Quaternary ammonium compounds and their pharmaceutical use

Abstract

This disclosure relates to quaternary ammonium compounds and their pharmaceutical uses. Specifically, this disclosure relates to a compound of formula IA or a pharmaceutical salt thereof, wherein the substituents are defined as defined in the specification.

Description

Quaternary ammonium compounds and their pharmaceutical uses Technical Field

[0001] The present invention relates to the field of medicine and relates to quaternary ammonium compounds and pharmaceutical uses thereof. Background Art

[0002] Neuromuscular-blocking drugs (NMBDs) play an important role in anesthesiology and can be divided into two categories based on their mechanism of action and efficacy: nondepolarizing and depolarizing. Nondepolarizing drugs (such as vecuronium) competitively bind to cholinergic receptors at the neuromuscular junction, blocking the effects of acetylcholine and causing muscle paralysis. Depolarizing drugs (such as succinacaine) interfere with the electrical potential of nerve terminal cell membranes, preventing normal muscle contraction.

[0003] WO2014005122 discloses a series of non-depolarizing ultrashort-acting, short-acting, and intermediate-acting neuromuscular blockers, wherein the neuromuscular block (NMB) induced by the agents is reversible, for example, by administration of cysteine ​​or related compounds. Summary of the Invention

[0004] The present disclosure provides a compound represented by Formula IA or a pharmaceutically acceptable salt thereof,

[0005] in:

[0006] W is selected from -C(R a R b R c )or

[0007] each independently selected from pharmaceutically acceptable anions;

[0008] R 3 、R 4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0009] L B , L C Each independently selected from -C(R a R b R c ) or alkylene, said alkylene being optionally substituted with one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0010] When L B -C(R a R b R c ), then there is no B1 ~R B5 substituted phenyl groups;

[0011] When L C -C(R a R b R c ), then there is no D1 ~R D5 substituted phenyl groups;

[0012] X A3 Selected from chemical bonds, -O-, -C(R d R e )-、-N(R f )-、-S(O)2-;

[0013] X 1 、X 5 Each is independently -C(R g R h )-;

[0014] X 2 、X 4 Each is independently -C(R i R j )-;

[0015] R f Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0016] R 1 、R 2 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、RC 、R D1 、R D2 、R D3 、R D4 、R D5 、R W1 、R W2 、R W3 、R W4 、R W5 、R a 、R b 、R c 、R d 、R e 、R g 、R h 、R i 、R j Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0017] Or, R 1 and R 2 、R d and R e 、R g and R h or R i and R j One or more groups together with the connected atoms form an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0018] Or, R g and R i Together with the atoms connected thereto, they form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0019] Or, any two adjacent R A1 、R A2 、R A3 、R A4 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0020] Or, any two adjacent R B1 、R B2 、R B3 、R B4 、R B5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0021] Or, any two adjacent R D1 、R D2 、R D3 、R D4 、R D5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0022] Or, any two adjacent R W1 、R W2 、R W3 、R W4 、R W5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-;

[0023] When X A3 Selected from chemical bonds, -C(R d R e )-hour,

[0024] (i)R d 、R e Cannot be hydrogen at the same time, or,

[0025] (ii)R d and R e 、R g and R h or R i and R j One or more groups together with the connected atoms form an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, or,

[0026] (iii)R g and R i Together with the atoms connected thereto, they form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0027] When X A3 When it is -O-,

[0028] (i)R g and R h or R i and R j One or more groups together with the connected atoms form an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, or,

[0029] (ii)R g and R i Together with the atoms connected thereto, they form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0030] x1 is selected from 1, 2, 3, 4, 5, 6;

[0031] x2 is selected from 1, 2, 3, 4, 5, 6;

[0032] x3 is selected from 0, 1, 2, 3, 4, 5.

[0033] In some embodiments, wherein X A3 Selected from chemical bonds, -C(Rd R e )- or -S(O)2-, R d 、R e As defined above.

[0034] In some embodiments, the compound represented by Formula IA is selected from the compound represented by Formula IIA1, Formula IIA2, Formula IIA3, Formula IIA4 or Formula IIA5, or a pharmaceutically acceptable salt thereof,

[0035] Ring A and Ring B are each independently selected from a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring;

[0036] L A is selected from alkylene or heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted by one or more halogen, hydroxy, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0037] L C1 is an alkylene group, wherein the alkylene group is optionally substituted by one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0038] R LC C 1-6 Alkyl, wherein the alkyl is optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0039] R 5 、R 6 、R 7 、R 8 Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups, and R 5 、R 6 It cannot be hydrogen at the same time.

[0040] Or, R 5 and R 6 Together with the atoms it is connected to, it forms an oxo group or a thio group;

[0041] x4 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0042] x5 is selected from 0, 1, 2, 3, 4;

[0043] x6 is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0044] x7 is selected from 0, 1, 2, 3, 4;

[0045] x8 is selected from 0, 1, 2, 3, 4;

[0046] x9 is selected from 0, 1, 2, 3;

[0047] W. L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 , x1, x2, x3 are as defined above.

[0048] In some embodiments, wherein Ring A is a 3 to 10 membered heterocyclic ring. In some embodiments, wherein Ring A is selected from In some embodiments, wherein Ring A is Ding ring.

[0049] In some embodiments, Ring B is selected from a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring. In some embodiments, Ring B is selected from a benzene ring, a pyridine ring, a pyran ring, a thiopyran ring. In some embodiments, Ring B is selected from a benzene ring, a pyridine ring.

[0050] In some embodiments, wherein L A Selected from -(CR k R l ) a -O-(CR k R l ) b -、-(CR k R l ) a -S-(CR k R l ) b -、-(CR k R l ) a -N(R f )-(CR k R l ) b -、-(CR k R l ) c -, preferably -(CR k R l ) a -O-(CR k R l ) b -、-(CR k R l ) c -,

[0051] R k 、R l Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0052] Or, R k and R lTogether with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0053] a is each independently selected from 0, 1, 2, 3, 4, 5;

[0054] b are each independently selected from 0, 1, 2, 3, 4, 5;

[0055] c are each independently selected from 1, 2, 3, 4, 5, 6;

[0056] R f As defined above.

[0057] In some embodiments, wherein a is 1.

[0058] In some embodiments, wherein b is 1.

[0059] In some embodiments, wherein L A For-(CR k R l )-O-(CR k R l )-.

[0060] In some embodiments, wherein R 5 、R 6 cannot be hydrogen at the same time, and are independently selected from hydrogen, halogen, C 1-6 In some embodiments, wherein R 5 、R 6 and R are not simultaneously hydrogen, and are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, and propoxy. 5 、R 6 They cannot be hydrogen at the same time and are each independently selected from hydrogen, fluorine and methoxy.

[0061] In some embodiments, the compound represented by Formula IA is selected from the compound represented by Formula IIIA1, Formula IIIA2, Formula IIIA3, Formula IIIA4 or Formula IIIA5, or a pharmaceutically acceptable salt thereof,

[0062] W. L B 、R 1 、R 2 、R3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 , x1, x2, x3, L C1 、R LC 、R 7 、R 8 ,x4,x5,x6,x7,x8,x9,R k 、R l As defined above.

[0063] In some embodiments, wherein L B Each independently selected from a chemical bond or C 1-6 Alkylene, preferably a chemical bond, methylene, ethylene, propylene, preferably methylene.

[0064] In some embodiments, wherein L C1 Each independently selected from a chemical bond or C 1-6 Alkylene, preferably a chemical bond, methylene, ethylene, propylene, preferably methylene.

[0065] In some embodiments, the compound represented by Formula IA is selected from the compound represented by Formula IVA1, Formula IVA2, Formula IVA3, Formula IVA4 or Formula IVA5, or a pharmaceutically acceptable salt thereof,

[0066] W. R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、RD4 、R D5 , x1, x2, x3, R LC 、R 7 、R 8 ,x4,x5,x6,x7,x8,x9,R k 、R l As defined above.

[0067] In some embodiments, wherein R A1 、R A4 、R B1 、R B2 、R B5 All are hydrogen.

[0068] In some embodiments, wherein R A2 、R A3 、R B3 、R B4 are each independently selected from hydrogen, C 1-6 In some embodiments, wherein R A2 、R A3 、R B3 、R B4 Each is independently selected from hydrogen, methoxy, ethoxy, propoxy. In some embodiments, wherein R A2 、R A3 、R B3 、R B4 Each is independently selected from hydrogen and methoxy.

[0069] In some embodiments, wherein W is methyl.

[0070] In some embodiments, wherein R D1 、R D4 、R D5 All are hydrogen.

[0071] In some embodiments, wherein R D2 、R D3 are independently selected from hydrogen, halogen, -C(O)-C 1-6 Alkyl, C 1-6 In some embodiments, wherein R D2 、R D3 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -C(O)-methyl, -C(O)-ethyl, methoxy, ethoxy, methanesulfonyl. In some embodiments, wherein R D2 、R D3 Each is independently selected from hydrogen, fluorine, bromine, -C(O)-ethyl, methoxy, and methanesulfonyl.

[0072] In some embodiments, the compound described by Formula IA, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0073]

[0074] As defined above.

[0075] In some embodiments, the compound of Formula IA, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a pharmaceutically acceptable salt thereof,

[0076]

[0077] As defined above.

[0078] In some embodiments, wherein Each is independently selected from the group consisting of halides, acetate, formate, benzoate, benzenesulfonate, camphorsulfonate, citrate, edisylate, fumarate, glucoheptanoate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, methanesulfonate, naphthoate, naphthylsulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate. In some embodiments, wherein are each independently selected from chloride, bromide, fluoride, iodide, trifluoroacetate, formate, methanesulfonate, and benzenesulfonate. Each is independently selected from chloride, bromide, trifluoroacetate, formate, methanesulfonate, and benzenesulfonate.

[0079] In some embodiments, the compound described by Formula IA, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0080] On the other hand, the present disclosure also provides a compound represented by Formula IB or a pharmaceutically acceptable salt thereof,

[0081] in:

[0082] X B3 Selected from chemical bonds, -O-, -C(R m R n )-、-N(Rf )-;

[0083] Y 1 、Y 2 Not present or each independently selected from -O-, -N(R f )-、-S-;

[0084] When Y 1 、Y 2 When both are -O-, L D for

[0085] When Y 1 、Y 2 When both do not exist, L D for

[0086] L D1 , L D2 Each is independently selected from alkylene or heteroalkylene, said alkylene or heteroalkylene being optionally substituted with one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0087] R m 、R n Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0088] Or, R m and R n Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0089] y1 is selected from 1, 2, 3, 4, 5, and 6;

[0090] y2 is selected from 1, 2, 3, 4, 5, and 6;

[0091] y3 is selected from 0, 1, 2, 3, 4, and 5;

[0092] W. L B , L C 、R 1 、R 2 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、X 1 、X 2 、X 4 、X 5 、R f As defined above.

[0093] In some embodiments, wherein X B3 It is -O-.

[0094] In some embodiments, the compound represented by Formula IB is selected from the compound represented by Formula IIB1 or Formula IIB2 or a pharmaceutically acceptable salt thereof,

[0095] y4 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0096] W. L B 、R 1 、R 2 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、RC 、R D1 、R D2 、R D3 、R D4 、R D5 , L C1 、R 7 , L D1 , L D2 , y1, y2, y3 are as defined above.

[0097] In some embodiments, wherein Selected from:

[0098] r is each independently selected from 0, 1, 2, 3, 4;

[0099] s is each independently selected from 0, 1, 2, 3, 4;

[0100] t is independently selected from 0, 1, 2, 3, and 4.

[0101] In some embodiments, wherein Selected from r, s, and t are as defined above.

[0102] In some embodiments, wherein Selected from r, s, and t are as defined above.

[0103] In some embodiments, wherein L D2 For-(CR m R n ) d -, d is selected from 1, 2, 3, 4, 5, 6, R m 、R n As defined above.

[0104] In some embodiments, the compound represented by Formula IB is selected from the compound represented by Formula IIIB1-a, Formula IIIB1-b or Formula IIIB2, or a pharmaceutically acceptable salt thereof,

[0105] y4 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0106] y5 is selected from 1, 2, 3, 4, 5, and 6;

[0107] W. L B 、R 1 、R 2 、R A1、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 , L C1 、R 7 、R m 、R n , y1, y2, y3, r, s, t are as defined above.

[0108] In some embodiments, the compound represented by Formula IB is selected from the compound represented by Formula IVB1-a, Formula IVB1-b or Formula IVB2, or a pharmaceutically acceptable salt thereof,

[0109] W. R 1 、R 2 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、R 7 、R m 、R n , y1, y2, y3, r, s, t, y4, y5 are as defined above.

[0110] In some embodiments, the compound of Formula IB or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0111] As defined above.

[0112] In some embodiments, the compound of Formula IB or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0113] As defined in claim 1.

[0114] In some embodiments, the compound of Formula IB or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0115] On the other hand, the present disclosure also provides a compound represented by Formula IC or a pharmaceutically acceptable salt thereof,

[0116] in,

[0117] X C3 Selected from chemical bonds, -O-, -C(R p R q )-、-N(R f )-;

[0118] L E , L F Each independently selected from -(CR p R q ) i -、-(CR p R q ) e -O-(CR p R q ) f -、-(CR p R q ) e -S-(CR p R q ) f -、-(CR p R q ) e -N(R f )-(CR p R q ) f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -;

[0119] R p 、R q Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0120] Or, R p and R q Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0121] Ring D is selected from 6 to 10 membered arylene or 5 to 10 membered heteroarylene, wherein the arylene and heteroarylene are optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1- 6 alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0122] When L G When both ring F and ring F do not exist,

[0123] Ring E is selected from a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0124] When L G When both ring F and ring F exist,

[0125] Ring E is selected from 3 to 10 membered cycloalkylene, 3 to 10 membered heterocyclylene, 6 to 10 membered arylene or 5 to 10 membered heteroarylene, wherein the alkylene, heterocyclylene, arylene or heteroarylene is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0126] L G Selected from -(CR p R q ) i -、-(CR p R q ) e -O-(CR p R q ) f -、-(CR p R q ) e -S-(CR p R q ) f -、-(CR p R q ) e -N(R f )-(CR p R q ) f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -,

[0127] Ring F is selected from a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0128] z1 is selected from 1, 2, 3, 4, 5, 6;

[0129] z2 is selected from 1, 2, 3, 4, 5, 6;

[0130] z3 is selected from 0, 1, 2, 3, 4, 5;

[0131] e is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0132] f are each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0133] i is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0134] W. L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R f 、X 1 、X 2 、X 4 、X 5 As defined above.

[0135] In some embodiments, wherein X C3 It is -O-.

[0136] In some embodiments, wherein ring D is selected from

[0137]

[0138] The ring D is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0139] In some embodiments, wherein Ring D is selected from

[0140]

[0141] The ring D is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0142] In some embodiments, wherein Ring D is selected from The ring D is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0143] In some embodiments, wherein when L G When both rings F and E are present, ring E is selected from

[0144] g is selected from 0, 1, 2, 3;

[0145] h is selected from 1, 2, 3, 4, 5;

[0146] The ring E is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0147] In some embodiments, wherein when L G When both rings F and E are present, ring E is selected from

[0148] The ring E is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, and g and h are as defined above.

[0149] In some embodiments, wherein when L G When both rings F and E are present, ring E is selected from The ring E is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, and g and h are as defined above.

[0150] In some embodiments, wherein when L GWhen both ring F and ring F are present, ring F is selected from benzene ring, pyridine ring, thiazine ring, pyrimidine ring, pyridazine ring, furan ring, pyrrole ring, thiophene ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, thiazole ring, benzofuran ring, isobenzofuran ring, isoindole ring, indole ring, benzothiophene ring, benzimidazole ring, indazole, benzoxazole, benzisoxazole, purine, benzothiazole ring, quinoline ring, isoquinoline ring, and the ring F is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6 In some embodiments, when L G When both ring F and ring F are present, ring F is selected from benzene ring, pyridine ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, thiazole ring, quinoline ring, isoquinoline ring, and the ring F is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0151] In some embodiments, wherein when L G When both ring F and ring F are present, ring F is selected from a benzene ring, a pyridine ring, a quinoline ring, an isoquinoline ring, and the ring F is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0152] In some embodiments, wherein when L G When both ring F and L exist, G Selected from -(CR p R q ) e -O-(CR p R q ) f -、-(CR p R q ) e -S-(CR p R q ) f -、-(CR p R q ) e -N(R f )-(CR p R q )f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -, R f 、R p 、R q , e, f are as defined above.

[0153] In some embodiments, wherein when L G When both ring F and L exist, G Selected from -(CR p R q ) e -N(R f )-(CR p R q ) f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -, R f 、R p 、R q , e, f are as defined above.

[0154] In some embodiments, wherein when L G When both ring F and L exist, G For-(CR p R q ) e -N(R f )-(CR p R q ) f -, R f 、R p 、R q , e, f are as defined above.

[0155] In some embodiments, wherein when L GWhen both ring F and ring E are absent, ring E is selected from a benzene ring, a pyridine ring, a thiazine ring, a pyrimidine ring, a pyridazine ring, a furan ring, a pyrrole ring, a thiophene ring, an imidazole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a benzofuran ring, an isobenzofuran ring, an isoindole ring, an indole ring, a benzothiophene ring, a benzimidazole ring, an indazole ring, a benzoxazole ring, a benzisoxazole ring, a purine ring, a benzothiazole ring, and a quinazoline ring, and the ring E is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0156] In some embodiments, wherein when L G When both ring F and ring E are absent, ring E is selected from a benzene ring, a pyridine ring, an imidazole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, and a quinazoline ring, and the ring E is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1- 6 alkoxy groups, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0157] In some embodiments, wherein when L G When both ring F and ring E are absent, ring E is selected from a benzene ring, a thiazole ring, a quinazoline ring, and said ring E is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0158] In some embodiments, wherein L E For-(CR p R q ) i -, R f 、R p 、R q , i is as defined above.

[0159] In some embodiments, wherein L F Selected from -(CR p R q ) e -O-(CR p R q ) f -、-(CR p R q )e -S-(CR p R q ) f -、-(CR p R q ) e -N(R f )-(CR p R q ) f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -, preferably -(CR p R q ) e -N(R f )-(CR p R q ) f -、-(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -, most preferably -(CR p R q ) e -C(O)-N(R f )-(CR p R q ) f -, R f 、R p 、R q , e, f are as defined above.

[0160] In some embodiments, the compound represented by Formula IC is selected from the compound represented by Formula IIC1, Formula IIC2 or Formula IIC3 or a pharmaceutically acceptable salt thereof,

[0161] in,

[0162] R 11 、R 21 、R 22 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0163] R G Each independently selected from halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0164] R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0165] Or, R 9 and R 10 Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0166] Or, R 12 and R 11 、R 13 and R 11 、R 14 and R 11 、R 15 and R 11、R 16 and R 11 、R 12 and R 21 、R 13 and R 21 、R 14 and R 21 、R 15 and R 21 or R 16 and R 21 Together with the atoms connected thereto, they form a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring, wherein the carbocyclic ring, the heterocyclic ring, the aromatic ring or the heteroaromatic ring is optionally substituted by one or more oxo groups, thio groups, halogen groups, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0167] Or, R 17 and R 18 or R 19 and R 20 Together with the atoms connected thereto, they form a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring, wherein the carbocyclic ring, the heterocyclic ring, the aromatic ring or the heteroaromatic ring is optionally substituted by one or more oxo groups, thio groups, halogen groups, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0168] z7 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0169] z8 are each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0170] z9 is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0171] z10 is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0172] z11 is selected from 0, 1, 2;

[0173] z12 is selected from 0 and 1;

[0174] z13 is selected from 0, 1, 2, 3, 4, 5, 6;

[0175] z14 is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0176] z15 is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0177] W. L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R 7 , z1, z2, z3, g, h are as defined above.

[0178] In some embodiments, wherein R 13 and R 11 Together with the atoms to which it is attached, it forms a 3- to 6-membered heterocyclic ring,

[0179] The heterocyclic ring is optionally substituted by one or more oxo groups, thio groups, halogen groups, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0180] In some embodiments, wherein R 12 and R 21 Together with the atoms to which it is attached, it forms a 3- to 6-membered heterocyclic ring,

[0181] The heterocyclic ring is optionally substituted by one or more oxo groups, thio groups, halogen groups, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0182] In some embodiments, wherein R 17 and R 18 Together with the atoms connected thereto, a 6-membered aromatic ring or a 5- to 6-membered heteroaromatic ring is formed, wherein the aromatic ring or heteroaromatic ring is optionally substituted with one or more oxo groups, thio groups, halogen groups, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0183] In some embodiments, wherein g is 3.

[0184] In some embodiments, wherein h is 3.

[0185] In some embodiments, the compound represented by Formula IC is selected from the compound represented by Formula IIIC1, Formula IIIC2 or Formula IIIC3, or a pharmaceutically acceptable salt thereof,

[0186] Z 1 , Z 3 Each is independently -C(R p R q )-;

[0187] Z 2 , Z 4 Each independently selected from -O-, -C(R p R q )-、-N(R f )-;

[0188] R 23 Each independently selected from halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, or 5- to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, or cyano groups;

[0189] z4 is selected from 0, 1, 2, 3;

[0190] z5 is selected from 0, 1, 2, 3, 4;

[0191] z6 is selected from 0, 1, 2, 3, 4, 5, 6;

[0192] W. L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R f 、R 7 、R p、R q 、z1、z2、z3、g、h、R G 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 , z7, z8, z9, z10, z11, z12 are as defined above.

[0193] In some embodiments, wherein Z 2 , Z 4 Each is independently -N(R f )-,R f As defined above.

[0194] In some embodiments, wherein Z 1 , Z 3 are each independently selected from -C(O)- or -C(S)-. In some embodiments, wherein Z 1 , Z 3 Each is independently -C(S)-.

[0195] In some embodiments, the compound represented by Formula IC is selected from the compound represented by Formula IVC1, Formula IVC2 or Formula IVC3, or a pharmaceutically acceptable salt thereof,

[0196] W. L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R f 、R 7 、R p 、R q 、z1、z2、z3、g、h、R G 、R 9 、R 10 、R11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 22 ,z7,z8,z9,z10,z11,z12,R 23 , z4, z5, z6 are as defined above.

[0197] In some embodiments, the compound of Formula IC or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0198] As defined above.

[0199] In some embodiments, the compound of Formula IC or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0200] As defined in claim 1.

[0201] In some embodiments, the compound of Formula IC or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0202] On the other hand, the present disclosure also provides a compound represented by Formula ID or a pharmaceutically acceptable salt thereof,

[0203] in,

[0204] Y 3 Selected from -O-, -N(R f )-、-S-;

[0205] Y 4 Selected from -O-, -N(R f )-、-S-、-C(R r R s )-;

[0206] X D1 、X D5 Each is independently -C(R g R h )-;

[0207] X D3 、X D3’ Each independently selected from a chemical bond, -O-, -C(R d R e )-、-N(R f )-;

[0208] X D2 、X D4 Each independently selected from a chemical bond, -C(R i R j )-;

[0209] L H , L I Each is independently selected from alkylene or heteroalkylene, said alkylene or heteroalkylene being optionally substituted with one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0210] R r 、R s 、R 24 、R 25 Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0211] Or, R r and R s or R 24 and R 25 Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0212] When X D3 Selected from chemical bonds, -C(R d R e )-hour,

[0213] (i)R d 、R e Cannot be hydrogen at the same time, or,

[0214] (ii)R d and R e 、R g and R h or R i and R j One or more groups together with the connected atoms form an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, or,

[0215] (iii)R g and R i Together with the atoms connected thereto, they form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0216] When X D3 When it is -O-,

[0217] (i)R g and R h or R i and R j One or more groups together with the connected atoms form an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, sulfhydryl, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups, or,

[0218] (ii)R g and R i Together with the atoms connected thereto, they form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0219] v1 is selected from 1, 2, 3, 4, 5;

[0220] L C 、R D1 、R D2 、R D3 、R D4 、R D5 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、X 1 、X 2 、X 4 、X 5 As defined above.

[0221] In some embodiments, wherein X D3 Selected from chemical bonds, -C(R d R e )-,R d 、R e As defined above.

[0222] In some embodiments, wherein X D3’ It is -O-.

[0223] In some embodiments, wherein Y 3 It is O.

[0224] In some embodiments, wherein Y 4 It is -O-.

[0225] In some embodiments, the compound represented by Formula ID is selected from the compound represented by Formula IID1 or Formula IID2 or a pharmaceutically acceptable salt thereof,

[0226] Ring G is selected from a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring;

[0227] R 26 、R 27 Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups, and R 26 、R 27 It cannot be hydrogen at the same time.

[0228] Or, R 26 and R 27 Together with the atoms it is connected to, it forms an oxo group or a thio group;

[0229] v2 is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0230] v3 is independently selected from 0 and 1;

[0231] v4 is independently selected from 0 and 1;

[0232] v5 is selected from 0, 1, 2, 3, 4;

[0233] v6 is selected from 0, 1, 2, 3, 4;

[0234] R D1 、R D2 、R D3 、R D4 、R D5 , L C1 、R 7 、R 8 , L H , L I 、R 24 、R 25 , v1 is as defined above.

[0235] In some embodiments, when v3 and v4 are both 1, ring G is a 3- to 10-membered carbocyclic ring. In some embodiments, when v3 and v4 are both 1, ring G is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In some embodiments, when v3 and v4 are both 1, ring G is cyclopropane.

[0236] In some embodiments, wherein v3 and v4 are both 0, ring G is a 3- to 10-membered heterocyclic ring. In some embodiments, wherein v3 and v4 are both 0, ring G is selected from In some embodiments, when v3 and v4 are both 0, ring G is Ding ring.

[0237] In some embodiments, wherein R 26 、R 27 cannot be hydrogen at the same time, and are independently selected from hydrogen, halogen, C 1-6 In some embodiments, wherein R 26 、R 27 and R are not simultaneously hydrogen, and are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, and propoxy. 26 、R 27 They cannot be hydrogen at the same time and are each independently selected from hydrogen, fluorine and methoxy.

[0238] In some embodiments, wherein L H Selected from -(CR s R t ) j -、-(CR s R t ) m -O-(CR s R t ) n -、-(CR s R t ) m -S-(CR s R t ) n -、-(CR s R t ) m -N(R f )-(CR s R t ) n -、-(CR s R t ) m -C(O)-N(R f )-(CR s R t ) n -, preferably -(CR s R t ) j -、-(CR s R t )j -、-(CR s R t ) m -O-(CR s R t ) n -、-(CR s R t ) m -S-(CR s R t ) n -、-(CR s R t ) m -N(R f )-(CR s R t ) n -, most preferably -(CR s R t ) j -;

[0239] j is selected from 1, 2, 3, 4, 5, 6;

[0240] m is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0241] n is each independently selected from 0, 1, 2, 3, 4, 5, 6;

[0242] R f 、R s 、R t As defined above.

[0243] In some embodiments, wherein L I Selected from -(CR s R t ) j -、-(CR s R t ) m -O-(CR s R t ) n -、-(CR s R t ) m -S-(CR s R t ) n -、-(CR s R t ) m -N(R f )-(CR s R t ) n -、-(CR s Rt ) m -C(O)-N(R f )-(CR s R t ) n -, preferably -(CR s R t ) j -、-(CR s R t ) m -O-(CR s R t ) n -、-(CR s R t ) m -S-(CR s R t ) n -、-(CR s R t ) m -N(R f )-(CR s R t ) n -, most preferably -(CR s R t ) j -or-(CR s R t ) m -O-(CR s R t ) n -,

[0244] R f 、R s 、R t , j, m, n are as defined above.

[0245] In some embodiments, the compound represented by Formula ID is selected from the compound represented by Formula IIID1, Formula IIID2-a or Formula IIID2-b, or a pharmaceutically acceptable salt thereof,

[0246] in,

[0247] R 28 、R 29 Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups, and R 26 、R 27 It cannot be hydrogen at the same time.

[0248] Or, R 28 and R 29 Together with the atoms it is connected to, it forms an oxo group or a thio group;

[0249] v7 is each independently selected from 1, 2, 3, 4, 5, 6;

[0250] v8 is selected from 1, 2, 3, 4, 5, 6;

[0251] v9 is selected from 1, 2, 3, 4, 5, 6;

[0252] v10 is selected from 1, 2, 3, 4, 5, 6;

[0253] R D1 、R D2 、R D3 、R D4 、R D5 , L C1 、R 7 、R 8 、R 24 、R 25 , v1, v2, v3, v4, v5, and v6 are as defined above.

[0254] In some embodiments, the compound represented by Formula ID is selected from the compound represented by Formula IBD1, Formula IBD2-a or Formula IBD2-b, or a pharmaceutically acceptable salt thereof,

[0255] R D1 、R D2 、R D3 、R D4 、R D5 、R 7 、R 8 、R 24 、R 25 , v1, v2, v3, v4, v5, v6, R 28 、R 29 , v7, v8, v9, and v10 are as defined above.

[0256] In some embodiments, the compound described by Formula ID or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0257]

[0258] As defined above.

[0259] In some embodiments, the compound described by Formula ID or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0260] On the other hand, the present disclosure also discloses a compound or a pharmaceutically acceptable salt thereof, which is selected from

[0261] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is selected from

[0262] The present disclosure also provides a compound of formula V or a pharmaceutically acceptable salt thereof,

[0263] in, R 1 、R 2 、R D1 、R D2 、R D3 、R D4 、R D5 、R 7 , L A , L C1 , x2, x6, x9 are as defined above.

[0264] In some embodiments, the compound of formula V or a pharmaceutically acceptable salt thereof is selected from the compound of formula VI or a pharmaceutically acceptable salt thereof,

[0265] in, R 1 、R 2 、R D1 、R D2 、R D3 、R D4 、R D5 、R 7 , L C1 , x2, x6, x9, R k 、Rl As defined above.

[0266] In some embodiments, the compound of Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0267] in, As defined above.

[0268] In some embodiments, the compound of Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0269] On the other hand, the present disclosure also provides a method for preparing a compound represented by Formula IA or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by Formula A with a compound represented by Formula B in the presence of a condensing agent and a catalyst,

[0270] On the other hand, the present disclosure also provides a method for preparing a compound represented by Formula IIA3 or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by Formula A-1 with a compound represented by Formula V in the presence of a condensing agent and a catalyst.

[0271] On the other hand, the present disclosure also provides a method for preparing a compound represented by formula IIIA3-a or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by formula A-2 with a compound represented by formula VI in the presence of a condensing agent and a catalyst.

[0272] In some embodiments, the condensing agent includes but is not limited to HATU.

[0273] In some embodiments, the catalyst includes but is not limited to DMAP.

[0274] The present disclosure also provides isotopic substitutions of the aforementioned compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substitutions are deuterated.

[0275] The present disclosure also provides use of a compound of Formula V or Formula VI or a pharmaceutically acceptable salt thereof in the preparation of a neuromuscular blocker.

[0276] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0277] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0278] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0279] The present disclosure also provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in preparing a drug for neuromuscular blockade.

[0280] In certain embodiments, the neuromuscular blockade induced by the neuromuscular blocking agent can be reversed by a neuromuscular blocking agent antagonist, such as L-cysteine, D-cysteine, or a mixture thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or a combination thereof.

[0281] The present disclosure further provides a method for inducing neuromuscular blockade in a mammal for therapeutic purposes, comprising administering to the mammal an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The mammal may be a human or a non-human mammal, and the mammal may be subjected to general anesthesia. The therapeutic purpose may include surgical operation.

[0282] In certain embodiments, the method may further comprise the step of reversing neuromuscular blockade in the mammal, comprising administering to the mammal a neuromuscular blocker antagonist, such as L-cysteine, D-cysteine, or a mixture thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or a combination thereof.

[0283] The present disclosure further provides a kit comprising the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. In certain embodiments, the kit may further comprise a neuromuscular blocker antagonist.

[0284] Pharmaceutically acceptable salts of the compounds disclosed herein may be selected from inorganic salts or organic salts. The inorganic salts may be selected from hydrochlorides, hydrobromides, phosphates, or sulfates; and the organic salts may be selected from acetates, trifluoroacetates, methanesulfonates, p-toluenesulfonates, citrates, maleates, tartrates, fumarates, citrates, or lactates.

[0285] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0286] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0287] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations. For example, the compounds disclosed herein It can be any one of the following configurations, or it can include both of the following configurations.

[0288] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations. For example, the compounds disclosed in this invention Any one of the following configurations, or both of the following configurations.

[0289] Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0290] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as compounds of the present disclosure comprising tautomeric changes between A and B as shown below:

[0291] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0292] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P.32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0293] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0294] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0295] Compared with the control compound, the disclosed compound has significant advantages in terms of in vivo efficacy and safety window.

[0296] Explanation of terms:

[0297] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0298] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0299] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0300] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. The alkyl group includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, including but not limited to halogen, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0301] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0302] The cycloalkyl or carbocyclic ring may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, including but not limited to halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0303] The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 6 to 10 ring atoms. Examples of monocyclic heterocycloalkyls include, but are not limited to, piperazine, piperidine, oxirane, thiophene, oxadiazine ... butyl ring, azetidine ring, thietidine ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, tetrahydropyran ring, tetrahydrothiopyran ring, etc.; polycyclic cycloalkyl groups include spiro ring, condensed ring and bridged ring heterocycloalkyl groups.

[0304] Heterocycloalkyl, heterocyclyl or heterocycle may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0305] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl or binaphthyl. Unless otherwise specified, an aryl group or aromatic ring may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0306] The term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaromatic rings within the scope of this definition include, but are not limited to, pyridine, thiazine, pyrimidine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzofuran, isobenzofuran, isoindole, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, purine, benzothiazole, quinoline, isoquinoline, quinazoline, quinazolinone, and thioquinazolinone. Unless otherwise specified, heteroaryl or heteroaromatic rings may be substituted or unsubstituted.

[0307] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0308] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0309] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0310] The term "hydroxy" refers to -OH.

[0311] The term "amino" refers to -NH2.

[0312] The term "cyano" refers to -CN.

[0313] The term "nitro" refers to -NO2.

[0314] The term "oxo" or "oxo" refers to "=0".

[0315] The term "thio" or "thio" refers to "=S".

[0316] The term "carbonyl" refers to C=O.

[0317] The term "carboxy" refers to -C(O)OH.

[0318] The term "halo" refers to substitution with one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0319] The term "monovalent group" refers to a compound from which a univalent atom or group is "formally" eliminated.

[0320] The term "subunit" refers to an atom or group of atoms formed by "formally" eliminating two monovalent or one divalent atoms from a compound.

[0321] The term "alkylene" refers to the residue remaining after removing two hydrogen atoms from an alkane molecule, including straight-chain and branched subgroups of 1 to 20 carbon atoms. Examples of alkylene groups containing 1 to 6 carbon atoms include, but are not limited to, methylene (-CH2-) and ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted.

[0322] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- atoms are replaced by a heteroatom selected from N, O and S, wherein the alkylene group is as defined above. Unless otherwise specified, a heteroalkylene group may be substituted or unsubstituted.

[0323] The term "cycloalkylene" refers to a group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkyl group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. Cycloalkyl is as defined above.

[0324] The term "heterocyclylene" refers to a heterocyclic group having two monovalent radical centers, wherein the monovalent radical centers are derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent heterocyclic ring, by removing two hydrogen atoms from two nitrogen atoms of a parent heterocyclic ring, or by removing a hydrogen atom from a nitrogen atom and a hydrogen atom from a carbon atom of a parent heterocyclic ring. Examples of such heterocyclylene groups include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, azetidine-1,3-diyl, and pyrrolidine-1,3-diyl. Wherein, heterocyclyl is as defined above.

[0325] The term "arylene" refers to a monovalent radical having two centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent aryl group. Examples of arylene groups include, but are not limited to Here, the aryl group is as defined above.

[0326] The term "heteroarylene" refers to a heteroaryl system having two points of attachment to the rest of the molecule. Examples of heteroarylene include, but are not limited to,

[0327] Here, heteroaryl is as defined above.

[0328] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. DETAILED DESCRIPTION

[0329] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0330] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0331] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0332] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

[0333] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50mm, 5um column. The samples were scanned in positive / negative ion mode with a mass scan range of 80-1200.

[0334] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0335] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0336] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0337] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0338] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0339] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0340] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0341] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0342] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0343] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0344] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0345] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0346] Example 1 Preparation of Compound 1

[0347] Step 1)

[0348] To a 100 mL three-necked flask, add compound 1a (1.8 g, 6.2 mmol, purchased from Leyan), methanol (604 mg, 18.86 mmol), and THF (50 mL). Stirring was initiated, the atmosphere was replaced with nitrogen three times, and lithium borohydride (410 mg, 18.86 mmol) was then added all at once. The reaction was stirred at elevated temperature until complete, then cooled to room temperature. The reaction solution was quenched by adding it dropwise to 150 mL of water. Extraction was performed with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1.430 g of compound 1b (yield: 93%).

[0349] MS (ESI): m / z 245.1 [M+H]+ .

[0350] Step 2)

[0351] Compound 1b (1.3 g, 5.32 mmol), acetonitrile (26 ml), and 2,6-lutidine (228 mg, 2.13 mmol) were added to a 50 mL three-necked flask. The atmosphere was replaced with nitrogen three times, and the mixture was then cooled to approximately 5°C. Carbon tetrabromide (3.0 g, 9.05 mmol) was added and the reaction was continued with stirring at room temperature until completion. The mixture was concentrated under reduced pressure, and 60 mL of water was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by column chromatography (EA / PE = 1:3) to afford 1.410 g of compound 1c (yield: 86%).

[0352] MS (ESI): m / z 307.1 [M+H] + .

[0353] Step 3)

[0354] To a 50 mL three-necked flask, compound 1c (1.4 g, 4.56 mmol), acetonitrile (28 mL), morpholine (476 mg, 5.47 mmol), and potassium carbonate (945 mg, 6.84 mmol) were added. The atmosphere was replaced with nitrogen three times and the reaction was stirred at room temperature until completion. The mixture was concentrated under reduced pressure, 30 mL of water was added, and extraction with ethyl acetate (30 mL x 3) was performed. The organic phases were combined, dried, filtered, and concentrated to afford 1.390 g of compound 1d (yield: 97%).

[0355] MS (ESI): m / z 314.1 [M+H] + .

[0356] Step 4)

[0357] Compound 1d (1.39 g, 4.44 mmol) and 4N HCl / dioxane (15 mL) were added to a 50 mL three-necked flask and stirred at room temperature until the reaction was complete. The mixture was concentrated under reduced pressure to obtain 1.26 g of compound 1e (yield: 99%).

[0358] MS (ESI): m / z 214.1 [M+H] + .

[0359] Step 5)

[0360] To a 100 mL three-necked flask were added compound 1e (1.26 g, 4.04 mmol), DMF (12 mL), compound 1f (1.0 g, 6.06 mmol, purchased from Adamas), and DIPEA (2.840 g, 22.01 mmol). The atmosphere was replaced with nitrogen three times, cooled to approximately 5°C, and then HATU (2.510 g, 6.6 mmol) was added. The reaction was stirred at room temperature until completion. The reaction solution was added dropwise to 60 mL of saturated sodium bicarbonate and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM / MeOH = 5 / 1) to afford 1.060 g of compound 1g (yield: 66%).

[0361] MS (ESI): m / z 363.1 [M+H] + .

[0362] Step 6)

[0363] Under nitrogen, compound 1g (1.060 g, 2.92 mmol), methanol (30 mL), and palladium on carbon (202 mg, 10% Pd / C) were added to a 100 mL single-necked flask. The atmosphere was replaced three times with a hydrogen balloon, and then stirred at room temperature under a hydrogen atmosphere until the reaction was complete. The mixture was filtered and concentrated to afford 0.961 g of compound 1h (yield: 98%).

[0364] MS (ESI): m / z 333.1 [M+H] + .

[0365] Step 7)

[0366] Compound 1h (0.9 g, 2.71 mmol), ethanol (18 mL), potassium hydroxide (0.152 g, 2.71 mmol), and carbon disulfide (0.206 g, 2.71 mmol) were added to a 50 mL single-necked flask and heated until the reaction was complete. The reaction mixture was added to saturated sodium bicarbonate and ethyl acetate (20 mL / 30 mL) at room temperature and filtered to obtain 0.657 g of crude product (yield: 64%).

[0367] MS (ESI): m / z 375.1 [M+H] + .

[0368] Step 8)

[0369] To a 100 mL three-necked flask, add compound 1i (0.430 g, 1.15 mmol), acetonitrile (43 mL), and sultone (0.475 g, 3.44 mmol). The atmosphere was replaced with nitrogen three times and the mixture was stirred under heating until the reaction was complete. Filter the mixture, dissolve the filter cake in methanol (10 mL), add concentrated sulfuric acid, and stir under heating in an oil bath until the reaction was complete. Cool to room temperature, exchange the mixture with chloride ion exchange resin, and purify the mixture by column chromatography (eluting with methanol) to afford 0.356 g of compound 1j (yield: 71%).

[0370] MS (ESI): m / z 433.1 [M-Cl - ] + .

[0371] Step 9)

[0372] To a 50 mL three-necked flask, compound 1k (0.055 g, 0.115 mmol, prepared using the method disclosed in patent WO2014005122A2), dichloromethane (2 mL), and DMF were added. The atmosphere was replaced with nitrogen three times, cooled to 5°C, and then a dichloromethane solution of oxalyl chloride (117 mg of oxalyl chloride dissolved in 1 mL of dichloromethane) was added dropwise. Stirring continued until the reaction was complete. The mixture was concentrated under reduced pressure, dissolved in 1 mL of dichloromethane, and then added dropwise to an ice-water-cooled solution of compound 1j (0.050 g, 0.115 mmol) in acetonitrile (5 mL). The reaction was stirred at room temperature until completion, concentrated, and analyzed by HPLC to yield 0.021 g of compound 1 (yield: 20%).

[0373] MS (ESI): m / z 449.7 [(M-2CF3COO - ) / 2] +

[0374] 1H NMR (400MHz, CDCl3) δ8.07-8.05(m,1H),7.97-7.96(m,1H),7.66-7.64(m,1H),7.48-7.46(m,1H),7.32 -7.30(m,1H),6.83-6.76(m,4H),6.65-6.64(m,2H),6.01(s,2H),5.65(s,1H),5.35-5.33(m,1H),4.91 -4.89(m,2H),4.68-4.66(m,1H),4.21-4.14(m,4H),4.10-3.86(m,2H),3.85(s,3H),3.84-3.76(m,2H) ,3.78(s,6H),3.70-3.40(m,8H),3.39(s,4H),2.40-2.10(m,2H),2.03-1.92(m,4H),1.40-1.20(m,4H).

[0375] Example 2 Preparation of Compound 2

[0376] Step 1)

[0377] In a 50 mL reaction flask, compound 2a (300 mg, 1.74 mmol, purchased from Leyan) was weighed and added to acetonitrile (6 mL), potassium carbonate (721 mg, 5.22 mmol), and 3-bromopropanol (605 mg, 4.36 mmol). Under nitrogen, the mixture was heated in an oil bath until the reaction was complete. The product was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 0-8%) to afford 290 mg of compound 2b (yield: 90%).

[0378] MS (ESI): m / z 186.2 [M+H] + .

[0379] Step 2)

[0380] To a 100 mL reaction flask were added compound 2b (290 mg, 1.57 mmol), acetonitrile (30 mL), potassium carbonate (648 mg, 4.70 mmol), and 3,4-dimethoxybenzyl bromide (434 mg, 1.88 mmol, purchased from Acon) under nitrogen protection. The mixture was heated in an oil bath until the reaction was complete. The reaction was filtered and concentrated. Column chromatography (MeOH / DCM = 0-8%) gave 360 ​​mg of compound 2c (yield: 68%).

[0381] 1HNMR(400MHz,DMSO-d6)δ7.08-7.03(m,3H),4.88-4.87(t,1H),4.47(s,2H),4.39(s,2H),4.32(s,2H),3.79-3.78(d,6 H),3.53-3.49(m,2H),3.44-3.42(m,1H),3.24-3.20(m,6H),2.24-2.20(m,2H),2.14-2.08(m,2H),1.98-1.95(m,1H).

[0382] MS (ESI): m / z 336.1 [M-Br - ] + .

[0383] Step 3)

[0384] In a 50 mL reaction vial, compound 2c (200 mg, 0.60 mmol) was dissolved in ultra-dry N,N-dimethylformamide (5 mL). Compound 1k (288 mg, 0.60 mmol), diisopropylethylamine (307 mg, 2.38 mmol), 4-dimethylaminopyridine (73 mg, 0.60 mmol), and HATU (339 mg, 0.8925 mmol) were added. The atmosphere was replaced with nitrogen three times and stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (ammonium formate buffer) to afford 36 mg of compound 2 (yield: 7.5%).

[0385] MS (ESI): m / z 402.3 [(M-2HCOO - ) / 2] + .

[0386] 1 H NMR(400MHz,DMSO-d6)δ8.45(s,2H),7.05-6.98(m,5H),6.87-6.85(d,2H),6.82(s,1H),6. 66-6.65(d,2H),5.55(s,1H),4.64-4.62(d,1H),4.50(s,2H),4.40(s,2H),4.33(s,2H),4.2 5(s,2H),4.18(s,2H),3.94-3.90(m,1H),3.78-3.76(d,6H),3.72-3.70(d,6H),3.62-3.59( d,2H),3.34(s,4H),3.30(s,4H),3.20(s,5H),3.11(s,2H),2.91-2.85(t,1H),2.22(s,8H).

[0387] Example 3 Preparation of Compound 3

[0388] Step 1)

[0389] In a 250 mL reaction flask, compound 3a (2.2 g, 13.16 mmol, purchased from Bidex Pharmaceuticals) was weighed, methanol (40 mL) and formaldehyde solution (2.37 g, 78.95 mmol, 37% w / w) were added, and sodium triacetoxyborohydride (13.94 g, 65.79 mmol) was added portionwise. The reaction was stirred at room temperature until completion, concentrated, and saturated sodium bicarbonate solution was added to adjust the pH to greater than 7. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried, filtered, and concentrated. The mixture was purified by column chromatography (DCM / MeOH = 7 / 1) to obtain 2.25 g of compound 3b (yield: 87.58%).

[0390] MS (ESI): m / z 196.2 [M+H] + .

[0391] 1 H NMR (400MHz, CDCl3) δ6.88(d,1H),6.80(m,2H),3.89(s,3H),3.87(s,3H),3.36(s,2H),2.23(s,6H).

[0392] Step 2)

[0393] In a 100 mL reaction flask, compound 3b (1.2 g, 6.15 mmol) was weighed, acetonitrile (12 mL) was added, and propylene sulfate (1.70 g, 12.29 mmol, purchased from Bidex Pharmaceuticals) was added. The reaction was heated until completion. Methyl tert-butyl ether (50 mL) was added to the mixture at room temperature for slurrying. The mixture was filtered and dried to obtain 1.8 g of compound 3c (yield: 88%).

[0394] MS (ESI): m / z 334.2 [M+H] + .

[0395] 1 H NMR (400MHz, DMSO-d6) δ7.12-7.05(m,3H),4.43(s,2H),3.84(t,2H),3.80(s,6H),3.38-3.31(m,2H),2.93(s,6H),2.13-2.07(m,2H).

[0396] Step 3)

[0397] Compound 3c (1.01 g, 3.00 mmol) and concentrated sulfuric acid (23.52 mg, 239.95 μmol) were weighed into a 50 mL reaction flask. Methanol (10 mL) was added and the mixture was heated until the reaction was complete. The reaction solution was cooled to room temperature, exchanged with chloride ion exchange resin, and concentrated and lyophilized to obtain 0.78 g of compound 3d (yield: 102.24%).

[0398] MS (ESI): m / z 254.2 [M-Cl - ] + .

[0399] Step 4)

[0400] In a 50 mL reaction vial, compound 1k (450 mg, 0.93 mmol), compound 3d (283 mg, 1.12 mmol), HATU (530 mg, 1.4 mmol), and 4-methylpyridine (172 mg, 1.4 mmol) were weighed, and N,N-dimethylformamide (10 mL) was added. The reaction was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (trifluoroacetic acid buffer system) and lyophilized to obtain 205 mg of compound 3 (yield: 30.6%).

[0401] MS (ESI): m / z 360.4 [(M-2CF3COO - ) / 2] + .

[0402] 1 H NMR(400MHz,DMSO-d6)δ7.32-6.98(m,6H),6.87-6.82(m,3H),6.66(s,2H),5. 55(s,1H),4.65-4.62(m,1H),4.45(s,1H),4.27-4.24(m,2H),4.19-4.12(m,2 H),3.93-3.88(m,1H),3.78(d,J=2.4Hz,6H),3.72(d,J=2.8Hz,6H),3.67-3.6 5(m,2H),3.51-3.34(m,6H),3.2(S,3H),3.11-3.07(m,2H),2.96(S,6H),2.91 -2.85(m,1H),2.85 -2.06(m,4H).

[0403] Example 4 Preparation of Compound 4

[0404] Step 1):

[0405] In a 100 mL reaction flask, compound 4a (2.00 g, 13.19 mmol, purchased from Leyan), potassium carbonate (5.47 g, 39.57 mmol), and potassium iodide (218 mg, 1.31 mmol) were weighed. Acetone (40 mL) was added, and 3-bromopropanol (1.65 g, 11.87 mmol) was added dropwise. The reaction was heated in an oil bath until the reaction was complete. The mixture was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 1:10) to afford 2.17 g of compound 4b (94% yield).

[0406] MS (ESI): m / z 174.3 [M+H] + .

[0407] Step 2):

[0408] In a 100 mL reaction flask, compound 4b (1.00 g, 5.77 mmol) was weighed and dissolved in anhydrous acetonitrile (40 mL). 3,4-Dimethoxybenzyl bromide (1.33 g, 5.77 mmol) was added. Heat in an oil bath until the reaction was complete. The filtrate was concentrated and purified by column chromatography (MeOH / DCM = 1:10) to afford 1.29 g of compound 4c (yield: 55%).

[0409] MS (ESI): m / z 324.1 [M-Br - ] + .

[0410] 1 H NMR (400MHz, CD3OD) δ7.20-7.15(m,2H),7.10-7.05(m,1H),4.60(s,1H),4.52(s,1H),3.91-3.87(m,6H),3.76-3.67(m,2H),3.63 -3.58(m,1H),3.57-3.45(m,3H),3.45-3.38(m,4H),3.38-3.35(m,3H),2.39-2.26(m,1H),2.21-2.06(m,3H),2.05-1.92(m,2H).

[0411] Step 3):

[0412] In a 50 mL reaction flask, compound 1k (500 mg, 961.50 μmol), compound 4c (584 mg, 1.44 μmol), and HATU (549 mg, 1.44 mmol) were weighed and dissolved in anhydrous DMF (10 mL). 4-Methylpyridine (177 mg, 1.45 mmol) was added, and the reaction was stirred at room temperature until the reaction was complete. The reaction solution was subjected to HPLC (trifluoroacetic acid buffer system) to obtain 513 mg of compound 4 (yield: 52%).

[0413] MS (ESI): m / z 395.4 [(M-2CF3COO - ) / 2] + .

[0414] 1 H NMR(400MHz,DMSO-d6)δ7.14-6.95(m,5H),6.90-6.83(m,2H),6.82(s,1H),6.72-6.60(m,2H ),5.54(s,1H),4.64-4.58(m,1H),4.54-4.48(m,2H),4.30-4.23(m,2H),4.18-4.12(m,2H),3 .80-3.75(m,6H),3.74-3.69(m,6H),3.68-3.55(m,3H),3.52-3.27(m,11H),3.27-3.21(m,4 H),3.20(s,3H),3.14-3.05(m,2H),2.92-2.83(m,1H),2.26-2.15(m,4H),2.14-1.77(m,4H).

[0415] Example 5 Preparation of Compound 5

[0416] Step 1)

[0417] In a 50 mL reaction flask, compound 5a (1.00 g, 6.68 mmol, purchased from Leyan), potassium carbonate (2.77 g, 20.05 mmol), and potassium iodide (111 mg, 668.66 μmol) were weighed. Acetone (10 mL) and 3-bromopropanol (0.929 g, 6.68 mmol) were added and heated with stirring until the reaction was complete. The mixture was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 0-8%) to afford 1.02 g of compound 5b (yield: 89%).

[0418] MS (ESI): m / z 172.2 [M+H] + .

[0419] Step 2)

[0420] Compound 5b (1.00 g, 5.84 mmol) was weighed into a 50 mL reaction flask, and acetonitrile (10 mL) and 3,4-dimethoxybenzyl bromide (1.48 g, 6.42 mmol) were added. The mixture was heated and stirred until the reaction was complete. The reaction solution was concentrated and purified by column chromatography (MeOH / DCM = 0-8%) to afford 1.26 g of compound 5c (yield: 53%).

[0421] MS (ESI): m / z 322.3 [M-Br - ] + .

[0422] 1 H NMR (400MHz, DMSO-d6) δ7.17-6.98(m,3H),5.09-4.64(m,2H),4.44-4.20(m,3H),4.02-3.55(m,13H),3.10-2.52(m,2H),2.38-1.80(m,5H).

[0423] Step 3)

[0424] In a 50 mL reaction vial, compound 1k (450 mg, 928.66 μmol), compound 5c (449 mg, 1.12 μmol), HATU (530 mg, 1.39 mmol), DMAP (171 mg, 1.40 mmol), and anhydrous DMF (10 mL) were weighed and stirred at room temperature until the reaction was complete. The reaction mixture was purified by HPLC (ammonium formate buffer) to yield 280 mg of compound 5 (yield: 34%).

[0425] MS (ESI): m / z 394.4 [(M-2HCOO - ) / 2] + .

[0426] 1 H NMR(400MHz,DMSO-d6)δ8.46(s,2H),7.11-6.89(m,5H),6.88-6.79(m,3H),6.69-6.53(m,2H) ,5.55(s,1H),4.70-4.41(m,3H),4.36-4.23(m,3H),4.19-4.11(m,2H),4.07-3.89(m,3H),3.7 9(s,3H),3.75(s,3H),3.73-3.68(m,7H),3.64-3.55(m,4H),3.35-3.30(m,4H),3.20(s,3H),3 .13-3.01(m,3H),2.91-2.84(m,1H),2.70-2.55(m,2H),2.38-2.25(m,4H),2.24-1.94(m,4H).

[0427] Example 6 Preparation of Compound 6

[0428] Step 1)

[0429] Compound 6a (600 mg, 931.98 μmol, prepared by the method disclosed in WO2008 / 132746 A1) was weighed into a 50 mL reaction vial. Dichloromethane (10 mL) and trifluoroacetic acid (10 mL) were added. The mixture was stirred at room temperature until the reaction was complete and concentrated to afford 0.53 g of compound 6b (yield: 96%).

[0430] MS (ESI): m / z 430.3 [M-PhSO3 - ] + .

[0431] Step 2)

[0432] Compound 6b (0.53 g, 901.85 μmol) was weighed into a 50 mL reaction flask. Tetrahydrofuran (5 mL) and borane-tetrahydrofuran solution (1.0 M, 10 ml) were added. The mixture was stirred at room temperature until the reaction was complete. The mixture was concentrated and purified by column chromatography (ACN / H2O = 1:10) to obtain 503 mg of compound 6c (yield: 97%).

[0433] MS (ESI): m / z 416.3 [M-PhSO3 - ] + .

[0434] Step 3)

[0435] In a 50 mL reaction vial, compound 6c (250 mg, 901.85 μmol) was weighed and added to acetonitrile (8 mL), 1,4-dioxane-2,6-dione (253 mg, 2.18 mmol, purchased from Shaoyuan Technology), and triethylamine (221 mg, 2.18 mmol). The reaction was stirred at room temperature until the reaction was complete, concentrated, and purified by column chromatography (ACN / H2O = 1:10) to give 228 mg of compound 6d (yield: 75%).

[0436] MS (ESI): m / z 532.2 [M-PhSO3 - ] + .

[0437] Step 4)

[0438] In a 50 mL reaction vial, compound 6d (200 mg, 289.95 μmol), compound 6c (217 mg, 378.25 μmol), HATU (166 mg, 436.57 μmol), and N-methylpyridine (54 mg, 442.00 μmol) were weighed. N,N-dimethylformamide (4 mL) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by HPLC (trifluoroacetic acid buffer) to obtain 96 mg of compound 6 (yield: 28%).

[0439] MS (ESI): m / z 465.3 [(M-2CF3COO - ) / 2] + .

[0440] 1 H NMR(400MHz,DMSO-d6)δ6.87-6.82(m,4H),6.69-6.62(m,2H),6.55-6.51 (m,2H),5.68-5.63(m,2H),4.67-4.58(m,2H),4.13-3.94(m,8H),3.91-3. 81(m,2H),3.74-3.69(m,12H),3.66-3.61(m,12H),3.34-3.28(m,8H),3. 26-3.22(m,6H),3.14-3.03(m,4H),2.92-2.84(m,2H),2.21-2.07(m,4H).

[0441] Example 7 Preparation of Control Compound 1

[0442] Prepared by referring to the method disclosed in patent WO2021115413.

[0443] Example 8 Preparation of Compound 8

[0444] Step 1)

[0445] In a 25 mL reaction flask, compound E1 (2.4 g, 6.21 mmol, prepared by the method disclosed in patent WO2021115413A1) and diglycolic anhydride (1.08 g, 9.31 mmol) were weighed and acetonitrile (25 mL) was added. Triethylamine (942.51 mg, 9.31 mmol) was added dropwise under ice-water bath. The reaction was stirred under ice-water bath until the reaction was complete, concentrated, diluted with dichloromethane (20 mL), and extracted with deionized water (3×10 mL). The aqueous phases were combined, the pH was adjusted to 3 with 1N HCl, solid sodium chloride was added to saturate the acidic aqueous solution, and then extracted with dichloromethane / acetonitrile (5 / 1 v / v, 5×20 mL). The organic phases were combined, dried, filtered, and concentrated. 1.75 g of compound E3 (yield 56.08%) was obtained by column chromatography (DCM / MeOH = 3 / 1).

[0446] MS (ESI): m / z 502.2 [M-Cl - ] + .

[0447] 1H NMR(400MHz,DMSO-d6)δ7.00-6.99(d,2H),6.87-6.84(m,3H),5.57(s,1H),5.34(d,1H),4.64(dd,1H),4.07-4.04(m,5H),3.94- 3.86(m,1H),3.72(s,6H),3.64-3.59(m,2H),3.34-3.30(m,5H),3.32(s,3H),3.12-3.05(m,2H),2.87(t,1H),2.20-2.12(m,2H).

[0448] Step 2)

[0449] In a 250 mL reaction flask, compound 8a (5 g, 30.09 mmol, purchased from Leyan), morpholine (5.24 g, 60.18 mmol), dichloroethane (75 mL), and sodium triacetoxyborohydride (19.13 g, 90.27 mmol) were weighed and stirred at room temperature until the reaction was complete. 200 mL of water was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (PE / EtOAc = 1 / 3 to 0 / 1) afforded 5.2 g of compound 8c (yield: 72.8%).

[0450] MS (ESI): m / z 238.2 [M+H] + .

[0451] 1 H NMR (400MHz, CDCl3) δ6.91(d,1H),7.31-7.36(m,2H),3.89(s,3H),3.87(s,3H),3.73(t,4H),3.49(s,2H),2.49(s,4H).

[0452] Step 3)

[0453] In a 100 mL reaction flask, compound 8c (2.5 g, 10.54 mmol) and propylene sulfate (4.37 g, 31.61 mmol) were weighed and dissolved in acetonitrile (13 mL). The mixture was heated in an oil bath until the reaction was complete. Methyl tert-butyl ether (50 mL) was added at room temperature to slurry the mixture, yielding 2.15 g of compound 8d (yield: 54.4%).

[0454] MS m / z(ESI):376.2[M+H] + .

[0455] 1H NMR(400MHz,DMSO-d6)δ7.15-7.04(m,3H),4.57(s,2H),3.98-3.93(m,4H),3.86(t,2H) ),3.82(s,3H),3.80(s,3H),3.50-3.44(m,2H),3.40-3.36(m,4H),2.18-2.10(m,2H).

[0456] Step 4)

[0457] Compound 8d (2.0 g, 5.33 mmol) and concentrated sulfuric acid (41.80 mg, 426.17 μmol) were weighed into a 100 mL reaction flask. Methanol (20 mL) was added and heated until the reaction was complete. The mixture was cooled to room temperature, exchanged with chloride ion exchange resin, and concentrated and lyophilized to obtain 1.85 g of compound 8e (yield: 117%).

[0458] MS (ESI): m / z 296.2 [M-Cl - ] + .

[0459] 1 H NMR(400MHz,DMSO-d6)δ7.15-7.14(m,2H),7.06(d,1H),5.01(m,1H),4.60(s,2H),3.97-3.92(m ,4H),3.80(s,6H),3.56-3.53(m,3H),3.49-3.45(m,2H),3.40-3.31(m,3H),2.01-1.96(m,2H).

[0460] Step 5)

[0461] In a 25 mL reaction vial, compound E3 (0.402 g, 799.88 μmol), compound 8e (355.60 mg, 1.20 mmol), 4-methylpyridine (146.58 mg, 1.20 mmol), and HATU (456.21 mg, 1.20 mmol) were weighed and added to N,N-dimethylformamide (4 mL). The mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by preparative HPLC (ammonium formate buffer) and lyophilized to afford 0.14 g of compound 8 (yield: 22%).

[0462] MS (ESI): m / z 390.4 [(M-2HCOO - ) / 2] + .

[0463] 1H NMR(400MHz,DMSO-d6)δ8.33(s,2H),7.08-7.06(m,3H),7.00-6.96(m,2H),6.88-6.82(m,2H) ,5.56(s,1H),4.62-4.57(m,3H),4.19-4.15(m,4H),4.09-4.03(m,4H),3.98-3.92(m,3H),3.7 9(s,6H),3.71(s,6H),3.67-3.61(m,2H),3.60-3.56(m,2H),3.41-3.38(m,4H),3.36-3.33(m, 2H),3.32-3.28(m,5H),3.21(s,3H),3.12-3.06(m,2H),2.91-2.84(m,1H),2.22-2.14(m,4H).

[0464] Example 9 Preparation of Compound 9

[0465] Step 1)

[0466] In a 100 mL reaction flask, compound 9a (5.0 g, 36.19 mmol, purchased from Bidex Pharmaceuticals) and paraformaldehyde (6.3 g, 72.38 mmol, purchased from Titan Technology, CAS: 30525-89-4) were weighed, glacial acetic acid (20 mL) was added, and hydrobromic acid in acetic acid (33% solution, 15 mL) was added under ice bath. The reaction was incubated at room temperature until the reaction was complete, filtered, and dried to obtain 5.1 g of compound 9b (yield: 43%).

[0467] 1 H NMR (400MHz, CDCl3-d6) δ6.84(s,2H),4.64(s,4H),3.90(s,6H).

[0468] Step 2)

[0469] In a 100 mL reaction flask, compound 9b (1.5 g, 4.63 mmol), 3-(methylamino)-1-propanol (412 mg, 4.63 mmol), and N,N-diisopropylethylamine (598.0 mg, 4.63 mmol) were weighed, and dioxane (25 mL) was added. The mixture was heated in an oil bath until the reaction was complete, filtered, and dried to obtain 1.0 g of compound 9c (yield: 86%).

[0470] MS (ESI): m / z 252.2 [M-Br - ] + .

[0471] 1H NMR (400MHz, DMSO-d6) δ7.05 (s, 2H), 4.85-4.80 (m, 3H), 4.71 (d, J = 12.4Hz, 2H), 3 .77(s,6H),3.67-3.63(m,2H),3.52-3.46(m,2H),3.18(s,3H),1.89-1.85(m,2H).

[0472] Step 3)

[0473] In a 50 mL reaction vial, compound 1k (192 mg, 0.40 mmol), compound 9c (121 mg, 0.48 mmol), HATU (228 mg, 0.60 μmol), and N,N-diisopropylethylamine (78 mg, 0.60 mmol) were weighed. N,N-dimethylformamide (8 mL) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction solution was purified by preparative HPLC (ammonium formate buffer) and lyophilized to obtain 100 mg of compound 9 (yield: 34.8%).

[0474] MS (ESI): m / z 359.4 [(M-2HCOO - ) / 2] + .

[0475] 1 H NMR(400MHz,DMSO-d6)δ8.50(brs,2H),7.05-6.82(m,7H),6.67(s,2H),5.54(s,1H),4.83-4.60(m,5H),4.25-4.14( m,5H),3.77(s,15H),3.62-3.50(m,2H),3.33-3.31(m,3H),3.30(s,6H),3.22-3.11(m,2H),2.96-2.91(m,2H),2.13 -1.98(m,4H).

[0476] Example 10 Preparation of Compound 10

[0477] Step 1)

[0478] In a 100 mL reaction flask, compound 10a (1.5 g, 2.33 mmol, prepared by the method disclosed in WO2008 / 132746A1) was weighed and dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added and the reaction was stirred at room temperature until completion. The reaction was concentrated to obtain crude compound 10b, which was directly used in the next step.

[0479] MS (ESI): m / z 430.2 [M-PhSO3 -] + .

[0480] Step 2)

[0481] To a 100 mL reaction flask, compound 10b (1.0 g, 2.32 mmol) and tetrahydrofuran (2 mL) were added. Borane-tetrahydrofuran complex (35 mL) was added at 0°C and stirred at room temperature until the reaction was complete. Methanol was added and stirred to quench the reaction. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 30:1-6:1) and concentrated. The residue was exchanged with a chloride ion exchange resin to give 700 mg of compound 10c (yield: 89%).

[0482] MS (ESI): m / z 416.2 [M-Cl - ] + .

[0483] 1 H NMR(400MHz,DMSO-d6)δ6.87-6.84(m,2H),6.59-6.53(m,2H),5.73(s,1H),4.84-4.80(m,1H),3.73(s,3H),3.71(s,3H) ),3.64(s,3H),3.60-3.43(m,8H),3.25(s,3H),3.12-3.05(m,2H),3.00(s,3H),2.90-2.86(m,1H),2.20-2.09(m,2H).

[0484] Step 3)

[0485] In a 100 mL reaction flask, compound 10c (1.6 g, 3.54 mmol) and maleic anhydride (0.52 g, 5.31 mmol) were dissolved in 1,2-dichloroethane (15 mL) and acetonitrile (16 mL). Triethylamine (0.39 g, 3.89 mmol) was then added. The reaction was stirred at low temperature until completion. The mixture was concentrated and purified by column chromatography (DCM:MeOH = 30:1-6:1) to give 800 mg of compound 10d (yield: 42%).

[0486] MS (ESI): m / z 514.1 [M-Cl - ] + .

[0487] 1H NMR (400MHz, DMSO-d6) δ6.87-6.84(m,2H),6.59-6.39(m,4H),5.76(s,1H),5.70(s,1H),4.84-4.81(m,1H),4.34-4.28(m,2H),3.73(s ,3H),3.71(s,3H),3.64(s,3H),3.60-3.43(m,7H),3.25(s,3H),3.14-3.05(m,3H),3.01(s,3H),2.87-2.85(m,1H),2.36-2.33(m,2H).

[0488] Step 4)

[0489] In a 50 mL reaction flask, compound 10d (0.2 g, 0.39 mmol) was dissolved in dichloromethane (2 mL). Oxalyl chloride (0.26 g, 2.02 mmol) was added dropwise to the solution under an ice-water bath. The reaction was stirred until completion, concentrated, and the mixture was dissolved in dichloromethane (2 mL). The mixture was added dropwise to a solution of compound 3d (0.12 g, 0.43 mmol) in acetonitrile (2 mL). The reaction was stirred at room temperature until completion, concentrated, and the reaction solution was purified by HPLC (ammonium formate buffer system) to yield 50 mg of compound 10 (yield: 18%).

[0490] MS (ESI): m / z 375.3 [(M-2HCOO - ) / 2] + .

[0491] 1 H NMR(400MHz,DMSO-d6)δ8.37(s,2H),7.13-7.05(m,3H),6.89-6.84(m,4H),6.56-6.53(m,2H),5.69 (s,1H),4.80-4.74(m,1H),4.46(s,2H),4.38-4.35(m,2H),4.30-4.25(m,2H),3.93(s,3H),3.91(s ,3H),3.71(s,3H),3.63(s,3H),3.53-3.52(m,2H),3.45-3.40(m,3H),3.25(s,3H),3.15-3.05(m,2 H),3.01(s,3H),2.94(s,6H),2.87-2.85(m,1H),2.39-2.36(m,2H),2.23-2.19(m,2H),2.08(s,3H).

[0492] Example 11 Preparation of Compound 11

[0493] Step 1)

[0494] In a 100 mL reaction flask, compound 11a (1.1 g, 4.95 mmol, purchased from Anaiji) was weighed and dissolved in tetrahydrofuran (10 mL). Borane dimethyl sulfide solution (14.9 ml, 1.66 M / L) was added under ice bath and reacted under ice bath until the reaction was complete. Methanol (20 ml) was added and stirred to quench the reaction. The mixture was concentrated and purified by column chromatography (EA / PE = 4 / 6) to obtain 1.1 g of compound 11b (yield: 99.1%).

[0495] MS (ESI): m / z 225.2 [M+H] + .

[0496] 1 H NMR (400MHz, CDCl3-d) δ7.28-7.20(m,3H),4.58(s,2H),2.48(brs,1H),2.23(s,6H).

[0497] Step 2)

[0498] In a 100 mL reaction flask, compound 11b (1.1 g, 4.91 mmol) was weighed and dissolved in dichloromethane (10 mL). Triphenylphosphine (1.67 g, 6.38 mmol) and carbon tetrabromide (2.12 g, 6.38 mmol) were added under ice-cooling, and the reaction was stirred at room temperature until completion. Dichloromethane (50 mL) and water (60 mL) were added, and the organic phase was separated, dried, filtered, and concentrated. The organic phase was purified by column chromatography (EA / PE = 3 / 7) to afford 680 mg of compound 11c (yield: 48.3%).

[0499] 1 H NMR (400MHz, CDCl3-d) δ7.29-7.24 (m, 2H), 7.16 (d, J = 8.4Hz, 1H), 4.45 (s, 2H), 2.29 (s, 6H).

[0500] Step 3)

[0501] In a 100 mL reaction bottle, compound 11c (700 mg, 2.44 mmol) and 3-(4-morpholine)-1-propanol (354 mg, 2.44 mmol, purchased from Shaoyuan Technology) were weighed, and acetonitrile (15 mL) was added. The mixture was heated until the reaction was complete, filtered, and dried to obtain 620 mg of compound 11d (yield: 72%).

[0502] MS (ESI): m / z 352.2 [M-Br - ] + .

[0503] Step 4)

[0504] In a 50 mL reaction flask, compound E3 (156 mg, 0.31 mmol) was weighed and added to dichloromethane (5 mL). Oxalyl chloride (119 mg, 0.94 mmol) was added under ice-cooling and stirred until the reaction was complete. The mixture was then concentrated under low temperature and dichloromethane (5 mL) was added. The reaction mixture was set aside. In another 50 mL three-necked flask, compound 11d (110 mg, 0.31 mmol) was weighed and added to acetonitrile (5 mL). The reaction mixture was added dropwise and stirred until the reaction was complete. The mixture was concentrated under low temperature and analyzed by HPLC (trifluoroacetic acid buffer) to obtain 60 mg of compound 11 (yield: 22.97%).

[0505] MS (ESI): m / z 418.4 [(M-2CF3COO - ) / 2] + .

[0506] 1 H NMR(400MHz,DMSO-d6)δ7.50-7.44(m,3H),6.98-6.96(m,2H),6.87-6.84(m,3H),5 .56(s,1H),4.71(s,2H),4.62-4.60(m,1H),4.18-4.15(m,4H),4.09(s,2H),4.07-4 .04(m,2H),3.98-3.89(m,5H),3.72(s,6H),3.68-3.61(m,3H),3.43-3.31(m,9H), 3.22(s,3H),3.10-3.06(m,3H),2.90-2.85(m,1H),2.30(s,6H),2.21-2.14(m,4H).

[0507] Example 12 Compound 12

[0508] Step 1)

[0509] In a 50 mL reaction flask, 3-morpholin-4-ylmethylbenzoic acid (350 mg, 1.51 mmol), prepared using the method disclosed in WO2018 / 169777A1, was weighed. HATU (600 mg, 1.51 mmol) and diisopropylethylamine (780 mg, 5.80 mmol) were added. The mixture was dissolved in N,N-dimethylformamide (4 mL). Compound 12a (400 mg, 1.16 mmol, prepared using the method disclosed in WO2022 / 67094A1) was added and stirred at room temperature until the reaction was complete. The mixture was washed twice with ethyl acetate (100 mL) and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 1 / 1) to afford 0.59 g of compound 12b (yield: 80%).

[0510] MS (ESI): m / z 547.20 [M+H] + .

[0511] Step 2)

[0512] Compound 12b (580.0 mg, 1.06 mmol) was weighed into a 50 mL reaction flask and dissolved in acetonitrile (3 mL). Propylene sulfate (293.0 mg, 2.12 mmol) was added and heated until the reaction was complete. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1 to 1 / 1) to afford 0.18 g of compound 12c (yield: 30%).

[0513] MS (ESI): m / z 685.2 [M+H] + .

[0514] Step 3)

[0515] Compound 12c (180.0 mg, 0.27 mmol) was weighed into a 50 mL reaction flask and dissolved in methanol (3 mL). H₂SO₄ (0.1 mL) was then added and heated until the reaction was complete. The reaction solution was exchanged with chloride ion exchange resin and concentrated to afford 0.1 g of compound 12d (yield: 60%).

[0516] MS (ESI): m / z 605.2 [M-Cl - ] + .

[0517] 1H NMR(400MHz,CD3OD)δ8.80(d,1H),8.11-8.04(m,4H),7.82-7.66(m,3H),7.45-7.30(m,2H),4.28-3.96 (m,7H),3.77-3.75(m,2H),3.78-3.52(m,7H),2.42-2.38(m,1H),2.22-2.17(m,6H),1.86-1.71(m,3H).

[0518] Step 4)

[0519] Compound 1k (264 mg, 0.55 mmol) was weighed into a 50 mL reaction vial and dissolved in N,N-dimethylformamide (4.4 mL). HATU (209 mg, 0.55 mmol), diisopropylethylamine (147 mg, 1.08 mmol), and compound 12d (220 mg, 0.36 mmol) were then added. The mixture was stirred at room temperature until completion. The reaction solution was purified by HPLC (trifluoroacetic acid buffer) to obtain 32 mg of compound 12 (yield: 7%).

[0520] MS (ESI): m / z 535.5 [(M-2HCOO - ) / 2] + .

[0521] 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.62(s,1H),8.41(s,2H),8.08-8.03(m,2 H),7.91-7.88(m,1H),7.75-7.54(m,4H),6.99-6.62(m,8H),5.54(s,1H),4.78 (s,2H),4.64-4.62(m,1H),4.15-3.80(m,14H),3.71(s,3H),3.70(s,3H),3.61 -3.58(m,2H),3.33(s,3H),3.21(s,3H),3.10-2.84(m,5H),2.40-1.29(m,15H).

[0522] Example 13 Preparation of Compound 13

[0523] Step 1)

[0524] Compound 13a (5.51 g, 30 mmol, purchased from Leyan) was weighed into a 100 mL reaction flask, and methanol (300 mL) was added. Formaldehyde aqueous solution (5.85 g, 195 mmol, 37%) and sodium acetate borohydride (31.8 g, 150 mmol) were added under an ice-water bath. The mixture was stirred at room temperature under nitrogen protection until the reaction was complete. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 1:5) to obtain 4 g of compound 13b (yield: 76%).

[0525] MS (ESI): m / z 176.2 [M+H] + .

[0526] 1 HNMR (400MHz, CD3OD) δ3.55(s,3H),3.38-3.35(m,1H),2.65-2.60(m,1H),2.51-2.42(m,1H),2.28(s,6H).

[0527] Step 2)

[0528] In a 100 mL reaction flask, compound 13b (4.0 g, 22.83 mmol) was dissolved in dichloromethane (5 mL). Trimethylsilyl alcohol (4.05 g, 34.25 mmol), HATU (10.42 g, 27.40 mmol), 4-methylpyridine (2.79 g, 22.83 mmol), and diisopropylethylamine (8.85 g, 68.50 mmol, 11.93 mL) were added under ice-water bath and stirred at room temperature until the reaction was complete. Water (100 mL) was added to the reaction flask, and the mixture was extracted with dichloromethane (50 mL x 4). The organic phases were combined, dried, filtered, and concentrated. The mixture was purified by column chromatography (PE / EA = 1:1) to afford 3.2 g of compound 13c (yield: 50.9%).

[0529] MS (ESI): m / z 276.4 [M+H] + .

[0530] 1 H NMR(400MHz,DMSO-d6)δ4.14-4.09(m,2H),3.55(s,3H),3.53-3.51(m,1H),2.7 4-2.67(m,1H),2.53-2.47(m,1H),2.20(s,6H),0.95-0.91(m,2H),0.01(s,9H).

[0531] Step 3)

[0532] In a 50 mL reaction flask, compound 13c (3.2 g, 11.62 mmol) was weighed and dissolved in methanol (50 mL) and water (10 mL). The mixture was placed in an ice-water bath. Lithium hydroxide (278.85 mg, 11.62 mmol) was added and stirred at room temperature until the reaction was complete. The mixture was concentrated and purified by column chromatography (MeOH / DCM = 1:10) to obtain 2.1 g of compound 13d (yield: 69.1%).

[0533] 1 H NMR (400MHz, DMSO-d6) δ4.16-4.11(m,2H),3.54-3.50(m,1H),2.67-2.61(m,1H),2.45-2.40(m,1H),2.23(s,6H),0.99-0.95(m,2H),0.03(s,9H).

[0534] Step 4)

[0535] In a 25 mL reaction flask, compound 13d (784 mg, 3.00 mmol) was weighed and dissolved in dichloromethane (20 mL). Oxalyl chloride (1.52 g, 12.00 mmol) and DMF were added dropwise under an ice-water bath. The mixture was stirred at room temperature under argon protection until the reaction was complete. The mixture was concentrated to obtain compound 13e, which was used directly in the next reaction.

[0536] Step 5)

[0537] In a 25 mL reaction flask, compound 8e (592.76 mg, 2 mmol) was dissolved in dichloromethane (5 mL). Stirring was carried out under an ice-water bath. A solution of compound 13e (820 mg) in dichloromethane (5 mL) was added dropwise. Stirring was continued at room temperature under argon until the reaction was complete. Column chromatography (MeOH / DCM = 1:3) afforded 650 mg of compound 13f (yield: 60.2%).

[0538] MS (ESI): m / z 539.2 [M-Br - ] + .

[0539] Step 6)

[0540] In a 25 mL reaction flask, compound 13f (600 mg, 1.11 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (581.29 mg, 2.22 mmol, 1.0 M) was added under ice-water bath and stirred at room temperature until the reaction was complete. The mixture was exchanged with chloride ion exchange resin and concentrated. Column chromatography (ACN / H2O = 1:3) gave 350 mg of compound 13g (yield: 71%).

[0541] MS (ESI): m / z 439.2 [M-Cl- ] + .

[0542] 1 H NMR(400MHz,DMSO-d6)δ7.15-7.11(m,3H),4.65(s,2H),4.48-4.45(m,1H),4.22-4.19(m,2H),3.99-3.95(m,4H),3 .81(s,6H),3.80(s,2H),3.47-3.42(m,4H),3.26-3.21(m,1H),3.09-3.03(m,1H),2.81(s,6H),3.23-2.20(m,1H).

[0543] Step 7)

[0544] In a 10 mL reaction vial, compound 13g (300 mg, 0.68 mmol) was weighed and dissolved in N,N-dimethylformamide (10 mL). Compound E1 (316.57 mg, 0.82 mmol), HATU (389.29 mg, 1.02 mmol), 4-methylpyridine (83.39 mg, 0.68 mmol), and diisopropylethylamine (352.86 mg, 2.73 mmol) were added under an ice-water bath. The mixture was stirred at room temperature under nitrogen until the reaction was complete. The reaction solution was purified by preparative HPLC (ammonium formate buffer) to yield 30 mg of compound 13 (yield 5.4%).

[0545] MS (ESI): m / z 404.2 [(M-2HCOO - ) / 2] + .

[0546] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,2H),7.09-7.06(m,3H),6.99-6.97(m,2H),6.87-6.82(m,3H),5.57(s,1H),4.60(s,3H),4.09-3.68(m,29H),33. 46-3.34(m,4H),3.26-3.21(m,9H),3.21(s,3H),3.17-2.98(m,2H),2.9 1-2.84(m,1H),2.64-2.59(m,1H),2.20-2.11(m,4H),2.07-1.99(m,4H).

[0547] Example 14 Preparation of Compound 14

[0548] Step 1)

[0549] In a 250 mL reaction flask, compound 14a (10.0 g, 36.50 mmol, purchased from Jiangsu Aikang) was weighed and dissolved in anhydrous acetonitrile (100 mL). Morpholine (3.81 g, 43.76 mmol) and potassium carbonate (12.59 mg, 91.24 mmol) were added. Under nitrogen, the reaction was heated until completion. The product was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 1:10) to afford 7.97 g of compound 14b (yield: 78%).

[0550] MS (ESI): m / z 281.2 [M+H] + .

[0551] Step 2)

[0552] In a 250 mL reaction flask, compound 14b (7.97 g, 28.46 mmol) was weighed and dissolved in tetrahydrofuran (40 mL). Lithium hydroxide (1.022 g, 42.69 mmol) and water (40 mL) were added and reacted at room temperature until the reaction was complete. The pH was adjusted to 5-6, the mixture was concentrated, and column chromatography (MeOH / DCM = 1:10) was performed to obtain 5.26 g of compound 14c (yield: 69%).

[0553] MS (ESI): m / z 267.2 [M+H] + .

[0554] Step 3)

[0555] In a 250 mL reaction flask, compound 14c (1.72 g, 6.47 mmol) was weighed and dissolved in ultra-dry N,N-dimethylformamide (40 mL). 2-Thiazolidinemethylamine (0.74 g, 6.47 mmol, purchased from Bismuth), diisopropylethylamine (2.50 g, 19.40 mmol), and HATU (2.95 g, 7.76 mmol) were added. The atmosphere was replaced with nitrogen three times and allowed to react at room temperature until the reaction was complete. Water (100 mL) was added and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH / DCM = 1:10) to afford 1.40 g of compound 14d (yield: 60%).

[0556] MS (ESI): m / z 363.2 [M+H] + .

[0557] Step 4)

[0558] In a 100 mL reaction flask, compound 14d (1.27 g, 3.51 mmol) was weighed and dissolved in ethanol (20 mL) and water (5 mL). Ammonium chloride (1.92 g, 35.08 mmol) and iron powder (1.566 g, 28.065 mmol) were added. The reaction was allowed to proceed at room temperature until completion. The mixture was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 1:10) to afford 1.10 g of compound 14e (yield: 94%).

[0559] MS (ESI): m / z 333.2 [M+H] + .

[0560] 1 H NMR(400MHz,DMSO-d6)δ9.10-9.07(t,1H),7.73-7.72(d,1H),7.62-7.61(d,1H),7.49(s,2H),7.16-7.14 (d,1H),6.71-6.69(d,1H),6.47(s,2H),4.70-4.68(d,2H),4.12-4.11(m,1H),3.61(s,4H),3.14(s,4H).

[0561] Step 5)

[0562] In a 100 mL reaction flask, compound 14e (1.10 g, 3.31 mmol) was weighed and dissolved in ethanol (20 mL). Carbon disulfide (12.60 g, 165.46 mmol) and potassium hydroxide (0.41 g, 7.28 mmol) were added. The reaction was heated until completion. The product was concentrated and purified by column chromatography (MeOH / DCM = 1:10) to afford 0.88 g of compound 14f (yield: 70%).

[0563] MS (ESI): m / z 375.3 [M+H] + .

[0564] 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),7.89-7.88(d,1H),7.74-7.72(dd,1H),7.69-7.68(d,1H), 7.62-7.63(d,1H),7.41-7.39(d,1H),5.95(s,2H),3.60-3.56(t,4H),3.52(s,2H),2.35(s,4H).

[0565] Step 6)

[0566] In a 100 mL reaction flask, compound 14f (0.35 g, 0.94 mmol) was weighed and dissolved in acetonitrile (20 mL). 3-bromopropanol (0.16 g, 1.122 mmol) and potassium carbonate (0.39 g, 2.81 mmol) were added. The reaction was heated until completion. The product was concentrated and purified by column chromatography (MeOH / DCM = 1:10) to afford 0.38 g of compound 14g (yield: 94%).

[0567] MS (ESI): m / z 433.3 [M-Br - ] + .

[0568] 1 H NMR(400MHz,DMSO-d6)δ8.02-8.01(d,1H),7.79-7.76(dd,1H),7.73-7.72(d,1H),7.70-7.69(d,1H),5.61(s,2 H),4.64-4.60(t,1H),3.59-3.57(s,7H),3.52-3.48(m,2H),3.33-3.29(t,2H),2.38(s,4H),2.27-2.24(t,2H).

[0569] Step 7)

[0570] In a 50 mL reaction flask, compound 14g (200 mg, 0.46 mmol) was weighed and dissolved in ultra-dry N,N-dimethylformamide (5 mL). Compound 1k (268 mg, 0.55 mmol), diisopropylethylamine (239 mg, 1.85 mmol), 4-dimethylaminopyridine (56 mg, 0.46 mmol), and HATU (263 mg, 0.69 mmol) were added. The atmosphere was nitrogen-protected and replaced three times, and the reaction was stirred at room temperature until completion. The reaction solution was lyophilized by HPLC (trifluoroacetic acid buffer) to obtain 96 mg of compound 1 (yield: 23%).

[0571] MS (ESI): m / z 450.3 [(M-2CF3COO - ) / 2] + .

[0572] 1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.31(s,1H),7.89-7.87(dd,1H),7.72-7.70(m,2H),7.65-7.63(d,1H),6.99 -6.97(d,2H),6.86-6.84(d,2H),6.81(s,1H),6.64-6.63(d,1H),5.63(s,1H),5.55(s,1H),4.63-4.59(dd,1H),4. 48(s,2H),4.28-4.25(t,2H),4.19-4.17(m,2H),3.95-3.87(m,4H),3.72(s,4H),3.70(s,4H),3.65(m,1H),3.61-3 .57(dd,4H),3.35(s,5H),3.21(s,4H),3.11-3.09(d,2H),2.89-2.84(t,1H),2.19-2.18(m,2H),2.11-2.08(t,2H).

[0573] Example 15 Preparation of Compounds 5A, 5B, 5C, and 5D

[0574] Step 1: Chiral separation of compound 5c

[0575] Chiral column: ChiralCel OX, 250×30 mm ID, 10 μm; Mobile phase: A: CO2, B: ethanol; Gradient: B 50%; Flow rate: 120 mL / min; Pressure: 100 bar; Column temperature: 38°C; Wavelength: 220 nm. The retention time of compound 5c-A was 3.095 min, and the retention time of compound 5c-B was 4.487 min.

[0576] 5c-A: 1 H NMR (400MHz, DMSO-d6) δ7.10-6.4(m,3H),5.10-4.96(m,2H),4.83(s,1H),4.75-4.60(m,2H),3.98(s ,2H),3.84-3.67(m,8H),3.44-3.37(m,2H),3.08-2.97(m,2H),2.30-2.14(m,4H),1.96-1.84(m,2H).

[0577] 5c-B: 1H NMR(400MHz,DMSO-d6)δ7.14-7.11(m,2H),7.05(d,1H),5.08(brs,1H),4.41(s,2H),4.27(d,2H),3.92(brs ,2H),3.81(s,3H),3.80(s,3H),3.63-3.56(m,6H),2.59-2.57(m,2H),2.28-2.23(m,2H),2.13-2.06(m,2H).

[0578] Step 2A: Preparation of compound 5A

[0579] In a 50 mL reaction vial, compound 1k (450 mg, 928.66 μmol), compound 5c-A (449 mg, 1.12 μmol), HATU (530 mg, 1.39 mmol), DMAP (171 mg, 1.40 mmol), and anhydrous DMF (10 mL) were weighed and stirred at room temperature until the reaction was complete. The reaction mixture was purified by HPLC (ammonium formate buffer) to afford 280 mg of compound 5A (yield: 34%).

[0580] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,2H),7.05-6.90(m,5H),6.89-6.80(m,3H),6.54(s ,2H),5.55(s,1H),5.06(s,2H),4.73-4.59(m,3H),4.23-4.11(m,4H),4.10-4.01(m ,2H),4.00-3.83(m,2H),3.76(s,3H),3.70(s,6H),3.67-3.56(m,3H),3.42-3.32( m,5H),3.22-3.18(m,3H),3.14-3.00(m,4H),2.92-2.84(m,1H),2.37-2.08(m,8H).

[0581] MS (ESI): m / z 394.4 [(M-2HCOO - ) / 2] + .

[0582] Retention time: 11.923min.

[0583] Step 2B: Preparation of compound 5B

[0584] In a 50 mL reaction vial, compound 1k (450 mg, 928.66 μmol), compound 5c-B (449 mg, 1.12 μmol), HATU (530 mg, 1.39 mmol), DMAP (171 mg, 1.40 mmol), and anhydrous DMF (10 mL) were weighed and stirred at room temperature until the reaction was complete. The reaction mixture was purified by HPLC (ammonium formate buffer) to yield 280 mg of compound 5B (yield: 34%).

[0585] MS (ESI): m / z 394.4 [(M-2HCOO - ) / 2] + .

[0586] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,2H),δ7.10-6.96(m,5H),6.88-6.80(m,3H),6.70-6.58(m,2H),5.55 (s,1H),4.65-4.58(m,1H),4.43(s,2H),4.36-4.21(m,4H),4.18-4.11(m,2H),4.01-3.86(m,3H),3.7 8(s,3H),3.75(s,3H),3.71(s,3H),3.70(s,3H),3.63-3.54(m,5H),3.48-3.35(m,6H),3.23-3.17(m ,3H),3.13-3.04(m,2H),2.92-2.83(m,1H),2.64-2.53(m,2H),2.37-2.24(m,4H),2.24-2.16(m,2H).

[0587] Retention time: 12.137 min.

[0588] Step 2C: Preparation of compound 5C

[0589] Take 100 mg of compound 5A and use 2 g 1×8 chloride form was ion exchanged 5 times with methanol as eluent, and concentrated to obtain 72 mg of compound 5C (yield 72%).

[0590] MS (ESI): m / z 394.4 [(M-2Cl - ) / 2] + .

[0591] 1H NMR(400MHz,DMSO-d6)δ7.03-6.90(m,5H),6.89-6.80(m,3H),6.55(s,2H),5.55(s ,1H),5.05(s,2H),4.70-4.57(m,3H),4.23-4.11(m,4H),4.07-4.01(m,2H),4.00-3 .83(m,2H),3.76(s,3H),3.72(s,6H),3.70(s,3H),3.70-3.56(m,3H),3.42-3.32( m,5H),3.22-3.18(m,3H),3.14-3.00(m,4H),2.92-2.84(m,1H),2.31-2.06(m,8H).

[0592] Step 2D: Preparation of compound 5D

[0593] Take 200mg of compound 5B and use 5g 1×8 chloride form was ion exchanged 5 times with methanol as eluent, and concentrated to obtain 160 mg of compound 5C (yield 80%).

[0594] MS (ESI): m / z 394.4 [(M-2Cl - ) / 2] + .

[0595] 1 H NMR(400MHz,DMSO-d6)δ7.10-7.08(m,1H),7.03-6.98(m,4H),6.88-6.83(m,3H),6.68(d,1H),6.62(d,1H),5.5 5(s,1H),4.69-4.63(m,1H),4.46(s,2H),4.33-4.30(m,3H),4.27(s,1H),4.18-4.12(m,2H),4.00(brs,2H),3. 99-3.96(m,1H),3.79(s,3H),3.76(s,3H),3.72(s,3H),3.71(s,3H),3.63-3.55(m,5H),3.38-3.44(m,2H),3.3 6(s,3H),3.32-3.30(m,1H),3.23(s,3H),3.13-3.02(m,2H),2.88(t,1H),2.63-2.54(m,2H),2.36-2.21(m,6H).

[0596] Example 16 Preparation of Control Compound 2

[0597] Prepared by referring to the method disclosed in US4761418A.

[0598] Example 17 Preparation of Control Compound 3

[0599] The preparation method was disclosed in reference (Anesthesiology November 2018, Vol. 129, 970988.).

[0600] Example 18 Preparation of Compound 15

[0601] Step 1) Preparation of compound 15b

[0602] Compound 15a (950 mg, 5.81 mmol, purchased from Jiangsu Aikang) was dissolved in acetone (19 mL). Potassium carbonate (1.60 g, 11.61 mmol), sodium iodide (87 mg, 580.41 μmol), and (3-bromopropoxy)(tert-butyl)diphenylsilane (2.19 g, 5.81 mmol, obtained using the known method "Angewandte Chemie - International Edition, 2015, vol. 54, #51, pp. 15497–15500") were added with stirring at room temperature. After complete addition, the mixture was stirred at 65°C for 18 hours. The reaction mixture was filtered and dried, and purified by column chromatography (0-25% EA in PE) to afford compound 15b (2.29 g, 93% yield).

[0603] MS (ESI): m / z = 424.4 [M+1] + .

[0604] 1 H NMR (400MHz, CD3OD) δ7.69-7.64(m,4H),7.45-7.35(m,6H),3.92-3.86(m,2H),3.78-3.71(m,4H),2.85-2.79(m,2H),2. 52(s,2H),2.46-2.32(m,1H),2.09-1.98(m,2H),1.73-1.64(m,2H),1.61-1.53(m,1H),1.51-1.43(m,2H),1.04(s,9H).

[0605] Step 2) Preparation of compound 15c

[0606] Compound 15b (1.00 g, 2.36 mmol) was weighed and dissolved in anhydrous acetonitrile (10 mL). 3,4-Dimethoxybenzyl bromide (818 mg, 3.54 mmol) was added. After complete addition, the mixture was stirred at 80°C for 2 hours. The reaction mixture was dried and purified by column chromatography (0-4% MeOH in DCM) to afford compound 15c (1.08 g, 79% yield).

[0607] MS (ESI): m / z = 574.5 [M-Br - ] + .

[0608] Step 3) Preparation of compound 15d

[0609] Compound 15c (1.06 g, 1.62 mmol) was weighed and dissolved in methanol (10 mL). 4.0 M HCl / Dioxane solution (10 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was dried and purified by column chromatography (0-15% MeOH in DCM) to afford compound 15d (561 mg, 83% yield).

[0610] MS (ESI): m / z = 336.3 [M-Br - ] + .

[0611] 1 H NMR(400MHz,CD3OD)δ7.19-7.09(m,2H),7.08-7.03(m,1H),5.04(s,1H),

[0612] 4.94-3.98(m,6H),3.91-3.84(m,6H),3.75-3.46(m,6H),2.95-1.74(m,8H).

[0613] Step 4: Preparation of compound 15

[0614] Compound 1k (100 mg, 192.30 μmol) and compound 15d (96 mg, 230.57 μmol) were dissolved in anhydrous DMF (2 mL). HATU (110 mg, 289.29 μmol) and DMAP (35 mg, 286.48 μmol) were added with stirring in an ice bath. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with reverse-phase trifluoroacetic acid to yield compound 15 (76 mg, 45% yield).

[0615] MS(ESI):m / z=401.2[(M-2CF3COO - ) / 2] + .

[0616] 1 H NMR(400MHz,DMSO-d6)δ7.08-7.02(m,1H),7.01-6.94(m,4H),6.90-6.81(m,3H),6.63-6.55(m, 2H),7.08(s,1H),5.55(s,1H),5.09-4.75(m,3H),4.65-4.39(m,2H),4.33-3.87(m,8H),3.77-3 .76(m,3H),3.75(s,3H),3.73-3.72(m,3H),3.71-3.70(m,3H),3.69-3.45(m,8H),3.42-3.35(m ,2H),3.33(s,3H),3.14-3.06(m,2H),2.92-2.71(m,2H),2.39-2.17(m,6H),2.10-1.93(m,2H).

[0617] Biological evaluation

[0618] Test Example 1 Pharmacodynamics Test

[0619] 1. Test compound

[0620] Samples: Compound 4, Compound 5, Control Compound 1, and Control Compound 2, all prepared with physiological saline.

[0621] 2. Experimental Animals

[0622] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0623] 3. Experimental steps

[0624] 1) Weigh the rat and anesthetize it by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the rat loses consciousness and is no longer reflexed, secure it in a prone position on a foam board. Depilate the right hind limb. Isolate the trachea and external jugular vein, intubate the trachea and intravenously, and prepare a ventilator.

[0625] 2) Behind the hip joint, make an incision in the skin at the mid-thigh, just outside the femur. Using a glass needle, bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the calf at the ankle joint, sever the anterior ankle ligament, separate the gastrocnemius muscle, and tie a ligature around the gastrocnemius tendon at the ankle. The tendon is severed distal to the ligature.

[0626] 3) Use a biofunctional experimental system to collect and record signals. Connect the gastrocnemius ligature to the tension transducer and the stimulator to the sciatic nerve. The experiment was set to investigate the effect of stimulation intensity on skeletal muscle contraction. The parameters were set to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms wave width, 10 ms wave interval, 8 Hz frequency, 0.350 V intensity, 0 intensity increment, 4 train lengths, and a 12 s main cycle. The muscle tension curve was recorded.

[0627] 4) After the signal stabilizes, different doses of the test compound are injected into the jugular vein and the suppression of muscle tension after administration is recorded. During the measurement, the muscle nerve is kept moist with physiological saline at all times, and moistened every five minutes.

[0628] Experimental indicators:

[0629] ED 95 (Dose for 95% neuromuscular blockade) is calculated as follows:

[0630] With X as the logarithmic dose and Y as the unit of muscle tension inhibition percentage, the drug dose-response regression equation was established using the non-linear regression method to calculate the ED 95 .

[0631] 4. Results

[0632] The disclosed compounds have a muscle relaxant effect on rats ED 95 As shown in Table 1 below.

[0633] Table 1

[0634] Compared with the control compounds, compound 5 of the present disclosure exhibits excellent neuromuscular blocking efficacy and is superior to control compound 1 and control compound 2.

[0635] Test Example 2 Histamine Release Detection

[0636] 1. Test compound

[0637] Samples: Compound 4, Compound 5, Control Compound 1, Control Compound 2, and Control Compound 3, all prepared with physiological saline.

[0638] 2. Experimental Animals

[0639] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0640] 3. Experimental steps

[0641] 1) Rats were weighed and anesthetized by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the animals lost consciousness and were no longer reflexed, they were secured in a prone position on a foam board. The right hind limb was depilated. One jugular vein was cannulated for drug injection, and the other for blood collection.

[0642] 2) After stabilization for 15 minutes, draw 0.5 mL of venous blood into an EP tube containing sodium heparin saline (1:9), mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice. After stabilization for 15 minutes, administer the test drug intravenously at a dose of 20 mg / kg. Immediately 1 minute after administration, draw 0.5 mL of venous blood, mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice.

[0643] 3) After the plasma was processed, the histamine levels in the rat plasma before and after administration were determined by LC-MS / MS. Formula: Histamine increase factor = Histamine level in rat plasma after administration / Histamine level in rat plasma before administration.

[0644] 4. Results

[0645] The disclosed compound was intravenously administered to rats at a dose of 20 mg / kg. The changes in the amount of histamine released in the rat plasma before and after administration are shown in Table 2 below (* represents P<0.05; ** represents P<0.01).

[0646] Table 2

[0647] A common adverse reaction to the clinical use of muscle relaxants is histamine release. Histamine release after muscle relaxant injection can induce bronchospasm, increased heart rate, and decreased blood pressure, endangering the patient's health. In this test, the control compound showed significant (P < 0.05 or P < 0.01) histamine release after administration, while no significant increase in histamine was observed after administration of compound 5 described in the present disclosure. Compound 5 described in the present disclosure is significantly safer than the control compound.

[0648] Test Example 3 Pharmacodynamics Test

[0649] 1. Test compound

[0650] Samples: Compound 5A, Compound 5B, and control compound 3, all prepared with normal saline.

[0651] 2. Experimental Animals

[0652] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0653] 3. Experimental steps

[0654] 1) Weigh the rat and anesthetize it by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the rat loses consciousness and is no longer reflexed, secure it in a prone position on a foam board. Depilate the right hind limb. Isolate the trachea and external jugular vein, intubate the trachea and intravenously, and prepare a ventilator.

[0655] 2) Behind the hip joint, make an incision in the skin at the mid-thigh, just outside the femur. Using a glass needle, bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the calf at the ankle joint, sever the anterior ankle ligament, separate the gastrocnemius muscle, and tie a ligature around the gastrocnemius tendon at the ankle. The tendon is severed distal to the ligature.

[0656] 3) Use a biofunctional experimental system to collect and record signals. Connect the gastrocnemius ligature to the tension transducer and the stimulator to the sciatic nerve. The experiment was set to investigate the effect of stimulation intensity on skeletal muscle contraction. The parameters were set to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms wave width, 10 ms wave interval, 8 Hz frequency, 0.350 V intensity, 0 intensity increment, 4 train lengths, and a 12 s main cycle. The muscle tension curve was recorded.

[0657] 4) After the signal stabilizes, different doses of the test compound are injected via the jugular vein, and the suppression of muscle tension after administration is recorded. During the measurement, the muscle and nerve are kept moist with normal saline at all times, and moistened every five minutes.

[0658] Experimental indicators:

[0659] ED 95 (95% neuromuscular tissue drug dose), and the corresponding onset time and duration of efficacy indicators, the calculation method is as follows:

[0660] ED 95 Calculation method: X is the logarithmic dose, Y is the probability unit of the percentage of muscle twitch inhibition, and the linear regression method is used to establish the drug dose-response regression equation to calculate the ED 95 .

[0661] 4. Results

[0662] The disclosed compounds have a muscle relaxant effect on rats ED 95 As shown in Table 3 below.

[0663] Table 3

[0664] Compared with the control compound, the compound 5B of the present disclosure exhibits superior neuromuscular blocking efficacy.

[0665] Test Example 4 Pharmacodynamics Test

[0666] 1. Test compound

[0667] Samples: Compound 5B, Compound 15, and Control Compound 3, all prepared with normal saline.

[0668] 2. Experimental Animals

[0669] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0670] 3. Experimental steps

[0671] 1) Weigh the rat and anesthetize it by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the rat loses consciousness and is no longer reflexed, secure it in a prone position on a foam board. Depilate the right hind limb. Isolate the trachea and external jugular vein, intubate the trachea and intravenously, and prepare a ventilator.

[0672] 2) Behind the hip joint, make an incision in the skin at the mid-thigh, just outside the femur. Using a glass needle, bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the calf at the ankle joint, sever the anterior ankle ligament, separate the gastrocnemius muscle, and tie a ligature around the gastrocnemius tendon at the ankle. The tendon is severed distal to the ligature.

[0673] 3) Use a biofunctional experimental system to collect and record signals. Connect the gastrocnemius ligature to the tension transducer and the stimulator to the sciatic nerve. The experiment was set to investigate the effect of stimulation intensity on skeletal muscle contraction. The parameters were set to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms wave width, 10 ms wave interval, 8 Hz frequency, 0.350 V intensity, 0 intensity increment, 4 train lengths, and a 12 s main cycle. The muscle tension curve was recorded.

[0674] 4) After the signal stabilizes, inject 0.3 mg / kg of the different test compounds via the jugular vein and record the suppression of muscle tension after administration. During the measurement, keep the muscles and nerves moist with saline at all times, moistening them every five minutes.

[0675] Experimental indicators:

[0676] Muscle tone inhibition %=(baseline muscle tone-muscle tone after drug administration) / baseline muscle tone*100%.

[0677] 4. Results

[0678] The inhibition rate of muscle tension of rats by 0.3 mg / kg of the disclosed compound is shown in Table 4 below.

[0679] Table 4

[0680] Compared with the control compound, the disclosed compounds 5B and 15 exhibited excellent neuromuscular blocking efficacy at the same dose, and were superior to the control compound 3.

[0681] Test Example 5 Histamine Release Detection

[0682] 1. Test compound

[0683] Samples: Compound 5B, Compound 15, and Control Compound 3, all prepared with normal saline.

[0684] 2. Experimental Animals

[0685] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0686] 3. Experimental steps

[0687] 1) Rats were weighed and anesthetized by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the animals lost consciousness and were no longer reflexed, they were secured in a prone position on a foam board. The right hind limb was depilated. One jugular vein was cannulated for drug injection, and the other for blood collection.

[0688] 2) After stabilization for 15 minutes, draw 0.5 mL of venous blood into an EP tube containing sodium heparin saline (1:9), mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice. After stabilization for 15 minutes, administer the test drug intravenously at a dose of 20 mg / kg. Immediately 1 minute after administration, draw 0.5 mL of venous blood, mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice.

[0689] 3) After the plasma was processed, the histamine levels in the rat plasma before and after administration were determined by LC-MS / MS. Formula: Histamine increase factor = Histamine level in rat plasma after administration / Histamine level in rat plasma before administration.

[0690] 4. Results

[0691] The disclosed compound was intravenously administered to rats at a dose of 20 mg / kg. The changes in the amount of histamine released in the rat plasma before and after administration are shown in Table 5 below (* represents P<0.05).

[0692] Table 5

[0693] A common adverse reaction to the clinical use of muscle relaxants is histamine release. Histamine release after muscle relaxant injection can induce bronchospasm, increased heart rate, and decreased blood pressure, endangering the patient's health. In this test, the control compound showed significant (P < 0.05) histamine release after administration, while no significant increase in histamine was observed after administration of compound 5B and compound 15 described in the present disclosure. Compound 5B and compound 15 described in the present disclosure are significantly safer than the control compound.

Claims

1. A compound of formula IA or a pharmaceutically acceptable salt thereof, Wherein: W is selected from -C(R a R b R c ) or each independently selected from pharmaceutically acceptable anions; R 3 and R 4 each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; L B and L C are each independently selected from -C(R a R b R c ) or alkylene, where the alkylene is optionally substituted by one or more halogen, hydroxy, mercapto, nitro, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, oxo, thioxo or sulfonyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; When L B is -C(R a R b R c ), there is no phenyl group having R B1 ~R B5 substituents; When L C is -C(R a R b R c ), there is no phenyl group having R D1 ~R D5 substituents; X A3 Selected from a chemical bond, -O-, -C(R d R e )-, -N(R f )-, -S(O)2-; X 1 and X 5 each independently is -C(R g R h )-; X 2 and X 4 each independently is -C(R i R j )-; R f selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more halogen, hydroxyl, mercapto, carboxyl, amino, cyano; R 1 、R 2 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、R W1 、R W2 、R W3 、R W4 、R W5 、R a 、R b 、R c 、R d 、R e 、R g 、R h 、R i 、R j are each independently selected from hydrogen, halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the C 1-6 alkyl, C 1-6 alkoxy, 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring are optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano, Alternatively, R 1 and R 2 、R d and R e 、R g and R h or R i and R j One or more groups among them, together with the connected atoms, form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring. The 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, and the C 1-6 alkyl groups, C 1-6 alkoxy groups are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups. Alternatively, R g and R i together with the atoms to which they are attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, said 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, said C 1-6 alkyl, C 1-6 alkoxy being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano. Alternatively, any two adjacent Rs A1 , R A2 , R A3 , R A4 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs B1 , Rs B2 , Rs B3 , Rs B4 , Rs B5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs D1 , R D2 , R D3 , R D4 , R D5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs W1 , Rs W2 , Rs W3 , Rs W4 , Rs W5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-; When X A3 is selected from a chemical bond, -C(R d R e ), (i)R d and R e cannot both be hydrogen, or, (ii)R d and R e 、R g and R h or R i and R j One or more groups of the groups in and R together with the attached atoms form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, and the 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl, C 1-6 alkoxy, and the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, or, (iii)R g and R i together with the atoms to which it is attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, said 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, and said C 1-6 alkyl, C 1-6 alkoxy being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; When X A3 is -O-, (i)R g and R h or R i and R j One or more groups of the groups together with the attached atoms form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, and the 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl, C 1-6 alkoxy, and the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, or, (ii)R g and R i together with the atoms to which they are attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, said 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring, 5- to 10-membered heteroaromatic ring being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, and said C 1-6 alkyl, C 1-6 alkoxy being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; x1 is selected from 1, 2, 3, 4, 5, 6; x2 is selected from 1, 2, 3, 4, 5, 6; x3 is selected from 0, 1, 2, 3, 4, 5.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X A3 is selected from a chemical bond, -C(R d R e )-, or -S(O)2-, and R d , R e is as defined in claim 1.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein the compound represented by formula IA is selected from the compounds represented by formula IIA1, formula IIA2, formula IIA3, formula IIA4 or formula IIA5 or their pharmaceutically acceptable salts, Ring A and ring B are each independently selected from a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring; L A Selected from alkylene or heteroalkylene, said alkylene or heteroalkylene being optionally substituted by one or more halogen, hydroxy, mercapto, nitro, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, oxo, thioxo or sulfonyl, said C 1-6 alkyl, C 1-6 alkoxy being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; L C1 is an alkylene group, and the alkylene group is optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, nitro groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, oxo groups, thio groups or sulfonyl groups, and the C 1-6 alkyl groups and C 1-6 alkoxy groups are optionally substituted by one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups or cyano groups; R LC is C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, cyano; R 5 、R 6 、R 7 、R 8 each independently selected from hydrogen, halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the C 1-6 alkyl, C 1-6 alkoxy, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring is optionally substituted by one or more of halogen, hydroxy, mercapto, carboxy, amino, cyano, and R 5 、R 6 cannot both be hydrogen, Alternatively, R 5 and R 6 together with the atoms to which they are attached form an oxo group or a thioxo group; x4 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; x5 is selected from 0, 1, 2, 3, 4; x6 are each independently selected from 0, 1, 2, 3, 4, 5, 6; x7 is selected from 0, 1, 2, 3, 4; x8 is selected from 0, 1, 2, 3, 4; x9 is selected from 0, 1, 2, 3; W、 L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、x1, x2, x3 are as defined in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein ring A is a 3- to 10-membered heterocycle, preferably oxetane ring, azetidine ring, thietane ring, pyrrolidine ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, tetrahydropyran ring, tetrahydrothiopyran ring, most preferably oxetane ring.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein ring B is a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, preferably a benzene ring, a pyridine ring, a pyran ring, a thiopyran ring, most preferably a benzene ring, a pyridine ring.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein L A is selected from -(CR k R l ) a -O-(CR k R l ) b -、-(CR k R l ) a -S-(CR k R l ) b -、-(CR k R l ) a -N(R f )-(CR k R l ) b -、-(CR k R l ) c - and preferably -(CR k R l ) a -O-(CR k R l ) b -、-(CR k R l ) c -. R k and R l each independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring or 5- to 10-membered heteroaromatic ring, and the C 1-6 alkyl, C 1-6 alkoxy, 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring or 5- to 10-membered heteroaromatic ring is optionally substituted by one or more halogen, hydroxyl, mercapto, carboxyl, amino, cyano Alternatively, R k and R l together with the atoms to which they are attached form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, and the 3- to 10-membered carbocyclic ring, 3- to 10-membered heterocyclic ring, 6- to 10-membered aromatic ring or 5- to 10-membered heteroaromatic ring is optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, and the C 1-6 alkyl groups and C 1-6 alkoxy groups are optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups; a are each independently selected from 0, 1, 2, 3, 4, 5; b are each independently selected from 0, 1, 2, 3, 4, 5; c are each independently selected from 1, 2, 3, 4, 5, 6; R f As defined in claim 1.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6 alkoxy, preferably hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, most preferably hydrogen, fluorine, methoxy, and R 5 、R 6 cannot both be hydrogen at the same time.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound represented by formula IA is selected from the compounds represented by formula IIIA1, formula IIIA2, formula IIIA3, formula IIIA4 or formula IIIA5, or a pharmaceutically acceptable salt thereof. W、 L B 、R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、x1, x2, x3 are defined as in claim 1, L C1 、R LC 、R 7 、R 8 、x4, x5, x6, x7, x8, x9 are defined as in claim 3, R k 、R l As defined in claim 6.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein L B is independently selected from a chemical bond or C 1-6 alkylene, preferably a chemical bond, methylene, ethylene, propylene, preferably methylene.

10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 8, wherein L C1 is independently selected from a chemical bond or C 1-6 alkylene, preferably a chemical bond, methylene, ethylene, propylene, preferably methylene.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound represented by formula IA is selected from the compounds represented by formula IVA1, formula IVA2, formula IVA3-a, formula IVA3-b, formula IVA4 or formula IVA5, or a pharmaceutically acceptable salt thereof. W、 R 1 、R 2 、R 3 、R 4 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、x1, x2, x3 are as defined in claim 1, R LC 、R 7 、R 8 、x4, x5, x6, x7, x8, x9 are as defined in claim 3, R k 、R l is as defined in claim 6.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R A1 , R A4 , R B1 , R B2 , R B5 , R D1 , R D4 , R D5 are all hydrogen.

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R A2 , R A3 , R B3 , R B4 are each independently selected from hydrogen, C 1-6 alkoxy, preferably hydrogen, methoxy, ethoxy, propoxy, most preferably hydrogen, methoxy.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein W is methyl.

15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R D2 , R D3 are each independently selected from hydrogen, halogen, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, mesyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, -C(O)-methyl, -C(O)-ethyl, methoxy, ethoxy, mesyl, most preferably hydrogen, fluorine, bromine, -C(O)-ethyl, methoxy, mesyl.

16. A compound of formula IA or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, As defined in claim 1.

17. The compound of formula IA or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, As defined in claim 1.

18. The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein each independently selected from halide ions, acetate, formate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecyl sulfate, malate, maleate, mesylate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, polygalacturonate, succinate, sulfate, sulfosalicylic acid, tartrate, toluenesulfonate, trifluoroacetate, preferably chloride, bromide, fluoride, iodide, trifluoroacetate, formate, mesylate, benzenesulfonate, most preferably chloride, bromide, trifluoroacetate, formate, mesylate, benzenesulfonate. The compound of formula IA or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, 20. An isotopically substituted compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, preferably, the isotopically substituted compound is a deuterated compound.

21. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, or an isotopically substituted compound according to claim 20, and a pharmaceutically acceptable excipient.

22. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, or an isotopically substituted compound according to claim 20, or a pharmaceutical composition according to claim 21 in the manufacture of a medicament for neuromuscular blockade. The compound of formula V or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2 、R D1 、R D2 、R D3 、R D4 、R D5 As defined in claim 1, R 7 、L A 、L C1 、x2, x6, x9 are as defined in claim 3.

24. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein the compound represented by formula V is selected from the compounds represented by formula VI or a pharmaceutically acceptable salt thereof, Among them, R 1 、R 2 、R D1 、R D2 、R D3 、R D4 、R D5 As defined in claim 1, R 7 、L C1 、x2, x6, x9 as defined in claim 3, R k 、R l As defined in claim 6. The compound of formula V or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, Among them, As defined in claim 1.

26. The compound of formula V or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, 27. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 26 in the manufacture of a neuromuscular blocking agent.

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