (I-2-A), Formula (II-1-1), Formula (II-2-1), Formula (III-1-1), Formula (III-2-1) are shown above; or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0039] Y is selected from

[0040] R YB is independently selected at each occurrence from hydrogen, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 haloalkyl, -O-C 1-3 haloalkyl, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 alkyl), -O(C 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), -S(C 3-7 cycloalkyl), -C(=O)(C 1- 3alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -S(=O)(=NH)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1- 3alkyl)2, -NHC(=O)(C 1-3 alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 alkyl)2, -NHS(=O)(C1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl;

[0041] each (R 1A , R 1B , R 2A , R 2B , or R 2C ) is, at each occurrence, independently selected from hydrogen, halogen, -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C 1-3 haloalkyl, -O-C 1-3 haloalkyl, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -S(=O)(=NH)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1- alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 alkyl)2, -NHS(=O)(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl;

[0042] optionally, (R 1A and R 1BTogether with the C atoms respectively connected to it, they form an optional n S3 R S3 Substituted 3-7 membered carbocyclic groups, 3-7 membered heterocyclic groups, phenyl groups, or 5-10 membered heteroaryl groups; wherein, n S3 Selected from 0, 1, 2, 3, and 4;

[0043] Optional, (R) 2A and R 2B Together with the C atoms respectively connected to it, they form an optional n S3 R S3 Substituted 3-7 membered carbocyclic groups, 3-7 membered heterocyclic groups, phenyl groups, or 5-10 membered heteroaryl groups; wherein, n S3 Selected from 0, 1, 2, 3, and 4;

[0044] R A 、or R B Each time it appears, it is independently selected from hydrogen, -C 1-4 Alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl group, -C 1-3 Haloalkyl, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered carbocyclic, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, the R A 、or R B Optionally, it is selected from one or more halogens, -C 1-3 Alkyl, CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -C(=O)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-3 Alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Substituents of alkyl groups (2, 3-7 membered carbon cycloyl groups, 3-7 membered heterocyclic groups, phenyl groups, or 5-10 membered heteroaryl groups);

[0045] R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Haloalkyl, -(C 0-3 alkylene)-(3-7 membered carbon cycloyl), -(C 0-3 alkylene)-(3-10 membered heterocyclic group), -(C 0-3 alkylene)-phenyl, -(C 0- 3-alkylene)-(5-10 heteroaryl); wherein, each R C Optionally by n SC R SC Instead, the R SC Selected from halogens, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl, -CN, oxo, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(C 1- 3-alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl), -C(=O)OH, -C(=O)(OC 1-3 Alkyl), -OC (=O)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1- 3alkyl)2、-NHC(=O)(C 1-3 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-3alkyl), -S(=O)2N(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl;

[0046] n SC is selected from 0, 1, 2, 3, 4, 5, and 6;

[0047] n1, n2, n3, n4, n5, n6, n7, n8, n9, n 14 , or n 15 is independently selected from 0, 1, 2, 3, and 4;

[0048] n6 + n7 + n8 + n9 < 6;

[0049] n 14 + n 15 < 5;

[0050] m is 1, or 2;

[0051] z is 1, or 2;

[0052] n S6 , n S8 or is independently selected from 0, 1, 2, 3, and 4 at each occurrence;

[0053] R S1 , R S2 , R S6 , and R S8 are as defined in formula (I).

[0054] In another aspect, the present application relates to a compound as represented by formula (I-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2), the general structure of formula (I-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2) is shown above; further preferably a compound as represented by formula (I-2-A), formula (II-1-1), formula (II-2-1), formula (III-1-1), formula (III-2-1), the general structure of formula (I-2-A), formula (II-1-1), formula (II-2-1), formula (III-1-1), formula (III-2-1) is shown above; or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0055] Y is selected from

[0056] R YBEach time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl)2、-NH(C 3-7 cycloalkyl), -OH, -O(C 1-3 Alkyl), -O(C) 3-7 cycloalkyl), -SH, -S(C 1-3 alkyl), -S(C 3-7 cycloalkyl), -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl)2, -S(=O)NH2, -S(=O)NH(C 1- 3-alkyl), -S(=O)N(C 1-3 Alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-3 Alkyl), -S(=O)2N(C 1-3 Alkyl) 2-membered and 3-7-membered cycloalkyl;

[0057] In some implementations, each (R) 1A R 1B R 2A R 2B 、or R 2C Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups, and 3-7 membered cycloalkyl groups, and 3-7 membered heterocyclic groups.

[0058] Optional, (R) 1A and R 1B Together with the C atoms they are connected to, they form

[0059] Optional, (R) 2A and R 2B Together with the C atoms they are connected to, they form

[0060] R A Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -C 1-3 Haloalkyl, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered carbon cycloyl, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0061] R B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, -C1-3 haloalkyl, -C(=O)(C 1-3 Alkyl), -S(=O)(C 1-3 Alkyl), -S(=O)2(C 1-3 Alkyl), -S(=O)(=NH)(C 1-3 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-3 Alkyl), -C(=O)N(C 1-3 Alkyl) 2, 3-7 membered carbon cycloyl, 3-7 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0062] R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -(C 0-3 alkylene)-(3-7 membered carbon cycloyl), -(C 0-3 alkylene)-(3-10 membered heterocyclic group), -(C 0-3 alkylene)-phenyl, -(C 0-3 (alkylene)-(5-10 heteroaryl); wherein each R C Optionally by n SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3alkyl)2, -OH, -0(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=0)(OC 1-3 alkyl), and -OC(=0)(C 1-3 alkyl) substituted on the carbon atom;

[0063] n SC is selected from 0, 1, 2, 3, and 4;

[0064] n1, n2, n3, n4, n5, n6, n7, n8, n9, n 14 , or n 15 is independently selected from 0, 1, 2, 3, and 4;

[0065] n6 + n7 + n8 + n9 < 6;

[0066] n 14 + n 15 < 5;

[0067] m is 1, or 2;

[0068] z is 1, or 2;

[0069] n S6 , n S8 , or is independently selected from 0, 1, 2, 3, and 4 at each occurrence;

[0070] R S1 , R S2 , R S6 , and R S8 are as defined in formula (I).

[0071] In another aspect, the present application relates to a compound as represented by formula (I-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2), the general structures of formula (I-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2) are shown above; further preferably a compound as represented by formula (I-2-A), formula (II-1-1), formula (II-2-1), formula (III-1-1), formula (III-2-1), the general structures of formula (I-2-A), formula (II-1-1), formula (II-2-1), formula (III-1-1), formula (III-2-1) are shown above; or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0072] Or its stereoisomers, pharmaceutically acceptable salts or cocrystals, pharmaceutically acceptable salts or cocrystals of its stereoisomers, its solvates, its prodrugs, its deuterated derivatives, or its metabolites, wherein,

[0073] Y is selected from

[0074] R YB Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups and 3-7 membered cycloalkyl groups;

[0075] R A Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0076] R B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0077] R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -(C 1-2 alkylene)-(3-7 membered carbon cycloyl), -(C 1-2 alkylene)-(3-10 membered heterocyclic group), -(C 1-2 alkylene)-phenyl, and -(C 1-2 (alkylene)-(5-10 heteroaryl); the -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, 3-10 heterocyclic, 3-7 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally n- SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 alkyl);

[0078] n SC Selected from 0, 1, 2, 3, and 4;

[0079] Optionally,

[0080] (1) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0081] (R 2A and R 2B ) together with the C atom to which they are respectively attached form Preferably, (R 2A and R 2B ) together with the C atom to which they are respectively attached form

[0082] R 2C is independently at each occurrence -H;

[0083] (2) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0084] R 2B is independently at each occurrence -O(C 1-3 alkyl);

[0085] R 2A , or R 2C is independently at each occurrence -H;

[0086] (3) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0087] R 2A , or R 2B is independently at each occurrence -O(C 1-3 alkyl);

[0088] R 2C is independently at each occurrence -H;

[0089] (4) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0090] R 2A , R 2B , or R 2C is independently at each occurrence -O(C 1-3 alkyl); or

[0091] (5) R 1A , and R 1B are independently selected from -O(C1-3 alkyl);

[0092] R 2A , R 2B , or R 2C is independently at each occurrence -H;

[0093] n1is selected from 1, and 2; preferably, n1is 1;

[0094] n2is selected from 1, and 2; preferably, n2is 2;

[0095] n3is selected from 0, and 1; preferably, n3is selected from 0;

[0096] n4is selected from 0, and 1; preferably, n4is selected from 0;

[0097] n5is selected from 1, and 2; preferably, n5is 2;

[0098] fragment is selected from

[0099] m is 1, or 2;

[0100] z is 1, or 2;

[0101] n S6 , or n S8 is independently at each occurrence selected from 0, 1, 2, 3, and 4;

[0102] R S1 , R S2 , R S6 , and R S8 are as defined in formula (I).

[0103] In another aspect, the present application relates to a compound represented by formula (II-1), formula (II-2), formula (III-1), or formula (III-2),

[0104] Further preferred is a compound represented by formula (II-1-1), formula (II-2-1), formula (III-1-1), or formula (III-2-1),

[0105] or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0106] R A is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl;

[0107] R B Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, or -C 1-3 Halogenated alkyl groups;

[0108] R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -(C 1-2 alkylene)-(3-7 membered carbon cycloyl), -(C 1-2 alkylene)-(3-10 membered heterocyclic group), -(C 1-2 alkylene)-phenyl, and -(C 1-2 (alkylene)-(5-10 heteroaryl); the -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, 3-10 heterocyclic, 3-7 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally n- SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 Alkyl); the n SC Selected from 0, 1, 2, 3, and 4;

[0109] Choose any location

[0110] (1)R 1A and R 1B Independently selected from -O(C 1-3 alkyl);

[0111] (R 2A and R 2B Together with the C atoms they are connected to, they form Preferably, (R) 2A and R 2B Together with the C atoms they are connected to, they form

[0112] R 2C It is independently -H each time it appears;

[0113] (2)R 1A, and R 1B independently selected from -O(C 1-3 alkyl);

[0114] R 2B independently at each occurrence is -O(C 1-3 alkyl);

[0115] R 2A , or R 2C independently at each occurrence is -H;

[0116] (3) R 1A , and R 1B independently selected from -O(C 1-3 alkyl);

[0117] R 2A , or R 2B independently at each occurrence is -O(C 1-3 alkyl);

[0118] R 2C independently at each occurrence is -H;

[0119] (4) R 1A , and R 1B independently selected from -O(C 1-3 alkyl);

[0120] R 2A , R 2B , or R 2C independently at each occurrence is -O(C 1-3 alkyl); or

[0121] (5) R 1A , and R 1B independently selected from -O(C 1-3 alkyl);

[0122] R 2A , R 2B , or R 2C independently at each occurrence is -H;

[0123] n1is selected from 1, and 2; preferably, n1is 1;

[0124] n2is selected from 1, and 2; preferably, n2is 2;

[0125] n3is selected from 0, and 1; preferably, n3is selected from 0;

[0126] n4is selected from 0, and 1; preferably, n4is selected from 0;

[0127] n5is selected from 1, and 2; preferably, n5is 2;

[0128] fragment selected from

[0129] m is 1, or 2;

[0130] z is 1, or 2;

[0131] n S6 , or n S8 is independently selected at each occurrence from 0, 1, 2, 3, and 4;

[0132] R S1 , R S2 , R S6 , and R S8 are as defined for formula (I).

[0133] In another aspect, the present application relates to a compound represented by formula (II-1A), formula (II-2A), formula (III-1A), or formula (III-2A),

[0134] Further preferred is a compound represented by formula (II-1A-1), formula (II-2A-1), formula (III-1A-1), or formula (III-2A-1),

[0135] or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0136] R A is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl;

[0137] R B is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl;

[0138] R SC is selected from halogen, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(OC 1-3 alkyl), and -OC(=O)(C 1-3 alkyl); said n SC is selected from 0, 1, 2, 3, and 4;

[0139] optionally,

[0140] (1) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0141] (R 2A and R 2B ) together with the C atom to which they are respectively attached form a preferably, (R 2A and R 2B ) together with the C atom to which they are respectively attached form a

[0142] R 2C is independently at each occurrence -H;

[0143] (2) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0144] R 2B is independently at each occurrence -O(C 1-3 alkyl);

[0145] R 2A , or R 2C is independently at each occurrence -H;

[0146] (3) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0147] R 2A , or R 2B is independently at each occurrence -O(C 1-3 alkyl);

[0148] R 2C is independently at each occurrence -H;

[0149] (4) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl);

[0150] R 2A , R 2B , or R 2C is independently at each occurrence -O(C 1-3 alkyl); or

[0151] (5) R 1A , and R1B independently selected from -O(C 1-3 alkyl);

[0152] R 2A , R 2B , or R 2C is independently at each occurrence -H;

[0153] n1is selected from 1, and 2; preferably, n1is 1;

[0154] n2is selected from 1, and 2; preferably, n2is 2;

[0155] n3is selected from 0, and 1; preferably, n3is selected from 0;

[0156] n4is selected from 0, and 1; preferably, n4is selected from 0;

[0157] n5is selected from 1, and 2; preferably, n5is 2;

[0158] moiety is selected from

[0159] m is 1, or 2;

[0160] z is 1, or 2;

[0161] n S6 , or n S8 is independently at each occurrence selected from 0, 1, 2, 3, and 4;

[0162] R S1 , R S2 , R S6 , and R S8 are as defined in formula (I).

[0163] In another aspect, the present application relates to a compound represented by formula (IV-1A), or formula (IV-2A),

[0164] Further preferred are compounds represented by formula (IV-1A-1), or formula (IV-2A-1),

[0165] or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, wherein,

[0166] R SC is selected from halogen, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 alkyl), the n SC Selected from 0, 1, 2, 3, and 4; or n SC The value is 2, and two adjacent R values ​​are... SC Together with the C atoms connected to it, they form Where R S3 and n S3 The definition is the same as that described in any one of claims 1-23; preferably, the two adjacent R SC Together with the C atoms connected to it, they form

[0167] The remaining groups R 1A R 1B R 2A R 2B R 2C m and X z- The definition is the same as that described in any one of claims 1-23; and / or optionally, one or more of the following conditions are met:

[0168] (1)R 1A and R 1B Independently H or -O(C) 1-3 alkyl);

[0169] (R 2A and R 2B Together with the C atoms they are connected to, they form Where R S3 and n S3 The definition is the same as that described in any one of claims 1-23; preferably, (R 2A and R 2B Together with the C atoms they are connected to, they form

[0170] R 2C It is independently -H each time it appears;

[0171] (2)R 1A and R 1B Independently H or -O(C) 1-3 alkyl);

[0172] R 2B It is independently H or -O(C) each time it appears. 1-3 alkyl);

[0173] R 2A Or R 2Cindependently at each occurrence -H;

[0174] (3) R 1A and R 1B are independently selected from H or -O(C 1-3 alkyl);

[0175] R 2A or R 2B are independently -H or -O(C 1-3 alkyl);

[0176] R 2C is independently -H at each occurrence;

[0177] (4) R 1A and R 1B are independently -O(C 1-3 alkyl);

[0178] R 2A , R 2B , or R 2C are independently -O(C 1-3 alkyl) at each occurrence;

[0179] (5) R 1A and R 1B are independently -O(C 1-3 alkyl);

[0180] R 2A , R 2B , or R 2C are independently -H at each occurrence;

[0181] (6) (R 1A and R 1B ) together with the C atom to which they are respectively attached form wherein R S3 and n S3 are as defined in any one of claims 1-23; preferably, (R 1A and R 1B ) together with the C atom to which they are respectively attached form

[0182] (R 2A and R 2B ) together with the C atom to which they are respectively attached form wherein R S3 and n S3 are as defined in any one of claims 1-23; preferably, (R 2A and R 2B ) together with the C atom to which they are respectively attached form

[0183] R 2C independently at each occurrence is -H.

[0184] Further preferably, R SC is selected from F, and -OCH3; said n SC is selected from 0, 1, and 2; or n SC is 2, and the two adjacent R SC together with the C atom to which they are respectively attached form

[0185] the remaining R 1A , R 1B , R 2A , R 2B , R 2C , m and X z- are as defined in any one of claims 1-23; and / or optionally one or more of the following conditions are met:

[0186] (1) R 1A and R 1B are independently -OCH3;

[0187] (R 2A and R 2B ) together with the C atom to which they are respectively attached form

[0188] R 2C independently at each occurrence is -H;

[0189] (2) R 1A and R 1B are independently -OCH3;

[0190] R 2B independently at each occurrence is -OCH3;

[0191] R 2A or R 2C independently at each occurrence is -H;

[0192] (3) (R 1A and R 1B ) together with the C atom to which they are respectively attached form

[0193] (R 2A and R 2B ) together with the C atom to which they are respectively attached form

[0194] R 2C independently at each occurrence is -H.

[0195] In some embodiments, the compound of Formula (I) is selected from:

[0196] In another aspect, the present application provides a method of preparing a compound of Formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, comprising the following scheme and steps:

[0197] Scheme 1:

[0198] The compound of Formula (V-1) is reacted with to obtain the compound of Formula (V-2) by esterification reaction, and the compound of Formula (V-2) is reacted with the compound of Formula (V-3) to obtain the compound of Formula (V) by esterification reaction; wherein, preferably maleic anhydride, or 2H-pyran-2,6(3H)-dione; preferably maleic anhydride;

[0199] Scheme 2:

[0200] The compound of Formula (VI-1) is reacted with to obtain the compound of Formula (VI-2) by esterification reaction, and the compound of Formula (VI-2) is reacted with the compound of Formula (V-3) to obtain the compound of Formula (VI) by esterification reaction; wherein LG1and LG2are each a leaving group or -OH, the leaving group is selected from halogen (e.g., -Cl, -Br, or -I), or -OX1, wherein the X1is selected from -C 1-3 alkyl, preferably X1is tert-butyl; the preferably (E)-4-chloro-4-oxobut-2-enoic acid tert-butyl ester

[0201] Scheme 3:

[0202] Compound of formula (VII-1) and Compound (VII-2) is obtained by esterification, and compound (VII-2) and compound (V-3) are esterified to obtain compound (VII); wherein LG3 and LG4 are leaving groups or -OH, respectively, the leaving groups being selected from halogens (e.g., -Cl, -Br or -I), or -OX2, wherein X2 is selected from -C. 1-3 Alkyl group, preferably, X2 is tert-butyl; Preferred is tert-butyl 4-chloro-4-oxobutyrate.

[0203] In each of the general formulas, each R 1A R 1B R 2A R 2B R 2C R SC R A R B R C R SC ,n1,n2,n3,n4,n5,n6,n7,n8,n9,m,X z- R S1 Y1, R S2 R S6 R S8 n SC n S6 and n S8 The definition is the same as that of formula (I).

[0204] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described in the present invention, or a stereoisomer thereof, a pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutically acceptable salt or cocrystal thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0205] On the other hand, the present invention provides the use of a compound of formula (I) of the present invention, or a stereoisomer thereof, a pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutically acceptable salt or cocrystal thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof; or a pharmaceutical composition containing the above-mentioned compound in the preparation of a medicament for neuromuscular blockade.

[0206] In another aspect, the present application provides a method of treating a subject having a neuromuscular blockade related disease, the method comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, a pharmaceutically acceptable salt of the stereoisomer, a solvate thereof, a prodrug thereof, or a deuterated derivative thereof; or a pharmaceutical composition containing the above-mentioned compound.

[0207] In another aspect, the present application provides a use of a compound represented by Formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the stereoisomer, a pharmaceutically acceptable salt or co-crystal of the stereoisomer, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof; or a pharmaceutical composition containing the above-mentioned compound in the treatment of a neuromuscular blockade related disease.

[0208] Definitions of terms

[0209] Unless otherwise indicated, the following terms have the following meanings. Other terms are defined elsewhere throughout the specification.

[0210] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims can be drafted to exclude any optional element. Thus, the recitation of one or more elements in the specification, examples, or claims that have alternative embodiments should not be interpreted as excluding those alternative embodiments. The recitation of one or more elements in the specification, examples, or claims that have alternative embodiments should not be interpreted as excluding those alternative embodiments.

[0211] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "an alkyl group optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0212] The term "substituted" means that a hydrogen atom or atom group is formally replaced by a "substituent" that is attached to another group. The term "substitution" means any number of substitutions, e.g., mono-, di-, tri-, tetra- or penta-substitution, if such substitution is allowed. Substituents are independently selected, and substitution can be at any chemically accessible position. It will be understood that substitution at a particular atom is limited by valence. The term "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single bivalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0213] The term "Cn-m" represents a range, inclusive of the recited endpoints, wherein n and m are integers representing the number of carbons. For example, the term "C1-6" represents a range of 1 to 6 carbons, inclusive of the recited endpoints. 1-6"Alkyl" specifically refers to individual groups of methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. "C0alkyl" refers to a covalent bond.

[0214] It should also be understood that certain features of the application described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the application, which are, for brevity, described in the context of separate embodiments, can also be provided separately or in any suitable

[0215] The term "alkyl," as used herein, alone or in combination, means a straight-chain or branched- chain, saturated hydrocarbon group. Alkyl groups can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. Similarly, C 1-6 , C 1-8 Alkyl is defined as the group having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0216] The term "haloalkyl," as used herein, means an alkyl group as defined above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogen (e.g., -F, -Cl, or -Br). In some embodiments, haloalkyl is interchangeable with -C 1-10 haloalkyl or haloC 1-10 alkyl, wherein -C 1-10 haloalkyl or haloC 1-10 alkyl, wherein -C 1-10 represents the total number of carbon atoms in the alkyl group is 1 to 10. In some embodiments, -C 1-10 haloalkyl is -CF3. 1-6 haloalkyl. In some embodiments, -C 1-6 haloalkyl is -CF3. 1-3 haloalkyl. In some embodiments, -C 1-3 haloalkyl is -CF3. 1-3 haloalkyl is -CF3.

[0217] The term "alkylene," as used herein, means a bifunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. In some embodiments, the alkylene group is C 0-6alkylene. In some embodiments, the C 0-6 alkylene is C 1-3 alkylene. In some embodiments, the C 0-6 represents the total number of carbon atoms in the alkylene group is 0 to 6, and 0 indicates that the alkylene group is directly attached at both ends. Non-limiting alkylene groups include methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0218] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain having one or more double bonds, typically between 2 and 10, 2 and 6, 2 and 4, or 2 and 3 carbon atoms in length. In some embodiments, an alkenyl group is -C 2-10 alkenyl. In some embodiments, -C 2-10 alkenyl is -C 2-6 alkenyl. Embodiments of alkenyl include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like. Alkenyl groups appearing herein are defined consistent with this definition. Alkenyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0219] The term "alkenylene" means a divalent unsaturated hydrocarbon chain having 2 to 10, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, which can be straight or branched, and contains at least one double bond, which can be "C 2-10 alkenylene," "C 2-6 alkenylene," or "C 2-3 alkenylene," wherein "C 2-3 alkenylene" means a straight or branched alkenylene group having 2 to 3 carbon atoms, including, but not limited to, -CH=CH-, -C(CH3)=CH-, -CH=CHCH2-, and -CH2CH=CH-, and the like.

[0220] The term "alkynyl" as used herein, unless otherwise indicated, means a straight and branched chain, substituted or unsubstituted, unsaturated hydrocarbon group having at least one, and usually one, two, or three carbon-carbon triple bonds, having a main chain of 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain. In some embodiments, the alkynyl is -C 2-10 alkynyl. In some embodiments, -C 2-10 alkynyl is -C 2-6 alkynyl. In some embodiments, -C 2-10 alkynyl. Alkynyl embodiments include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonyl, 3-nonyl, 1-decynyl, 4-decynyl, and the like; the alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0221] The term "alkynylene" means a divalent unsaturated hydrocarbon chain containing 2 to 10 carbon atoms, which can be straight or branched, and contains at least one carbon-carbon triple bond. Specifically, these hydrocarbon chains can be "C 2-10 alkynylene", "C 2-6 alkynylene", "C 2-4 alkynylene", or "C 2-3 alkynylene". For example, "C 2-4 alkynylene" means a straight or branched chain alkynylene group having 2 to 4 carbon atoms, including but not limited to -CºC-, -CºCCH2-, -CH(CH3)CHºC-, and -CH2CºCCH2-, and the like.

[0222] The term "alkoxy" refers to an alkyl group, as described herein, attached to the remainder of the molecule through an oxygen atom. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms. In one embodiment, the alkoxy group contains 1 to 5 carbon atoms; in another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group can optionally be substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l- propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0223] The term "carbocyclo" as used herein, unless otherwise indicated, refers to a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring comprising only carbon atoms as ring members. In some embodiments, a carbocyclo is a 3- to 20-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) carbocyclo and is fully saturated or has one or more degrees of unsaturation. The carbocyclo includes a cycloalkyl ring in which all ring carbon atoms are saturated, a cycloalkenyl ring containing at least one double bond (preferably containing one double bond), and a cycloalkynyl ring containing at least one triple bond (preferably containing one triple bond). The carbocyclo group includes monocyclic carbocyclo groups having only one ring, and bicyclic or polycyclic carbocyclo groups sharing 1, 2, 3, or more atoms between rings. Monocyclic carbocyclo groups having only one ring include saturated monocyclic-cycloalkyl rings, monocyclic-cycloalkenyl rings containing at least one double bond, and monocyclic-cycloalkynyl rings. Exemplary monocyclic-cycloalkyl rings include, but are not limited to, a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, a cyclooctyl ring, a cyclononyl ring, a cyclodecyl ring, and the like. Exemplary monocyclic-cycloalkenyl rings include, but are not limited to, a cyclopropenyl ring, a cyclobutenyl ring, a cyclopentenyl ring, a cyclohexenyl ring, a cycloheptenyl ring, a cyclooctenyl ring, a cyclononenyl ring, a cyclodecenyl ring, and the like. A carbocyclo having only one ring sharing one ring atom with another ring is referred to as a "spiro-carbocyclo group." In some embodiments, the spiro-carbocyclo group is a bicyclic spiro ring. The "spiro-carbocyclo group" includes saturated "spiro-cycloalkyl rings" and "spiro-cycloalkenyl rings" containing at least one double bond and "spiro-cycloalkynyl rings" containing at least one triple bond. Non-limiting examples of "spiro-cycloalkyl rings" include spiro[2.2]pentane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. A carbocyclo having only one ring sharing two adjacent ring atoms with another ring is referred to as a "fused-carbocyclo group." In some embodiments, the "fused-carbocyclo group" is a bicyclic fused ring. The "fused-carbocyclo group" includes saturated "fused-cycloalkyl rings," "fused-cycloalkenyl rings" containing at least one double bond, and "fused-cycloalkynyl rings" containing at least one triple bond. A monocyclic carbocyclo fused with an aromatic ring (e.g., phenyl) is included in the definition of fused carbocyclo. The term "bridged-carbocyclo group" refers to a carbocyclo comprising at least two bridgehead carbon atoms and at least one bridging carbon atom. The bridged carbocyclo includes a bicyclic bridged carbocyclo comprising two bridgehead carbon atoms and a polycyclic bridged carbocyclo comprising more than two bridgehead carbon atoms.The "bridged ring-carbocyclyl ring" includes saturated "bridged ring-cycloalkyl rings," "bridged ring-cycloalkenyl rings" containing at least one double bond, and "bridged ring-cycloalkynyl rings" containing at least one triple bond. In some embodiments, the "bridged ring-carbocyclyl ring" is a bicyclic bridged carbocycle. Non-limiting examples of bicyclic "fused ring-cycloalkyl rings" / bicyclic "bridged ring-cycloalkyl rings" include bicyclo[l. l.0]butane, bicyclo[2. l.0]pentane, bicyclo[l. l. l]pentane, bicyclo[3. l.0]hexane, bicyclo[2. l. l]hexane, bicyclo[3.2.0]heptane, bicyclo[4. l.0]heptane, bicyclo[2.2. l]heptane, bicyclo[3. l. l]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, bicyclo[4. l. l]octane, bicyclo[3.3. l]nonane, bicyclo[4.2. l]nonane, bicyclo[3.3.2]decane, bicyclo[4.2.2]decane, bicyclo[4.3. l]decane, bicyclo[3.3.3]undecane, bicyclo[4.3.2]undecane, or bicyclo[4.3.3]dodecane, and the like. The "carbocycle" and "carbocyclyl ring" are interchangeable in the present application.

[0224] The term "carbonyl," as used herein, means a -C(O)- group.

[0225] The term "heterocycle" as used herein, unless otherwise indicated, refers to a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring that includes one or more (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms as ring members in addition to carbon atoms. Preferred heteroatoms include N, O, S, N oxide (NO), S oxide (SO), and S dioxide (SO2). A heterocycle that includes only N atoms is referred to as an azo-heterocycle, a heterocycle that includes only O atoms is referred to as an oxa-heterocycle, and a heterocycle that includes only S atoms is referred to as a thia-heterocycle. In some embodiments, a heterocycle is a monocyclic, bicyclic, tricyclic, or polycyclic system having 3 to 20 ring atoms (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered), and 1 to 3 heteroatoms when the heterocycle is monocyclic (e.g., 3- to 8-membered monocyclic), 1 to 6 heteroatoms when the heterocycle is bicyclic (e.g., 8- to 12-membered bicyclic), and 1 to 9 heteroatoms when the heterocycle is tricyclic or polycyclic. The heterocycle includes saturated heterocycloalkyl rings, heterocycloalkenyl rings that include at least one double bond (preferably one double bond), and heterocycloalkynyl rings that include at least one triple bond (preferably one triple bond). The heterocyclyl ring includes monocyclic heterocyclyl rings having only one ring, and bicyclic or polycyclic heterocyclyl rings that share atoms between rings by 1, 2, 3, or more atoms. The monocyclic heterocyclyl rings having only one ring include saturated monocyclic heterocycloalkyl rings, monocyclic heterocycloalkenyl rings that include at least one double bond, and monocyclic heterocycloalkynyl rings that include at least one triple bond. Examples of exemplary monocyclic heterocycloalkyl rings include piperazine, piperidine, tetrahydrothiophene, tetrahydropyran, dioxane, morpholine, tetrahydrofuran, azetidine, aziridine, azepine, pyrrolidine, oxetane, oxirane, tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole, tetrahydropyran, thiomorpholine, and the like. Examples of exemplary monocyclic heterocycloalkenyl rings include A heterocycle in which each ring shares only one ring atom with another ring is referred to as a "spiro-heterocyclyl ring." In some embodiments, the spiro ring is a bicyclic spiro ring. The "spiro-heterocyclyl ring" includes saturated "spiro-heterocycloalkyl rings" and "spiro-heterocycloalkenyl rings" containing at least one double bond and "spiro-heterocycloalkynyl rings" containing at least one triple bond. Non-limiting examples of "spiro-heterocycloalkyl rings" include: 2-azaspiro[2.2]pentyl ring, 4-azaspiro[2.5]octyl ring, 1-azaspiro[3.5]nonyl ring, 2-azaspiro[3.5]nonyl ring, 7-azaspiro[3.5]nonyl ring, 2-azaspiro[4.4]nonyl ring, 6-azaspiro[2.6]nonyl ring, 1,7-diazaspiro[4.5]decyl ring, 7-azaspiro[4.5]decyl ring, 2,5-diazaspiro[3.6]decyl ring, 3-azaspiro[5.5]undecyl ring, 2-oxaspiro[2.2]pentyl ring, 4-oxaspiro[2.5]octyl ring, 1-oxaspiro[3.5]nonyl ring, 2-oxaspiro[3.5]nonyl ring, 7-oxaspiro[3.5]nonyl ring, 2-oxaspiro[4.4]nonyl ring, 6-oxaspiro[2.6]nonyl ring, 1,7-dioxaspiro[4.5]decyl ring, 2,5-dioxaspiro[3.6]decyl ring, 1-oxaspiro[5.5]undecyl ring, 3-oxaspiro[5.5]undecyl ring, 3-oxa-9-azaspiro[5.5]undecyl ring, and the like. A heterocycle in which each ring shares two adjacent ring atoms with another ring is referred to as a "fused-heterocyclyl ring." In some embodiments, the fused ring is a bicyclic fused ring. The "fused-heterocyclyl ring" includes saturated "fused-heterocycloalkyl rings" and "fused-heterocycloalkenyl rings" containing at least one double bond and "fused-heterocycloalkynyl rings" containing at least one triple bond. Single ring heterocycles fused to an aromatic ring (e.g., phenyl) are included in the definition of fused heterocycles. The term "bridged-heterocyclyl ring" refers to a heterocycle comprising at least two bridgehead ring carbon atoms and at least one bridging carbon atom. The bridged heterocycle includes bicyclic bridged heterocycles comprising two bridgehead carbon atoms and polycyclic bridged heterocycles comprising more than two bridgehead carbon atoms. The "bridged-heterocyclyl ring" includes saturated "bridged-heterocycloalkyl rings," "bridged-heterocycloalkenyl rings" containing at least one double bond, and "bridged-heterocycloalkynyl rings" containing at least one triple bond. In some embodiments, the "bridged-heterocyclyl ring" is a bicyclic bridged heterocycle.Non-limiting examples of "fused ring-heterocycloalkyl rings" / "bridged ring- heterocycloalkyl rings" include: 2-azabicyclo[l. l.0]butyl ring, 2-azabicyclo[2. l.0] pentyl ring, 2-azabicyclo[l. l. l]pentyl ring, 3-azabicyclo[3. l.0]hexyl ring, 5- azabicyclo[2. l. l]hexyl ring, 3-azabicyclo[3.2.0]heptyl ring, octahydrocyclopenta[c]pyrrolyl ring, 3-azabicyclo[4. l.0]heptyl ring, 7-azabicyclo[2.2. l]heptyl ring, 6- azabicyclo[3. l. l]heptyl ring, 7-azabicyclo[4.2.0]octyl ring, 2-azabicyclo[2.2.2]octyl ring, 3-azabicyclo[3.2. l]octyl ring, 2-oxabicyclo[l. l.0]butyl ring, 2-oxabicyclo[2. l.0]pentyl ring, 2-oxabicyclo[l. l. l]pentyl ring, 3-oxabicyclo[3. l.0]hexyl ring, 5-oxabicyclo[2. l. l]hexyl ring, 3-oxabicyclo[3.2.0]heptyl ring, 3-oxabicyclo[4. l.0]heptyl ring, 7-oxabicyclo[2.2. l]heptyl ring, 6-oxabicyclo[3. l. l]heptyl ring, 7-oxabicyclo[4.2.0]octyl ring, 2-oxabicyclo[2.2.2]octyl ring, 3-oxabicyclo[3.2. l]octyl ring, and the like. "Heterocycle" and "heterocyclyl ring" are used interchangeably in the present application.

[0226] The term "heterocyclyl," as used herein, means a monovalent radical derived from a heterocycle, as previously defined, by removal of one hydrogen atom from a ring carbon.

[0227] The term "aryl" or "aromatic ring," as used herein, means a monocyclic or polycyclic aromatic ring system containing only carbon ring atoms, unless otherwise specified. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryl groups.

[0228] Heteroaryl refers to an aromatic group of 6 to 20 carbon atoms having a complete conjugated pi-electron system, with at least one ring containing O, N, and / or S heteroatoms, or heteroaryl refers to an aromatic ring containing at least one O, N, and / or S heteroatom and 1 to 6 carbon atoms. Preferred heteroaryls contain 1 to 4, more preferably 1, 2, or 3 O and / or N heteroatoms. Non-limiting examples of heteroaryls include: pyrrole ring, furan ring, thiophene ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, tetrazole ring, pyrazole ring, triazole ring, thiadiazole ring, oxadiazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring, isoindole ring, indolizine ring, benzofuran ring, isobenzofuran ring, benzo[b]thiophene ring, benzo[c]thiophene ring, indazole ring, benzo[d]imidazole ring, pyrrolo[3,2-b]pyridine ring, pyrrolo[3,2-c]pyridine ring, pyrrolo[2,3-c]pyridine ring, pyrrolo[2,3-b]pyridine ring, pyrrolo[3,4-b]pyridine ring, pyrrolo[3,4-c]pyridine ring, benzo[d]isoxazole ring, benzo[d]oxazole ring, furopyridine ring, furanopyridine ring, furanopyridine ring, benzo[c]isoxazole ring, furanopyridine ring, furanopyridine ring, benzo[d]isothiazole ring, benzo[d]thiazole ring, thienopyridine ring, thienopyridine ring, benzo[d][l,2,3]triazole ring, pyrazolopyridine ring, pyrazolopyridine ring, pyrazolopyridine ring, pyrazolopyridine ring, imidazopyridine ring, imidazopyridine ring, imidazopyridine ring, imidazopyridine ring, pyrrolopyridazine ring, pyrrolopyrimidine ring, pyrrolopyrazine ring, pyrrolopyridazine ring, pyrrolopyrimidine ring, pyrrolopyridazine ring, pyrrolopyridazine ring, pyrrolopyrimidine ring, pyrrolopyridazine ring, pyrrolopyrimidine ring, pyrrolopyrimidine ring, pyrrolopyrimidine ring, 6H-pyrrolopyridazine ring, and the like.

[0229] The term "oxo" refers to an oxygen substituent attached through a double bond (i.e., =0), unless otherwise indicated.

[0230] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless in context otherwise clear, all stereoisomers, such as enantiomers and diastereomers, are intended to be covered by the scope of the application. Compounds described herein containing asymmetrically substituted carbon atoms can be in the form of an optically active or racemic form. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, and the like can also exist, and all such isomers are contemplated in the scope of the present application.

[0231] Cis and trans geometric isomers of the compounds described herein are also within the scope of the application, either isolated in mixtures of isomers or as isolated isomers. In particular, in the chemical structures of the compounds described herein, the double bond " = " is generally not designated as having a specific configuration, i.e., it can be in the Z or E configuration, or both, unless specifically indicated.

[0232] The compounds described herein also include tautomers. Tautomers arise from the exchange of a single bond and an adjacent double bond, with concomitant migration of a proton. Tautomers include proton transfer tautomers, which have the same chemical formula and overall charge. Exemplary proton transfer tautomers include keto-enol tautomerism, amide-imidic acid tautomerism, lactam-lactim tautomerism, amide-imidic acid tautomerism, and enamine-imine tautomerism, where the proton can be interchanged in a cyclic structure at two or more positions in a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; certain hydroxyl substituted compounds can exist as tautomers, as shown below: Tautomers can be in equilibrium, or can be fixed in space by appropriate substitution to form one form. Where tautomers exist for the compounds of the application, the application includes any possible tautomer, and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

[0233] In some cases, the compounds described herein can exist in the form of a rotamer. The description of the compounds of the application is intended to encompass any individual rotamer, as well as mixtures of rotamers in any ratio, and is not intended to represent a particular rotamer. The description of a particular rotamer is intended to mean the described rotamer substantially free of other rotamers.

[0234] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers," for example, enantiomers and diastereomers. The compounds of the present application can have one or more asymmetric centers; thus, such compounds can be produced as, and / or isolated as, individual (R)- or (S)-stereoisomers, or as mixtures of such stereoisomers. Unless otherwise specified, descriptions or nominations of specific compounds herein are intended to include all racemic or other stereoisomeric forms of the substance, and mixtures thereof. When a structure is presented wherein there is one chiral center but the specific stereochemistry of that center is not indicated, then the structure includes both enantiomers, either individually or as a mixture of enantiomers. When a structure is presented wherein there is more than one chiral center but the specific stereochemistry of the centers is not indicated, then the structure includes all enantiomers and diastereomers, either individually or as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0235] The present application further includes isotopically-labeled compounds or intermediates of the present application. An "isotope" refers to an atom having the same number of protons but a different number of neutrons as compared with a reference atom, and thus the same atomic number. For example, isotopes of hydrogen include protium and deuterium. In some embodiments, the compounds of the present application, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed and / or detected. Partially separated can include, for example, a composition enriched in a compound of the present application. Substantially separated can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of a compound of the present application, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0236] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the compounds described herein wherein the parent compound is modified by converting at least one of the existing acid or base moieties into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the application include the non-toxic salts of the parent compound which are formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, alcohols [e.g., methanol, ethanol, isopropanol, or butanol] or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each incorporated herein by reference in its entirety.

[0237] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0238] A "pharmaceutically acceptable excipient" refers to a nontoxic, biologically tolerable, and otherwise biologically suitable material that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent in facilitating administration of a pharmaceutical agent and is compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0239] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, tautomers, deuterated analogs, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or co-crystals thereof, and other chemical components, where the "other chemical components" refer to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic or active agents.

[0240] A "prodrug" means a compound which is converted into a specified biologically active compound of the application in vivo. Prodrugs of the compounds of the application are prepared by modifying the amino or carboxyl groups of the compounds of the application in such a way that the modifications can be easily removed in vivo to form the parent compound. When a prodrug of the application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0241] A "co-crystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein both the pure state of the API and the pure state of the CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including both binary co-crystals formed between two neutral solids, and multi-component co-crystals formed between a neutral solid and a salt or a solvate.

[0242] A "carrier" means a material which does not cause significant irritation to an organism, and does not abrogate the biological activity and properties of an administered compound.

[0243] A "solvate" means that the compound of Formula I has one or more solvent molecules.

[0244] A "leaving group" means an atom or group of atoms which is displaced in a chemical reaction and is a stable species carrying a bond electron, for example, typically forming an anion. Preferably, the leaving group is selected from the group consisting of: halogen, especially chlorine, bromine or iodine, (methylsulfonyl)oxy-, [(4-methylphenyl)sulfonyl]oxy-, [(trifluoromethyl)sulfonyl]oxy-, [(nonafluorobutyl)sulfonyl]oxy-, [(4-bromophenyl)sulfonyl]oxy-, [(4-nitrophenyl)sulfonyl]oxy-, [(2-nitrophenyl)sulfonyl]oxy-, [(4-isopropylphenyl)sulfonyl]oxy-, [(2,4,6-triisopropylphenyl)sulfonyl]oxy-, [(2,4,6-trimethylphenyl)sulfonyl]oxy-, [(4-tert-butyl-tert-butylphenyl)sulfonyl]oxy-, (phenylsulfonyl)oxy-, and [(4-ethoxymethoxyphenyl)sulfonyl]oxy.

[0245] The term "one or more" as used herein, means one or more than one, unless otherwise indicated. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means up to 6.

[0246] The pharmaceutical compositions can be in a form suitable for oral use (for example as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for injection (for example as aqueous or oil suspensions or solutions, or as emulsions, with or without surfactants, with or without pharmaceutically acceptable adjuvants), for topical application (for example as creams, ointments, jellies, or aqueous or oily solutions or suspensions), for inhalation (for example as a finely divided or aerosolized substance), for insufflation (for example as a finely divided powder), or for rectal or vaginal administration (for example as suppositories).

[0247] The compositions can be obtained by conventional procedures well known in the art using conventional pharmaceutical excipients. Thus, compositions intended for oral use can contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0248] An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for medical use can be effective to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a proliferative disorder mentioned herein.

[0249] The amount of active ingredient that is required to combine with one or more excipients to produce a single dosage form varies with the subject being treated, and the particular route of administration. For example, preparations for oral administration to humans typically contain from, for example, 0.1 mg to 1000 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in conjunction with suitable and appropriate amounts of excipients which can vary from about 5 to about 98% by weight of the total composition.

[0250] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the particular route of administration.

[0251] The compounds of Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising these compounds can be administered to a subject by any convenient method of administration whether systemically / peripherally or locally (i.e., at the site where the effect is desired). Methods of administration include, but are not limited to: orally (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., through patches, plasters, etc.); transmucosal (including, e.g., through patches, plasters, etc.); intranasally (e.g., by nasal spray); ocularly (e.g., by eye drops); pulmonarily (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectally (e.g., by suppositories or enemas); vaginally (e.g., by pessaries); parenterally, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant or implantation (e.g., of a capsule, e.g., under the skin or muscle); and in a chronic or sustained manner, e.g., using implantation of a pump-liner or other device.

[0252] The methods generally comprise administering to a subject a therapeutically effective amount of a compound of the application. The therapeutically effective amount of a combination of compounds of interest can vary according to the intended application (in vitro or in vivo) or the subject and disease condition being treated, e.g., the subject's body mass and age, the severity of the disease condition, the manner of administration, etc., as can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., a reduction in proliferation or down-regulation of activity of a target protein. The specific dose will vary depending on the particular compound chosen, the dosing regimen being followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0253] Unless otherwise indicated herein, when a value is expressed as "about" X or "approximately" X, the stated value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0254] Unless otherwise indicated herein, or otherwise apparent from context, all methods described herein can be performed in any suitable order. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed.

[0255] These and other aspects will become apparent from the following written description of the application. DETAILED DESCRIPTION

[0256] The compounds of the present application can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes and the general schemes below are intended for the guidance of the ordinarily skilled synthetic chemist who will readily appreciate that the solvents, concentrations, reagents, protecting groups, order of synthetic steps, time, temperature, and the like can be modified as required within the skill and judgment of the ordinarily skilled worker.

[0257] “room temperature” and “r.t” in the present application, as used in the art, generally refers to a temperature, e.g., a reaction temperature, that is about the temperature of the ambient environment at which the reaction is being carried out, e.g., a temperature of about 20 °C to about 30 °C.

[0258] Examples

[0259] The following examples are provided to better illustrate the application. Unless otherwise indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0260] Preparation of intermediates

[0261] Intermediate A1 (INT A1)

[0262] A mixture of benzaldehyde (3.18 g, 30 mmol, 1.0 eq.), 4-piperidone glycol (8.59 g, 60.0 mmol, 2.0 eq.), acetic acid (5.40 g, 90.0 mmol, 3.0 eq.) and DCM (100 mL) was stirred at room temperature for 30 min, then NaBH4(2.27 g, 60.0 mmol, 2.0 eq.) was added slowly. The reaction mixture was stirred at room temperature overnight, quenched with water (50 mL) and adjusted pH to 8-9 with NaOH (2 N, aq.), then extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give INT A1-1 (4.97 g, yield 71%). LCMS: m / z = 234 [M+1] + .

[0263] A solution of INT A1-1 (4.97 g, 21.3 mmol, 1.0 eq.) and 1,3-propanediol cyclic sulfate (5.89 g, 42.6 mmol, 2.0 eq.) in CH3CN (120 mL) was purged with nitrogen and kept under nitrogen atmosphere, filtered after stirring at 50 °C for 18 h. The resulting filter cake was dried under vacuum to give INT A1-2 (5.7 g, yield 72%). LCMS: m / z = 372 [M+1] + .

[0264] Acetyl chloride (12.1 g, 153.5 mmol, 10.0 eq.) was added dropwise to MeOH (150 mL) at 0 °C, the resulting solution was stirred for 30 min before adding INT A1-2 (5.7 g, 15.35 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NaHC03solution, then extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na2S04, then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give INT A1 (4.26 g, yield 85%). LCMS: m / z = 292 [M+1] + .

[0265] The following intermediates were synthesized using the synthetic method of intermediate A1 with the corresponding starting materials:

[0266] Intermediate B1 (INT B1)

[0267] INT B1-1 (8.2 g, 23.9 mmol, 1.0 eq., ref: WO2003095426), 37% aqueous formaldehyde solution (9.7 g, 119.4 mmol, 5.0 eq.) and NaBH4(2.71 g, 71.6 mmol, 3.0 eq.) were dispersed into MeOH (200 mL). The reaction mixture was purged and kept under an inert atmosphere of nitrogen, stirred at room temperature overnight then concentrated under reduced pressure to give a residue. The residue was dispersed in DCM (100 mL), quenched with HC1 (2 N, aq.), then extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na2S04, then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give INT B1-2 as a solid (6.5 g, yield 76%). LCMS: m / z = 328 [M+1] + .

[0268] INT B1-2 (6.5 g, 19.8 mmol, 1.0 eq.) and 1,3-propanediol cyclic sulfate (5.48 g, 39.7 mmol, 2.0 eq.) were dispersed into CH3CN (180 mL). The reaction mixture was purged and kept under an inert atmosphere of nitrogen, stirred at 50 °C for 18 h then filtered. The resulting filter cake was dried under vacuum to give INT B1-3 as a solid (3.2 g, yield 35%). LCMS: m / z = 466 [M+1] + .

[0269] Acetyl chloride (4.2 g, 53.7 mmol, 10.0 eq.) was added dropwise to MeOH (100 mL) at 0 °C, the resulting solution was stirred for 30 min, then INT B1-3 (2.5 g, 5.4 mmol, 1.0 eq.) was added, stirred at room temperature overnight, quenched with saturated aqueous NaHC03solution, then extracted with DCM (50 mL x 3). The organic phases were combined, dried over anhydrous Na2S04, then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give INT B1 (2.68 g, yield 87%) as a solid. LCMS: m / z = 386 [M] + .

[0270] Intermediate B2 (INT B2)

[0271] INT B2 was synthesized according to the synthetic procedure of Step 1 to Step 3 of Intermediate B1 using INT B2-1 (Reference: CN107778234A) as the reactant. LCMS: m / z = 416 [M] + .

[0272] Intermediate B3 (INT B3)

[0273] A mixture of piperonyl acetic acid (20 g, 111.0 mmol, 1.0 eq.), HATU (84.4 g, 222.0 mmol, 2.0 eq.) and DIEA (43.0 g, 333.0 mmol, 3.0 eq.) and DMF (400 mL) was purged with nitrogen and maintained under a nitrogen atmosphere, then 3,4-dimethoxyphenethylamine (22.1 g, 122.1 mmol, 1.1 eq.) was added. The reaction mixture was stirred at room temperature overnight, water (400 mL) was added to precipitate the solid, which was filtered. The resulting filter cake was recrystallized in ethanol to give INT B3-1 (35.5 g, yield 93%). LCMS: m / z = 344 [M+1] + .

[0274] A solution of INT B3-1 (19.8 g, 57.7 mmol, 1.0 eq.) in toluene (250 mL) was purged with nitrogen and maintained under nitrogen atmosphere, POCl3(88.5 g, 577.0 mmol, 10.0 eq.) was added dropwise at 20 °C. The reaction mixture was stirred at 80 °C for 4 h, cooled to room temperature, concentrated under reduced pressure to give a residue. The residue was dispersed in DCM (200 mL), quenched with NaOH (2 N, aq.), then extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude INT B3-2 (19.0 g), which was used directly in the next step without further purification. LCMS: m / z = 326 [M+1] + .

[0275] A mixture of the crude INT B3-2 (19.0 g), NaBH4(4.4 g, 116.8 mmol, 2.0 eq.) and methanol (150 mL) was purged with nitrogen and maintained under nitrogen atmosphere, stirred at room temperature overnight, quenched with water (50 mL), concentrated under reduced pressure to give a residue. The residue was dispersed in water (100 mL), then extracted with DCM (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give INT B3-3 (12.7 g, yield 66%) as a solid. LCMS: m / z = 328 [M+1] + .

[0276] INT B3 was obtained from intermediates INT B3-4 and INT B3-5 according to the synthetic method of Intermediate B1, respectively. LCMS: m / z = 400 [M] + .

[0277] Intermediate B4 (INT B4)

[0278] INT B4 was synthesized according to the similar synthetic method of Intermediate B3, using piperonyl acetic acid and 3,4-methylenedioxyphenethylamine as reactants. LCMS: m / z = 384 [M] + .

[0279] Intermediate B3A and Intermediate B3B (INT B3A and INT B3B)

[0280] INT B3-4 (9.32 g) was subjected to chiral separation. The separation conditions were as follows: Instrument: SFC-150 preparative SFC (SFC-2); Chiral column: Chiralpak IK, 250 x 50 mm I.D., 10 pm; Mobile phase A: C02; Mobile phase B: EtOH (0.1% NH3H20); Gradient: V CO2 / V MeOH(0.1％NH3) = 50 / 50; Flow rate: 130 mL / min; Column temperature: 40 °C; Detection wavelength: 220 nm. Compound INT B3-4A (retention time: 0.847 min, 4.28 g) and compound INT B3-4B (retention time: 1.618 min, 4.39 g) were obtained thereby. Wherein INT B3-4A and INT B3-4B are enantiomers of each other.

[0281] INT B3-4A and INT B3-4B were subjected to the synthesis method of intermediate Bl to obtain INT B3A and INT B3B, respectively. LCMS (INT B3A): m / z = 400 [M] + , LCMS (INT B3B): m / z = 400 [M] + .

[0282] Intermediate B3B-a and intermediate B3B-b (INT B3B-a and INT B3B-b)

[0283] INT B3B (6.6 g) was subjected to chiral separation. The separation conditions were as follows: Instrument: SFC-150 preparative SFC (SFC-2); Chiral column: Chiralcel OX, 250 x 50 mm I.D., 10 pm; Mobile phase A: C02; Mobile phase B: EtOH (0.1% NH3H20); Gradient: V CO2 / V MeOH(0.1％NH3) = 50 / 50; Flow rate: 150 mL / min; Column temperature: 40 °C; Detection wavelength: 220 nm. Compound INT B3B-a (retention time: 2.168 min, 2.43 g) and compound INT B3B-b (retention time: 3.049 min, 1.38 g) were obtained thereby. Wherein INT B3B-a and INT B3B-b are epimers of each other. LCMS (INT B3B-a): m / z = 400 [M] + , LCMS (INT B3B-b): m / z = 400 [M] + .

[0284] Intermediate B1-a and Intermediate B1-b (INT B1-a and INT B1-b)

[0285] INT B1 (6.5 g) was subjected to chiral separation. Its separation conditions were as follows: instrument: SFC-350 preparative SFC (SFC-3); chiral chromatographic column: Chiralcel OX, 250 x 50 mm I.D., 10 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% NH3H2O); gradient: V CO2 / V MeOH(0.1％NH3) = 55 / 45; flow rate: 200 mL / min; column temperature: 40 °C; detection wavelength: 220 nm. Thus, compound INT B1-a (retention time: 1.852 min, 4.02 g) and compound INT B1-b (retention time: 2.080 min, 1.82 g) were obtained. Wherein, INT B1-a and INT B1-b are epimers of each other. LCMS (INT B1-a): m / z = 386 [M] + , LCMS (INT B1-b): m / z = 386 [M] + .

[0286] Preparation of Examples

[0287] Example 1

[0288] Step 1. A solution of INT A1 (2.0 g, 6.10 mmol, 1.0 eq.) and maleic anhydride (0.90 g, 9.15 mmol, 1.5 eq.) in CH3CN (100 mL) was purged with nitrogen and maintained under a nitrogen atmosphere, and triethylamine (0.68 g, 6.71 mmol, 1.1 eq.) was added dropwise at 0-5 °C. The reaction mixture was stirred at 0 °C for 3 hours, and concentrated under reduced pressure. The resulting residue was dispersed in DCM (50 mL), and the water phase was combined after washing with water (30 mL x 3), and NaCl was added to saturation, and the pH was adjusted to 2-3 with HC1 (2N, aq.), and then extracted with a mixed solution of DCM and CH3CN (V DCM :V CH3CN = 5:1) (30 mL x 5). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product of compound 1-1 (2.1 g), which was used directly in the next step without further purification. LCMS: m / z = 390 [M] + .

[0289] Step 2. A solution of INT B1 (1.20 g, 2.84 mmol, 1.0 eq.) and compound 1-1 (1.82 g, 4.27 mmol, 1.5 eq.) in DCM (100 mL) was purged with nitrogen and maintained a nitrogen atmosphere, HATU (2.16 g, 5.69 mmol, 2.0 eq.) was added slowly at 0-5 °C, after stirring at room temperature for 30 min, pyridine (0.90 g, 11.38 mmol, 4.0 eq.) was added. The reaction mixture was stirred at room temperature overnight, quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue, the obtained residue was purified by preparative high performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 1 (0.83 g, yield 35%). LCMS: m / z = 379 [M] 2+ .

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (dq, J = 21.0, 7.4 Hz, 5H), 6.99 (d, J = 8.2 Hz, 2H), 6.91 - 6.76 (m, 3H), 6.67 (s, 2H), 5.54 (s, 1H), 4.77 - 4.59 (m, 3H), 4.28 (t, J = 5.6 Hz, 2H), 4.17 (q, J = 5.5 Hz, 2H), 3.93 (s, 5H), 3.71 (d, J = 4.4 Hz, 8H), 3.63 - 3.50 (m, 5H), 3.35 (s, 6H), 3.19 (s, 3H), 3.10 (d, J = 6.9 Hz, 2H), 2.87 (t, J = 11.5 Hz, 1H), 2.23 (s, 4H), 2.10 (q, J = 9.2, 7.3 Hz, 2H), 1.96 (d, J = 14.7 Hz, 2H).

[0291] Example 2

[0292] Compound 2 was synthesized according to the synthetic method of Step 1 to Step 2 of Example 1 using INT A2 as the reactant. LCMS: m / z = 394 [M] 2+ .

[0293] 1H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.39 (m, 2H), 7.00 (dd, J = 8.7, 4.3 Hz, 4H), 6.91 - 6.77 (m, 3H), 6.68 (d, J = 2.1 Hz, 2H), 5.54 (s, 1H), 4.62 (d, J = 11.4 Hz, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.16 (q, J = 5.5 Hz, 2H), 3.93 (d, J = 2.1 Hz, 5H), 3.77 (s, 3H), 3.71 (d, J = 4.4 Hz, 6H), 3.60 (dd, J = 12.8, 3.9 Hz, 1H), 3.48 - 3.36 (m, 12H), 3.19 (s, 3H), 3.09 (t, J = 9.1 Hz, 2H), 2.92 - 2.83 (m, 1H), 2.22 (s, 4H), 2.09 (d, J = 11.3 Hz, 2H), 1.94 (d, J = 14.6 Hz, 2H).

[0294] Example 3

[0295] Compound 3 was synthesized by following the procedure of Example 1, Step 1 to Step 2 using INT A3 as the reactant. LCMS: m / z = 409 [M] 2+ .

[0296] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.39 (m, 2H), 7.00 (dd, J = 8.7, 4.3 Hz, 4H), 6.91 - 6.77 (m, 3H), 6.68 (d, J = 2.1 Hz, 2H), 5.54 (s, 1H), 4.62 (d, J = 11.4 Hz, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.16 (q, J = 5.5 Hz, 2H), 3.93 (d, J = 2.1 Hz, 5H), 3.77 (s, 3H), 3.71 (d, J = 4.4 Hz, 6H), 3.60 (dd, J = 12.8, 3.9 Hz, 1H), 3.48 - 3.36 (m, 12H), 3.19 (s, 3H), 3.09 (t, J = 9.1 Hz, 2H), 2.92 - 2.83 (m, 1H), 2.22 (s, 4H), 2.09 (d, J = 11.3 Hz, 2H), 1.94 (d, J = 14.6 Hz, 2H).

[0297] Example 4

[0298] Following the synthetic procedure of Example 1, Step 1 to Step 2, INT A4 was used as the reactant to synthesize compound 4. LCMS: m / z = 424 [M] 2+ .

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 6.99 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 19.7 Hz, 5H), 6.66 (s, 2H), 5.55 (s, 1H), 4.67 - 4.60 (m, 1H), 4.57 (s, 2H), 4.29 (t, J = 6.1 Hz, 2H), 4.14 (p, J = 5.4 Hz, 2H), 3.94 (s, 5H), 3.80 (s, 6H), 3.73 - 3.67 (m, 9H), 3.63 - 3.57 (m, 1H), 3.46 (d, J = 16.9 Hz, 12H), 3.21 (s, 3H), 3.10 (d, J = 7.3 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.28 - 2.04 (m, 6H), 1.96 (d, J = 14.5 Hz, 2H).

[0300] Example 5

[0301] Following the synthetic procedure of Example 1, Step 1 to Step 2, INT A5 was used as the reactant to synthesize compound 5. LCMS: m / z = 408 [M] 2+ .

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H), 6.99 (d, J = 8.3 Hz, 3H), 6.92 (d, J = 8.3 Hz, 1H), 6.89 - 6.79 (m, 3H), 6.78 - 6.58 (m, 2H), 5.54 (s, 1H), 4.65 (dd, J = 10.2, 3.9 Hz, 1H), 4.55 (s, 2H), 4.38 - 4.20 (m, 6H), 4.16 (q, J = 5.3 Hz, 2H), 3.93 (s, 5H), 3.71 (d, J = 4.1 Hz, 7H), 3.62 - 3.57 (m, 1H), 3.41 (s, 7H), 3.34 (s, 4H), 3.19 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.21 (s, 4H), 2.14 - 2.04 (m, 2H), 1.93 (d, J = 14.6 Hz, 2H).

[0303] Example 6

[0304] Step 1. Follow the synthetic method of Step 1 of Example 1 to synthesize compound 6-1 using INT A5 as the reactant. LCMS: m / z = 448 [M] + .

[0305] Step 2. Follow the synthetic method of Step 2 of Example 1 to synthesize compound 6 using INT B2 and compound 6-1 as the reactants. LCMS: m / z = 423 [M] 2+ .

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.78 - 6.59 (m, 3H), 6.53 (dd, J = 8.2, 2.0 Hz, 1H), 5.64 (s, 1H), 4.72 (dd, J = 10.4, 4.1 Hz, 1H), 4.56 (s, 2H), 4.26 (p, J = 5.5, 5.1 Hz, 6H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 5H), 3.71 (s, 7H), 3.64 (s, 4H), 3.35 (s, 11H), 3.22 (s, 3H), 3.09 (t, J = 4.8 Hz, 2H), 2.88 (dd, J = 12.8, 10.2 Hz, 1H), 2.21 (p, J = 6.0 Hz, 4H), 2.10 (ddd, J = 15.1, 9.9, 4.1 Hz, 2H), 1.93 (d, J = 14.6 Hz, 2H).

[0307] Example 7

[0308] Follow the synthetic method of Step 1 to Step 2 of Example 1 to synthesize compound 7 using INT A6 as the reactant. LCMS: m / z = 401 [M] 2+ .

[0309] 1H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.07 - 6.96 (m, 4H), 6.87 - 6.78 (m, 3H), 6.77 - 6.61 (m, 2H), 6.07 (s, 2H), 5.54 (s, 1H), 4.66 (dd, J = 10.5, 3.8 Hz, 1H), 4.58 (s, 2H), 4.27 (t, J = 5.6 Hz, 2H), 4.17 (d, J = 6.4 Hz, 2H), 3.93 (s, 6H), 3.71 (d, J = 3.5 Hz, 8H), 3.60 (dd, J = 12.7, 3.8 Hz, 2H), 3.39 - 3.30 (m, 8H), 3.19 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.20 (d, J = 10.8 Hz, 4H), 2.11 (t, J = 11.6 Hz, 2H), 1.93 (d, J = 14.5 Hz, 2H).

[0310] Example 8

[0311] Step 1. Follow the procedure of Step 1 of Example 1 using INT A1 as reactant to synthesize compound 8-1. LCMS: m / z = 390 [M] + .

[0312] Step 2. Follow the procedure of Step 2 of Example 1 using INT B3 and compound 8-1 as reactants to synthesize compound 8. LCMS: m / z = 386 [M] 2+ .

[0313] 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.07 - 6.96 (m, 4H), 6.87 - 6.78 (m, 3H), 6.77 - 6.61 (m, 2H), 6.07 (s, 2H), 5.54 (s, 1H), 4.66 (dd, J = 10.5, 3.8 Hz, 1H), 4.58 (s, 2H), 4.27 (t, J = 5.6 Hz, 2H), 4.17 (d, J = 6.4 Hz, 2H), 3.93 (s, 6H), 3.71 (d, J = 3.5 Hz, 8H), 3.60 (dd, J = 12.7, 3.8 Hz, 2H), 3.39 - 3.30 (m, 8H), 3.19 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.20 (d, J = 10.8 Hz, 4H), 2.11 (t, J = 11.6 Hz, 2H), 1.93 (d, J = 14.5 Hz, 2H).

[0314] Example 9

[0315] Step 1. A solution of INT A6 (2.60 g, 7.00 mmol, 1.0 eq.) and maleic anhydride (1.03 g, 10.49 mmol, 1.5 eq.) in CH3CN (100 mL) was purged with nitrogen and maintained under nitrogen atmosphere, triethylamine (0.78 g, 7.69 mmol, 1.1 eq.) was added dropwise at 0-5 °C. The reaction mixture was stirred at 0 °C for 3 h, concentrated under reduced pressure. The resulting residue was dispersed in DCM (50 mL), washed with water (30 mL x 3), the combined aqueous phase was washed with NaCl to saturation, adjusted pH to 2-3 with HC1 (2N, aq.), then extracted with a mixture of DCM and CH3CN (V DCM :V CH3CN = 5:1) (30 mL x 5). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude compound 9-1 (2.7 g), which was used directly in the next step without further purification. LCMS: m / z = 434 [M] + .

[0316] Step 2. A solution of INT B3 (1.50 g, 3.44 mmol, 1.0 eq.) and compound 9-1 (2.43 g, 5.16 mmol, 1.5 eq.) in DCM (100 mL) was purged with nitrogen and maintained under nitrogen atmosphere, HATU (2.62 g, 6.88 mmol, 2.0 eq.) was added slowly at 0-5 °C, pyridine (1.09 g, 13.76 mmol, 4.0 eq.) was added after stirring at room temperature for 30 min. The reaction mixture was stirred at room temperature overnight, quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue, which was purified by preparative high performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 9 (1.13 g, 37% yield). LCMS: m / z = 408 [M] 2+ .

[0317] 1H NMR (400 MHz, DMSO-d6) δ 7.12 (d, J = 1.7 Hz, 1H), 7.08 - 6.92 (m, 2H), 6.91 - 6.76 (m, 3H), 6.76 - 6.53 (m, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 6.07 (s, 2H), 5.97 (d, J = 4.4 Hz, 2H), 5.69 (s, 1H), 4.68 (dd, J = 10.3, 4.0 Hz, 1H), 4.59 (s, 2H), 4.28 (t, J = 5.7 Hz, 2H), 4.16 (q, J = 6.1 Hz, 2H), 3.93 (s, 5H), 3.71 (s, 4H), 3.62 - 3.55 (m, 1H), 3.48 - 3.37 (m, 8H), 3.33 (s, 3H), 3.29 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.86 (dd, J = 12.8, 10.3 Hz, 1H), 2.30 - 2.03 (m, 6H), 1.93 (d, J = 14.3 Hz, 2H).

[0318] Example 10

[0319] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A6 as the reactant to synthesize compound 10-1. LCMS: m / z = 434 [M] + .

[0320] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B4 and compound 10-1 as the reactants to synthesize compound 10. LCMS: m / z = 400 [M] 2+ .

[0321] 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 1.6 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.93 - 6.78 (m, 3H), 6.76 - 6.57 (m, 2H), 6.47 (dd, J = 7.9, 1.7 Hz, 1H), 6.07 (s, 2H), 6.03 - 5.93 (m, 3H), 5.85 (d, J = 8.2 Hz, 2H), 4.64 (d, J = 9.1 Hz, 1H), 4.56 (s, 2H), 4.28 (t, J = 5.6 Hz, 2H), 4.15 (d h, J = 17.5, 5.9 Hz, 2H), 3.94 (s, 4H), 3.89 - 3.80 (m, 1H), 3.65 (d, J = 13.5 Hz, 1H), 3.56 - 3.50 (m, 2H), 3.29 (s, 10H), 3.07 (d, J = 16.5 Hz, 2H), 2.88 (dd, J = 13.2, 9.7 Hz, 1H), 2.28 - 2.05 (m, 6H), 1.93 (d, J = 14.4 Hz, 2H).

[0322] Example 11

[0323] Step 1. Follow the synthesis method of Step 1 of Example 1, use INT A7 as the reactant to synthesize compound 11-1. LCMS: m / z = 408 [M] + .

[0324] Step 2. Follow the synthesis method of Step 2 of Example 1, use INT B3 and compound 11-1 as the reactants to synthesize compound 11. LCMS: m / z = 395 [M] 2+ .

[0325] 1H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.57 (m, 2H), 7.31 (t, J = 8.8 Hz, 2H), 6.85 - 6.80 (m, 2H), 6.78 (d, J = 1.7 Hz, 1H), 6.66 (d, J = 2.3 Hz, 2H), 6.49 (dd, J = 7.9, 1.7 Hz, 1H), 5.97 (dd, J = 4.4, 1.0 Hz, 2H), 5.68 (s, 1H), 4.70 - 4.61 (m, 3H), 4.28 (t, J = 5.9 Hz, 2H), 4.16 (h, J = 5.4 Hz, 2H), 3.98 - 3.87 (m, 5H), 3.71 (s, 4H), 3.57 (dd, J = 12.8, 3.9 Hz, 1H), 3.46 - 3.38 (m, 11H), 3.29 (s, 3H), 3.10 (d, J = 7.3 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.22 (s, 4H), 2.11 (t, J = 12.3 Hz, 2H), 1.95 (d, J = 14.5 Hz, 2H).

[0326] Example 12

[0327] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A8 as the reactant to synthesize compound 12-1. LCMS: m / z = 446 [M] + .

[0328] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B1 and compound 12-1 as the reactants to synthesize compound 12. LCMS: m / z = 407 [M] 2+ .

[0329] 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 (d, J = 8.3 Hz, 3H), 6.89 - 6.78 (m, 3H), 6.66 (d, J = 3.2 Hz, 2H), 5.54 (s, 1H), 4.64 (dd, J = 10.7, 3.9 Hz, 1H), 4.55 (s, 2H), 4.27 (t, J = 5.9 Hz, 2H), 4.14 (hept, J = 5.7 Hz, 2H), 3.92 (q, J = 10.8, 8.0 Hz, 1H), 3.77 (d, J = 5.7 Hz, 6H), 3.71 (d, J = 4.3 Hz, 6H), 3.60 (dd, J = 12.8, 4.0 Hz, 1H), 3.34 (s, 7H), 3.28 (d, J = 13.0 Hz, 5H), 3.20 (s, 3H), 3.10 (d, J = 7.3 Hz, 2H), 2.87 (dd, J = 12.7, 10.4 Hz, 1H), 2.20 (s, 4H), 1.79 (s, 2H), 1.59 (h, J = 6.3, 5.0 Hz, 6H), 1.48 (dt, J = 13.4, 6.4 Hz, 4H).

[0330] Example 13

[0331] A solution of INT A8 (1.50 g, 3.91 mmol, 1.0 eq.) and TEA (0.79 g, 7.81 mmol, 2.0 eq.) in DCM (25 mL) was purged with nitrogen and maintained under nitrogen atmosphere, (E)-tert-butyl 4-chloro-4-oxobut-2-enoate (0.82 g, 4.30 mmol, 1.1 eq.) was added dropwise at 0-5 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with water (50 ml) and extracted with DCM (25 mL x 3). The combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue. The residue was dispersed in DCM (20 mL), TFA (5.0 mL) was added dropwise at 0-5 °C, stirred at room temperature for 3 h, quenched with saturated aqueous NaHC03solution and extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give compound 13-1 (1.07 g, yield 57%). LCMS: m / z = 446 [M+1] at 2.48 min. + .

[0332] Step 2: Follow the synthesis method of step 2 of example 1, use INT B1 and compound 13-1 as reactants to synthesize compound 13. LCMS: m / z = 407 [M] 2+ .

[0333] 1 H NMR (400 MHz, DMSO-d6) δ 7.12 - 7.03 (m, 2H), 6.99 (dd, J = 8.4, 1.8 Hz, 3H), 6.90 - 6.80 (m, 3H), 6.66 (d, J = 3.0 Hz, 2H), 5.55 (s, 1H), 4.66 - 4.60 (m, 1H), 4.53 (s, 2H), 4.27 (t, J = 5.9 Hz, 2H), 4.16 (p, J = 5.9 Hz, 2H), 3.96 - 3.87 (m, 1H), 3.77 (d, J = 5.4 Hz, 6H), 3.71 (d, J = 4.4 Hz, 7H), 3.63 - 3.57 (m, 1H), 3.32 (s, 11H), 3.20 (s, 3H), 3.09 (t, J = 9.0 Hz, 2H), 2.88 (dd, J = 12.6, 10.5 Hz, 1H), 2.20 (s, 4H), 1.79 (s, 2H), 1.60 (s, 6H), 1.49 (dd, J = 14.6, 6.7 Hz, 4H).

[0334] Example 14

[0335] Step 1. Follow the synthesis method of step 1 of example 13, use INT A1 as reactant to synthesize compound 14-1. LCMS: m / z = 390 [M] + .

[0336] Step 2: Follow the synthesis method of step 2 of example 1, use INT B1 and compound 14-1 as reactants to synthesize compound 14. LCMS: m / z = 379 [M] 2+ .

[0337] 1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.35 (m, 5H), 7.00 (d, J = 8.2 Hz, 2H), 6.93 - 6.76 (m, 3H), 6.68 (s, 2H), 5.56 (s, 1H), 4.80 - 4.58 (m, 3H), 4.29 (t, J = 5.9 Hz, 2H), 4.18 (q, J = 5.4 Hz, 2H), 3.94 (s, 5H), 3.72 (d, J = 4.3 Hz, 6H), 3.61 (dd, J = 12.8, 3.9 Hz, 1H), 3.53 - 3.37 (m, 12H), 3.21 (s, 3H), 3.11 (d, J = 7.4 Hz, 2H), 2.88 (t, J = 11.6 Hz, 1H), 2.37 - 2.19 (m, 4H), 2.18 - 2.08 (m, 2H), 1.97 (d, J = 14.7 Hz, 2H).

[0338] Example 15

[0339] Step 1. Follow the procedure of Example 13, Step 1 using INT A3 as the reactant to synthesize compound 15-1. LCMS: m / z = 450 [M] + .

[0340] Step 2: Follow the procedure of Example 1, Step 2 using INT B1 and compound 15-1 as the reactants to synthesize compound 15. LCMS: m / z = 409 [M] 2+ .

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.35 (m, 5H), 7.00 (d, J = 8.2 Hz, 2H), 6.93 - 6.76 (m, 3H), 6.68 (s, 2H), 5.56 (s, 1H), 4.80 - 4.58 (m, 3H), 4.29 (t, J = 5.9 Hz, 2H), 4.18 (q, J = 5.4 Hz, 2H), 3.94 (s, 5H), 3.72 (d, J = 4.3 Hz, 6H), 3.61 (dd, J = 12.8, 3.9 Hz, 1H), 3.53 - 3.37 (m, 12H), 3.21 (s, 3H), 3.11 (d, J = 7.4 Hz, 2H), 2.88 (t, J = 11.6 Hz, 1H), 2.37 - 2.19 (m, 4H), 2.18 - 2.08 (m, 2H), 1.97 (d, J = 14.7 Hz, 2H).

[0342] Example 16

[0343] Step 1. Follow the synthetic method of step 1 of Example 13 using INT A6 as the reactant to synthesize compound 16-1. LCMS: m / z = 434 [M] + .

[0344] Step 2: Follow the synthetic method of step 2 of Example 1 using INT B1 and compound 16-1 as the reactants to synthesize compound 16. LCMS: m / z = 401 [M] 2+ .

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 7.10 (d, J = 1.6 Hz, 1H), 7.08 - 6.91 (m, 4H), 6.90 - 6.77 (m, 3H), 6.75 - 6.60 (m, 2H), 6.07 (s, 2H), 5.54 (s, 1H), 4.63 (d, J = 10.3 Hz, 1H), 4.56 (s, 2H), 4.28 (t, J = 5.8 Hz, 2H), 4.16 (s, 2H), 3.94 (s, 5H), 3.71 (d, J = 3.9 Hz, 6H), 3.65 - 3.56 (m, 2H), 3.33 (s, 11H), 3.20 (s, 3H), 3.10 (d, J = 7.1 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.21 (s, 4H), 2.10 (t, J = 10.0 Hz, 2H), 1.93 (d, J = 14.5 Hz, 2H).

[0346] Example 17

[0347] Step 1. Follow the synthetic method of step 1 of Example 13 using INT A1 as the reactant to synthesize compound 17-1. LCMS: m / z = 390 [M] + .

[0348] Step 2: Follow the synthetic method of step 2 of Example 1 using INT B3 and compound 17-1 as the reactants to synthesize compound 17. LCMS: m / z = 386 [M] 2+ .

[0349] 1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.44 (m, 5H), 6.89 - 6.77 (m, 3H), 6.67 (d, J = 1.1 Hz, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.2 Hz, 2H), 5.69 (s, 1H), 4.72 - 4.61 (m, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.17 (h, J = 5.5 Hz, 2H), 3.98 - 3.84 (m, 5H), 3.71 (s, 4H), 3.58 (dd, J = 12.8, 4.0 Hz, 1H), 3.51 - 3.36 (m, 10H), 3.29 (s, 4H), 3.09 (t, J = 8.8 Hz, 2H), 2.90 - 2.82 (m, 1H), 2.23 (s, 4H), 2.11 (q, J = 9.2, 7.0 Hz, 2H), 1.96 (d, J = 14.7 Hz, 2H).

[0350] Example 18

[0351] Step 1. Follow the synthesis method of step 1 of example 13, use INT A6 as the reactant to synthesize compound 18-1. LCMS: m / z = 434 [M] + .

[0352] Step 2: Follow the synthesis method of step 2 of example 1, use INT B3 and compound 18-1 as the reactants to synthesize compound 18. LCMS: m / z = 408 [M] 2+ .

[0353] 1H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 7.08 - 6.94 (m, 2H), 6.89 - 6.75 (m, 3H), 6.75 - 6.58 (m, 2H), 6.49 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H), 5.98 (d, J = 4.4 Hz, 2H), 5.69 (s, 1H), 4.66 (d, J = 9.5 Hz, 1H), 4.57 (s, 2H), 4.28 (s, 2H), 4.17 (s, 2H), 3.94 (s, 5H), 3.71 (d, J = 2.1 Hz, 4H), 3.57 (d, J = 12.3 Hz, 1H), 3.34 (d, J = 16.1 Hz, 11H), 3.29 (d, J = 2.1 Hz, 3H), 3.09 (t, J = 9.1 Hz, 2H), 2.86 (t, J = 11.5 Hz, 1H), 2.21 (s, 4H), 2.11 (t, J = 11.8 Hz, 2H), 1.93 (d, J = 14.9 Hz, 2H).

[0354] Example 19

[0355] Step 1. Follow the synthesis method of step 1 of example 1, use INT A9 as the reactant to synthesize compound 19-1. LCMS: m / z = 366 [M] + .

[0356] Step 2. Follow the synthesis method of step 2 of example 1, use INT B1 and compound 19-1 as the reactants to synthesize compound 19. LCMS: m / z = 367 [M] 2+ .

[0357] 1H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.54 (m, 2H), 7.48 - 7.36 (m, 3H), 7.32 (s, 4H), 6.99 (d, J = 8.6 Hz, 2H), 6.90 - 6.77 (m, 3H), 6.63 (s, 2H), 5.53 (s, 1H), 5.17 (d, J = 14.8 Hz, 2H), 4.90 (d, J = 14.8 Hz, 2H), 4.83 (s, 2H), 4.69 - 4.61 (m, 1H), 4.24 - 4.06 (m, 4H), 3.91 (q, J = 11.0, 8.4 Hz, 1H), 3.70 (d, J = 9.7 Hz, 6H), 3.58 (td, J = 11.5, 10.9, 4.1 Hz, 3H), 3.34 (s, 6H), 3.19 (s, 3H), 3.08 (t, J = 9.0 Hz, 2H), 2.87 (dd, J = 12.7, 10.5 Hz, 1H), 2.26 - 2.16 (m, 2H), 2.10 (s, 2H).

[0358] Example 20

[0359] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A9 as the reactant to synthesize compound 20-1. LCMS: m / z = 366 [M] + .

[0360] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B3 and compound 20-1 as the reactants to synthesize compound 20. LCMS: m / z = 374 [M] 2+ .

[0361] 1H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.55 (m, 2H), 7.41 (p, J = 6.9 Hz, 3H), 7.32 (s, 4H), 6.84 - 6.75 (m, 3H), 6.62 (s, 2H), 6.48 (dd, J = 8.0, 1.7 Hz, 1H), 5.97 (d, J = 4.3 Hz, 2H), 5.67 (s, 1H), 5.16 (d, J = 14.7 Hz, 2H), 4.89 (d, J = 14.8 Hz, 2H), 4.81 (s, 2H), 4.67 - 4.61 (m, 1H), 4.16 (dt, J = 18.1, 5.9 Hz, 4H), 3.93 - 3.83 (m, 1H), 3.69 (s, 4H), 3.60 - 3.52 (m, 3H), 3.31 (s, 4H), 3.28 (s, 4H), 3.09 (t, J = 9.2 Hz, 2H), 2.90 - 2.83 (m, 1H), 2.19 (s, 2H), 2.09 (d, J = 18.7 Hz, 2H).

[0362] Example 21

[0363] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A10 as the reactant to synthesize compound 21-1. LCMS: m / z = 396 [M] + .

[0364] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B3 and compound 21-1 as the reactants to synthesize compound 21. LCMS: m / z = 389 [M] 2+ .

[0365] 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.7 Hz, 2H), 7.35 (s, 4H), 6.95 (d, J = 8.7 Hz, 2H), 6.84 - 6.77 (m, 3H), 6.64 (s, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.3 Hz, 2H), 5.68 (s, 1H), 5.11 (d, J = 14.9 Hz, 2H), 4.85 (d, J = 14.7 Hz, 2H), 4.75 (s, 2H), 4.65 (dd, J = 10.5, 4.0 Hz, 1H), 4.16 (dt, J = 15.3, 5.9 Hz, 4H), 3.90 (q, J = 10.9, 8.2 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 4H), 3.32 (s, 8H), 3.28 (s, 3H), 3.09 (t, J = 9.0 Hz, 2H), 2.86 (dd, J = 12.8, 10.3 Hz, 1H), 2.19 (d, J = 7.1 Hz, 2H), 2.07 (s, 2H).

[0366] Example 22

[0367] Step 1. Follow the synthesis method of step 1 of Example 1 using INT A11 as the reactant to synthesize compound 22-1. LCMS: m / z = 426 [M] + .

[0368] Step 2. Follow the synthesis method of step 2 of Example 1 using INT B1 and compound 22-1 as the reactants to synthesize compound 22. LCMS: m / z = 397 [M] 2+ .

[0369] 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 4H), 7.18 - 7.08 (m, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.89 - 6.77 (m, 3H), 6.64 (s, 2H), 5.54 (s, 1H), 5.18 (d, J = 14.9 Hz, 2H), 4.88 (d, J = 14.9 Hz, 2H), 4.75 (s, 2H), 4.66 (dd, J = 10.6, 3.9 Hz, 1H), 4.17 (dt, J = 22.8, 5.8 Hz, 4H), 3.90 (dd, J = 13.2, 8.1 Hz, 1H), 3.72 (dd, J = 15.2, 8.0 Hz, 12H), 3.59 (tt, J = 8.6, 4.0 Hz, 3H), 3.35 (s, 6H), 3.19 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.92 - 2.82 (m, 1H), 2.19 (d, J = 10.1 Hz, 2H), 2.10 (t, J = 8.8 Hz, 2H).

[0370] Example 23

[0371] Step 1. Follow the synthesis method of step 1 of Example 1 using INT A11 as the reactant to synthesize compound 23-1. LCMS: m / z = 426 [M] + .

[0372] Step 2. Follow the synthesis method of step 2 of Example 1 using INT B3 and compound 23-1 as the reactants to synthesize compound 23. LCMS: m / z = 404 [M] 2+ .

[0373] 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 4H), 7.12 (dd, J = 4.4, 2.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.88 - 6.80 (m, 2H), 6.78 (d, J = 1.7 Hz, 1H), 6.63 (s, 2H), 6.53 - 6.46 (m, 1H), 5.98 (d, J = 4.2 Hz, 2H), 5.68 (s, 1H), 5.15 (d, J = 14.9 Hz, 2H), 4.86 (d, J = 14.8 Hz, 2H), 4.72 (s, 2H), 4.66 - 4.60 (m, 1H), 4.18 (dt, J = 18.5, 6.3 Hz, 4H), 3.93 - 3.84 (m, 1H), 3.75 (d, J = 7.1 Hz, 6H), 3.70 (s, 3H), 3.31 (s, 7H), 3.29 (s, 3H), 3.10 (d, J = 7.4 Hz, 3H), 2.90 - 2.83 (m, 1H), 2.23 - 2.15 (m, 2H), 2.08 (s, 3H).

[0374] Example 24

[0375] Step 1. Follow the synthesis method of step 1 of Example 1 using INT A11 as the reactant to synthesize compound 24-1. LCMS: m / z = 426 [M] + .

[0376] Step 2. Follow the synthesis method of step 2 of Example 1 using INT B4 and compound 24-1 as the reactants to synthesize compound 24. LCMS: m / z = 396 [M] 2+ .

[0377] 1H NMR (400 MHz, DMSO-d6) δ 7.34 (s, 4H), 7.12 (dd, J = 4.5, 2.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.89 - 6.77 (m, 3H), 6.66 (s, 2H), 6.48 (d, J = 8.4 Hz, 1H), 6.00 (d, J = 6.1 Hz, 2H), 5.96 (s, 1H), 5.87 (d, J = 3.6 Hz, 2H), 5.16 (d, J = 14.9 Hz, 2H), 4.87 (d, J = 14.9 Hz, 2H), 4.72 (s, 2H), 4.64 (d, J = 9.3 Hz, 1H), 4.18 (dt, J = 24.3, 7.6 Hz, 4H), 3.84 (s, 1H), 3.76 (d, J = 6.7 Hz, 6H), 3.68 (d, J = 7.1 Hz, 1H), 3.58 - 3.51 (m, 3H), 3.29 (s, 4H), 3.08 (d, J = 17.6 Hz, 3H), 2.92 - 2.84 (m, 1H), 2.21 - 2.06 (m, 4H).

[0378] Example 25

[0379] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A12 as the reactant to synthesize compound 25-1. LCMS: m / z = 410 [M] + .

[0380] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B1 and compound 25-1 as the reactants to synthesize compound 25. LCMS: m / z = 389 [M] 2+ .

[0381] 1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.25 (m, 4H), 7.16 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 8.0, 1.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.81 (s, 1H), 6.64 (s, 2H), 6.03 (s, 2H), 5.54 (s, 1H), 5.13 (d, J = 14.8 Hz, 2H), 4.86 (d, J = 14.9 Hz, 2H), 4.72 (s, 2H), 4.63 (d, J = 9.0 Hz, 1H), 4.15 (dq, J = 11.4, 5.7 Hz, 4H), 3.96 - 3.85 (m, 1H), 3.71 (d, J = 9.1 Hz, 6H), 3.63 - 3.57 (m, 1H), 3.56 - 3.49 (m, 2H), 3.43 - 3.34 (m, 6H), 3.19 (s, 3H), 3.10 (d, J = 7.3 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.20 (s, 2H), 2.07 (s, 2H).

[0382] Example 26

[0383] Step 1. Follow the synthesis method of step 1 of Example 1 using INT A12 as the reactant to synthesize compound 26-1. LCMS: m / z = 410 [M] + .

[0384] Step 2. Follow the synthesis method of step 2 of Example 1 using INT B2 and compound 26-1 as the reactants to synthesize compound 26. LCMS: m / z = 404 [M] 2+ .

[0385] 1H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.26 (m, 4H), 7.16 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 8.1, 1.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.88 - 6.79 (m, 2H), 6.65 (d, J = 9.1 Hz, 3H), 6.54 (dd, J = 8.2, 2.0 Hz, 1H), 6.03 (s, 2H), 5.64 (s, 1H), 5.13 (d, J = 14.8 Hz, 2H), 4.86 (d, J = 14.8 Hz, 2H), 4.70 (d, J = 15.7 Hz, 3H), 4.17 (q, J = 10.2, 8.0 Hz, 4H), 3.86 (t, J = 9.1 Hz, 1H), 3.70 (d, J = 4.4 Hz, 6H), 3.63 (s, 3H), 3.60 - 3.50 (m, 3H), 3.34 (s, 6H), 3.23 (s, 3H), 3.08 (t, J = 8.8 Hz, 2H), 2.90 (d, J = 11.5 Hz, 1H), 2.20 (s, 2H), 2.07 (s, 2H).

[0386] Example 27

[0387] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A12 as the reactant to synthesize compound 27-1. LCMS: m / z = 410 [M] + .

[0388] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B3 and compound 27-1 as the reactants to synthesize compound 27. LCMS: m / z = 396 [M] 2+ .

[0389] 1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.28 (m, 4H), 7.17 (d, J = 1.7 Hz, 1H), 7.08 (dd, J = 8.0, 1.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.86 - 6.76 (m, 3H), 6.64 (s, 2H), 6.49 (dd, J = 7.9, 1.7 Hz, 1H), 6.03 (s, 2H), 5.98 (d, J = 4.3 Hz, 2H), 5.68 (s, 1H), 5.14 (d, J = 14.8 Hz, 2H), 4.87 (d, J = 14.8 Hz, 2H), 4.73 (s, 2H), 4.65 (dd, J = 10.5, 3.9 Hz, 1H), 4.22 - 4.09 (m, 4H), 3.94 - 3.84 (m, 1H), 3.70 (s, 4H), 3.56 (td, J = 11.9, 11.3, 4.2 Hz, 3H), 3.32 (s, 5H), 3.29 (s, 3H), 3.08 (t, J = 9.0 Hz, 2H), 2.86 (dd, J = 12.8, 10.3 Hz, 1H), 2.20 (s, 2H), 2.08 (d, J = 5.9 Hz, 2H).

[0390] Example 28

[0391] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A12 as the reactant to synthesize compound 28-1. LCMS: m / z = 410 [M] + .

[0392] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B4 and compound 28-1 as the reactants to synthesize compound 28. LCMS: m / z = 388 [M] 2+ .

[0393] 1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 1.7 Hz, 4H), 7.16 (d, J = 1.8 Hz, 1H), 7.07 (dd, J = 8.0, 1.8 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.81 (t, J = 7.2 Hz, 3H), 6.65 (d, J = 1.6 Hz, 2H), 6.47 (dd, J = 8.0, 1.8 Hz, 1H), 6.09 - 5.91 (m, 5H), 5.85 (d, J = 4.5 Hz, 2H), 5.12 (d, J = 14.8 Hz, 2H), 4.85 (d, J = 14.9 Hz, 2H), 4.71 (s, 2H), 4.68 - 4.61 (m, 1H), 4.15 (dq, J = 23.1, 5.7 Hz, 4H), 3.84 (q, J = 11.1, 8.5 Hz, 1H), 3.66 (s, 1H), 3.28 (s, 7H), 3.07 (d, J = 17.2 Hz, 3H), 2.90 - 2.83 (m, 1H), 2.16 (s, 2H), 2.07 (s, 2H).

[0394] Example 29

[0395] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A13 as the reactant to synthesize compound 29-1. LCMS: m / z = 384 [M] + .

[0396] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B3 and compound 29-1 as the reactants to synthesize compound 29. LCMS: m / z = 383 [M] 2+ .

[0397] 1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.57 (m, 2H), 7.41 - 7.26 (m, 4H), 7.21 (t, J = 8.7 Hz, 2H), 6.89 - 6.75 (m, 3H), 6.64 (s, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.3 Hz, 2H), 5.68 (s, 1H), 5.17 (d, J = 14.9 Hz, 2H), 4.91 (d, J = 14.9 Hz, 2H), 4.83 (s, 2H), 4.67 - 4.60 (m, 1H), 4.16 (dq, J = 17.7, 5.6 Hz, 4H), 3.90 (q, J = 10.1, 8.2 Hz, 1H), 3.70 (s, 4H), 3.58 (tt, J = 8.2, 4.3 Hz, 4H), 3.32 (s, 4H), 3.29 (s, 3H), 3.09 (t, J = 8.9 Hz, 2H), 2.90 - 2.82 (m, 1H), 2.19 (s, 2H), 2.09 (d, J = 10.3 Hz, 2H).

[0398] Example 30

[0399] Step 1. A solution of INT A13 (2.10 g, 6.53 mmol, 1.0 eq.) and maleic anhydride (0.96 g, 9.79 mmol, 1.5 eq.) in CH3CN (100 mL) was purged with nitrogen and maintained under nitrogen atmosphere, triethylamine (0.73 g, 7.18 mmol, 1.1 eq.) was added dropwise at 0-5 °C. The reaction mixture was stirred at 0 °C for 3 h, concentrated under reduced pressure. The resulting residue was dispersed in DCM (50 mL), washed with water (30 mL x 3), the combined aqueous phase was adjusted to pH 2-3 with HCI (2N, aq.) and then extracted with a mixed solution of DCM and CH3CN (V DCM :V CH3CN = 5:1) (30 mL x 5). The combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude compound 30-1 (2.3 g), which was used directly in the next step without further purification. LCMS: m / z = 384 [M-H]- + .

[0400] Step 2. A solution of INT B4 (1.20 g, 2.86 mmol, 1.0 eq.) and compound 30-1 (2.01 g, 4.29 mmol, 1.5 eq.) in DCM (100 mL) was purged with nitrogen and maintained under nitrogen atmosphere, HATU (2.17 g, 5.72 mmol, 2.0 eq.) was added slowly at 0-5 °C, after stirring at room temperature for 30 min, pyridine (0.90 g, 11.43 mmol, 4.0 eq.) was added. The reaction mixture was stirred at room temperature overnight, quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue, which was purified by preparative high-performance liquid chromatography (C18 column, eluted with H2O / CH3CN) to give compound 30 (1.06 g, yield 45%). LCMS: m / z = 375 [M] 2+ .

[0401] 1 H NMR (400 MHz, DMSO-d6) d 7.71 - 7.58 (m, 2H), 7.31 (p, J = 4.9, 4.5 Hz, 4H), 7.21 (t, J = 8.8 Hz, 2H), 6.90 - 6.76 (m, 3H), 6.66 (s, 2H), 6.48 (dd, J = 8.0, 1.7 Hz, 1H), 6.04 - 5.92 (m, 3H), 5.86 (d, J = 4.9 Hz, 2H), 5.17 (d, J = 14.9 Hz, 2H), 4.96 - 4.79 (m, 4H), 4.66 (dd, J = 9.4, 4.0 Hz, 1H), 4.15 (ddt, J = 27.3, 11.3, 5.9 Hz, 4H), 3.89 - 3.78 (m, 1H), 3.62 (ddd, J = 34.8, 14.7, 6.6 Hz, 4H), 3.29 (s, 5H), 3.07 (d, J = 16.8 Hz, 2H), 2.88 (dd, J = 13.2, 9.6 Hz, 1H), 2.18 (d, J = 8.4 Hz, 2H), 2.10 (s, 2H).

[0402] Example 31

[0403] Step 1. Compound 31-1 was synthesized according to the synthetic method of Step 1 of Example 1 using INT A14 as the reactant. LCMS: m / z = 392 [M] + .

[0404] Step 2. Compound 31 was synthesized according to the synthetic method of Step 2 of Example 1 using INT B1 and compound 31-1 as the reactants. LCMS: m / z = 380 [M]2+ .

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.41 (m, 5H), 6.99 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.81 (s, 1H), 6.66 (d, J = 1.4 Hz, 2H), 5.54 (s, 1H), 4.66 (d, J = 6.9 Hz, 3H), 4.27 (t, J = 5.8 Hz, 2H), 4.17 (hept, J = 5.8 Hz, 2H), 3.91 (q, J = 10.8, 8.7 Hz, 1H), 3.71 (d, J = 5.4 Hz, 7H), 3.60 (dd, J = 12.7, 3.9 Hz, 1H), 3.29 (s, 13H), 3.19 (s, 3H), 3.12 (d, J = 7.7 Hz, 6H), 2.87 (t, J = 11.6 Hz, 1H), 2.31 - 2.10 (m, 6H), 2.03 (t, J = 7.6 Hz, 2H).

[0406] Example 32

[0407] Step 1. Follow the synthesis method of step 1 of Example 1, use INT A14 as the reactant to synthesize compound 32-1. LCMS: m / z = 392 [M] + .

[0408] Step 2. Follow the synthesis method of step 2 of Example 1, use INT B3 and compound 32-1 as the reactants to synthesize compound 32. LCMS: m / z = 387 [M] 2+ .

[0409] 1H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.39 (m, 5H), 6.92 - 6.75 (m, 3H), 6.66 (d, J = 1.6 Hz, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.2 Hz, 2H), 5.68 (s, 1H), 4.66 (d, J = 10.1 Hz, 3H), 4.27 (t, J = 5.8 Hz, 2H), 4.17 (hept, J = 5.8 Hz, 2H), 3.90 (q, J = 10.7, 8.9 Hz, 1H), 3.71 (s, 4H), 3.59 - 3.54 (m, 1H), 3.37 - 3.30 (m, 11H), 3.28 (s, 3H), 3.12 (d, J = 7.7 Hz, 8H), 2.91 - 2.82 (m, 1H), 2.29 - 2.09 (m, 6H), 2.06 - 1.95 (m, 2H).

[0410] Example 33

[0411] Step 1. Disperse INT A1 (1.50 g, 4.58 mmol, 1.0 eq.) and TEA (0.93 g, 9.15 mmol, 2.0 eq.) into DCM (25 mL). Purge the reaction mixture and keep it in an inert atmosphere of nitrogen, cool to 0-5 °C, then add tert-butyl 4-chloro-4-oxobutanoate (0.97 g, 5.03 mmol, 1.1 eq.) dropwise, stir the reaction mixture at 0 °C for 2 h, then quench with water (50 ml), then extract with DCM (25 mL x 3). Combine the organic phases, dry over anhydrous Na2SO4, then concentrate under reduced pressure to obtain a residue. Disperse the obtained residue into DCM (20 mL), cool to 0-5 °C, then add TFA (5.0 mL) dropwise, stir the reaction mixture at room temperature for 3 h, quench with saturated aqueous sodium bicarbonate solution, then extract with DCM (20 mL x 3). Combine the organic phases, dry over anhydrous Na2SO4, then concentrate under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (eluted with MeOH / DCM) to obtain compound 33-1 (1.24 g, yield 63%) as a solid. LCMS: m / z = 392 [M-H]-. + .

[0412] Step 2. Follow the synthesis method of Step 2 of Example 1, use INT B1 and compound 33-1 as reactants to synthesize compound 33. LCMS: m / z = 380 [M-H]- 2+ .

[0413] 1H NMR (400 MHz, DMSO-d6) δ 7.53 (q, J = 7.5 Hz, 5H), 7.00 (d, J = 8.3 Hz, 2H), 6.91 - 6.79 (m, 3H), 5.57 (s, 1H), 4.71 - 4.59 (m, 3H), 4.11 (t, J = 5.9 Hz, 2H), 4.00 (t, J = 6.1 Hz, 2H), 3.92 (s, 5H), 3.72 (d, J = 1.9 Hz, 7H), 3.62 - 3.55 (m, 1H), 3.46 - 3.34 (m, 13H), 3.22 (s, 3H), 3.08 (t, J = 9.5 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.47 - 2.42 (m, 2H), 2.22 - 2.03 (m, 6H), 1.95 (d, J = 14.7 Hz, 2H).

[0414] Example 34

[0415] Step 1. Follow the synthesis method of step 1 of example 33 using INT A2 as reactant to synthesize compound 34-1. LCMS: m / z = 422 [M] + .

[0416] Step 2. Follow the synthesis method of step 2 of example 1 using INT B1 and compound 34-1 as reactants to synthesize compound 34. LCMS: m / z = 395 [M] 2+ .

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (q, J = 7.5 Hz, 5H), 7.00 (d, J = 8.3 Hz, 2H), 6.91 - 6.79 (m, 3H), 5.57 (s, 1H), 4.71 - 4.59 (m, 3H), 4.11 (t, J = 5.9 Hz, 2H), 4.00 (t, J = 6.1 Hz, 2H), 3.92 (s, 5H), 3.72 (d, J = 1.9 Hz, 7H), 3.62 - 3.55 (m, 1H), 3.46 - 3.34 (m, 13H), 3.22 (s, 3H), 3.08 (t, J = 9.5 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.47 - 2.42 (m, 2H), 2.22 - 2.03 (m, 6H), 1.95 (d, J = 14.7 Hz, 2H).

[0418] Example 35

[0419] Step 1. Follow the synthesis method of step 1 of example 33 using INT A3 as reactant to synthesize compound 35-1. LCMS: m / z = 452 [M] + .

[0420] Step 2. Follow the synthesis method of step 2 of example 1 using INT B1 and compound 35-1 as reactants to synthesize compound 35. LCMS: m / z = 410 [M] 2+ .

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (s, 1H), 7.10 - 7.03 (m, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.88 - 6.81 (m, 3H), 5.57 (s, 1H), 4.64 (dd, J = 11.7, 2.9 Hz, 1H), 4.56 (s, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.92 (d, J = 2.0 Hz, 5H), 3.79 (d, J = 2.5 Hz, 6H), 3.72 (d, J = 1.6 Hz, 7H), 3.60 (dd, J = 12.7, 3.8 Hz, 1H), 3.34 (d, J = 16.6 Hz, 13H), 3.22 (s, 3H), 3.10 (d, J = 5.4 Hz, 2H), 2.88 (t, J = 11.5 Hz, 1H), 2.47 - 2.43 (m, 2H), 2.11 (q, J = 12.9, 11.5 Hz, 6H), 1.93 (d, J = 14.6 Hz, 2H).

[0422] Example 36

[0423] Step 1. INT A3 (1.50 g, 3.87 mmol, 1.0 eq.) and TEA (0.78 g, 7.73 mmol, 2.0 eq.) were dispersed into DCM (25 mL). The reaction mixture was purged and kept under nitrogen inert atmosphere, cooled to 0-5 °C, then tert-butyl 4-chloro-4-oxobutanoate (0.88 g, 4.25 mmol, 1.1 eq.) was added dropwise, the reaction mixture was stirred at 0 °C for 2 h, then quenched with water (50 ml), then extracted with DCM (25 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, then concentrated under reduced pressure to give a residue. The residue was dispersed into DCM (20 mL), cooled to 0-5 °C, then TFA (5.0 mL) was added dropwise, the reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous sodium bicarbonate solution, then extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with MeOH / DCM) to give compound 36-1 (1.02 g, yield 60%) as a solid. LCMS: m / z = 466 [M+1]. + .

[0424] Step 2. Follow the synthesis method of Step 2 of Example 1, use INT B1 and compound 36-1 as reactants to synthesize compound 36. LCMS: m / z = 417 [M+1] 2+ .

[0425] 1 H NMR (400 MHz, DMSO-d6) d 7.14 (d, J = 1.8 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.89 - 6.82 (m, 3H), 5.56 (s, 1H), 4.64 (dd, J = 10.6, 3.9 Hz, 1H), 4.57 (s, 2H), 4.11 (t, J = 6.0 Hz, 2H), 4.03 - 3.88 (m, 7H), 3.79 (d, J = 2.1 Hz, 6H), 3.72 (d, J = 1.9 Hz, 7H), 3.60 (dd, J = 12.8, 4.0 Hz, 1H), 3.41 (d, J = 19.9 Hz, 11H), 3.21 (s, 3H), 3.10 (d, J = 5.9 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.28 (t, J = 7.4 Hz, 2H), 2.22 - 2.04 (m, 8H), 1.93 (d, J = 14.6 Hz, 2H), 1.64 (p, J = 7.5 Hz, 2H).

[0426] Example 37

[0427] Step 1. Compound 15-1 was synthesized following the synthetic method of Step 1 of Example 1 using INT A15 as the reactant. LCMS: m / z = 420 [M] + .

[0428] Step 2. Compound 37 was synthesized following the synthetic method of Step 2 of Example 1 using INT B3 and compound 15-1 as the reactants. LCMS: m / z = 401 [M] 2+ .

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 8.7 Hz, 2H), 7.04 - 6.96 (m, 2H), 6.87 - 6.80 (m, 2H), 6.78 (d, J = 1.6 Hz, 1H), 6.67 (d, J = 2.4 Hz, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.2 Hz, 2H), 5.68 (s, 1H), 4.62 (d, J = 20.7 Hz, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.16 (h, J = 5.6 Hz, 2H), 3.93 (s, 5H), 3.77 (s, 3H), 3.71 (s, 3H), 3.57 (dd, J = 12.6, 4.0 Hz, 1H), 3.32 (s, 11H), 3.29 (s, 4H), 3.09 (t, J = 9.1 Hz, 2H), 2.90 - 2.83 (m, 1H), 2.22 (s, 4H), 2.08 (d, J = 12.2 Hz, 2H), 1.95 (d, J = 14.6 Hz, 2H).

[0430] Example 38

[0431] Step 1. Compound 38 was synthesized following the synthetic method of Step 2 of Example 1 using INT B1 and compound 11-1 as the reactants. LCMS: m / z = 388 [M] 2+ .

[0432] 1H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.58 (m, 2H), 7.31 (t, J = 8.7 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.90 - 6.80 (m, 3H), 6.67 (d, J = 2.0 Hz, 2H), 5.55 (s, 1H), 4.69 - 4.62 (m, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.20 - 4.14 (m, 2H), 3.96 - 3.89 (m, 5H), 3.72 (d, J = 4.7 Hz, 7H), 3.61 (dd, J = 12.8, 3.9 Hz, 1H), 3.51 - 3.40 (m, 6H), 3.35 (s, 5H), 3.20 (s, 3H), 3.12 - 3.04 (m, 2H), 2.88 (t, J = 11.6 Hz, 1H), 2.28 - 2.18 (m, 4H), 2.15 - 2.06 (m, 2H), 1.96 (d, J = 14.6 Hz, 2H).

[0433] Example 39

[0434] Step 1. Follow the procedure of Example 1, Step 2 using INT B4 and compound 11-1 as reactants to synthesize compound 39. LCMS: m / z = 387 [M] 2+ .

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.58 (m, 2H), 7.31 (t, J = 8.7 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.90 - 6.80 (m, 3H), 6.67 (d, J = 2.0 Hz, 2H), 5.55 (s, 1H), 4.69 - 4.62 (m, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.20 - 4.14 (m, 2H), 3.96 - 3.89 (m, 5H), 3.72 (d, J = 4.7 Hz, 7H), 3.61 (dd, J = 12.8, 3.9 Hz, 1H), 3.51 - 3.40 (m, 6H), 3.35 (s, 5H), 3.20 (s, 3H), 3.12 - 3.04 (m, 2H), 2.88 (t, J = 11.6 Hz, 1H), 2.28 - 2.18 (m, 4H), 2.15 - 2.06 (m, 2H), 1.96 (d, J = 14.6 Hz, 2H).

[0436] Example 40

[0437] Step 1. Follow the synthetic method of step 1 of example 13 using INT A2 as the reactant to synthesize compound 40-1. LCMS: m / z = 420 [M] + .

[0438] Step 2. Follow the synthetic method of step 2 of example 1 using INT B3 and compound 15-1 as the reactants to synthesize compound 40. LCMS: m / z = 401 [M] 2+ .

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.86 - 6.77 (m, 3H), 6.68 (d, J = 2.4 Hz, 2H), 6.49 (d, J = 7.6 Hz, 1H), 5.98 (d, J = 4.2 Hz, 2H), 5.69 (s, 1H), 4.69 - 4.55 (m, 3H), 4.29 (t, J = 5.8 Hz, 2H), 4.21 - 4.11 (m, 2H), 3.98 - 3.86 (m, 5H), 3.78 (s, 3H), 3.74 - 3.64 (m, 4H), 3.61 - 3.53 (m, 1H), 3.45 - 3.37 (m, 5H), 3.32-3.29 (m, 8H), 3.15 - 3.04 (m, 2H), 2.87 (t, J = 11.4, 2H), 2.30 - 2.05 (m, 6H), 1.95 (d, J = 14.7 Hz, 2H).

[0440] Example 41

[0441] Step 1. Follow the synthetic method of step 1 of example 13 using INT A16 as the reactant to synthesize compound 41-1. LCMS: m / z = 338 [M] + .

[0442] Step 2. Follow the synthetic method of step 2 of example 1 using INT B3 and compound 41-1 as the reactants to synthesize compound 41. LCMS: m / z = 401 [M] 2+ .

[0443] 1H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 1.7 Hz, 1H), 7.07 - 6.95 (m, 2H), 6.86 - 6.77 (m, 3H), 6.76 - 6.61 (m, 2H), 6.49 (dd, J = 7.9, 1.7 Hz, 1H), 6.07 (s, 2H), 5.99 (d, J = 4.4 Hz, 2H), 5.68 (s, 1H), 4.69 - 4.61 (m, 1H), 4.56 (s, 2H), 4.27 (t, J = 5.7 Hz, 2H), 4.17 (s, 2H), 3.96 - 3.86 (m, 1H), 3.74 - 3.65 (m, 4H), 3.62 - 3.53 (m, 1H), 3.34 - 3.29 (m, 14H), 3.16 - 3.06 (m, 8H), 2.87 (t, J = 11.6 Hz, 1H), 2.28 - 2.08 (m, 6H), 2.04 - 1.96 (m, 2H).

[0444] Example 42

[0445] Step 1. Follow the synthetic method of step 2 of Example 1, use INT B1-a and compound 1-1 as reactants to synthesize compound 1a. LCMS: m / z = 379 [M] 2+ .

[0446] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.44 (m, 5H), 7.00 (d, J = 8.6 Hz, 2H), 6.90 - 6.80 (m, 3H), 6.68 (s, 2H), 5.55 (s, 1H), 4.71 - 4.62 (m, 3H), 4.29 (t, J = 5.9 Hz, 2H), 4.21 - 4.15 (m, 2H), 3.96 - 3.89 (m, 6H), 3.72 (d, J = 4.8 Hz, 8H), 3.64 - 3.58 (m, 2H), 3.41 - 3.32 (m, 8H), 3.20 (s, 3H), 3.12- 3.07 (m, 2H), 2.88 (t, J = 10 Hz, 1H), 2.30 - 2.07 (m, 6H), 1.97 (d, J = 14.2 Hz, 2H).

[0447] Example 43

[0448] Step 1. Follow the synthetic method of step 2 of Example 1, use INT B3B-a and compound 8-1 as reactants to synthesize compound 8a. LCMS: m / z = 386 [M] 2+ .

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.44 (m, 5H), 6.86 - 6.77 (m, 3H), 6.67 (d, J = 1.1 Hz, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.1 Hz, 2H), 5.69 (s, 1H), 4.71 - 4.62 (m, 3H), 4.29 (t, J = 5.8 Hz, 2H), 4.18 (q, J = 5.6 Hz, 2H), 3.97 - 3.86 (m, 5H), 3.75 - 3.66 (m, 4H), 3.58 (dd, J = 12.8, 3.9 Hz, 1H), 3.50 - 3.39 (m, 9H), 3.33 - 3.28 (m, 5H), 3.12 - 3.07 (m, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.30 - 2.07 (m, 6H), 2.01 - 1.92 (m, 2H).

[0450] Example 44

[0451] Step 1. Follow the procedure of Example 1, Step 2 using INT B3B-a and compound 9-1 as reactants to synthesize compound 9a. LCMS: m / z = 408 [M] 2+ .

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.44 (m, 5H), 6.86 - 6.77 (m, 3H), 6.67 (d, J = 1.1 Hz, 2H), 6.49 (dd, J = 8.0, 1.7 Hz, 1H), 5.98 (d, J = 4.1 Hz, 2H), 5.69 (s, 1H), 4.71 - 4.62 (m, 3H), 4.29 (t, J = 5.8 Hz, 2H), 4.18 (q, J = 5.6 Hz, 2H), 3.97 - 3.86 (m, 5H), 3.75 - 3.66 (m, 4H), 3.58 (dd, J = 12.8, 3.9 Hz, 1H), 3.50 - 3.39 (m, 9H), 3.33 - 3.28 (m, 5H), 3.12 - 3.07 (m, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.30 - 2.07 (m, 6H), 2.01 - 1.92 (m, 2H).

[0453] Example 45

[0454] Step 1. Follow the synthetic method of step 2 of example 1, use INT B3B-b and compound 9-1 as reactants to synthesize compound 9b. LCMS: m / z = 408 [M] 2+ .

[0455] 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (s, 1H), 7.09 - 6.99 (m, 2H), 6.94 - 6.80 (m, 3H), 6.67 (d, J = 1.7 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.11 (s, 2H), 5.99 (s, 2H), 5.73 (s, 1H), 4.78 (d, J = 9.7 Hz, 1H), 4.58 (s, 2H), 4.41 - 4.25 (m, 4H), 3.94 (s, 4H), 3.74 (s, 4H), 3.56 - 3.42 (m, 14H), 3.17 - 3.11 (m, 2H), 3.00 (s, 3H), 2.83 (t, J = 11.9 Hz, 1H), 2.42 - 2.32 (m, 2H), 2.28 - 2.17 (m, 2H), 2.16 - 2.05 (m, 2H), 1.94 (d, J = 14.5 Hz, 2H).

[0456] Example 46

[0457] Step 1. Follow the synthetic method of step 2 of example 1, use INT B3B-a and compound 17-1 as reactants to synthesize compound 17a. LCMS: m / z = 386 [M] 2+ .

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (s, 1H), 7.09 - 6.99 (m, 2H), 6.94 - 6.80 (m, 3H), 6.67 (d, J = 1.7 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.11 (s, 2H), 5.99 (s, 2H), 5.73 (s, 1H), 4.78 (d, J = 9.7 Hz, 1H), 4.58 (s, 2H), 4.41 - 4.25 (m, 4H), 3.94 (s, 4H), 3.74 (s, 4H), 3.56 - 3.42 (m, 14H), 3.17 - 3.11 (m, 2H), 3.00 (s, 3H), 2.83 (t, J = 11.9 Hz, 1H), 2.42 - 2.32 (m, 2H), 2.28 - 2.17 (m, 2H), 2.16 - 2.05 (m, 2H), 1.94 (d, J = 14.5 Hz, 2H).

[0459] The compounds listed in Table 2 below can be synthesized using similar methods as those listed in the above examples:

[0460] Pharmacological test examples

[0461] The selected control drug CW-1759-50 of the present application has the structural formula as shown below, which can be prepared according to the method described in the specification of international patent document WO2014005122A1, pages 43-45.

[0462] Pharmacological test example 1: rat muscle relaxation experiment 1

[0463] The rats were weighed, intravenously anesthetized with propofol (induction dose 15 mg / kg, maintenance dose 100 mg / kg), then fixed on the rat operating bed in a supine position, and the skin was prepared. The sciatic nerve and tibialis anterior muscle were separated respectively, the tibialis anterior muscle was connected with a tension sensor, and a stimulating electrode was placed at the sciatic nerve; the trachea was separated for tracheal intubation and connected with a small animal respirator. Single stimulation method was used to stimulate the sciatic nerve to induce muscle contraction of skeletal muscle. After stabilization for a period of time, a normal muscle contraction curve was recorded. After the signal was stable, different doses of test compounds were injected intravenously, the inhibition of muscle tension after administration was recorded, and the neuromuscular blocking efficacy of each compound, i.e. ED 95 was calculated. The onset time (TOF=0), duration time (TOF=25%) and recovery time (TOF=90%) of the control drug and the compound of the present application at the equivalent dose were compared.

[0464] Table 1-1: Onset, duration and recovery time of drug on rat muscle relaxation

[0465] From the above test results, it can be seen that the compound of the present application exhibits excellent neuromuscular blocking efficacy, can rapidly produce muscle relaxation in rats, and the duration and recovery time of muscle relaxation are significantly shorter than the control drug CW1759-50 or at least comparable. The above results show that the compound of the present application has the characteristics of ultra-short duration, and has the advantage of shorter efficacy compared with CW1759-50. In particular, compared with CW1759-50, the duration and recovery time of some compounds are at least shortened by 30%, or even by half.

[0466] Pharmacological test example 2: rat muscle relaxation experiment 2

[0467] The rats were weighed, anesthetized intravenously with propofol (induction dose 15 mg / kg, maintenance dose 100 mg / kg / hr), and then fixed on the rat operating bed in a supine position. The sciatic nerve and tibialis anterior muscle were separated by operation, the tibialis anterior muscle was connected with a tension sensor, and a stimulating electrode was placed at the sciatic nerve. The trachea was separated for tracheal intubation and connected with a small animal respirator. The sciatic nerve was stimulated to induce muscle contraction of skeletal muscle by TOF, and the muscle tension was measured at 2 times the ED 95 Dose, and the onset time (from administration to T1=0), the action time (from the end of administration to T1 recovery 25%), and the recovery time (TOFr≥0.9) were counted.

[0468] Table 2-1: Onset, duration and recovery time of muscle relaxation of 2 times the ED 95 Dose of the drug on rats

[0469] From the above test results, it can be seen that the compound of the present application can rapidly produce muscle relaxation in rats at 2 times the ED 95 Dose, and the muscle relaxation duration and recovery time are significantly shorter than those of the control drug CW1759-50, which has the advantage of shorter duration.

[0470] Pharmacological test example 3: pharmacodynamic experiment

[0471] The rats were weighed, anesthetized intravenously with propofol (induction dose 15 mg / kg, maintenance dose 100 mg / kg / hr), and then fixed on the rat operating bed in a supine position. The sciatic nerve and tibialis anterior muscle were separated by operation, the tibialis anterior muscle was connected with a tension sensor, and a stimulating electrode was placed at the sciatic nerve. The trachea was separated for tracheal intubation and connected with a small animal respirator. The sciatic nerve was stimulated to induce muscle contraction of skeletal muscle by TOF, and the muscle tension was measured at 2 times the ED

[0472] Table 3-1: Comparison of muscle relaxant efficacy of compounds at the same dose of 0.6 mg / kg

[0473] From the above test results, it can be seen that, compared with CW-1759-50, the compound of the present application exhibits more excellent neuromuscular blocking efficacy.

[0474] If any of the publications in the field art that are cited herein are incorporated by reference, it is understood that such incorporation is in no way limiting to the scope of the present application. All publications, patents, patent applications and published patent applications referred to herein are incorporated herein by reference in their entirety. Although the application has been described in detail with particular reference to certain illustrative examples, it should be understood that various other modifications can be made to the described embodiments. Accordingly, the description and examples are not intended to limit the scope of the application.

Claims

1. A compound represented by Formula (I-2), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, Formula (I-2) ###0001### 1-2 wherein: Y is selected from R YA is independently selected at each occurrence from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -O-C 1-6 haloalkyl, oxo, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3- 10 cycloalkyl), -OH, -O(C 1-6 alkyl), -O(C 3-10 cycloalkyl), -SH, -S(C 1-6 alkyl), -S(C 3-10 cycloalkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1- 6alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; R YB independently at each occurrence selected from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -O-C 1-6 haloalkyl, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-10 cycloalkyl), -OH, -O(C 1-6 alkyl), -O(C 3-10 cycloalkyl), -SH, -S(C 1-6 alkyl), -S(C 3-10 cycloalkyl), -C(=O)(C 1- 6alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1- 6alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each (R) 1A R 1B R 2A R 2B 、or R 2C Each time it appears, it is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1- 6-alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 Alkyl groups, 3-10 membered carbon cycloyl groups, 3-10 membered heterocyclic groups, phenyl groups, and 5-10 membered heteroaryl groups; optionally substituted by one or more R 1A and R 1B together with the C atom to which they are respectively attached form a 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl optionally substituted by one or more R S3 S3 substituents;​ optionally substituted by one or more R 2A and R 2B together with the C atom to which they are respectively attached form a 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl optionally substituted by one or more R S3 S3 substituents;​ n1 is selected from 0, 1, 2, 3, 4, 5, and 6; n2, n3, n4, and n5 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; n6, n7, n8, and n9 are each independently selected from 0, 1, 2, 3, 4, 5, and 6; and n6 + n7 + n8 + n9 < 6; n 14 , and n 15 each independently is selected from 0, 1, 2, 3, 4, 5, and 6; and n 14 + n 15 ≤ 5; R A is independently selected at each occurrence from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein the R A is optionally substituted with one or more substituents selected from halogen, -C 1-6 alkyl, CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1- 6alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; R B is independently selected at each occurrence from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -O-C 1-6 haloalkyl, -CN, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -NH(C 3-10 cycloalkyl), -OH, -O(C 1-6 alkyl), -O(C 3-10 cycloalkyl), -SH, -S(C 1-6 alkyl), -S(C 3-10 cycloalkyl), -C(=O)(C 1- 6alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1- 6alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Each R C Each time it appears, it is independently selected from hydrogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Haloalkyl, -(C 0-6 alkylene)-(3-14-membered carbon cycloyl), -(C 0-6 alkylene)-(3-14 membered heterocyclic group), -(C 0-6 alkylene)-(6-14 aryl), -(C 0-6 (alkylene)-(5-14-membered heteroaryl); wherein each R C Optionally by n SC R SC Instead, the R SC Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NO2, -N3, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1- 6-alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=0)2N(C 1-6 alkyl), -S(=0)2N(C 1-6 alkyl), -S(=0)2N(C 1-6 alkyl), -S(=0)2N(C 1-6 alkyl), 3-14 membered carbocyclyl, 3-14 membered heterocyclyl, 6-14 membered aryl, and 5-14 membered heteroaryl; n SC is selected from 0, 1, 2, 3, 4, 5, and 6; X Z- is a pharmaceutically acceptable anion; m is selected from 1, 2, 3, and 4; Z is selected from 1, 2, 3, and 4; Each (R) S1 R S2 R S3 R S6 、or R S8 Each time it appears, it is independently selected from halogens, -C 1-6 Alkyl, -C 2- 6-alkenyl, -C 2-6 alkynyl group, -C 1-6 Halogenated alkyl, -C 1-6 Halogenated alkoxy groups, -CN, oxo, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -O(C) 1-6 Alkyl), -SH, -S(C 1-6 Alkyl), -S (halogenated C) 1-6 Alkyl), -C(=O)(C 1- 6-alkyl), -S(=O)(C 1-6 Alkyl), -S(=O)2(C 1-6 Alkyl), -S(=O)(=NH)(C 1-6 Alkyl), -C(=O)OH, -C(=O)(OC 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl groups), -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1- 6-alkyl)2、-NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -S(=O)(OC 1-6 Alkyl), -OS (=O) (C 1-6 Alkyl groups), -S(=O)NH2, -S(=O)NH(C 1-6 Alkyl), -S(=O)N(C 1-6 Alkyl)2、-NHS(=O)(C 1- 6-alkyl), -N(C) 1-6 Alkyl)S(=O)(C 1-6 Alkyl), -S(=O)2(OC 1-6 Alkyl), -OS(=O)2(C 1-6 Alkyl groups), -S(=O)2NH2, -S(=O)2NH(C 1-6 Alkyl), -S(=O)2N(C 1-6 alkyl)2、-NHS(=O)2(C 1-6 alkyl), -N(C) 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein each (R S1 , R S2 , R S3 , R S6 , or R S8 is independently optionally substituted with one or more selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C 1-6 haloalkoxy, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1- 6alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 1-6 alkyl), -C(=O)(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -S(=O)(=NH)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1- 6alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1- 6alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)2(C 1- 6alkyl), -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl; Each n S3 n S6 、 or n S8 Independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each heterocyclyl independently comprises 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S at each occurrence; each heteroaryl independently comprises 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S at each occurrence.

2. The compound of claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, Y is R YB as defined in claim 1.

3. The compound of any one of claims 1-2, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R YB independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, and 3-7 membered cycloalkyl; Preferably, R YB It is selected independently from hydrogen each time it appears.

4. The compound of any one of claims 1-3, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, n3 is selected from 0, 1, 2, and 3; preferably, n3 is selected from 0, 1, and 2; more preferably, n3 is selected from 0, or 1; n4 is selected from 0, 1, 2, and 3; preferably, n4 is selected from 0, 1, and 2; more preferably, n4 is selected from 0, or 1.

5. The compound of any one of claims 1-4, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, fragment is selected from ethenylene, propenylene, and butenylene.

6. The compound of any one of claims 1-5, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, fragment For 7. The compound of any one of claims 1-6, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, n6 is selected from 0, 1, 2, and 3; preferably, n6 is selected from 0, 1, and 2; further preferably, n6 is selected from 0, and 1; n7 is selected from 0, 1, 2, and 3; preferably, n7 is selected from 0, 1, and 2; further preferably, n7 is selected from 0, and 1; n8 is selected from 0, 1, 2, and 3; preferably, n8 is selected from 0, 1, and 2; further preferably, n8 is selected from 0, and 1; n9 is selected from 0, 1, 2, and 3; preferably, n9 is selected from 0, 1, and 2; further preferably, n9 is selected from 0, and 1; n 14 is selected from 0, 1, 2, and 3; preferably, n 14 is selected from 0, 1, and 2; further preferably, n 14 is selected from 0, and 1; n 15 is selected from 0, 1, 2, and 3; preferably, n 15 is selected from 0, 1, and 2; further preferably, n 15 is selected from 0, and 1; n6 + n7 + n8 + n9 < 6; and n 14 + n 15 ≤ 5.

8. The compound of any one of claims 1-7, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, fragment selected from the group consisting of 9. The compound of any one of claims 1-8, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, Fragment selected from the group consisting of 10. The compound of any one of claims 1-9, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, Each (R) 1A R 1B R 2A R 2B 、or R 2C Each time it appears, it is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl groups, and 3-7 membered cycloalkyl groups, and 3-7 membered heterocyclic groups; R 1A , R 1B , R 2A , R 2B , or R 2C ) is independently selected at each occurrence from hydrogen, halogen, -C 1-3 (C1-6alkyl), -C 1-3 (C1-6haloalkyl), -OH, and -O(C 1-3 C1-6alkyl).

11. The compound of any one of claims 1-10, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, (R 1A and R 1B ), or (R 2A and R 2B ) together with the C atom to which they are respectively attached form a Preferably, (R 1A and R 1B ), or (R 2A and R 2B ) together with the C atom to which they are respectively attached form a 12. The compound of any one of claims 1-11, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, (R 1A and R 1B ), or (R 2A and R 2B ) together with the C atom to which they are respectively attached form a Preferably, (R 1A and R 1B ), or (R 2A and R 2B ) together with the C atom to which they are respectively attached form a 13. The compound of any one of claims 1-12, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R 1A , or R 1B is independently selected from -O(C 1-3 alkyl); (R 2A and R 2B ) together with the C atom to which they are respectively attached form a R 2C independently at each occurrence -H; or R 1A , or R 1B is independently selected at each occurrence from -O(C 1-3 alkyl); R 2B is independently -O(C 1- 3alkyl) at each occurrence; R 2A , or R 2C is independently -H at each occurrence; or R 1A , or R 1B is independently selected from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently -O(C 1-3 alkyl); or R 1A , or R 1B is independently selected at each occurrence from -O(C 1-3 alkyl); R 2A , or R 2B is independently selected at each occurrence from -O(C 1-3 alkyl); R 2C is independently -H at each occurrence; or R 1A , or R 1B is independently selected at each occurrence from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently -H at each occurrence; or (R 1A and R 1B ) and the C atom to which they are respectively attached form, together (R 2A and R 2B ) and the C atom to which they are respectively attached form, together R 2C independently at each occurrence -H; or (R 1A and R 1B ) and the C atom to which they are respectively attached form, together R 2B independently at each occurrence -O(C 1-3 alkyl); R 2A , or R 2C independently at each occurrence -H; or (R 1A and R 1B ) and the C atom to which they are respectively attached form, together R 2A , R 2B , or R 2C is independently, at each occurrence, -O(C 1-3 alkyl); or (R 1A and R 1B ) and the C atom to which they are respectively attached form, together R 2A , or R 2B is independently selected at each occurrence from -O(C 1- 3alkyl); R 2C is independently -H at each occurrence; or (R 1A and R 1B ) and the C atom to which they are respectively attached form, together R 2A , R 2B , or R 2C is independently at each occurrence -H.

14. The compound of any one of claims 1-13, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, X Z- selected from halogen, acetate, benzoate, camphorsulfonate, citrate, glucoheptonate, gluconate, glucuronate, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, fumarate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthalenesulfonate, stearate, oleate, oxalate, embonate, nitrate, phosphate, sulfate, hydrogenphosphate, dihydrogenphosphate, polygalacturonate, succinate, sulfosalicylate, tartrate, trifluoroacetate, hippurate, D-glucuronate, glycolate, mucate, orotate, pamoate, glycinate, alaninate, arginate, lysinate, cinnamate, propionate, valerate, triphenylacetate, L-prolinate, ferulate, mandelate, malonate, gentisinate, salicylate, and glutarate.

15. The compound of any one of claims 1-14, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, X Z- selected from Cl - , Br - , I - , triflate, mesylate, p-tosylate, and phenylsulfonate.

16. The compound of any one of claims 1-15, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -(C 1-3 alkylene)-(3-7 membered carbon cycloyl), -(C 1-3 alkylene)-(3-10 membered heterocyclic group), -(C 1-3 alkylene)-phenyl, and -(C 1-3 (alkylene)-(5-10 heteroaryl); the -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, 3-10 heterocyclic, 3-7 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally n- SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 Alkyl); the n SC Selected from 0, 1, 2, 3, and 4; Preferably, R C Each time it appears, it is independently selected from -(C 1-3 (alkylene)-phenyl, wherein the phenyl is optionally n- SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1- 3-alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 Alkyl); the n SC Selected from 0, 1, 2, 3, and 4.

17. The compound of any one of claims 1-16, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R C independently at each occurrence selected from -H, -CH3, 18. The compound of any one of claims 1-17, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R A is independently selected at each occurrence from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; more preferably, R A is independently selected at each occurrence from -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH3, or -CF2CH3; preferably, R A is independently selected at each occurrence from -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2.

19. The compound of any one of claims 1-18, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R B is independently at each occurrence selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, and 3-7 membered cycloalkyl; preferably, R B is independently at each occurrence selected from hydrogen.

20. The compound of any one of claims 1-19, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the same, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative, or a metabolite thereof, characterized in that, m is 1, or 2; preferably, m is 2.

21. The compound of any one of claims 1-20, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, Z is 1, or 2; preferably, Z is 2.

22. The compound of any one of claims 1-21, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the stereoisomer, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, n2, or n5 is each independently selected from 0, 1, 2, 3, and 4; preferably, n2, or n5 is each independently selected from 0, 1, and 2; more preferably, n2, or n5 is each independently selected from 2.

23. The compound of any one of claims 1-22, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the same, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative, or a metabolite thereof, characterized in that, n1 is selected from 0, 1, 2, 3, and 4; preferably, n1 is selected from 0, 1, and 2; more preferably, n1 is 1.

24. A compound represented by Formula (I-2-A), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, Formula (I-2-A) ​ wherein, R 1A , R 1B , R 2A , R 2B , R 2C , R A , R B , R C , n1, n2, n3, n4, n5, n6, n7, n8, n9, n 14 , n 15 , m, X z- , Y, R S1 , R S2 , R S6 , R S8 , n S6 , and n S8 are as defined in any one of claims 1 to 23.

25. A compound of formula (II-1), formula (II-1A), formula (II-2), or formula (II-2A), or a stereoisomer thereof, a pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutically acceptable salt or cocrystal thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof. Further preferred are compounds according to any of formula (II-1-1), (II-1A-1), (II-2-1), and (II-2A-1): wherein, each R 1A , R 1B , R 2A , R 2B , R 2C , R SC , R A , R B , R C , R SC , n1, n2, n3, n4, n5, n6, n7, n8, n9, n 14 , n 15 , m, X z- , R S1 , R S2 , R S6 , R S8 , n SC , n S6 , and n S8 are as defined in any one of claims 1-23.

26. A compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, Further preferred are compounds of formula (II-1-1), (II-2-1), (III-1-1), or (III-2-1), wherein, R A independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R B is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R C Each time it appears, it is independently selected from hydrogen, -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl group, -(C 1-2 alkylene)-(3-7 membered carbon cycloyl), -(C 1-2 alkylene)-(3-10 membered heterocyclic group), -(C 1-2 alkylene)-phenyl, and -(C 1-2 (alkylene)-(5-10 heteroaryl); the -C 1-3 Alkyl, -C 2-3 alkenyl, -C 2-3 Alkyne, 3-10 heterocyclic, 3-7 heterocyclic, phenyl, and 5-10 heteroaryl groups are optionally n- SC R SC Instead, the R SC Selected from halogens, -CN, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -OH, -O(C) 1-3 Alkyl), -SH, -S(C 1-3 Alkyl), -C(=O)(OC) 1-3 Alkyl), and -OC (=O)(C 1-3 Alkyl); the n SC Selected from 0, 1, 2, 3, and 4; optionally, (1) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); (R 2A and R 2B ) and the C atom to which they are respectively attached form, together Preferably, (R 2A and R 2B ) together with the C atom to which they are respectively attached form a R 2C independently at each occurrence -H; (2) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); R 2B independently at each occurrence -O(C 1-3 alkyl); R 2A , or R 2C is independently at each occurrence -H; (3) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); R 2A , or R 2B independently for each occurrence -O(C 1-3 alkyl); R 2C independently at each occurrence -H; (4) R 1A , and R 1B is independently selected from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently, at each occurrence, -O(C 1-3 alkyl); or (5) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently at each occurrence -H; n1 is selected from 1, and 2; preferably, n1 is 1; n2 is selected from 1, and 2; preferably, n2 is 2; n3 is selected from 0, and 1; preferably, n3 is selected from 0; n4 is selected from 0, and 1; preferably, n4 is selected from 0; n5 is selected from 1, and 2; preferably, n5 is 2; fragment selected from the group consisting of m is 1, or 2; z is 1, or 2; n S6 , or n S8 is independently selected at each occurrence from 0, 1, 2, 3, and 4; R S1 , R S2 , R S6 , and R S8 are as defined in any one of claims 1-23.

27. A compound of Formula (II-1A), Formula (II-2A), Formula (III-1A), or Formula (III-2A), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, Further preferred are compounds of formula (II-1A-1), (II-2A-1), (III-1A-1), or (III-2A-1), wherein, R A independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R B is independently at each occurrence selected from hydrogen, -C 1-3 alkyl, or -C 1-3 haloalkyl; R SC selected from halogen, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(OC 1-3 alkyl), and -OC(=O)(C 1-3 alkyl); said n SC is selected from 0, 1, 2, 3, and 4; optionally, (1) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); (R 2A and R 2B ) and the C atom to which they are respectively attached form, together Preferably, (R 2A and R 2B ) together with the C atom to which they are respectively attached form a R 2C independently at each occurrence -H; (2) R 1A , and R 1B are independently selected from -O(C 1-3 alkyl); R 2B independently at each occurrence -O(C 1-3 alkyl); R 2A , or R 2C independently at each occurrence is -H; (3) R 1A , and R 1B is independently selected from -O(C 1-3 alkyl); R 2A , or R 2B independently for each occurrence -O(C 1-3 alkyl); R 2C independently at each occurrence -H; (4) R 1A , and R 1B is independently selected from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C independently for each occurrence -O(C 1-3 alkyl); or (5) R 1A , and R 1B is independently selected from -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently at each occurrence -H; n1 is selected from 1, and 2; preferably, n1 is 1; n2 is selected from 1, and 2; preferably, n2 is 2; n3 is selected from 0, and 1; preferably, n3 is selected from 0; n4 is selected from 0, and 1; preferably, n4 is selected from 0; n5 is selected from 1, and 2; preferably, n5 is 2; fragment selected from the group consisting of m is 1, or 2; z is 1, or 2; n S6 , or n S8 is independently selected at each occurrence from 0, 1, 2, 3, and 4; R S1 , R S2 , R S6 , and R S8 are as defined in any one of claims 1-23.

28. A compound of Formula (IV-1A), or Formula (IV-2A), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, Formula (IV-1A) Formula (IV-2A) ​ Further preferred are compounds of formula (IV-1A-1), or of formula (IV-2A-1), wherein, R SC selected from halogen, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(OC 1-3 alkyl), and -OC(=O)(C 1-3 alkyl), said n SC is selected from 0, 1, 2, 3 and 4; or n SC is 2, and the two adjacent R SC form together with the C atom to which they are attached a wherein R S3 and n S3 are as defined in any one of claims 1-23. the remaining radicals R 1A , R 1B , R 2A , R 2B , R 2C , m and X z- are as defined in any one of claims 1 to 23; and / or optionally one of the following conditions is met: (1) R 1A and R 1B are independently H or -O(C 1-3 alkyl); (R 2A and R 2B ) and the C atom to which they are respectively attached form, together wherein R S3 and n S3 are as defined in any one of claims 1 to 23; preferably (R 2A and R 2B ) together with the C atom to which they are respectively attached form a R 2C independently at each occurrence -H; (2) R 1A and R 1B are independently H or -O(C 1-3 alkyl); R 2B independently at each occurrence H or -O(C 1-3 alkyl); R 2A or R 2C independently at each occurrence -H; (3) R 1A and R 1B are independently selected from H or -O(C 1-3 alkyl); R 2A or R 2B independently at each occurrence H or -O(C 1-3 alkyl); R 2C independently at each occurrence -H; (4) R 1A and R 1B independently -O(C 1-3 alkyl); R 2A , R 2B , or R 2C independently for each occurrence -O(C 1-3 alkyl); (5) R 1A and R 1B independently -O(C 1-3 alkyl); R 2A , R 2B , or R 2C is independently at each occurrence -H; (6) (R 1A and R 1B ) and the C atom to which they are attached, respectively, form wherein R S3 and n S3 are as defined in any one of claims 1 to 23; preferably (R 1A and R 1B ) together with the C atom to which they are respectively attached form a (R 2A and R 2B ) and the C atom to which they are respectively attached form, together wherein R S3 and n S3 are as defined in any one of claims 1 to 23; preferably (R 2A and R 2B ) together with the C atom to which they are respectively attached form a R 2C independently at each occurrence -H.

29. The compound of claim 28, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof, characterized in that, R SC is selected from F, and -OCH3; said n SC is selected from 0, 1, and 2; or n SC is 2, and the two adjacent R SC form, together with the C atom to which they are respectively attached, a the remaining R 1A , R 1B , R 2A , R 2B , R 2C , m and X z- are as defined in any one of claims 1 to 23; and / or optionally one of the following conditions is met: (1) R 1A and R 1B is independently -OCH3; (R 2A and R 2B ) and the C atom to which they are respectively attached form, together R 2C independently at each occurrence -H; (2) R 1A and R 1B is independently -OCH3; R 2B independently at each occurrence -OCH3; R 2A or R 2C independently at each occurrence -H; (3) (R 1A and R 1B ) together with the C atom to which they are respectively attached form (R 2A and R 2B ) and the C atom to which they are respectively attached form, together R 2C independently at each occurrence -H.

30. The compound of any one of claims 1-29, or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the compound or the stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deuterated derivative thereof, or a metabolite thereof, characterized in that, the compound is selected from the compounds shown in Preparative Examples 1-46 and the compounds shown in Table 2.

31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-30, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof; and one or more pharmaceutically acceptable carriers or excipients.

32. Use of a compound of Formula (I-2) according to any one of claims 1-30, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof; or a pharmaceutical composition according to claim 31, in the manufacture of a medicament for neuromuscular blockade.

33. A method of treating a subject having a neuromuscular blockade-related disease, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I-2) according to any one of claims 1-30, or a stereoisomer, a pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof; or a pharmaceutical composition according to claim 31.

34. Use of a compound of Formula (I-2), or a stereoisomer thereof, a pharmaceutically acceptable salt or co-crystal of the compound of Formula (I-2), a pharmaceutically acceptable salt or co-crystal of a stereoisomer thereof, a solvate, a prodrug, a deuterated derivative thereof, or a metabolite thereof; or a pharmaceutical composition of claim 31 in the treatment of a neuromuscular blockade related disease, according to any one of claims 1-30.

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