Cyclic compound, pharmaceutical composition thereof and use thereof

Abstract

A compound represented by formula (I). The compound has good agonistic activity on an APJ receptor, can effectively inhibit the production of cAMP, has weak ability to recruit β-arrestin, and has good pharmacokinetic properties.

Description

Cyclic compounds, their pharmaceutical compositions and their applications

[0001] This application claims priority to the following Chinese patent applications: Chinese patent application CN2024119289182, filed on December 25, 2024; Chinese patent application CN2025106341046, filed on May 16, 2025; and Chinese patent application CN2025119067957, filed on December 16, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to cyclic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0003] The APJ receptor (Apelin receptor, APLNR) is a member of the G protein-coupled receptor (GPCR) family. Its endogenous ligand, apelin, plays a vital biological role. The Apelin / APJ system is distributed in multiple tissues, including the heart, kidneys, pancreas, and lungs. Previous in vitro and preclinical models have shown that apelin plays a role in cardiovascular homeostasis and metabolism, enhancing myocardial contractility and potentially serving as a treatment for heart failure (Barnes et al., Heart 96: 1011-1016, 2010). Furthermore, the Apelin / APJ system is involved in important biological functions such as gastrointestinal regulation, endocrine metabolism, angiogenesis, inflammation, and neuroprotection (Zhang et al., Journal of Jining Medical College, 2017, 40(6): 425-428, 433).

[0004] In addition to its physiotrophic effects, apelin, as a "motor factor" peptide, can interact with skeletal muscle, the heart, and the central nervous system to regulate metabolism and promote muscle regeneration. Studies have shown that overall apelin levels in the human body gradually decline with aging, while individuals with higher apelin levels exhibit stronger physical function and longer lifespans. Clinical studies by the anti-aging company BioAge using its APJ receptor agonist BGE-105 have demonstrated that the drug can significantly improve muscle size, mass, and muscle protein synthesis in healthy subjects, which has significant practical and clinical value for addressing muscle atrophy (loss of muscle mass and strength), a common problem in human aging. BGE-105 is a balanced agonist that not only activates the APJ G protein (cAMP) but also recruits β-arrestin. Some studies suggest that the cardioprotective effect induced by apelin is mainly attributed to APJ Gi signaling, while APJ β-arrestin signaling leads to harmful cardiac hypertrophy, decreased blood pressure, and potential hepatotoxicity. Therefore, there is growing interest in developing G protein-biased APJ agonists as potential drugs for treating heart failure and increasing muscle mass. ANPA-0073 is a biased agonist and has progressed to the clinical stage. However, it still has drawbacks such as low cAMP agonist activity and insufficient selectivity for β-arrestin. Therefore, clinical research still needs to improve the research in this field by using biased agonist drugs with higher activity and better selectivity to meet the actual needs of patients in reality.

[0005] Given the importance of APJ receptor agonists, there is an urgent need to develop APJ receptor bias agonists with novel structures. Summary of the Invention

[0006] The technical problem this invention aims to solve is the deficiency in existing technologies where APJ receptors exhibit insufficient agonist activity and selectivity. To address this, this invention provides a cyclic compound, its pharmaceutical composition, and its applications. The cyclic compound of this invention possesses one or more of the following advantages: novel structure, good agonist activity towards the APJ receptor, effective inhibition of cAMP production, weak recruitment ability for β-arrestin, favorable pharmacokinetic properties, ability to reduce drug dosage, reduction of potential toxic side effects, increased patient compliance, and improved therapeutic efficacy.

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

[0008] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] X 1 X 2 and X 3 Independently N or CR 3 ;

[0011] R 3 Independently hydrogen, deuterium, halogen, R 3-1 -N(R) 3-1 )C(=O)R 3-1 -N(R) 3-1 )C(=O)OR 3-1 -N(R) 3-1 )C(=O)N(R 3-1 )2、-N(R 3-1 )C(=NR 3-1 )N(R 3- 1 )2、-NR 3-1 S(=O)2R 3-1 -C(=O)R 3-1 -C(=O)OR 3-1 -C(=O)N(R) 3-1 )2、-C(=O)N(R 3-1 OR 3-1 -C(=O)N(R) 3-1 )C(=O)R 3-1 -OR 3-1 -SR 3-1 -N(R) 3-1 )2、-Si(R 3-1 3. -S (=O) n R 3-1 -S(=O)(=NR) 3-1 )R 3-1 -S(=O)2N(R) 3-1 )2、-OC(=O)R 3-1 -OC(=O)N(R) 3-1 )2、-P(=O)(R 3- 1 )2、-P(=O)(OR 3-1 )2、-OP(=O)(R 3-1 )2 or -OP(=O)(OR 3-1 )2;

[0012] R 3-1 Independently, it can be hydrogen, -CN, -NO2, -OH, -SH, -NH2, C1-C8 alkyl, C3-C 12 cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C2-C8 alkenyl, C2-C8 ynyl, C6-C 10 aryl or 5-10 heteroaryl; wherein the C1-C8 alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 10 aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 3-1-1 The substituted 3-12-membered heterocyclic alkyl and 3-12-membered heterocyclic alkenyl groups are independently selected from one or more of N, O, S, S(=O), S(=O)2 and C(=O), and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

[0013] R 3-1-1 Independently, it can be deuterium, halogen, -CN, -NO2, oxo (=O), -OH, -SH, -NH2, -C(=O)NH2, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, or -S(=O). n -(C1-C6 alkyl);

[0014] n is 1 or 2;

[0015] L 1 For chemical bonds, Side a is connected to ring A;

[0016] L 11 It is H, C1-C6 alkyl, or C1-C6 haloalkyl;

[0017] L 12 It is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0018] L 2 For L 21 L 22 or L 23 -L 22 -L 23 ;

[0019] L 21 For C1-C 10 Alkylene, C1-C 10 Heteroalkyl, C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C1-C10 Alkylene and C1-C 10 The heteroalkyl group is optionally surrounded by one, two, or three L-members. 1a Instead, the C2-C 10 alkenyl and C2-C 10 The hesylene group is optionally surrounded by one, two, or three L-members. 1b Instead, the C1-C 10 Heteroalkyl groups are C1-C 10 One or more -CH2- in the alkylene group are independently separated by -O-, -NL 1c -、-C(=NL 1c C1-C obtained by replacing )-, -S-, -S(=O)-, -S(=O)2- or -C(=O)- 10 Heteroalkylene; the C2-C 10 The hesperidium group is C2-C. 10 One or more -CH2- groups in the alkenyl group are independently separated by -O-, -NL 1c -、-C(=NL 1c The C2-C obtained by replacing )-, -S-, -S(=O)-, -S(=O)2- or -C(=O)- is 10 Hesperyl;

[0020] L 22 Independently for C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic cycloalkenyl, C6-C 10 arylene or 5-10 heteroarylene, the C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic cycloalkenyl, C6-C 10 The arylene and 5-10 heteroarylene groups are optionally surrounded by one, two, or three L groups. 1a Substitution; in the 3-12-membered heterocyclic alkylene and 4-12-membered heterocyclic alkenylene, the heteroatom or heteroatomic group is selected from one or more of O, N, S, S(=O), S(=O)2 and C(=O), and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-10-membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0021] L 23 Independently, it is a C1-C4 alkylene or C1-C4 heteroalkylene, wherein the C1-C4 alkylene or C1-C4 heteroalkylene is optionally surrounded by one, two, or three L... 1aThe C1-C4 heteroalkylene group is a C1-C4 heteroalkylene group obtained by independently replacing one or more -CH2- with -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0022] L 1a Independently, it can be hydrogen, deuterium, halogen, -CN, -NO2, C1-C6 alkyl, -O-(C1-C6 alkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0023] L 1a-1 Independently halogenated, C6-C 10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0024] L 1a-2 The definition is the same as R 3 ;

[0025] L 1b Independently halogen, -OH, -CN, C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 1 0-aryl and 5-10-membered heteroaryl groups are optionally surrounded by 1, 2 or 3 L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0026] L 1cIndependently, it can be hydrogen, CN, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, -C(=O)N(C1-C6 alkyl)2, C6-C 10 The aryl or 5-10-membered heteroaryl group; in the 3-12-membered heterocyclic alkyl and 4-12-membered heterocyclic alkenyl groups, the heteroatom or heteroatomic group is independently selected from one or more of N, O, S, S(=O), S(=O)2 and C(=O), and the number of heteroatoms is independently 1, 2, 3, 4 or 5; in the 5-10-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0027] L 3 -C(R) 3-1 )2-, -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)- or -NR 3-1 -;

[0028] Ring A is a 5-10 quintile heteroaromatic ring, wherein the 5-10 quintile heteroaromatic ring is optionally surrounded by one, two, or three R atoms. A1 Replace, R A1 Independently, it can be deuterium, halogen, OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -S(=O)-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) or C1-C6 alkyl; in the 5-10 membered heteroaryl ring, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0029] R 1 C 1-8 Alkyl, -O-(C1-C8 alkyl), -C1-C6 alkylene, -O-(C1-C6 alkyl), C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C 1-8Alkyl, -O-(C1-C8 alkyl), -C1-C6 alkylene, -O-(C1-C6 alkyl), C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C3-C 12 Cycloalkyl and 3-12 membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 1a Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by 1, 2, 3 or 4 R groups. 1b Substitution; in the 3-12-membered heterocyclic alkyl and 4-12-membered heterocyclic alkenyl groups, the heteroatoms or heteroatomic groups are independently selected from one or more of N, O, S, S(=O) and S(=O)2, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; in the 5-10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0030] R 1a It can be independently a halogen, -CN, C1-C6 alkyl, -O-(C1-C6 alkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo group (=O);

[0031] R 1b Independently, it can be deuterium, -F, -Cl, -Br, -I, -CN, -NO2, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, -S-(C1-C6 alkyl), -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -C1-C6 alkylene-O-(C1-C6 alkyl), -C1-C6 alkylene-O-(C1-C6 haloalkyl), -OH, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, -C(=O)-O-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH (C1-C6 alkyl), -C(=O)N (C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C4-C 12 Cycloalkenyl or 4-12-membered heterocyclic alkenyl; in the 3-12-membered heterocyclic alkyl and 4-12-membered heterocyclic alkenyl groups, the heteroatoms or heteroatomic groups are independently selected from one or more of N, O, S, S(=O) and S(=O)2, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

[0032] R 2 The definition is the same as R 3 .

[0033] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or a solvate of a pharmaceutically acceptable salt thereof are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0034] In one aspect of the present invention, the compound represented by formula (I)

[0035] X 1 X 2 and X 3 Independently N or CR 3 ;

[0036] R 3 Independently, it can be H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2 or -S(=O)2-(C1-C6 alkyl);

[0037] L 1 for Side a is connected to ring A;

[0038] L 11 It is H or C1-C6 alkyl;

[0039] L 12 It is a C1-C6 alkyl group;

[0040] L 2 For L 21 L 22 or L 23 -L 22 -L 23 ;

[0041] L 21 C1-C10 alkylene, C1-C10 heteroalkylene, C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C1-C 10 Alkylene and C1-C 10 The heteroalkyl group is optionally surrounded by one, two, or three L-members. 1a Instead, the C2-C 10 alkenyl and C2-C 10The hesylene group is optionally surrounded by one, two, or three L-members. 1b Instead, the C1-C 10 Heteroalkyl groups are C1-C 10 The C1-C obtained by independently replacing one or more -CH2- in an alkylene group with -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. 10 Heteroalkylene, the C2-C 10 The hesperidium group is C2-C. 10 The C2-C obtained by independently replacing one or more -CH2- in the alkenyl group with -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. 10 Hesperyl;

[0042] L 22 Independently for C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic cycloalkenyl, C6-C 10 arylene or 5-10 heteroarylene, the C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic cycloalkenyl, C6-C 10 The arylene and 5-10 heteroarylene groups are optionally surrounded by one, two, or three L groups. 1a Substitution; in the 3-12-membered heterocyclic alkylene and 4-12-membered heterocyclic alkenylene, the heteroatom is selected from one or more of -O-, -NH-, -S-, -S(=O)-, -S(=O)2- and -C(=O)-, and the number of heteroatoms is 1, 2 or 3; in the 5-10-membered heteroarylene, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0043] L 23 Independently, it is a C1-C4 alkylene or C1-C4 heteroalkylene, wherein the C1-C4 alkylene or C1-C4 heteroalkylene is optionally surrounded by one, two, or three L... 1a The C1-C4 heteroalkylene group is a C1-C4 heteroalkylene group obtained by independently replacing one or more -CH2- with -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0044] L 1aIndependently, it can be deuterium, halogen, -CN, C1-C6 alkyl, -O-(C1-C6 alkyl), OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. la-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. la-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0045] L 1a-1 Independently halogenated, C6-C 10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0046] L 1a-2 It is independently a cyano, halogen, C1-C6 alkoxy, or C1-C6 alkyl group;

[0047] L 1b Independently halogen, -OH, -CN, C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0048] L 3 It can be -O-, -S-, or -NH-;

[0049] Ring A is a 5-10 quintile heteroaromatic ring, wherein the 5-10 quintile heteroaromatic ring is optionally surrounded by one, two, or three R atoms. A1 Replace, R A1Independently, it is a halogen, OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or C1-C6 alkyl; in the 5-10 membered heteroaryl ring, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0050] R 1 C 1-8 Alkyl, -O-(C1-C8 alkyl), -C1-C6 alkylene, -O-(C1-C6 alkyl), C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C 1-8 Alkyl, -O-(C1-C8 alkyl), -C1-C6 alkylene, -O-(C1-C6 alkyl), C4-C 12 Cycloalkenyl, 4-12 membered heterocyclic alkenyl, C3-C 12 Cycloalkyl and 3-12 membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 1a Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by 1, 2, 3 or 4 R groups. 1b Substitution; in the 3-12-membered heterocyclic alkyl and 4-12-membered heterocyclic alkenyl groups, the heteroatom is independently selected from one or more of N, O, S, S(=O) and S(=O)2, and the number of heteroatoms is independently 1, 2 or 3; in the 5-10-membered heteroaryl groups, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0051] R 1a It can be independently a halogen, -CN, C1-C6 alkyl, -O-(C1-C6 alkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo group (=O);

[0052] R 1b Independently, it can be deuterium, -F, -Cl, -Br, -I, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -C1-C6 alkylene-O-(C1-C6 alkyl), -C1-C6 alkylene-O-(C1-C6 haloalkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2 or -S(=O)2-(C1-C6 alkyl);

[0053] R 2 It can be H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2 or -S(=O)2-(C1-C6 alkyl).

[0054] In one aspect of the invention, each "halogen" is independently F, Cl, Br or I, for example F or Cl.

[0055] In one embodiment of the invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0056] In one embodiment of the present invention, each “C1-C6 alkylene” is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene.

[0057] In one embodiment of the invention, each "C1-C6 haloalkyl group" is independently a C1-C6 alkyl group substituted with one, two, or three halogens, wherein the halogens are F, Cl, or B. r Or I.

[0058] In one embodiment of the invention, each “C2-C8 alkenyl” is independently a C2-C6 alkenyl, such as vinyl, propenyl or allyl.

[0059] In one embodiment of the invention, each “C2-C6 alkenyl” is independently a C2-C4 alkenyl, such as vinyl, propenyl, or allyl.

[0060] In one aspect of the present invention, each “C2-C8 ynyl group” is independently a C2-C6 ynyl group, such as ethynyl, propynyl or propynyl.

[0061] In one aspect of the present invention, each “C2-C6 ynyl group” is independently a C2-C4 ynyl group, such as ethynyl, propynyl, or propynyl.

[0062] In one embodiment of the present invention, each "C1-C" 10Each alkylene group is independently -(CH2)n-, where n is 1-10, for example -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7- or -(CH2)8-.

[0063] In one embodiment of the present invention, each "C1-C10 heteroalkylene group" is independently obtained by replacing one or more -CH2- groups in -(CH2)n- with -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-, where n is 1-10; for example, it is obtained by replacing one, two, or three -CH2- groups in -(CH2)n- with -O-, -NH-, or -C(=O)-, where n is 3, 4, 5, 6, 7, or 8, and further for example... Preferred

[0064] In one embodiment of the present invention, each "C2-C" 10 "Alkenyl" groups are each independently C2-C 10 Straight-chain alkenyl groups, such as C4, C5, C6, C7, or C8 straight-chain alkenyl groups, wherein the number of -CH=CH- groups is one, and the configuration of -CH=CH- is Z-configuration, E-configuration, or a mixture thereof, further for example... Preferred

[0065] In one embodiment of the present invention, each "C2-C" 10 Each of the "heteroene groups" is independently C2-C. 10 One or more -CH2- groups in the hesene group are independently replaced by -O-, -NH-, or -S-, for example...

[0066] In one embodiment of the present invention, each "C3-C" 12 Each "cycloalkylene group" is independently a C4-C7 monocyclic cycloalkylene group or a C6-C6 monocyclic cycloalkylene group. 12 cyclohexanediol, C6-C 12 Bridged cyclohexene alkyl or C6-C 12 Spirocyclic cycloalkylene compounds, such as cyclobutylene, cyclopentylene, or cyclohexylene, further for example...

[0067] In one embodiment of the present invention, each "3-12-membered heterocyclic alkylene group" is independently a 4-7-membered monocyclic heterocyclic alkylene group, a 6-12-membered fused-ring heterocyclic alkylene group, a 6-12-membered bridged-ring heterocyclic alkylene group, or a 6-12-membered spirocyclic heterocyclic alkylene group, for example, a 4-7-membered monocyclic heterocyclic alkylene group with heteroatoms of -N- and / or -C(=O)- and a number of heteroatoms of 1 or 2, further for example...

[0068] In one embodiment of the present invention, each "C4-C" 12 Each of the "cycloene-olefins" is independently a C4-C7 monocyclic cycloene-olefin or a C6-C... 12 cyclohexene-olefin, C6-C 12 Bridged ring cyclohexene group or C6-C 12 Spirocyclic cycloene group.

[0069] In one embodiment of the present invention, each “4-12 member heterocyclic alkenyl group” is independently a 4-7 member monocyclic heterocyclic alkenyl group, a 6-12 member fused cyclic heterocyclic alkenyl group, a 6-12 member bridged cyclic heterocyclic alkenyl group, or a 6-12 member spirocyclic heterocyclic alkenyl group.

[0070] In one embodiment of the present invention, each "C6-C" 10 Each of the arylene groups is independently arylene or naphthylene, for example, arylene, and further for example...

[0071] In one embodiment of the present invention, each "5-10 cyclic heteroaryl" is independently a 5-6 cyclic monocyclic heteroaryl or an 8-10 bicyclic heteroaryl.

[0072] In one embodiment of the present invention, each “C1-C4 alkylene” is independently a C1-C4 straight-chain alkylene, such as methylene, ethylene, or n-propylene.

[0073] In one embodiment of the present invention, each “C1-C4 heteroalkylene” is obtained by independently replacing one or more -CH2- in a C1-C4 straight-chain heteroalkylene with -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0074] In one embodiment of the present invention, each "C6-C" 10 Each aryl group can be either phenyl or naphthyl, for example, phenyl.

[0075] In one embodiment of the present invention, each "5-10 member heteroaryl" is independently a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl, for example, a 5-6 member monocyclic heteroaryl with N heteroatom and one or two heteroatoms, further for example, pyridyl or pyrimidinyl, preferably.

[0076] In one aspect of the present invention, each "5-10 member heteroaromatic ring" is independently a 5-6 member monocyclic heteroaromatic ring or an 8-10 member bicyclic heteroaromatic ring. For example, a 5-6 member monocyclic heteroaromatic ring with N as the heteroatom and the number of heteroatoms being 1, 2, or 3, or an 8-10 member bicyclic heteroaromatic ring with N as the heteroatom and the number of heteroatoms being 1, 2, 3, or 4, further for example, a triazole ring, an imidazopyrazine ring, or an imidazopyridazine ring.

[0077] In one embodiment of the present invention, each "C" 1-8 Each alkyl group is independently C10. 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0078] In one embodiment of the present invention, each "C3-C" 12 Each "cycloalkenyl" group can be independently a C4-C7 monocyclic cycloalkenyl or a C6-C cycloalkenyl. 12 cycloalkenyl, C6-C 12 Bridged ring cycloalkenyl or C6-C 12 Spirocyclic cycloalkenyl.

[0079] In one embodiment of the present invention, each "C4-C" 12 Each "cycloalkenyl" group can be independently a C4-C7 monocyclic cycloalkenyl or a C6-C cycloalkenyl. 12 cycloalkenyl, C6-C 12 Bridged ring cycloalkenyl or C6-C 12 Spirocyclic cycloalkenyl.

[0080] In one embodiment of the present invention, each “3-12 member heterocyclic alkenyl group” is independently a 4-7 member monocyclic heterocyclic alkenyl group, a 6-12 member fused heterocyclic alkenyl group, a 6-12 member bridged heterocyclic alkenyl group, or a 6-12 member spirocyclic heterocyclic alkenyl group.

[0081] In one embodiment of the present invention, each "4-12 membered heterocyclic alkenyl group" is independently a 4-7 membered monocyclic heterocyclic alkenyl group, a 6-12 membered fused heterocyclic alkenyl group, a 6-12 membered bridged heterocyclic alkenyl group, or a 6-12 membered spirocyclic heterocyclic alkenyl group, for example...

[0082] In one embodiment of the present invention, each "C3-C" 12 Each cycloalkyl group is independently a C4-C7 monocyclic cycloalkyl group or a C6-C cycloalkyl group. 12 cycloalkyl, C6-C 12 Bridged cycloalkyl or C6-C 12 Spirocyclic cycloalkyl.

[0083] In one embodiment of the present invention, each “3-12 membered heterocyclic alkyl” is independently a 4-7 membered heterocyclic alkyl, a 6-12 membered fused heterocyclic alkyl, a 6-12 membered bridged heterocyclic alkyl, or a 6-12 membered spirocyclic heterocyclic alkyl.

[0084] In one aspect of the present invention, X 1 X 2 and X 3 Independent for CR 3 For example, CH.

[0085] In one aspect of the present invention, L 1 for Side a is connected to ring A.

[0086] In one aspect of the present invention, L 1 for End a is connected to ring A, L 1 For example

[0087] In one aspect of the present invention, L 2 For L 21 or L 23 -L 22 -L 23 ;

[0088] L 21 For C1-C 10 Alkylene, C1-C 10 Heteroalkyl, C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C1-C 10 Alkylene and C1-C 10 The heteroalkyl group is optionally surrounded by one, two, or three L-members. 1a Instead, the C2-C 10 alkenyl and C2-C 10 The hesylene group is optionally surrounded by one, two, or three L-members. 1b replace;

[0089] L 1a Independently OH, C1-C6 alkyl, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace;

[0090] L 1a-1 Independently for C6-C 10Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace;

[0091] L 1a-2 It is independently a halogen or a C1-C6 alkyl group;

[0092] L 1b Independently C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace;

[0093] L 22 Independently for C3-C 12 Cycloalkylene, 3-12 membered heterocycloalkylene, C6-C 10 arylene or 5-10 quinone heteroarylene;

[0094] L 23 It is independently a C1-C4 alkylene or C1-C4 heteroalkylene.

[0095] In one aspect of the present invention, L 2 For L 21 or L 23 -L 22 -L 23 ;

[0096] L 21 It is a C3-C8 alkylene, C3-C8 heteroalkylene, C3-C8 alkenylene, or C3-C8 heteroalkylene, wherein the C3-C8 alkylene and C3-C8 heteroalkylene are optionally surrounded by one, two, or three L- groups. 1a The C3-C8 alkenyl and C3-C8 heteroalkenyl groups are optionally replaced by one, two, or three L- groups. 1b replace;

[0097] L 1a Independently OH, C1-C6 alkyl, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. la-2 replace;

[0098] L la-1 Independently for C6-C10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace;

[0099] L 1a-2 It is independently a halogen or a C1-C6 alkyl group;

[0100] L 1b Independently C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace;

[0101] L 22 It is independently a C3-C6 cycloalkylene group, a 3-6 membered heterocycloalkylene group, a phenylene group, or a 5-6 membered heteroarylene group;

[0102] L 23 It is independently a C1-C4 alkylene or C1-C4 heteroalkylene.

[0103] In one aspect of the present invention, L 2 Option 1 or Option 2 is as follows:

[0104] Option 1:

[0105] Option 2:

[0106] in, This indicates that the double bond is Z-configuration, E-configuration, or a mixture thereof. For example, Z-configuration; "*" indicates that the carbon atom it marks is R-configuration, S-configuration, or a mixture thereof; b-terminus and L 1 Connected.

[0107] In one aspect of the present invention, L 2 Option I or Option II are as follows:

[0108] Option I:

[0109] Option II:

[0110] Among them, b end and L 1 Connected.

[0111] In one aspect of the present invention, L 2 for in, This indicates that the double bond is Z-configuration, E-configuration, or a mixture thereof. For example, Z-configuration; "*" indicates that the carbon atom it marks is R-configuration, S-configuration, or a mixture thereof; b-terminus and L 1 Connected.

[0112] L 2 For example, Among them, b end and L 1 Connected.

[0113] In one aspect of the present invention, L 3 -O- or -NH-

[0114] In one aspect of the present invention, L 3 It is -O-.

[0115] In one embodiment of the present invention, ring A is a 5-6 membered monocyclic heteroaromatic ring with N heteroatoms and 1, 2, 3, or 4 heteroatoms, wherein the 5-6 membered monocyclic heteroaromatic ring is optionally surrounded by 1, 2, or 3 R atoms. A1 replace.

[0116] In one embodiment of the present invention, ring A is an 8-10 membered bicyclic heteroaromatic ring with N heteroatoms and 1, 2, 3, or 4 heteroatoms, wherein the 8-10 membered bicyclic heteroaromatic ring is optionally surrounded by 1, 2, or 3 R atoms. A1 replace.

[0117] In one aspect of the present invention, R A1 It can be halogen, -NH2 or C1-C6 alkyl independently.

[0118] In one embodiment of the present invention, ring A is:

[0119] G1: Among them, c side and R 1 Connected, d side and L 1 Connected;

[0120] G2: Among them, c side and R 1 Connected, d side and L 1 Connected;

[0121] For example:

[0122] G11: Among them, c side and R1 Connected, d side and L 1 Connected; or,

[0123] G21: Among them, c side and R 1 Connected, d side and L 1 Connected;

[0124] For example:

[0125] G11-1: Among them, c side and R 1 Connected, d side and L 1 Connected; or,

[0126] G21-1: Among them, c side and R 1 Connected, d side and L 1 Connected.

[0127] In one aspect of the present invention, R 1 It is a 5-10-membered heteroaryl or 5-10-membered heterocyclic alkenyl group, wherein the 5-10-membered heteroaryl or 5-10-membered heterocyclic alkenyl group is optionally surrounded by 1, 2, 3 or 4 R groups. 1b replace.

[0128] In one aspect of the present invention, R 1 The 5-6-membered heteroaryl group is optionally surrounded by 1, 2, 3 or 4 R groups. 1b replace.

[0129] In one aspect of the present invention, R 1b It is independently C1-C6 alkyl or -O-(C1-C6 alkyl).

[0130] In one aspect of the present invention, R 1 for

[0131] In one aspect of the present invention, R 1 for For example

[0132] In one aspect of the present invention, R 2 It is a halogen, -O-(C1-C6 alkyl), C2-C6 alkenyl, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally converted by one or more R 3-1-1 The R that was replaced 3-1-1 It can be halogen, -OH, oxo (=O), -SH, -NH2, -NH (C1-C6 alkyl) or -N (C1-C6 alkyl)2 independently.

[0133] In one aspect of the present invention, R 2 For methoxy, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3、

[0134] In one aspect of the present invention, R 2 It is -O-(C1-C6 alkyl), such as methoxy.

[0135] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1) or formula (I-2):

[0136] Among them, X 1 X 2 X 3 L 1 L 2 L 3 Ring A, R 1 and R 2 The definition is as described in any embodiment of this invention.

[0137] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds: Among the above compounds, This indicates that the double bond is of E configuration, Z configuration, or a mixture thereof, corresponding to Structure express Or a mixture thereof, e side with L 3 Connected; the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof;

[0138] For example:

[0139] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0140] A stereoisomer of [the substance] has a retention time of 2.48 min under the following conditions: chiral column: AS 20*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 65 / 35; flow rate: 100 ml / min;

[0141] A stereoisomer of [the substance] has a retention time of 3.09 min under the following conditions: chiral column: AS 20*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 65 / 35; flow rate: 100 ml / min;

[0142] A stereoisomer of [a substance] has a retention time of 1.42 min under the following conditions: chiral column: column: IK 25*250mm, 10µm; column temperature: 25℃; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 60 / 40; flow rate: 100 ml / min;

[0143] A stereoisomer of [a substance] has a retention time of 1.65 min under the following conditions: chiral column: column: IK 25*250mm, 10µm; column temperature: 25℃; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 60 / 40; flow rate: 100 ml / min;

[0144] The compound that elutes first under the following conditions: chiral column: IG 25*250mm, 10µm; column temperature: room temperature; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 50 / 50; flow rate: 120ml / min; preferably, under the above conditions, the retention time of the compound that elutes first is 1.71min.

[0145] Compounds that elute later under the following conditions: chiral column: IG 25*250mm, 10µm; column temperature: room temperature; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 50 / 50; flow rate: 120ml / min; preferably, under the conditions described above, the retention time of the compound that elutes later is 2.64min.

[0146] The compound that elutes first under the following conditions: chiral column (R,R) WHELK-O1 25*250mm, 10µm; column temperature: room temperature; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 70 / 30; flow rate: 100ml / min; preferably, under the conditions described, the retention time of the compound that elutes first is 2.13min.

[0147] Compounds eluting later under the following conditions: chiral column (R,R) WHELK-O1 25*250mm, 10µm; column temperature: room temperature; mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 70 / 30; flow rate: 100ml / min; preferably, under the conditions described, the retention time of the compounds eluting later is 3.18min;

[0148] The compound that elutes first under the following conditions: chiral column: AD 25*250mm, 10um (Daicel); column temperature: 25℃; mobile phase: CO2 / [EtOH(0.2%NH3(7MinMeOH)]=65 / 35; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the compound that elutes first is 1.14min;

[0149] Compounds that elute later under the following conditions: chiral column: AD 25*250mm, 10um (Daicel); column temperature: 25℃; mobile phase: CO2 / [EtOH(0.2% NH3(7MinMeOH)]=65 / 35; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the compound that elutes later is 3.14min;

[0150] The first eluting compound under the following conditions: chiral column: OD 25*250mm, 10um (Daicel); column temperature: 25℃; mobile phase: CO2 / [MeOH(0.5%NH3(7M in MeOH)]=60 / 40; flow rate: 100ml / min; preferably, under the conditions described, the retention time of the first eluting compound is 0.92min;

[0151] Compounds with later elution under the following conditions: chiral column: OD 25*250mm, 10um (Daicel); column temperature: 25℃; mobile phase: CO2 / [MeOH(0.5%NH3(7M in MeOH)]=60 / 40; flow rate: 100ml / min; preferably, under the conditions described, the retention time of the compounds with later elution is 1.30min;

[0152] The compound that elutes first under the following conditions: chiral column: AD 25*250mm, 10um (Daicel); column temperature: room temperature; mobile phase: CO2 / [MEOH(0.2% NH3(7M in MeOH)]=55 / 45; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the compound that elutes first is 1.03min;

[0153] Compounds that elute later under the following conditions: chiral column: AD 25*250mm, 10um (Daicel); column temperature: room temperature; mobile phase: CO2 / [MEOH(0.2% NH3(7M in MeOH)]=55 / 45; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the compound that elutes first is 1.59min;

[0154] Mixture 1 and Mixture 2 were a mixture with a retention time of 1.54 min under the following conditions: Column: Ultimate Prep C18 10 μm 21.2 × 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 32-62% B in 8 min, stop at 16 min; Flow rate: 30 ml / min. Mixture 1 was... The mixture, wherein the mixture 2 is A mixture;

[0155] Compounds of mixtures 1 and 2 with a retention time of 1.74 min under the following conditions: Column: Ultimate Prep C18 10 μm 21.2 × 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 32-62% B in 8 min, stop at 16 min; Flow rate: 30 ml / min, wherein mixture 1 is... The mixture, wherein the mixture 2 is A mixture;

[0156] Compounds in mixtures 3 and 4 with a retention time of 1.51 min under the following conditions: Column: Ultimate Prep C18 10 μm 21.2 × 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 30-60% B in 8 min, stop at 16 min; Flow rate: 30 ml / min, wherein mixture 3 is... The mixture, wherein the mixture 4 is A mixture;

[0157] Compounds in mixtures 3 and 4 with a retention time of 1.60 min under the following conditions: Column: Ultimate Prep C18 10 μm 21.2 × 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 30-60% B in 8 min, stop at 16 min; Flow rate: 30 ml / min; Mixture 3 is... The mixture, wherein the mixture 4 is A mixture;

[0158] Mixtures 1 and 2 are mixtures of enantiomers that elute first under the following conditions: Boston Prep C18 10μm 21.2×250mm; mobile phase: A: water (0.2% FA), B: acetonitrile; gradient: 25%-55% B in 8 min, stop at 16 min; flow rate: 30 ml / min. Mixture 1 is... The mixture, wherein the mixture 2 is The mixture; preferably, under the conditions described, the retention time of the first eluting peak of the mixture is 8.3 min;

[0159] Mixtures 1 and 2 are mixtures of enantiomers that elute later under the following conditions: Boston Prep C18 10 μm 21.2 × 250 mm; mobile phase: A: water (0.2% FA), B: acetonitrile; gradient: 25%-55% B in 8 min, stop at 16 min; flow rate: 30 ml / min. Mixture 1 is... The mixture, wherein the mixture 2 is The mixture; preferably, under the conditions described, the retention time of the mixture with the later elution peak is 9.5 min;

[0160] A rotational isomer, wherein... and Its relative spatial position is the same as that of compound A below, wherein compound A is Compounds that elute later under the following conditions: chiral column: AD 25*250mm, 10um (Daicel); column temperature: 25℃; mobile phase: CO2 / [EtOH(0.2% NH3(7MinMeOH)]=65 / 35; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the compound that elutes later is 3.14min; Compounds with a retention time of 2.512 min under the following conditions: chiral column DAICEL CHIRALPAK IBN-10 25*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / [MeOH]=50 / 50; flow rate: 45ml / min; Compounds with a retention time of 2.942 min under the following conditions: chiral column DAICEL CHIRALPAK IBN-10 25*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / [MeOH]=50 / 50; flow rate: 45ml / min; Compounds with a retention time of 1.499 min under the following conditions: chiral column (S,S)-Whelk-O-1 25*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / [MeOH / ACN]=50 / 50; flow rate: 45ml / min; Compounds with a retention time of 1.811 min under the following conditions: chiral column (S,S)-Whelk-O-125*250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / [MeOH / ACN]=50 / 50; flow rate: 45ml / min;

[0161] The first eluting compound was selected under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 65min and 78min, stop at 8min; Flow rate: 20ml / min; Preferably, the retention time of the first eluting compound was 1.682min.

[0162] Compounds eluting later under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 65 min and 7.8 min, stop at 8 min; Flow rate: 20 ml / min; Preferably, the retention time of the compound eluting later is 1.723 min.

[0163] A rotational isomer of compound A, which is the compound that elutes first when separated from compound A under the following conditions: chiral column: AD 25*250mm, 10µm (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 50 / 50; flow rate: 100mL / min; preferably, the retention time of the first-eluting compound is 0.863min; compound A is... The first eluting compound was selected under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 6.5 min and 7.8 min, stop at 8 min; Flow rate: 20 ml / min; Preferably, the retention time of the first eluting compound was 1.682 min.

[0164] A rotational isomer of compound A, which is the compound that elutes later when separated from compound A under the following conditions: chiral column: AD 25*250mm, 10µm (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 50 / 50; flow rate: 100mL / min; preferably, the retention time of the compound that elutes later is 2.246min; compound A is... The first eluting compound was selected under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 6.5 min and 7.8 min, stop at 8 min; Flow rate: 20 ml / min; Preferably, the retention time of the first eluting compound was 1.682 min.

[0165] A rotational isomer of compound B, which is the compound that elutes first when separated from compound B under the following conditions: chiral column: IG 25*250mm, 10µm (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 45 / 55; flow rate: 120mL / min; preferably, the retention time of the first-eluting compound is 1.178min; compound B is... Compounds eluting later under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 6.5 min and 7.8 min, stop at 8 min; Flow rate: 20 ml / min; Preferably, the retention time of the compound eluting later is 1.723 min.

[0166] A rotational isomer of compound B, which is the compound that elutes later when separated from compound B under the following conditions: chiral column: IG 25*250mm, 10µm (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 45 / 55; flow rate: 120mL / min; preferably, the retention time of the compound that elutes later is 2.067min; compound B is... Compounds eluting later under the following conditions: Column: YMC-Actus Triart C18, 150*20mm, 5µm; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 65min and 78min, stop at 8min; Flow rate: 20ml / min; Preferably, the retention time of the compound eluting later is 1.723min.

[0167] The first-eluting compound was selected under the following conditions: chiral column: OZ 25*250mm, 10µm (Daicel); mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=50 / 50; flow rate: 120mL / min; preferably, the retention time of the first-eluting compound was 1.115min;

[0168] Compounds that elute later under the following conditions: chiral column: OZ 25*250mm, 10um (Daicel); mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=50 / 50; flow rate: 120mL / min. Preferably, the retention time of the compounds that elute later is 3.221min.

[0169] The above retention time test conditions are not intended to limit the compounds. As long as the retention time obtained using the above test conditions is the same as or within the error range described above, and the compound is a stereoisomer of the compounds defined by retention time, it falls within the protection scope of this invention. Some compounds defined by the above separation conditions should actually be mixtures, such as compound A or compound B, which can be further separated to obtain multiple isomers. In this case, compound A or compound B should be understood as a mixture. Therefore, the understanding of the above content should not contradict conventional technical knowledge in the art.

[0170] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0171] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of an APJ receptor agonist.

[0172] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for an APJ receptor-related disease, preferably, the APJ receptor-related disease being a cardiovascular disease or muscle atrophy, the cardiovascular disease being, for example, pulmonary hypertension or heart failure.

[0173] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for increasing muscle mass, or for preventing and / or treating cardiovascular disease or muscle atrophy, said cardiovascular disease being, for example, pulmonary hypertension or heart failure.

[0174] The present invention also provides a method for preparing the compound shown in formula (I) above, which is one of the following methods: method 1, method 2, method 3 or method 4:

[0175] Method 1: It comprises the following steps: In a solvent, under the action of a ruthenium carbene complex catalyst, the compound shown in formula (IA) undergoes a cyclization reaction as shown below to prepare the compound shown in formula (I);

[0176] Among them, X 1 X 2 X 3 R 1 R 2 L 1 L 3 The definition of ring A is as described in any embodiment of the present invention;

[0177] L 2 L 2-1 and L 2-2 The definition is any of the following schemes:

[0178] Option 1:

[0179] L 2 For C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C2-C 10 alkenyl and C2-C 10 The hesylene group is optionally surrounded by one, two, or three L-members. 1b replace;

[0180] L 2-1 and L 2-2 Independently, it is a C2-C6 alkenyl or C2-C6 heteroalkenyl, wherein the C2-C6 alkenyl or C2-C6 heteroalkenyl is optionally surrounded by one, two, or three L... 1b replace;

[0181] L 1b The definition is as described in any embodiment of this invention;

[0182] Option 2: L 2 -C1-C4 alkylene-C3-C6 cycloalkylene-NL 2m -C(=O)-C1-C4 alkylene- or -C1-C4 alkylene-NL 2m -C(=O)-C1-C4 alkylene-; L 2m It is H or C1-C6 alkyl;

[0183] L 2-1 -C1-C4 alkylene-C3-C6 cycloalkylene-NHL 2m or -C1-C4 alkylene-NHL 2m L 2-2 It is a -C1-C4 alkylene-COOH;

[0184] Or, L 2-1 It is a -C1-C4 alkylene-COOH, L 2-2 -C1-C4 alkylene-C3-C6 cycloalkylene-NHL 2 m or -C1-C4 alkylene-NHL 2m ;

[0185] L 2m It is H or C1-C6 alkyl;

[0186] Preferably, in method 1, the ruthenium carbene complex catalyst is a Grubbs II catalyst;

[0187] Preferably, in method 1, the solvent is a halocarbon solvent, such as dichloromethane;

[0188] Method 2: It comprises the following steps: in a solvent, under the action of a reducing agent, the compound shown in formula (IB) undergoes the following reduction reaction to prepare the compound shown in formula (I);

[0189] Among them, X 1 X 2 X 3 R 1 R 2 L 1 L 3 The definition of ring A is as described in any embodiment of the present invention;

[0190] L 2' For C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C2-C 10 alkenyl and C2-C 10 The hesylene group is optionally surrounded by one, two, or three L-members. 1b replace;

[0191] L 2 For C2-C 10 Alkylene or C2-C 10 Heteroalkylene, the C2-C 10 Alkylene and C2-C 10 The heteroalkyl group is optionally surrounded by one, two, or three L-members. 1b replace;

[0192] L 1b The definition is as described in any embodiment of this invention;

[0193] Preferably, in method 2, the reducing agent is Pd / C;

[0194] Preferably, in method 2, the solvent is an alcohol solvent, such as ethanol;

[0195] Method 3: It comprises the following steps: in a solvent, in the presence of methanesulfonic acid, a compound of formula (IC) undergoes a condensation reaction to prepare a compound of formula (I);

[0196] Preferably, the solvent is a cyclic ether solvent, such as 1,4-dioxane;

[0197] Preferably, the temperature of the condensation reaction is 80–100°C, for example, 90°C;

[0198] Method 4: It comprises the following steps: in a solvent, the compound shown in formula (ID) undergoes a condensation reaction with the compound shown in formula (IE) to prepare the compound shown in formula (I);

[0199] Among them, X 1 X 2 X 3 R 1 R 2 L 1 L 3 The definition of ring A is as described in any embodiment of the present invention;

[0200] L 2 -C(=O)-NHL 2m -C1-C6 alkylene- ## The end marked with "##" is connected to L. 1 Connected;

[0201] L 2-2 -C1-C6 alkylene-NHL 2m ;

[0202] L 2m It is H or C1-C6 alkyl;

[0203] R s1 and R s2 Each is independently a C1-C6 alkyl group substituted with one or more halogens;

[0204] Preferably, the compound represented by formula (IE) is

[0205] Preferably, the solvent is a haloalkane solvent, such as dichloromethane.

[0206] The present invention also provides a compound as shown in formula (IA):

[0207] Among them, X 1 X 2 X 3 R 1 R 2 L 1 L 3 L 2-1 L 2-2 The definition of ring A is as described in any embodiment of the present invention.

[0208] In one embodiment of the present invention, the compound represented by formula (IA) is any one of the following compounds: Among them, corresponding Structure express Or a mixture thereof, e side with L 3 Connected; the carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof;

[0209] For example:

[0210] Terminology Explanation

[0211] The term "halogen" refers to F, Cl, Br, and I.

[0212] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C1-C1). 10 Alkyl groups are straight-chain or branched, saturated monovalent hydrocarbon groups (C1-C8, C1-C6, or C1-C4). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0213] The term "alkylene" refers to a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkyl".

[0214] The term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond.

[0215] The term "heteroalkenyl" refers to an alkenyl group in which one or more -CH2- are independently replaced by -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. The definition of "alkenyl" is the same as above.

[0216] The term "alkenyl" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkenyl".

[0217] The term "alkynyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 3 Three keys.

[0218] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- are independently replaced by -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. The definition of "alkylene" is the same as above.

[0219] The term "hemenyl" refers to the group in which one or more -CH2- are independently replaced by -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. The definition of "hemenyl" is the same as above.

[0220] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C3-C). 12 ( ) A monovalent cyclic group consisting of saturated monocyclic, bridged, or spirocyclic rings composed only of carbon atoms.

[0221] The term "cycloalkylene" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "cycloalkylene".

[0222] The term "heterocyclic alkyl" refers to a monovalent cyclic group having a specified number of ring atoms (e.g., 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5, preferably 1, 2, or 3), and a specified type of heteroatom (one or more of -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, and -C(=O)-), which is a monocyclic, fused, bridged, or spirocyclic group, and each ring is saturated. It should be clearly stated that in the said heterocyclic alkyl group, the number of heteroatoms should be less than the number of ring atoms.

[0223] The term "heterocyclic alkyl" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "heterocyclic alkyl".

[0224] The term "cycloalkenyl" refers to a group having a specified number of carbon atoms (e.g., C4-C). 12 A cyclic, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bonds, which are monocyclic, fused, bridged, or spirocyclic, are not aromatic.

[0225] The term "cycloalkenyl" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "cycloalkenyl".

[0226] The term "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 4-12), a specified number of heteroatoms (e.g., 1, 2, or 3, 4, or 5, preferably 1, 2, or 3), and a specified heteroatom type (one or more of O-, -NH-, -S-, -S(=O)-, -S(=O)2-, and -C(=O)-), having one or more (e.g., 1, 2, or 3) carbon-carbon sp-axis groups. 2 The double bond, which is a monocyclic, fused, bridged, or spirocyclic ring, is not aromatic; or, at least one ring is not aromatic. It should be clearly stated that in the aforementioned heterocyclic alkyl group, the number of heteroatoms should be less than the number of ring atoms.

[0227] The term "heterocyclic alkenyl" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "heterocyclic alkenyl".

[0228] The term "heteroaryl" refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5, preferably 1, 2, 3, or 4), and a specified type of heteroatom (1, 2, or 3 of N, O, and S). It can be monocyclic or bicyclic; when bicyclic, each ring is aromatic. It should be clearly stated that in the heterocyclic alkyl group, the number of heteroatoms should be less than the number of ring atoms.

[0229] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 A cyclic, unsaturated monovalent hydrocarbon group, which is monocyclic or polycyclic (e.g., 2 or 3). When polycyclic, the monocyclic rings share two atoms and one bond, and (each ring) is aromatic.

[0230] The term "triaryl" refers to a divalent aryl group, and the definition of "aryl" is the same as above.

[0231] The term "hybrid aryl" refers to a divalent heteroaryl group, and the definition of "heteroaryl" is the same as above.

[0232] The term “heteroaryl ring” meets any of the following conditions, and the rest of the definition is the same as that of the term “heteroaryl group”: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0233] The term "one or more" can refer to 1, 2, 3, 4 or 5, with 1, 2 or 3 being preferred.

[0234] The term "one or more" can refer to 1, 2, 3, 4 or 5 types, with 1, 2 or 3 types being preferred.

[0235] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Representing the relative configuration of the stereocenter. The method of representing rotational isomers of a compound, using... Taking a rotational isomer as an example, it can be used It can also be expressed as, express.

[0236] The term "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0237] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0238] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by combining the compounds of the present invention with 1, substances prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or substances formed with a stoichiometric or non-stoichiometric solvent.

[0239] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0240] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0241] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0242] In the described uses, the agonist can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of APJ receptor agonistic effects.

[0243] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0244] The reagents and raw materials used in this invention are all commercially available.

[0245] The positive and progressive effects of this invention are as follows: the compounds of this invention have one or more of the following advantages:

[0246] (1) It has good agonistic activity against APJ receptors;

[0247] (2) It can effectively inhibit the production of cAMP;

[0248] (3) It has a weak ability to recruit β-arrestin;

[0249] (4) It has good pharmacokinetic properties. Detailed Implementation

[0250] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0251] Example 1: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thia-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound lA;

[0252] (E)-1 2-(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1B;

[0253] (Z)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1C;

[0254] (Z)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1D;

[0255] (E)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1E

[0256] Step 1: 3-Methoxy-2-nitrophenol 1b

[0257] Triphenylphosphine (22 g, 84.88 mmol, 1.3 eq) and methanol (2.5 g, 77.42 mmol, 1.2 eq) were added sequentially to ultradry tetrahydrofuran (400 mL) containing 2-nitrobenzene-1,3-diol (10 g, 64.52 mmol, 1 eq) under ice-water bath conditions. Then, diethyl azodicarbonate (14.6 g, 83.88 mmol, 1.3 eq) was slowly added dropwise to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 16 hours. Water (500 mL) was added, and the mixture was extracted three times with ethyl acetate (400 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20%-25%) to give a yellow solid product 1b (5.78 g, yield: 53%).

[0258] LCMS: RT=1.29min, m / z=168.3[M-1] + ;

[0259] 1 H NMR (400MHz, DMSO-d6): δ 10.89 (s, 1H), 7.29 (t, J=8.4Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 6.63 (dd, J=8.4, 0.8Hz, 1H), 3.82 (s, 3H).

[0260] Step 2: 1-Methoxy-3-(methoxymethoxy)-2-nitrobenzene 1c

[0261] Under ice-water bath conditions, N,N-diisopropylethylamine (8.4 g, 65 mmol, 2 eq) was added to a solution of 3-methoxy-2-nitrophenol 1b (5.5 g, 32.5 mmol, 1 eq) in N,N-dimethylformamide (60 mL). Then, bromomethyl methyl ether (8.13 g, 65 mmol, 2 eq) was slowly added dropwise. The reaction mixture was brought to room temperature and stirred for 16 hours. The mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed three times with water (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-9%) to give a white solid product 1c (2.16 g, yield: 31%).

[0262] LCMS: RT=1.72min, m / z=231.1[M+18] + ;

[0263] 1 H NMR (400MHz, DMSO-d6): δ7.46 (t, J=8.4Hz, 1H), 6.95 (t, J=8.4Hz, 2H), 5.30 (s, 2H), 3.87 (s, 3H), 3.35 (s, 3H).

[0264] Step 3: 2-Methoxy-6-(methoxymethoxy)aniline 1d

[0265] At room temperature, 10% palladium on carbon (1.25 g) was added to a 100 mL ethanol solution of 1-methoxy-3-(methoxymethoxy)-2-nitrobenzene 1c (6.24 g, 29.3 mmol, 1 eq) and reacted under hydrogen protection for 16 hours at room temperature. The reaction solution was filtered through diatomaceous earth, washed 2-3 times with methanol (20 mL), and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-2%) to give a colorless oily product 1d (5.1 g, yield: 95%).

[0266] LCMS: RT=1.57min, m / z=184.3[M+1] + ;

[0267] 1 H NMR (400MHz, DMSO-d6): δ 6.63-6.56 (m, 2H), 6.50 (t, J=8.0Hz, 1H), 5.12 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 3.39 (s, 3H).

[0268] Step 4: N-(5-chloro-3-((2-methoxy-6-(methoxymethoxy)phenyl)amino)pyrazin-2-yl)-6-ethoxypyridine amide 1e

[0269] At room temperature, in a 250 mL pressure-resistant bottle, 1 d of 2-methoxy-6-(methoxymethoxy)aniline (1.83 g, 10 mmol, 1 eq), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (1.16 g, 2 mmol, 0.2 eq), palladium acetate (227 mg, 1 mmol, 0.1 eq), and potassium carbonate (2.76 g, 20 mmol, 2 eq) were sequentially added to an ultra-dry toluene (60 mL) solution of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypyridinecarboxamide (3.56 g, 10 mmol, 1 eq). The mixture was bubbled with nitrogen for 5–10 minutes, and then the reaction mixture was reacted at 100 °C for 16 hours. The reaction solution was cooled to room temperature and diluted with 100 mL of a 10:1 mixture of dichloromethane and methanol. The solution was filtered through diatomaceous earth and washed 3-5 times with 50 mL of the same mixture. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-17%) to give a yellow solid product 1e (3.15 g, yield: 69%).

[0270] LCMS: RT=2.19min, m / z=460.0[M+1] + .

[0271] Step 5: 2-(6-chloro-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)-3-methoxyphenol 1f

[0272] At room temperature, N-(5-chloro-3-((2-methoxy-6-(methoxymethoxy)phenyl)amino)pyrazin-2-yl)-6-ethoxypyridine amide 1e (350 mg, 0.76 mmol, 1 eq) was dissolved in acetic acid (4 mL) in a microwave tube. The reaction mixture was then placed in a microwave reactor, heated to 130 °C, and reacted at this temperature for 1 hour. The reaction solution was cooled to room temperature, and the reaction mixture was transferred to a single-necked flask. Acetic acid was removed by concentration under reduced pressure. The mixture was diluted with a 10:1 mixture of dichloromethane and methanol (50 mL). The organic phase was washed twice with saturated sodium bicarbonate (50 mL). The organic phase was dried and concentrated under reduced pressure. Dichloromethane (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filter cake was washed with a small amount of dichloromethane. The solid was dried to give a yellow solid product 1f (185 mg, yield = 53%).

[0273] LCMS: RT=1.80min, m / z=398.0[M+1] +

[0274] Step 6: 1 g of 1-(2-(allyloxy)-6-methoxyphenyl)-6-chloro-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[0275] At room temperature, 3-bromoprop-1-ene (169 mg, 1.4 mmol, 2 eq) and potassium carbonate (193 mg, 1.4 mmol, 2 eq) were sequentially added to 2-(6-chloro-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-1-yl)-3-methoxyphenol 1e (270 mg, 0.7 mmol, 1 eq) in N,N-dimethylformamide (10 mL). The reaction mixture was then heated to 90 °C and stirred at this temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (100 mL). The aqueous phase was then separated, and the organic phase was washed once with water (100 mL) and saturated brine (100 mL) sequentially. The aqueous phases were then combined and extracted once with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15%-20%) to obtain 1 g (259 mg, yield: 82%) of yellow oily product.

[0276] LCMS: RT=1.99min, m / z=438.2[M+1] + ;

[0277] Step 7: N-(1-(2-(prop-3-en-1-yloxy)-6-methoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-3-en-1-sulfonamide 1h

[0278] At room temperature, but-3-ene-1-sulfonamide (63 mg, 0.47 mmol, 1.2 eq), cuprous iodide (148 mg, 0.78 mmol, 2 eq), potassium carbonate (108 mg, 0.78 mmol, 2 eq), and trans-(1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine (111 mg, 0.78 mmol, 2 eq) were sequentially added to a solution of 1 g (170 mg, 0.39 mmol, 1 eq) of 1-(2-(allyloxy)-6-methoxyphenyl)-6-chloro-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine in 5 mL of N,N-dimethylformamide. The reaction mixture was then placed in a microwave reactor and heated to 115 °C and reacted at this temperature for 5 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted three times with ethyl acetate (60 mL). The organic phases were combined and washed once each with water (100 mL) and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-40%), yielding a yellow oily product (130 mg, yield: 62%) over 1 hour.

[0279] LCMS: RT=1.64min, m / z=537.32[M+1] + ;

[0280] Step 8: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thia-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1A

[0281] At room temperature, Grubbs II catalyst (41 mg, 0.048 mmol, 0.2 eq) was added to a dry dichloromethane solution (130 mg, 0.24 mmol) of N-(1-(2-(prop-3-en-1-yloxy)-6-methoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)but-3-en-1-sulfonamide 1 h (130 mg, 0.24 mmol) (1 h) (130 mL). The reaction mixture was then protected with N2 and placed in an oil bath heated to 50 °C, and reacted at this temperature for 1 h. The reaction solution was cooled to room temperature. It was diluted with water (80 mL) and dichloromethane (30 mL), and the aqueous phase was extracted twice with dichloromethane (60 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was prepared by high performance liquid chromatography. The yellow solid product compound 1A (60 mg, yield: 41%) was a mixture of cis and trans olefin bonds.

[0282] LCMS: RT=1.76min, m / z=509.3[M+1] + ;

[0283] 1 H NMR (400MHz, MeOH-d4): δ8.54-8.36 (m, 1H), 7.91-7.76 (m, 2H), 7.44-7.3 9(m, 1H), 7.00-6.95(m, 1H), 6.78-6.71(m, 2H), 5.90-5.71(m, 1H), 5.65- 5.47(m, 1H), 4.75-4.41(m, 2H), 3.63-3.52(m, 3H), 3.45-3.33(m, 3H), 3. 17-3.10 (m, 1H), 2.89-2.76 (m, 1H), 2.58-2.32 (m, 2H), 1.09-1.04 (m, 3H).

[0284] High performance liquid chromatography (HPLC) preparation conditions: Column: Boston Prep C18 21.2×250mm, 10µm; Mobile phase: A: water (0.2% formic acid), B: acetonitrile; Gradient: 40-70% B in 8min; Flow rate: 30mL / min; Wavelength: 214 / 254nm; Number of needles: 3.

[0285] Step 9: Chiral resolution of compound 1A

[0286] 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1H-3-oxa-9-thia-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1A (60 mg, 0.12 mmol) underwent a first chiral resolution to obtain enantiomeric pure compounds 1D and 1E, as well as a mixture of compounds 1B and 1C. The mixture of compounds 1B and 1C was then subjected to a second chiral resolution to obtain enantiomeric pure compounds 1B and 1C. After two chiral resolutions, four enantiomeric pure compounds were obtained.

[0287] Compound 1B: (E)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide (10.4 mg, yellow solid).

[0288] Retention time of chiral column: RT = 1.42 min.

[0289] LCMS: RT=1.75min, m / z=509.2[M+1] + ;

[0290] 1 H NMR (400MHz, MeOH-d4): δ8.54 (s, 1H), 7.91-7.89 (m, 1H), 7.80-7.76 (m, 1H), 7.44 -7.40(m, 1H), 7.00-6.96(m, 1H), 6.78-6.75(m, 2H), 5.90-5.83(m, 1H), 5.53-5.47 (m, 1H), 4.75-4.70 (m, 1H), 4.45-4.41 (m, 1H), 3.60-3.53 (m, 4H), 3.45-3.36 (m, 2H ), 3.17-3.10 (m, 1H), 2.62-2.53 (m, 1H), 2.39-2.34 (m, 1H), 1.06 (t, J=6.8Hz, 3H).

[0291] Compound 1C: (Z)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide (4.6 mg, yellow solid).

[0292] Retention time of chiral column: RT = 1.65 min.

[0293] LCMS: RT=1.75min, m / z=509.4[M+1] + ;

[0294] 1 H NMR (400MHz, MeOH-d4): δ8.36 (s, 1H), 7.87-7.77 (m, 2H), 7.41 (t, J=8.8Hz, 1H), 6.96 (d, J=8.8Hz, 1H), 6.78-6.71 (m, 2H), 5.77-5.59 (m, 2H), 4.73-4.59 (m, 2H), 3.65-3.55 (m, 2H), 3.42 (s, 3H), 3.38-3.34 (m, 1H), 2.86-2.76 (m, 2H), 2.58-2.52 (m, 1H), 1.07 (t, J=6.8Hz, 3H).

[0295] Compound 1D: (Z)-1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide (5.4 mg, yellow solid).

[0296] Retention time of chiral column: RT = 2.48 min.

[0297] LCMS: RT=1.74min, m / z=509.4[M+1] + ;

[0298] 1 H NMR (400MHz, MeOH-d4): δ8.31 (s, 1H), 7.85-7.77 (m, 2H), 7.41 (t, J=8.4Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 6.77-6.70 (m, 2H), 5.75-5.63 (m, 2H), 4.74-4.57(m, 2H), 3.64-3.57(m, 2H), 3.42(s, 3H), 3.37-3.34(m, 1H), 2.83-2.78(m, 2H), 2.62-2.53(m, 1H), 1.07(t, J=6.8Hz, 3H).

[0299] Compound 1E: (E)-1 2 -(6-ethoxypyridin-2-yl)-2 6-Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide (9.6 mg, yellow solid).

[0300] Retention time of chiral column: RT = 3.09 min.

[0301] LCMS: RT=1.75min, m / z=509.4[M+1] + ;

[0302] 1 H NMR (400MHz, MeOH-d4): δ8.53 (s, 1H), 7.91-7.89 (m, 1H), 7.80-7.76 (m, 1H), 7.44 -7.40(m, 1H), 7.00-6.96(m, 1H), 6.77-6.75(m, 2H), 5.90-5.83(m, 1H), 5.51-5.46 (m, 1H), 4.76-4.67 (m, 1H), 4.45-4.41 (m, 1H), 3.59-3.52 (m, 4H), 3.48-3.37 (m, 2H ), 3.17-3.10 (m, 1H), 2.61-2.52 (m, 1H), 2.41-2.34 (m, 1H), 1.06 (t, J=7.2Hz, 3H).

[0303] First chiral separation conditions: Instrument: SFC-80 (Thar, Waters); Column: AS20*250mm, 10um (Daicel); Column temperature: 35℃; Mobile phase: CO2 / MeOH (0.2% Methanol Ammonia) = 65 / 35; Flow rate: 100ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 6min; Sample volume: 50mg sample dissolved in 40mL methanol; Injection volume: 4ml;

[0304] Second chiral separation conditions: Instrument: SFC-150 (Waters); Column: IK25*250mm, 10um (Daicel); Column temperature: 25℃; Mobile phase: CO2 / MeOH (0.2% Methanol Ammonia) = 60 / 40; Flow rate: 100ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 11min; Sample volume: 20mg sample dissolved in 8mL methanol; Injection volume: 4.0ml.

[0305] Example 2: (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2A;

[0306] (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2B;

[0307] (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2C;

[0308] (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2D;

[0309] (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2E; (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 2F

[0310] Step 1: 2-(allyloxy)-6-methoxyaniline 2b

[0311] At room temperature, 2-amino-3-methoxyphenol 2a (3 g, 21.6 mmol, 1 eq) was added to N,N-dimethylformamide (30 mL), followed by the addition of sodium hydride (0.863 g, 21.6 mmol, 1 eq) and stirring at room temperature for 10 minutes. Then, 3-bromoprop-1-ene (2.61 g, 21.6 mmol, 1 eq) was added to the reaction mixture, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was then poured into 100 mL of ice water and extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5%) to give a yellow solid product 2b (1.4 g, yield: 36.2%).

[0312] LCMS: RT=1.73min, m / z=180.1[M+1] + .

[0313] Step 2: 1-(allyloxy)-2-isothiocyanate-3-methoxybenzene 2c

[0314] At room temperature, 1,1′-thiocarbonylbis(pyridin-2(1H)-one) ((1.91 g, 8.21 mmol, 1.05 eq)) was added to a dichloromethane solution (50 mL) of 2-(allyloxy)-6-methoxyaniline 2b (1.4 g, 7.82 mmol, 1 eq), followed by purging with a nitrogen balloon four times and stirring overnight at this temperature. The reaction solution was directly concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5%) to give a yellow oily product 2c (1.9 g, yield: 100%).

[0315] LCMS: RT=2.00min, m / z=222.0[M+1] + .

[0316] Step 3: N′-(2-(allyloxy)-6-methoxyphenyl)-N-(but-3-en-1-ylsulfonyl)-2-(6-ethoxypyridinyl)hydrazine-1-carboximide 2f

[0317] At room temperature, but-3-ene-1-sulfonamide 2d (64.1 mg, 0.475 mmol, 1.05 eq) and cesium carbonate (192 mg, 0.588 mmol, 1.3 eq) were added sequentially to a solution of 1-(allyloxy)-2-isothiocyanate-3-methoxybenzene 2c (100 mg, 1.12 mmol, 1 eq) in acetonitrile (10 mL). The reaction mixture was then stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. The reaction mixture was cooled to 0 °C in an ice-water bath. 6-ethoxypyridinyl hydrazide 2e (181 mg, 0.484 mmol, 1.07 eq) and silver nitrate (154 mg, 0.905 mmol, 2 eq) were added sequentially to the above reaction mixture and stirred at 0 °C for 5 minutes, followed by stirring at room temperature for 5 minutes. The reaction mixture was concentrated directly under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 2%) to give a yellow solid product 2f (210 mg, yield: 92.3%).

[0318] LCMS: RT=1.92min, m / z=504.0[M+1] + .

[0319] Step 4: 2g of N-(4-(2-(allyloxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)but-3-ene-1-sulfonamide

[0320] At room temperature, methanesulfonic acid (140 mg, 1.46 mmol, 3.5 eq) was added to a solution of N′-(2-(allyloxy)-6-methoxyphenyl)-N-(but-3-en-1-ylsulfonyl)-2-(6-ethoxypyridinyl)hydrazine-1-carboximide 2f (210 mg, 0.417 mmol, 1 eq) in 1,4-dioxane (10 mL). The reaction mixture was then placed in an oil bath preheated to 90 °C and reacted at this temperature for 2 hours. The reaction mixture was cooled to room temperature, transferred to a single-necked flask, neutralized with saturated sodium carbonate solution, and extracted three times with dichloromethane:methanol = 10:1 (50 mL) solvent. The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give 2 g (200 mg) of crude yellow solid product, which was used directly in the next reaction without purification.

[0321] LCMS: RT=1.66min, m / z=486.2[M+1] + ;

[0322] Step 5: 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide 2h

[0323] At room temperature, Grubbs II (27.3 mg, 0.13 eq) was added to 2 g (120 mg, 0.247 mmol, 1 eq) of N-(4-(2-(allyloxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)but-3-ene-1-sulfonamide in 20 mL of dry dichloromethane. The reaction mixture was then protected with nitrogen and placed in an oil bath heated to 50 °C, where it was reacted for 2 hours. The reaction mixture was cooled to room temperature. It was diluted with 30 mL of water and 30 mL of dichloromethane. The aqueous phase was extracted twice with 30 mL of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (column: Ultimate Prep C18 10μm 21.2×250mm; mobile phase: A: water (0.2% formic acid) B: acetonitrile; gradient: 50-80% B in 8min, stop at 16min; flow rate: 30ml / min) to obtain a yellow solid product (18.3mg, yield = 16.2%), which was a mixture of olefinic and trans bonds.

[0324] LCMS: RT=1.71min, m / z=458.2[M+1] + ;

[0325] 1 H NMR (400MHz, MeOH-d4): 7.70-7.66 (m, 1H), 7.61-7.59 (m, 1H), 7.41 (t, J=8.4Hz, 1H), 6.89-6.85 (m, 2H), 6.68 (d, J=8Hz, 1H), 5.55-5.48 (m, 1H), 5.42-5.35 (m, 1H), 4.45-4.34 (m, 2H), 3.83 (s, 3H), 3.49-3.43 (m, 1H), 3.19-3.05 (m, 3H), 2.52-2.45 (m, 2H), 1.08-1.01 (m, 3H).

[0326] Step 6: Separation of cis and trans compounds by high performance liquid chromatography

[0327] The fifth step reaction was repeated and scaled up to obtain 500 mg for 2 h. The product was then purified by high performance liquid chromatography to obtain two isomers, cis and trans, compound 2A (70 mg) and compound 2B (30 mg).

[0328] High performance liquid chromatography conditions: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (0.2% formic acid) B: acetonitrile; Gradient: 50-80% B in 8min, stop at 16min; Flow rate: 30ml / min.

[0329] Step 7: Chiral column splitting

[0330] The compound 2A (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (70 mg, 0.13 mmol) was chirally resolved to give two isomers, compound 2C and compound 2D.

[0331] Chiral resolution conditions for compound 2A: Instrument: SFC-150 (Waters); Chiral column: IG 25*250mm, 10um (Daicel); Column temperature: 25℃; Mobile phase: CO2 / [0.2% Methanol Ammonia = 50 / 50]; Flow rate: 120ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 5.15min; Sample volume: 70mg sample dissolved in 45mL methanol; Injection volume: 4.8mL per injection.

[0332] Compound 2C: (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (36.1 mg), is a yellow solid.

[0333] Chiral column retention time: RT = 1.71 min;

[0334] LCMS: RT=1.71min, m / z=458.2[M+1] + ;

[0335] 1H NMR (400MHz, MeOH-d4): δ7.70-7.66 (m, 1H), 7.61-7.59 (m, 1H), 7.41 (t, J=8.4Hz, 1H), 6.89-6.85 (m, 2H), 6.68 (d, J=8Hz, 1H), 5.55-5.48 (m, 1H), 5.42-5.35(m, 1H), 4.43-4.33(m, 2H), 3.83(s, 3H), 3.51-3.43(m, 1H), 3. 35-3.31 (m, 1H), 3.18-3.07 (m, 2H), 2.54-2.44 (m, 2H), 1.05-1.01 (m, 3H).

[0336] Compound 2D: (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (24.4 mg), yellow solid.

[0337] Chiral column retention time: RT = 2.64 min;

[0338] LCMS: RT=1.71min, m / z=458.2[M+1] + ;

[0339] 1 H NMR (400MHz, MeOH-d4): δ7.70-7.66 (m, 1H), 7.61-7.59 (m, 1H), 7.41 (t, J=8.4Hz, 1H), 6.89-6.85 (m, 2H), 6.68 (d, J=8Hz, 1H), 5.53-5.48 (m, 1H), 5. 42-5.36(m, 1H), 4.41-4.33(m, 2H), 3.82(s, 3H), 3.49-3.43(m, 1H), 3.35- 3.30 (m, 1H), 3.16-3.11 (m, 2H), 2.52-2.44 (m, 2H), 1.03 (t, J=7.2Hz, 3H).

[0340] The (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (30 mg, 0.13 mmol) compound 2B was chirally resolved to give two isomers, compound 2E and compound 2F.

[0341] Chiral resolution conditions for compound 2B: Instrument: SFC-150 (Waters); Chiral column (R, R) WHELK-O1 25*250mm, 10µm (Regis); Column temperature: 25℃; Mobile phase: CO2 / [0.2% Methanol Ammonia] = 70 / 30; Flow rate: 100mL / mm; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 7.7min; Sample volume: 30mg sample dissolved in 30mL methanol; Injection volume: 4.7mL per injection.

[0342] Compound 2E: (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (11.0 mg), white solid.

[0343] Retention time of chiral column: RT = 2.13 min;

[0344] LCMS: RT=1.73min, m / z=458.2[M+1] + ;

[0345] 1 H NMR (400MHz, MeOH-d4): δ7.72-7.68(m, 1H), 7.59-7.56(m, 1H), 7.44-7.40(m, 1H) , 6.85-6.83(m, 1H), 6.75-6.70(m, 2H), 5.84-5.80(m, 2H), 4.70-4.66(m, 1H), 4.5 2-4.48(m, 1H), 3.60(s, 3H), 3.53-3.46(m, 1H), 3.39-3.34(m, 1H), 3.27-3.22(m, 1H), 2.94-2.87(m, 1H), 2.75-2.72(m, 1H), 2.45-2.42(m, 1H), 1.09-1.03(m, 3H).

[0346] Compound 2F: (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide (16.1 mg), yellow solid.

[0347] Retention time of chiral column: RT = 3.18 min;

[0348] LCMS: RT=1.73min, m / z=458.2[M+1]+ ;

[0349] 1 H NMR (400MHz, MeOH-d4): δ7.73-7.68(m, 1H), 7.62-7.58(m, 1H), 7.44-7.40(m, 1H) , 6.85 (d, J=8.4Hz, 1H), 6.74-6.70 (m, 2H), 5.87-5.77 (m, 2H), 4.70-4.66 (m, 1H), 4 .52-4.48(m, 1H), 3.60(s, 3H), 3.54-3.46(m, 1H), 3.38-3.34(m, 1H), 3.28-3.22(m , 1H), 2.93-2.86 (m, 1H), 2.79-2.70 (m, 1H), 2.47-2.38 (m, 1H), 1.07-1.04 (m, 3H).

[0350] Example 3: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-12-thia-13-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzene ring triazo-8-ene 12,12-dioxide compound 3

[0351] Following the same procedure as in Example 1, target compound 3 (5.4 mg) was prepared as a mixture of olefinic cis and trans bonds.

[0352] LCMS: RT=1.66min, m / z=551.3[M+1] + ;

[0353] 1 H NMR (400MHz, MeOH-d4): δ8.48 (s, 1H), 7.90 (d, J=7.6Hz, 1H), 7.76 (t, J=8.0Hz , 1H), 7.40 (t, J=8.4Hz, 1H), 6.79-6.73 (m, 3H), 5.44-5.41 (m, 2H), 4.05-4.01 (m, 1H), 3.94-3.89 (m, 1H), 3.62 (s, 3H), 3.51-3.42 (m, 4H), 2.53-2.39 (m, 2H) , 1.83-1.69 (m, 2H), 1.49-1.45 (m, 2H), 1.15-1.03 (m, 4H), 1.02-0.85 (m, 1H).

[0354] Example 4: 1 2 -(6-ethoxypyridin-2-yl)-26 -Methoxy-1 1 H-3-oxa-11-thia-12-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-phenylcyclododecane-8-ene 11,11-dioxide compound 4

[0355] Following the same procedure as in Example 1, target compound 4 (11.6 mg) was prepared as a mixture of olefinic cis and trans bonds.

[0356] LCMS: RT=1.58min, m / z=537.3[M+1] + ;

[0357] 1 H NMR (400MHz, MeOH-d4): δ8.24 (s, 1H), 7.86 (d, J=6.8Hz, 1H), 7.75 (t, J=8.0Hz, 1H), 7.44 (t, J=8.4Hz , 1H), 6.87 (d, J=8.0Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 6.73 (d, J=8.0Hz, 1H), 5.62.-5.55 (m, 1H), 5.52-5 .45(m, 1H), 4.53-4.46(m, 1H), 4.23-4.17(m, 1H), 3.97-3.92(m, 1H), 3.73-3.68(m, 1H), 3.61-3.51(m , 4H), 3.50-3.41 (m, 1H). 1.84-1.69 (m.2H), 2.58-1.52 (m.2H), 1.15-1.05 (m, 4H), 1.01-0.94 (m, 1H).

[0358] Example 5: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodecane-6-ene 9,9-dioxide compound 6

[0359] Following the same procedure as in Example 1, target compound 6 (4.5 mg) was prepared as a mixture of olefinic cis and trans bonds.

[0360] LCMS: RT=1.76min, m / z=509.2[M+1] + ;

[0361] 1H NMR (400MHz, MeOH-d4): δ8.52 (s, 1H), 7.86-7.77 (m, 2H), 7.41 (t, J=8.4Hz, 1H), 6.94 (d, J=8.0Hz, 1H), 6.77-6.68 (m, 2H), 5.49-5.36 ( m, 2H), 4.34-4.19 (m, 2H), 4.03-3.89 (m, 2H), 3.63-3.55 (m, 1H), 3.42 (s, 3H), 3.40-3.33 (m, 1H), 2.37-2.27 (m, 2H), 1.09-1.05 (m, 3H).

[0362] Example 6: 1 2 -(6-ethoxypyridin-2-yl)- 2 6-Methoxy-1 1 H-3-oxa-12-thio-3-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclotetrazane-7-ene 12,12-dioxide compound 7

[0363] Following the same procedure as in Example 1, target compound 7 (8.4 mg) was prepared as a mixture of olefinic cis and trans bonds.

[0364] LCMS: RT=1.88min, m / z=551.4[M+1] + ;

[0365] 1 H NMR (400MHz, MeOH-d4): δ8.42-8.37(m, 1H), 7.94-7.92(m, 1H), 7.79-7.75(m, 1H), 7.44 -7.39(m, 1H), 6.84-6.74(m, 3H), 5.14-5.09(m, 1H), 4.85-4.81(m, 1H), 4.00-3.97(m, 1 H), 3.77-3.71(m, 1H), 3.68-3.62(m, 3H), 3.53-3.39(m, 3H), 3.13-2.97(m, 1H), 2.06-2 .03 (m, 1H), 1.91-1.73 (m, 3H), 1.56-1.49 (m, 2H), 1.48-1.28 (m, 2H), 1.11-1.06 (m, 3H).

[0366] Example 7: 1-(6-ethoxypyridin-2-yl)-14-methoxy-6,9-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacycloundecene 5,5-dioxide compound 9

[0367] Following the same procedure as in Example 1, target compound 9 (3.2 mg) was prepared as a mixture of olefinic cis and trans bonds.

[0368] LCMS: RT=1.71min, m / z=444.2[M+1] + ;

[0369] 1 H NMR (400MHz, MeOH-d4): δ7.73-7.69 (m, 1H), 7.59-7.57 (m, 1H), 7.40 (t, J= 8.4Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 6.75-6.71 (m, 2H), 6.18-6.13 (m, 1H), 5 .95-5.88(m, 1H), 4.82-4.77(m, 1H), 4.64-4.59(m, 1H), 3.88-3.84(m, 2H) , 3.57 (s, 3H), 3.55-3.46 (m, 1H), 3.40-3.33 (m, 1H), 1.03 (t, J=7.2Hz, 3H).

[0370] Example 10: 1 5 -Methoxy-1-(5-methylpyridin-3-yl)-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 10

[0371] Following the same procedure as in Example 2, target compound 10 (3.3 mg) was prepared as a mixture of olefinic and trans bonds.

[0372] LCMS: RT=1.48min, m / z=428.2[M+1] + ;

[0373] 1 H NMR (400MHz, MeOH-d4): δ8.41 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.52-7.48 (m, 1H), 6.93-6.88 (m, 2H), 5. 58-5.43 (m, 2H), 4.47-4.38 (m, 2H), 3.88-3.82 (m, 3H), 3.21-3.15 (m, 2H), 2.51-2.42 (m, 2H), 2.28 (s, 3H).

[0374] Example 11: 1 2-(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-9-thio-10-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiallyl 9,9-ethane dioxide compound 11

[0375] At room temperature, add palladium on carbon (2 mg) to 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 A mixture of H-3-oxa-9-thia-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclodiphenyl-5-ene 9,9-dioxide compound 1A (10 mg, 0.02 mmol) and ethanol (2 ml) was prepared. The reaction mixture was purged three times with a hydrogen balloon and stirred at room temperature for half an hour. The reaction mixture was filtered, and the filter cake was washed three times with methanol. The filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (column: Ultimate Prep C18 10 μm 21.2 × 250 mm; mobile phase: A: water (10 mM NH4HCO3) B: acetonitrile; gradient: 2-10% B in 8 min, stop at 16 min; flow rate: 30 ml / min) to obtain the target product compound 11 (5 mg, yield: 50%), which was a white solid.

[0376] LCMS: RT=1.44min, m / z=511.0[M+1] + ;

[0377] 1H NMR (400MHz, MeOH-d4): δ8.37 (s, 1H), 7.88-7.86 (m, 1H), 7.81-7.77 (m, 1H), 7.42 (t, J=8.4Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.77-6.70 (m 2H), 4.28-4.23(m, 1H), 4.11-4.06(m, 1H), 3.64-3.54(m, 2H), 3.44(s, 3H ), 3.39-3.34(m, 1H), 3.03-2.96(m, 1H), 1.87-1.74(m, 3H), 1.57-1.42(m 2H), 1.28-1.23 (m, 1H), 1.07 (t, J=6.8Hz, 3H).

[0378] Example 12: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1H-3-oxa-12-thia-13-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzene ring tripiperidine 12,12-dioxide compound 12

[0379] The target compound 12 (14 mg) was prepared by following the same procedure as in Example 11, and was a racemic mixture.

[0380] LCMS: RT=1.73min, m / z=553.0[M+1] + ;

[0381] 1 H NMR (400MHz, MeOH-d4): δ8.59 (s, 1H), 7.92 (d, J=7.2Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7 .40(t, J=8.8Hz, 1H), 6.80-6.74(m, 3H), 4.01-3.99(m, 1H), 3.92-3.89(m, 1H), 3.64( s, 3H), 3.48 (dd, J=14.4, 7.2Hz, 2H), 1.77-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.52-1.4 9(m, 2H), 1.35-1.26(m, 2H), 1.14-1.06(m, 5H), 1.02-0.98(m, 2H), 0.90-0.86(m, 2H).

[0382] Example 13: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-10-thio-1-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocycloundecane 10,10-dioxide compound 13

[0383] Following the same procedure as in Example 11, target compound 13 (6.3 mg) was prepared as a racemic mixture.

[0384] LCMS: RT=1.82min, m / z=525.2[M+1] + ;

[0385] 1H NMR (400MHz, MeOH-d4): δ8.37 (s, 1H), 7.90-7.87 (m, 1H), 7.78-7.75 (m, 1H), 7.42 (t, J=8.4Hz, 1 H), 6.88 (d, J=8.0Hz, 1H), 6.76-6.70 (m, 2H), 4.24-4.18 (m, 1H), 3.99-3.94 (m, 1H), 3.64-3.60 ( m, 1H), 3.59-3.55 (m, 1H), 3.54 (s, 3H), 3.44-3.35 (m, 1H), 3.17-3.09 (m, 1H), 1.91-1.87 (m, 1H) , 1.59-1.55(m, 2H), 1.52-1.42(m, 2H), 1.26-1.14(m, 2H), 1.10-1.05(m, 3H), 1.01-0.95(m, 1H).

[0386] Example 14: 1 2 -(6-ethoxypyridin-2-yl)-2 6 -Methoxy-1 1 H-3-oxa-11-thio-12-aza-1(1,6)-imidazo[4,5-b]pyrazine-2(1,2)-benzocyclododecane 11,11-dioxide compound 14

[0387] Following the same procedure as in Example 11, target compound 14 (35.8 mg) was prepared as a racemic mixture.

[0388] LCMS: RT=1.87min, m / z=539.2[M+1] + ;

[0389] 1 H NMR (400MHz, MeOH-d4): δ8.33 (s, 1H), 7.87 (dd, J=0.8Hz, 7.2Hz, 1H), 7.78-7.74 (m, 1H ), 7.42 (t, J = 8.4Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 6.75-6.72 (m, 2H), 4.29-4.23 (m, 1H), 3.89-3.84(m, 1H), 3.65-3.53(m, 5H), 3.47-3.41(m, 1H), 3.00-2.93(m, 1H), 1.79-1.7 8(m, 1H), 1.65-1.46(m, 4H), 1.38-1.31(m, 1H), 1.23-1.15(m, 1H), 1.15-0.97(m, 6H).

[0390] Example 15: 12 -(6-ethoxypyridin-2-yl)-14-methoxy-6,7,8,9-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacycloundecene 5,5-dioxide compound 15

[0391] The target compound 15 (10.1 mg) was prepared by the same procedure as in Example 11, and was a racemic mixture.

[0392] LCMS: RT=1.71min, m / z=446.2[M+1] + ;

[0393] 1 H NMR (400MHz, MeOH-d4): δ7.74-7.70(m, 1H), 7.59-7.57(m, 1H), 7.43-7.38(m, 1H ), 6.92 (dd, J=0.8Hz, 8.4Hz, 1H), 6.74-6.70 (m, 2H), 4.42-4.37 (m, 1H), 4.13-4.0 7(m, 1H), 3.57-3.49(m, 4H), 3.38-3.32(m, 1H), 3.27-3.19(m, 1H), 3.00-2.94(m, 1H), 2.06-1.94(m, 2H), 1.84-1.76(m, 1H), 1.72-1.65(m, 1H), 1.05-1.01(m, 3H).

[0394] Example 16: 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide Compound 16

[0395] Following the same procedure as in Example 11, target compound 16 (6.3 mg) was prepared as a racemic mixture.

[0396] LCMS: RT=1.75min, m / z=460.2[M+1] + ;

[0397] 1H NMR (400MHz, MeOH-d4): δ7.72-7.68(m, 1H), 7.61-7.58(m, 1H), 7.42-7.38(m , 1H), 6.86-6.84(m, 1H), 6.72-6.69(m, 2H), 4.30-4.27(m, 1H), 4.12-4.07(m , 1H), 3.63(s, 3H), 3.51-3.46(m, 1H), 3.42-3.34(m, 1H), 3.11-3.06(m, 2H), 1.88-1.79 (m, 2H), 1.76-1.68 (m, 2H), 1.62-1.56 (m, 2H), 1.07-1.03 (m, 3H).

[0398] Example 17: (E)-1-(6-ethoxypyridin-2-yl)-15-fluoro-9,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 17

[0399] Following the same procedure as in Example 2, 2-amino-3-fluorophenol was used instead of 2-amino-3-methoxyphenol as the raw material to prepare target compound 17 (24.5 mg), which was a mixture of olefinic and trans bonds.

[0400] LCMS: RT=1.48, m / z=428.2[M+1] + ;

[0401] 1 H NMR (400MHz, MeOH-d4): δ8.41 (s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 7.52-7.48 (m, 1H), 6.93-6.88 (m, 2H), 5. 58-5.43 (m, 2H), 4.47-4.38 (m, 2H), 3.88-3.82 (m, 3H), 3.21-3.15 (m, 2H), 2.51-2.42 (m, 2H), 2.28 (s, 3H).

[0402] Example 18: (E)-1-(6-ethoxypyridin-2-yl)-9,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thio[4,6]diazacyclododecane 5,5-dioxide compound 18

[0403] Following the same procedure as in Example 2, 2-aminophenol was used instead of 2-amino-3-methoxyphenol as the raw material to prepare target compound 18 (37.9 mg), which was a mixture of olefinic and trans bonds.

[0404] LCMS: RT=1.71, m / z=428.2[M+1] + ;

[0405] 1 H NMR (400MHz, MeOH-d4): δ7.71-7.69 (m, 1H), 7.76-7.60 (m, 1H), 7.49-7.4 5(m, 2H), 7.27-7.22(m, 2H), 6.69-6.67(m, 1H), 5.45-5.38(m, 1H), 5.27- 5.23(m, 1H), 4.46-4.41(m, 1H), 4.22-4.17(m, 1H), 3.48-3.42(m, 1H), 3. 31-3.30 (m, 1H), 3.19-3.04 (m, 2H), 2.65-2.45 (m, 2H), 1.01-0.97 (m, 3H).

[0406] Example 19: (Z)-1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotridecene 5,5-dioxide compound 19;

[0407] (Z)-1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotridecene 5,5-dioxide compound 19A;

[0408] (Z)-1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotrideene 5,5-dioxide compound 19B

[0409] Following the same procedure as in Example 2, 4-bromobut-1-ene was used instead of 3-bromoprop-1-ene as the raw material to prepare target compound 19 (100 mg), which is a cis product.

[0410] LCMS: RT=1.90, m / z=472.3[M+1] + ;

[0411] 1 H NMR (400MHz, MeOH-d4): δ7.70-7.66(m, 1H), 7.59-7.57(m, 1H), 7.40-7.36(m, 1H), 6.75-6.68(m, 3H), 5.55-5.46( m, 2H), 4.16-411 (m, 2H), 3.68 (s, 3H), 3.51-3.38 (m, 2H), 3.23-3.18 (m, 2H), 2.50-2.31 (m, 4H), 1.09-1.06 (m, 3H).

[0412] Compound 19 (100 mg) was chirally resolved to give compound 19A (34 mg, yield: 34%) and compound 19B (33 mg, yield: 33%).

[0413] Chiral resolution conditions: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10um (Daicel); Column temperature: 25℃; Mobile phase: CO2 / [EtOH (0.2% NH3 (7M in MeOH)] (meaning ethanol mixed with 0.2% ammonia, which comes from a 7M ammonia methanol solution) = 65 / 35; Flow rate: 120ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 11.75min; Sample volume: 100mg sample dissolved in 24mL methanol; Injection volume: 4.5mL per injection.

[0414] Compound 19A:

[0415] Chiral column retention time: RT = 1.14 min;

[0416] LCMS: RT=1.45min, m / z=472.3[M+1] + ;

[0417] 1 H NMR (400MHz, MeOH-d4): δ7.70-7.66(m, 1H), 7.59-7.57(m, 1H), 7.40-7.36(m, 1H), 6.75-6.68(m, 3H), 5.58-5.46(m, 2H), 4.16-4.11(m, 2H), 3.67(s, 3H), 3.51-3.39(m, 2H), 3.24-3.14(m, 2H), 2.51-2.29(m, 4H), 1.07(t, J=7.2Hz, 3H).

[0418] Compound 19B:

[0419] Chiral column retention time: RT = 3.14 min;

[0420] LCMS: RT=1.45min, m / z=472.3[M+1] + ;

[0421] 1 H NMR (400MHz, MeOH-d4): δ7.70-7.66(m, 1H), 7.59-7.57(m, 1H), 7.40-7.36(m, 1H), 6.74-6.68(m, 3H), 5.59-5.44(m, 2H), 4.18-4.07 (m, 2H), 3.66 (s, 3H), 3.53-3.37 (m, 2H), 3.27-3.13 (m, 2H), 2.55-2.16 (m, 4H), 1.07 (t, J=7.2Hz, 3H).

[0422] Example 20: 1-(6-ethoxypyridin-2-yl)-17-methoxy-7,8,11,12-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,12]triazacyclohepten-9(10H)-one 5,5-dioxide compound 20

[0423] Step 1: Methyl 4-aminosulphobutyrate 20b

[0424] Methyl 4-(chlorosulfonyl)butyrate (200 mg, 1.0 mmol) was added to a microwave tube containing acetonitrile (5 mL) under ice-water bath conditions. Ammonia (5 mL) was then slowly added dropwise to the reaction mixture, which was stirred under ice-water bath conditions for 2 hours. The reaction mixture was concentrated under reduced pressure and added to a 10:1 mixture of dichloromethane and methanol (10 mL). The mixture was sonicated for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow liquid crude product (170 mg, yield: 94%).

[0425] 1 H NMR (500MHz, DMSO-d6): δ6.81 (s, 2H), 3.60 (s, 3H), 3.00 (t, J=7.5Hz, 2H), 2.48 (t, J=7.0Hz, 2H), 1.96-1.90 (m, 2H).

[0426] Step 2: 20 days of (2-(3-methoxy-2-nitrophenoxy)ethyl)carbamate tert-butyl ester

[0427] Potassium carbonate (1.24 g, 9.0 mmol) was added to a solution of 3-methoxy-2-nitrophenol (507 mg, 3.0 mmol) and (2-bromoethyl)carbamate tert-butyl ester (1 g, 4.5 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was reacted at 90 °C for 16 hours. Ethyl acetate (50 mL) was added, and the organic phase was washed three times with water (50 mL). The organic phase was dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give a yellow solid product (910 mg, yield: 97%).

[0428] LCMS: RT=1.90, m / z=213.1[M-100+1] + .

[0429] Step 3: (2-(2-amino-3-methoxyphenoxy)ethyl)tert-butyl carbamate 20e

[0430] At room temperature, palladium on carbon (167 mg) was added to a solution of tert-butyl (2-(3-methoxy-2-nitrophenoxy)ethyl)carbamate (835 mg, 2.68 mmol) in ethanol (10 mL), and the reaction was carried out at room temperature for 8 hours under hydrogen protection. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed 2-3 times with methanol (20 mL). The filtrates were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-2%) to give a brown crystalline solid product (677 mg, yield: 90%).

[0431] LCMS: RT=1.76, m / z=283.3[M+1] + .

[0432] Step 4: (2-(2-isothiocyano-3-methoxyphenoxy)ethyl)tert-butyl carbamate 20f

[0433] At room temperature, 585 mg (2.52 mmol) of 1,1′-thiocarbonylbis(pyridin-2(1H)-one) was added to a solution of tert-butyl (2-(2-amino-3-methoxyphenoxy)ethyl)carbamate (677 mg, 2.4 mmol, 1 eq) in dichloromethane (20 mL), and the reaction was carried out at room temperature for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to give a colorless oily product (638 mg, yield: 82%).

[0434] LCMS: RT=1.95, m / z=225.1[M-100+1] + .

[0435] Step 5: (Z)-4-(N-(((2-(2-(((tert-butoxycarbonyl)amino)ethoxy)-6-methoxyphenyl)imino)(2-(6-ethoxypyridinyl)hydrazyl)methyl)aminosulfonyl)butyrate methyl ester 20h

[0436] At room temperature, methyl 4-aminosulphobutyrate (170 mg, 0.94 mmol) and cesium carbonate (377 mg, 1.16 mmol) were added sequentially to a solution of tert-butyl (2-(2-isothiocyano-3-methoxyphenoxy)ethyl)carbamate (290 mg, 0.89 mmol) in acetonitrile (10 mL). The reaction mixture was then stirred overnight at room temperature. The reaction mixture was cooled to 0 °C in an ice-water bath, and then 6-ethoxypyridinyl hydrazine (170 mg, 0.94 mmol) and silver nitrate (320 mg, 1.88 mmol) were added sequentially to the above reaction mixture and stirred at 0 °C for 5 min, followed by stirring at room temperature for 5 min. The reaction mixture was directly concentrated under reduced pressure, dissolved in dichloromethane using a wet method, and then loaded onto a column. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to give a yellow solid product (475 mg, yield: 82%).

[0437] LCMS: RT=1.92, m / z=653.0[M+1] + .

[0438] Step 6: Methyl 4-(N-(4-(2-(2-aminoethoxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)aminosulfonyl)butyrate 20i

[0439] At room temperature, methanesulfonic acid (245 mg, 2.55 mmol) was added to a solution of (Z)-4-(N-(((2-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-methoxyphenyl)imino)(2-(6-ethoxypyridinyl)hydrazino)methyl)aminosulfonyl)butyrate (475 mg, 0.73 mmol) in 1,4-dioxane (10 mL). The reaction mixture was then placed in an oil bath preheated to 90 °C and reacted at this temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to Pre-HPLC (column: Ultimate Prep C18 5 μm 30 × 150 mm; mobile phase: A: water (0.2% FA) B: acetonitrile; gradient: 5-40% B in 8 min, stop at 16 min; flow rate: 30 mL / min) to prepare a white solid (235 mg, yield: 60%).

[0440] LCMS: RT=1.36, m / z=535.2[M+1]+ .

[0441] Step 7: 4-(N-(4-(2-(2-aminoethoxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)aminosulfonyl)butyric acid 20j

[0442] At room temperature, lithium hydroxide (32 mg, 1.32 mmol) was added to a 5:1 (6 mL) mixture of tetrahydrofuran and water in the form of methyl 4-(N-(4-(2-(2-aminoethoxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)aminosulfonyl)butyrate (235 mg, 0.44 mmol). The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, tetrahydrofuran (12 mL) was added, and the mixture was sonicated for 5 minutes and then filtered. The filter cake was washed three times with tetrahydrofuran (4 mL). The filtrate was concentrated under reduced pressure to give a yellow oily crude product (229 mg, yield: 100%), which was used directly in the next reaction without purification.

[0443] LCMS: RT=1.29, m / z=521.2[M+1] + .

[0444] Step 8: 1-(6-ethoxypyridin-2-yl)-17-methoxy-7,8,11,12-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,12]triazacyclohepten-9(10H)-one 5,5-dioxide compound 20

[0445] At room temperature, a 1-propylphosphonic anhydride solution (5 mL, 50% in EA) was added to a reaction mixture of 4-(N-(4-(2-(2-aminoethoxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)aminosulfonyl)butyric acid (220 mg, 0.42 mmol) and N,N-diisopropylethylamine (270 mg, 2.1 mmol) in tetrahydrofuran (20 mL). The reaction mixture was reacted at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to high performance liquid chromatography (HPLC) column (column: Boston Prep C18 10μm 21.2×250mm; mobile phase: A: water (0.2% FA) B: acetonitrile; gradient: 30%-60% B in 10min, stop at 16min; flow rate: 30ml / min) to obtain a yellow solid (4.0mg, yield: 2%).

[0446] LCMS: RT=1.67min, m / z=503.4[M+1] + ;

[0447] 1 H NMR (500MHz, DMSO-d6): δ13.20 (s, 1H), 7.89-7.86 (m, 1H), 7.80-7.76 (m, 1H), 7.5 7 (d, J=7.2Hz, 1H), 7.39 (t, J=8.4Hz, 1H), 6.82-6.74 (m, 3H), 4.08-4.04 (m, 1H), 3. 96-3.93(m, 1H), 3.62(s, 3H), 3.43-3.35(m, 2H), 3.30-3.28(m, 2H), 3.22-3.18(m , 1H), 2.91-2.87(m, 1H), 2.12-1.97(m, 2H), 1.90-1.86(m, 2H), 1.04-1.01(m, 3H).

[0448] Example 21: 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 21;

[0449] 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 21A;

[0450] 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 21B;

[0451] Following the same procedure as in Example 26, 3-methoxy-2-nitrophenol was used instead of 3-bromo-2-nitrophenol as the raw material to prepare target compound 21 (100 mg), which is a mixture of compound 21A and compound 21B.

[0452] LCMS: RT=1.54min, m / z=475.2[M+1] + ;

[0453] 1H NMR (400MHz, MeOH-d4): δ7.71 (t, J=8.4Hz, 1H), 7.65-7.64 (m, 1H), 7.47 (t, J=8 .4Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6.72 (d, J=8.4Hz, 1H), 5 .02(d, J=15.2Hz, 1H), 4.47(d, J=15.2Hz, 1H), 3.79-3.74(m, 1H), 3.70(s, 3H), 3.51-3.44(m, 2H), 3.41-3.35(m, 1H), 3.25-3.22(m, 1H), 1.06(t, J=7.2Hz, 3H).

[0454] Compound 21 (100 mg) was chirally resolved to give compound 21A (36 mg, yield: 36%) and compound 21B (36 mg, yield: 36%).

[0455] Chiral column separation conditions: Instrument: SFC-150 (Waters); Chiral column: OD 25*250mm, 10um (Daicel); Column temperature: 25℃; Mobile phase: CO2 / [MeOH(0.5% NH3(7MinMeOH))] (meaning methanol mixed with 0.5% ammonia, which comes from a 7M ammonia-methanol solution) = 60 / 40; Flow rate: 100ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 4.35min; Sample volume: 70mg sample dissolved in 20mL methanol; Injection volume: 4.0mL per injection.

[0456] Compound 21A:

[0457] Chiral column retention time: RT = 0.92 min;

[0458] LCMS: RT=1.25min, m / z=475.3[M+1] + ;

[0459] 1H NMR (400MHz, MeOH-d4): δ7.70 (t, J=8.0Hz, 1H), 7.65-7.63 (m, 1H), 7.46 (t, J=8 .4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6.71 (d, J=8.0Hz, 1H), 5 .02(d, J=15.2Hz, 1H), 4.46(d, J=15.2Hz, 1H), 3.80-3.74(m, 1H), 3.69(s, 3H), 3.53-3.42 (m, 2H), 3.40-3.34 (m, 1H), 3.26-3.20 (m, 2H), 1.06 (t, J=7.2Hz, 3H).

[0460] Compound 21B:

[0461] Chiral column retention time: RT = 1.30 min;

[0462] LCMS: RT=1.25min, m / z=475.3[M+1] + ;

[0463] 1 H NMR (400MHz, MeOH-d4): δ7.70 (t, J=8.0Hz, 1H), 7.65-7.63 (m, 1H), 7.46 (t, J=8 .4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.71 (d, J=8.0Hz, 1H), 5 .01(d, J=15.2Hz, 1H), 4.46(d, J=15.2Hz, 1H), 3.79-3.75(m, 1H), 3.69(s, 3H), 3.53-3.42 (m, 2H), 3.40-3.34 (m, 1H), 3.27-3.20 (m, 2H), 1.06 (t, J=7.2Hz, 3H).

[0464] Example 22: 15-Chloro-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 22

[0465] 15-Chloro-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 22A;

[0466] 15-Chloro-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 22B

[0467] Following the same procedure as in Example 26, 3-chloro-2-nitrophenol was used instead of 3-bromo-2-nitrophenol as the raw material to prepare target compound 22 (50 mg), which is a mixture of compound 22A and compound 22B.

[0468] Compound 22 (50 mg) was chirally resolved to give compound 22A (21 mg, yield: 42%) and compound 22B (18 mg, yield: 36%).

[0469] Chiral resolution conditions: Instrument: SFC-150 (Waters); Chiral column: AD 25*250mm, 10um (Daicel); Column temperature: Room temperature; Mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH))] (meaning methanol mixed with 0.2% ammonia, which comes from a 7M ammonia-methanol solution.) = 55 / 45; Flow rate: 120ml / min; Column pressure: 100bar; Detection wavelength: 214nm; Cycle time: 4.1min; Sample volume: 57mg sample dissolved in 8mL methanol and dichloromethane; Injection volume: 2.5mL per injection.

[0470] Compound 22A:

[0471] Chiral column retention time: RT = 1.03 min;

[0472] LCMS: RT=1.43min, m / z=479.1[M+1] + ;

[0473] 1 H NMR (400MHz, MeOH-d4): δ7.76-7.70 (m, 2H), 7.54-7.50 (m, 1H), 7.41 (d, J=8.4Hz, 1H), 7.28 (dd, J=0.8Hz, 8Hz, 1H), 6.75 (dd, J=1.6Hz, 7.6Hz, 1H), 5.00 (d, J=15.2Hz, 1H), 4.51 (d, J=15.2Hz, 1H), 3.74-3.71 (m, 1H), 3.53- 3.48 (m, 1H), 3.42-3.34 (m, 2H), 3.27-3.24 (m, 2H), 1.06 (t, J=7.2Hz, 3H).

[0474] Compound 22B:

[0475] Chiral column retention time: RT = 1.59 min;

[0476] LCMS: RT=1.43min, m / z=479.1[M+1] + ;

[0477] 1 H NMR (400MHz, MeOH-d4): δ7.75-7.70 (m, 2H), 7.53-7.49 (m, 1H), 7.40 (d, J=8.8Hz, 1H), 7.28 (d, J=8Hz, 1H), 6.74 (d, J=7.2Hz, 1H), 5.00 (d, J=14.8Hz, 1H), 4.50 (d, J=14.8Hz, 1H), 3.72-3.71 (m, 1H), 3.52-3.48 (m, 1H), 3.41-3.34 (m, 2H), 3.28-3.24 (m, 2H), 1.06 (t, J=7.2Hz, 3H).

[0478] Example 23: 15-Chloro-1-(6-ethoxypyridin-2-yl)-8-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 23

[0479] Following the same procedure as in Example 25, using compound 21 as a raw material, target compound 23 (11 mg) was prepared as a white solid.

[0480] LCMS: RT=1.38min, m / z=493.3[M+1] + ;

[0481] 1H NMR (400MHz, DMSO-d6): 13.75 (s, 1H), 7.82 (t, J=8Hz, 1H), 7.69-7.65 (m, 1 H), 7.58-7.51 (m, 1H), 7.33-7.25 (m, 2H), 6.83 (d, J=8.4Hz, 1H), 4.99 (d, J =12.4Hz, 1H), 4.81-4.49(m, 1H), 4.20-3.73(m, 1H), 3.55-3.47(m, 1H), 3. 32-3.23 (m, 3H), 3.09-3.00 (m, 1H), 2.86-2.76 (m, 3H), 1.02-0.98 (m, 3H).

[0482] Example 24: (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24A;

[0483] (Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24B;

[0484] (R,E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24C;

[0485] (S,E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24D;

[0486] (R,Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24E;

[0487] (S,Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24F;

[0488] Step 1: N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide 24b

[0489] At room temperature, 5.6 g (35.7 mmol) of 1-(chloromethyl)-4-methoxybenzene 24a was added to a mixed solution of but-3-ene-1-sulfonamide (1.6 g, 11.9 mmol), potassium carbonate (8.21 g, 59.5 mmol), and 2-butanone (50 mL). The reaction mixture was reacted at 75 °C for 24 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed twice with methanol, and the filtrates were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5-10%) to give compound 24b (3.38 g, yield: 76%) as a colorless liquid. LCMS: RT = 1.95 min, m / z = 398.0 [M + Na] + .

[0490] Step 2: N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide 24c

[0491] At room temperature, N,N-bis(4-methoxybenzyl)but-3-ene-1-sulfonamide 24b (750 mg, 2.0 mmol) was added to tetrahydrofuran (10 mL), then purged three times with nitrogen and cooled to -78 °C. A tetrahydrofuran solution of n-butyllithium (1 mL, 2.4 mmol, 2.5 M) was slowly added dropwise to the reaction solution and stirred at -78 °C for 1 hour. Then, a tetrahydrofuran solution of iodomethane (568 mg, 4 mmol) was slowly added dropwise to the reaction solution and stirred at the same temperature for 1 hour. The reaction solution was quenched with saturated brine and then extracted three times with ethyl acetate (150 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5-10%) to obtain 24c (560 mg, yield: 76%) as a white solid. LCMS: RT=1.99min, m / z=412[M+Na] + .

[0492] Step 3: Pentyl-4-ene-2-sulfonamide 24d

[0493] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of N,N-bis(4-methoxybenzyl)pent-4-ene-2-sulfonamide (560 mg, 1.44 mmol) in dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (150 mL), the organic phases were combined and dried, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 35%) to obtain 24d (200 mg, yield: 93%).

[0494] Step 4: 24g of N′-(2-(allyloxy)-6-methoxyphenyl)-2-(6-methoxypyridinyl)-N-(pent-4-en-2-ylsulfonyl)hydrazine-1-carboximide

[0495] At room temperature, pent-4-ene-2-sulfonamide 24d (112 mg, 0.75 mol) and cesium carbonate (319 mg, 0.98 mmol) were successively added to a solution of 1-(allyloxy)-2-isothiocyanate-3-methoxybenzene (166 mg, 0.75 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C in an ice-water bath, and 6-ethoxypyridinyl hydrazine (136 mg, 0.75 mmol) and silver nitrate (382 mg, 2.25 mmol) were successively added to the above reaction mixture and stirred at 0 °C for 5 min, then stirred at room temperature for 10 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10%) to give 24 g (299 mg, yield: 77%) as a yellow liquid. LCMS: RT=1.84min, m / z=518.4[M+1] + .

[0496] Step 5: N-(4-(2-9-allyloxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)pent-4-ene-2-sulfonamide for 24 hours

[0497] At room temperature, methanesulfonic acid (167 mg, 1.74 mmol) was added to a solution of N′-(2-(allyloxy)-6-methoxyphenyl)-2-(6-methoxypyridinyl)-N-(pent-4-en-2-ylsulfonyl)hydrazide-1-carboximide (24 g, 299 mg, 0.58 mmol) in 1,4-dioxane (10 mL). The reaction mixture was then placed in an oil bath preheated to 90 °C and reacted at this temperature for 2 hours. The reaction mixture was cooled to room temperature, transferred to a single-necked flask, neutralized with saturated sodium carbonate solution, and extracted three times with dichloromethane:methanol = 10:1 (50 mL). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10%) to obtain a yellow solid product (240 mg, yield: 83%). LCMS: RT=1.91min, m / z=500.2[M+1] + .

[0498] Step 6: (E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24A;

[0499] *Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24B;

[0500] At room temperature, Grubbs II (24 mg, 0.1 eq) was added to N-(4-(2-9-allyloxy)-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)pent-4-ene-2-sulfonamide 24h (240 mg, 0.48 mmol) in 240 mL of dry dichloromethane. The reaction mixture was then protected with nitrogen and placed in an oil bath heated to 50 °C, where it was reacted for 1 hour. The reaction mixture was cooled to room temperature. Water (100 mL) was added, and the aqueous phase was extracted twice with dichloromethane (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was subjected to preparative high-performance liquid chromatography (HPLC) (column: Ultimate Prep C18 10μm 21.2×250mm; mobile phase: A: water (0.1% TFA), B: acetonitrile; gradient: 40-70% B in 8 min, stop at 8 min; flow rate: 30 mL / min) to give compound 24A (30 mg, yield: 26.5%) and compound 24B (30 mg, yield: 26.5%). The products were yellow solid isomers. LCMS: RT = 1.75 min, m / z = 472.3 [M+1] + .

[0501] Step 7: (R,E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24C;

[0502] (S,E)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24D;

[0503] (R,Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24E;

[0504] (S,Z)-1-(6-ethoxypyridin-2-yl)-15-methoxy-6-methyl-7,10-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclododecane 5,5-dioxide compound 24F;

[0505] Compound 24A (30 mg) was purified again by alkaline high-performance liquid chromatography (column: Ultimate Prep C18 10 μm 21.2 × 250 mm; mobile phase: A: water (10 mmol NH4HCO3) B: acetonitrile; gradient: 32-62% B in 8 min, stop at 16 min; flow rate: 30 ml / mm) to obtain compounds 24C and 24D.

[0506] Compound 24C: 8.1 mg, is a white solid.

[0507] LCMS: RT=1.54min, m / z=472.3[M+1] + .

[0508] 1 H NMR (400MHz, DMSO-d6): δ7.64-7.56 (m, 2H), 7.28 (t, J=8.4Hz, 1H), 6.86 (d, J=8.4H , 1H), 6.78 (d, J=8.0Hz, 1H), 6.53 (d, J=7.6Hz, 1H), 5.61-5.53 (m, 1H), 5.36-5.29 (m 1H), 4.44-4.39(m, 1H), 4.19-4.15(m, 1H), 3.71(m, 3H), 3.62-3.55(m, 1H), 3.39-3.34(m , 2H), 3.22-3.18 (m, 1H), 2.21-2.14 (m, 1H), 1.18 (d, J=6.8Hz, 3H), 0.96 (t, J=7.2Hz, 3H).

[0509] Compound 24D: 2.5 mg, is a white solid.

[0510] LCMS: RT=1.74min, m / z=472.3[M+1] + .

[0511] 1H NMR (400MHz, DMSO-d6): δ7.76 (t, J=8.0Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.40 (t, J=8.4Hz, 1H), 6.90 (t, J=8.8Hz, 2H), 6.74 (d, J=8.4Hz, 1H), 5.50-5.42 (m, 1H), 5.17-5.09 (m, 1H), 4.44-4.40 (m, 1H), 4.25-4.20 (m, 1H), 3.76 (s, 3H), 3.42-3.36(m, 1H), 3.26-3.18(m, 1H), 3.03-2.99(m, 1H), 2.34-2.25(m 2H), 1.22 (d, J=6.8Hz, 3H), 0.97 (t, J=7.2Hz, 3H).

[0512] Compound 24B (30 mg) was purified by alkaline high-performance liquid chromatography (column: Ultimate Prep C18 10 μm 21.2 × 250 mm; mobile phase: A: water (10 mmol NH4HCO3) B: acetonitrile; gradient: 30-60% B in 8 min, stop at 16 min; flow rate: 30 ml / mm) to obtain compounds 24E and 24F.

[0513] Compound 24E: 11.9 mg, is a white solid.

[0514] LCMS: RT=1.51min, m / z=472.3[M+1] + .

[0515] 1 H NMR (400MHz, DMSO-d6): δ7.64-7.55 (m, 2H), 7.28 (t, J=8.4Hz, 1H), 6.74-6.71 (m, 2H), 6.52 (d, J=8.0Hz, 1H), 6.08 (s, 1H), 5.84-5.78 (m, 1H), 5.67-5.61 (m, 1 H), 4.39-4.26 (m, 2H), 3.62 (s, 3H), 3.40-3.34 (m, 1H), 3.31-3.25 (m, 1H), 2.93 -2.86 (m, 2H), 1.61-1.56 (m, 1H), 1.25 (d, J=6.8Hz, 3H), 0.98 (t, J=7.2Hz, 3H).

[0516] Compound 24F: 1.5 mg, a brown solid.

[0517] LCMS: RT=1.60min, m / z=472.3[M+1] + .

[0518] 1 H NMR (400MHz, DMSO-d6): δ7.74 (t, J=8.0Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.34 (t, J=8.4Hz, 1H), 6.78 -6.70(m, 3H), 5.71-5.65(m, 2H), 4.72-4.58(m, 2H), 3.55(s, 3H), 3.41-3.34(m, 2H), 2.97-2.91(m 1H), 1.83-1.76 (m, 1H), 1.21 (d, J=6.8Hz, 3H), 0.99 (t, J=7.2Hz, 3H).

[0519] Example 25: 1-(6-ethoxypyridin-2-yl)-15-methoxy-8-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 25

[0520] Sodium hydride (4 mg, 0.106 mmol, 60%) was added to a solution of 1-(6-ethoxypyridin-2-yl)-15-methoxy-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 21 (25 mg, 0.053 mmol) in N,N-dimethylformamide (3 mL) under ice water conditions, and stirred for 20 minutes at the same temperature. Then, iodomethane (15 mg, 0.106 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography to give compound 25 (10 mg, yield: 38%) of 1-(6-ethoxypyridin-2-yl)-15-methoxy-8-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide, as a white solid.

[0521] Preparative high performance liquid chromatography method: Column: Ultimate Prep C18 10μm 30×150mm; Mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 18%-48% B in 10min, stop at 16min; Flow rate (ml / min): 30; Retention time (min): 97; Wavelength (nm): 214 / 254;

[0522] LCMS: RT=1.39min, m / z=489.1[M+1] + .

[0523] 1 H NMR (400MHz, DMSO-d6): 13.62 (s, 1H), 7.82-7.76 (m, 1H), 7.63-7.56 (m, 1H), 7.47 -7.40 (m, 1H), 6.87-6.78 (m, 3H), 4.95-4.91 (m, 1H), 4.75-4.41 (m, 1H), 4.22-4.0 2(m, 1H), 3.87-3.81(m, 1H), 3.71-3.59(m, 1H), 3.53-3.44(m, 3H), 3.42-3.35(m, 1H), 3.30-3.24(m, 2H), 3.02-2.95(m, 1H), 2,85-2.76(m, 3H), 1.02-0.98(m, 3H).

[0524] Example 26: 15-bromo-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide Compound 26

[0525] Step 1: 2-(3-bromo-2-nitrophenoxy)tert-butyl acetate 26b

[0526] At room temperature, 3-bromo-2-nitrophenol (2.0 g, 9.22 mmol) was dissolved in (40 mL) N,N-dimethylformamide solution. Potassium carbonate (2.54 g, 18.4 mmol) and tert-butyl 2-bromoacetate (2.70 g, 13.8 mmol) were added sequentially to the reaction mixture. The reaction mixture was then stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was extracted three times with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5%) to give 26b as a white solid (2.5 g, yield: 81.9%). LCMS: RT = 1.20 min, m / z = 276.0 [M-56+1] + .

[0527] Step 2: 2-(2-amino-3-bromophenoxy)tert-butyl acetate 26c

[0528] At room temperature, 2.5 g (7.33 mmol) of 2-(3-bromo-2-nitrophenoxy)tert-butyl acetate 26b was dissolved in 50 mL of ethanol and water (10:1). Then, iron powder (2.11 g, 37.8 mmol) and ammonium chloride (2.04 g, 37.8 mmol) were added to the mixture. The reaction mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and washed three times with methanol (50 mL). After the organic phase was evaporated to dryness, 100 mL of water was added, and the mixture was extracted three times with dichloromethane:methanol (10:1, 100 mL). The organic phase was directly dried, and evaporated to dryness to obtain 26c (2.3 g), a yellow oily crude product. LCMS: RT = 1.38 min, m / z = 246.0 [M-56+1] + .

[0529] Step 3: 2-(3-bromo-2-isothiocyanophenoxy)tert-butyl acetate 26d

[0530] 26c of 62-(2-amino-3-bromophenoxy)acetic acid tert-butyl ester (1.0 g, 3.32 mmol) was dissolved in 20 mL of dichloromethane at room temperature, followed by the addition of 1,1′-thiocarbonylbis(pyridin-2(1H)-one) (0.770 g, 3.32 mmol). The reaction mixture was stirred overnight at room temperature. The reaction solution was directly evaporated to dryness to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5%) to give 26d (940 mg, yield: 82.5%) as a white solid. LCMS: RT = 1.51 mon, m / z = 288.0 [M-56+1] + .

[0531] Step 4: (E)-2-(3-bromo-2-((((2-((tert-butoxycarbonyl)amino)ethyl)sulfonamide)(2-(6-ethoxypyridinyl)hydrazine)methylene)amino)phenoxy)tert-butyl acetate 26g

[0532] 26g (940mg, 2.74mmol) of 2-(3-bromo-2-isothiocyanophenoxy)acetic acid tert-butyl ester was dissolved in 15mL of acetonitrile solution at room temperature. Then, tert-butyl (2-aminosulfonylethyl)carbamate (921mg, 4.11mmol) and cesium carbonate (1.79g, 5.48mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C in an ice-water bath. 6-ethoxypyridinyl hydrazide (521mg, 2.88mmol) and silver nitrate (931mg, 5.48mmol) were added sequentially to the reaction mixture, and the mixture was stirred at 0°C for 10 minutes. The reaction mixture was directly evaporated to dryness, wet-processed, and purified by silica gel column chromatography (dichloromethane:methanol = 8%) to obtain 26g (2g, yield: 85.9%) as a pure yellow solid. LCMS: RT = 1.41min, m / z = 715.2 [M+1] + .

[0533] Step 5: 2-(2-(3-((2-aminoethyl)sulfonamido)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-bromophenoxy)acetic acid for 26 hours

[0534] At room temperature, 26 g (1.6 g, 2.24 mmol) of (E)-2-(3-bromo-2-((((2-((tert-butyloxycarbonyl)amino)ethyl)sulfonamide)(2-(6-ethoxypyridinyl)hydrazyl)methylene)amino)phenoxy)tert-butyl acetate was dissolved in 20 mL of 1,4-dioxane, followed by the addition of 1.07 g (11.2 mmol) of methanesulfonic acid at room temperature. The reaction mixture was stirred overnight at 90 °C. The reaction mixture was directly evaporated to dryness to give a yellow crude product. The crude product was purified by C18 preparative column chromatography (0.1% NH4HCO3 aqueous solution: acetonitrile = 15%) to give a white solid product (900 mg, yield: 74.4%) after 26 h. LCMS: RT = 0.96 min, m / z = 541.0 [M+1] + .

[0535] Step 6: 15-Bromo-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 26

[0536] At room temperature, 2-(2-(3-((2-aminoethyl)sulfonamido)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-bromophenoxy)acetic acid 26h (100 mg, 0.185 mmol) was dissolved in 20 mL of ethyl acetate, followed by the addition of 50% ethyl acetate solution of 1-propionic cycloanhydride (0.5 mL) and N,N-diisopropylethylamine (215 mg, 1.67 mmol), and stirred overnight at 60 °C. A saturated aqueous solution of sodium bicarbonate (50 mL) was added to the reaction mixture, and the aqueous phase was extracted three times with a mixed solvent of dichloromethane and tetrahydrofuran (10:1, 100 mL). The organic phase was dried, filtered, and evaporated to dryness to give the crude product. This crude product was subjected to reverse preparative high-performance liquid chromatography to give compound 26 (30 mg, yield: 31.0%) as a white solid.

[0537] LCMS: RT=1.44min, m / z=523.0[M+1] + ;

[0538] 1 H NMR (400MHz, MeOH-d4): δ7.76-7.71 (m, 2H), 7.46-7.43 (m, 3H), 6.76-6.74 (m, 1H), 5.00 (d, J=15.2Hz, 1H), 4.50 (d, J=14.8Hz, 1H), 3.76-3.69 (m, 1H), 3.54-3.47 (m, 1H), 3.42-3.34 (m, 2H), 3.27-3.24 (m, 2H), 1.06 (t, J=7.2Hz, 3H);

[0539] Reverse preparative high performance liquid chromatography conditions: Column: Boston Prep C18 10μm 21.2×250mm; Mobile phase: A: water (0.2% FA) B: acetonitrile; Gradient: 35-55% in 8min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 10.5 / 11.5; Wavelength (nm): 214 / 254.

[0540] Example 27: 1-(6-ethoxypyridin-2-yl)-15-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 27

[0541] At room temperature, 15-bromo-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 26 (50 mg, 0.0957 mmol) was dissolved in (10 mL) of a mixture of 1,4-dioxane and water (10:1), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (14.0 mg, 0.0192 mmol), cesium carbonate (62.5 mg, 0.192 mmol), and trimethylboroxane (3.5 M in). THF (1 ml) was stirred at 130 °C for 4 hours. The reaction mixture was filtered with diatomaceous earth, and the filter cake was washed three times with ethyl acetate (50 ml). The organic phase was then evaporated to dryness to give the crude product. This crude product was subjected to reverse preparative high performance liquid chromatography to give compound 27 (10.6 mg, yield: 24.2%) as a white solid.

[0542] LCMS: RT=1.40min, m / z=459.3[M+1] + ;

[0543] 1 H NMR (400MHz, MeOH-d4): δ7.74-7.67 (m, 2H), 7.40 (t, J=8Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.07 (d, J=7.6Hz, 1H), 6.73-6.71 (m, 1H), 4.95 ( d, J=15.2Hz, 1H), 4.41 (d, J=15.2Hz, 1H), 3.80-3.74 (m, 1H), 3.48-3.34 (m, 3H), 3.27-3.18 (m, 2H), 2.11 (s, 2H), 1.05 (t, J=7.2Hz, 3H);

[0544] Reverse preparative high performance liquid chromatography conditions: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 15%-45% B in 8min, stop at 19min; Flow rate: 30ml / min; Retention time (min): 10; Wavelength (nm): 214 / 254.

[0545] Example 28: 1-(6-ethoxypyridin-2-yl)-15-vinyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 28

[0546] At room temperature, 20 mg (0.0383 mmol) of 15-bromo-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 26 was dissolved in (10 mL) of a mixed solution of 1,4-dioxane and water (10:1), and then [1,1'-bis(diphenylphosphine)dicenocene] was added. [Iron] Palladium dichloride (5.61 mg, 0.00766 mmol), cesium carbonate (25.0 mg, 0.0766 mmol), and potassium vinyltrifluoroborate (10.3 mg, 0.0766 mmol) were mixed and stirred at 120 °C for 4 hours. The reaction mixture was filtered with diatomaceous earth, and the filter cake was washed three times with ethyl acetate (50 mL). The organic phase was then evaporated to dryness to give the crude product, which was purified by reverse preparative high performance liquid chromatography to give compound 28 (4.1 mg, yield: 2.8%) as a white solid.

[0547] LCMS: RT=1.42min, m / z=471.3[M+1] + ;

[0548] 1 H NMR (400MHz, MeOH-d4): δ7.72-7.65 (m, 2H), 7.48 (t, J=8Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 7.29 (d, J = 8Hz, 1H), 6.69-6.67 (m, 1H), 6.45-6.37 (m, 1H), 5.73 (d, J = 17 .6Hz, 1H), 5.29 (d, J=11.2Hz, 1H), 4.97 (d, J=15.2Hz, 1H), 4.42 (d, J=15.2Hz, 1 H), 3.80-3.74(m, 1H), 3.48-3.35(m, 4H), 3.23-3.17(m, 1H), 1.05-1.01(m, 3H);

[0549] Reverse preparative high performance liquid chromatography conditions: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 10%-40% B in 8min, stop at 19min; Flow rate: 30ml / min; Retention time (min): 10.5; Wavelength (nm): 214 / 254.

[0550] Example 29: 1-(6-ethoxypyridin-2-yl)-15-ethyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide Compound 29

[0551] At room temperature, 1-(6-ethoxypyridin-2-yl)-15-vinyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 28 (18 mg, 0.0383 mmol) was dissolved in 5 mL of ethanol solution, and then palladium on carbon (5.0 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was filtered with diatomaceous earth, the filter cake was washed three times with ethanol (5 mL), and the organic phase was then evaporated to give a crude product. The crude product was lyophilized to give compound 29 (11.4 mg, yield: 63%) as a white solid.

[0552] LCMS: RT=1.26min, m / z=473.0[M+1] + ;

[0553] 1 H NMR (400MHz, MeOH-d4): δ7.73-7.67 (m, 2H), 7.48-7.44 (m, 1H), 7.23 (d, J=8Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 6.72 (dd, J=1.6Hz, 7.2Hz, 1H), 4. 97(d, J=15.2Hz, 1H), 4.41(d, J=15.2Hz, 1H), 3.81-3.75(m, 1H), 3.46- 3.33(m,3H), 3.27-3.22(m,2H), 2.44-2.37(m,2H), 1.10-1.02(m,6H).

[0554] Example 30: 15-(1,2-dihydroxyethyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 30A;

[0555] 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxaldehyde 5,5-dioxide compound 30B;

[0556] 1-(6-ethoxypyridin-2-yl)-15-(hydroxymethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 30C

[0557] Step 1: 15-(1,2-dihydroxyethyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 30A;

[0558] At room temperature, 1-(6-ethoxypyridin-2-yl)-15-vinyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 28 (40 mg, 0.0851 mmol) was dissolved in a mixture of tert-butanol and water (10 mL, 7:1), and then N-methylmorphine oxide (9.96 mg, 0.0851 mmol) and osmium tetroxide (0.1 M aqueous solution, 0.2 mL) were added and stirred overnight at room temperature. The reaction mixture was evaporated to dryness, filtered to give crude product, and purified by high performance liquid chromatography to give compound 30A (3.6 mg, yield: 8.4%) as a pale yellow solid.

[0559] LCMS: RT=1.27min, m / z=505.3[M+1] + ;

[0560] 1H NMR (400MHz, MeOH-d4): δ7.73-7.67(m, 2H), 7.53-7.48(m, 1H), 7.37-7.27(m, 2H), 6.69-6.66 (m, 1H), 5.00-4.96 (m, 1H), 4.41-4.37 (m, 1H), 5.73 (d, J=17.6 Hz, 1H), 5.29 (d, J=11.2Hz, 1H), 4.97 (d, J=15.2Hz, 1H), 4.42 (d, J=15.2Hz, 1H ), 3.86-3.75(m,2H), 3.49-3.32(m,5H), 3.27-3.15(m,2H), 1.05-1.02(m,3H);

[0561] High performance liquid chromatography method: Column: Ultimate Prep C18 10μm 30×150mm; Mobile phase: A: water (10mMNH4HCO3), B: CAN; Gradient: 10%-40% B in 10min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 2.3 / 9.2 / 9.5; Wavelength (nm): 214 / 254.

[0562] Step 2: 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxaldehyde 5,5-dioxide compound 30B

[0563] At room temperature, 15-(1,2-dihydroxyethyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 30A (40 mg, 0.0794 mmol) was dissolved in a mixture of tert-butanol and water (5 mL, 7:1), and then sodium periodate (25.5 mg, 0.119 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was extracted three times with dichloromethane:tetrahydrofuran (10:1, 100 mL), the organic phase was dried, filtered, and evaporated to dryness to give crude product, which was purified by high performance liquid chromatography to give compound 30B (8.7 mg, yield: 23.2%) as a white solid.

[0564] LCMS: RT=1.35min, m / z=473.3[M+1] + ;

[0565] 1 H NMR (400MHz, MeOH-d4): δ9.88 (s, 1H), 7.70-7.63 (m, 3H), 7.62-7.45 (m, 1H), 7.41-7.31 (m, 1H), 6.63-6.59 (m, 1H), 5.03-4.9 8(m, 1H), 4.46-4.39(m, 1H), 3.80-3.74(m, 1H), 3.61-3.37(m, 3H), 3.29-3.24(m, 1H), 3.14-3.05(m, 1H), 1.06-1.00(m, 3H);

[0566] High performance liquid chromatography method: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 2%-35% B in 8min, stop at 19min; Flow rate: 30ml / min; Retention time (min): 12; Wavelength (nm): 214 / 254.

[0567] Step 3: 1-(6-ethoxypyridin-2-yl)-15-(hydroxymethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 30C

[0568] At room temperature, 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxaldehyde 5,5-dioxide compound 30B (30 mg, 0.0636 mmol) was dissolved in 5 mL of methanol solution, and then sodium borohydride (4.83 mg, 0.127 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was quenched with 1 mL of water, and the mixture was then evaporated to dryness to obtain the crude product, which was purified by high performance liquid chromatography to give compound 30C (12 mg, yield: 39.8%) as a white solid.

[0569] LCMS: RT=1.32min, m / z=475.3[M+1] + ;

[0570] 1H NMR (400MHz, MeOH-d4): δ7.73-7.66 (m, 2H), 7.54-7.50 (m, 1H), 7.33-7.30 (m, 2H), 6.72-6.70 (m, 1H), 4.98-4. 95 (m, 1H), 4.48-4.38 (m, 3H), 3.76-3.74 (m, 1H), 3.46-3.34 (m, 3H), 3.26-3.21 (m, 2H), 1.05 (t, J = 7.2Hz, 3H);

[0571] High performance liquid chromatography method: Column: Boston Prep C18 10μm 21.2×250mm; Mobile phase: A: water (0.2% FA) B: acetonitrile; Gradient: 25-45% in 8min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 10.0-10.7; Wavelength (nm): 214 / 254.

[0572] Example 31: 15-((dimethylamino)methyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 31

[0573] At room temperature, 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecene-15-carboxaldehyde 5,5-dioxide compound 30B (30 mg, 0.0636 mmol) was dissolved in (3 mL) methanol solution, followed by the addition of a methanol solution of dimethylamine (3.5 M, 0. 0.2 mL of water was added to the reaction mixture and stirred at room temperature for 10 minutes. Acetic acid (1 drop) and sodium cyanoborohydride (8.01 mg, 0.127 mmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 0.2 mL of water was added to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain compound 31 (11.3 mg, yield: 35.5%), which was a white solid.

[0574] High Performance Liquid Chromatography (HPLC) Method: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile Phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 5%-40% B in 8min, stop at 19min; Flow Rate (ml / min): 30; Retention Time (min): 10; Wavelength (nm): 214 / 254;

[0575] LCMS: RT=1.40min, m / z=502.2[M+1] + ;

[0576] 1 H NMR (400MHz, MeOH-d4): δ8.18 (s, 2H), 7.72-7.71 (m, 2H), 7.65-7.61 (m, 1H), 7.53-7.51 (m, 1H), 7.40-7.38 (m, 1H), 6.71-6.69 (m, 1H), 4.85- 4.81(m, 1H), 4.42(d, J=14.8Hz, 1H), 4.21-4.10(m, 2H), 3.74-3.69(m , 1H), 3.49-3.37(m, 3H), 3.26(m, 2H), 2.74(s, 6H), 1.08-1.04(m, 3H).

[0577] Example 32: 1-(6-ethoxypyridin-2-yl)-15-(trifluoromethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 32

[0578] Following the same procedure as in Example 26, 3-trifluoromethyl-2-nitrophenol was used instead of 3-bromo-2-nitrophenol as the raw material to prepare target compound 32 (26.4 mg), which was a racemic mixture.

[0579] High Performance Liquid Chromatography (HPLC) Method: Column: Ultimate Prep C18 10μm 30×150mm; Mobile Phase: Water (10mM NH4HCO3)B: Acetonitrile; Gradient: 20%-50% in 10min, stop at 16min; Flow Rate: 30ml / min; Retention Time (min): 10; Wavelength (nm): 214 / 254;

[0580] LCMS: RT=1.46min, m / z=513.2[M+1]+ ;

[0581] 1 H NMR (400MHz, MeOH-d4): δ7.78-7.70 (m, 4H), 7.53 (d, J=7.6Hz, 1H), 6.73-6.69 (m, 1H), 5.06 (d, J=14.8 Hz, 1H), 4.52 (d, J=14.4Hz, 1H), 3.70-3.68 (m, 1H), 3.52-3.48 (m, 1H), 3.33-3.31 (m, 1H), 3.30-3.15 (m 3H), 1.03 (t, J=7.2Hz, 3H).

[0582] Example 33: 1-(6-ethoxypyridin-2-yl)-15-methoxy-6,7,9,10-tetrahydro-4H-benzo[k][1,2,4]triazolo[3,4-i][1,4]dioxa[7]thio[8,10]diazacyclododecane 5,5-dioxide Compound 33

[0583] Step 1: 2-(2-bromoethoxy)ethane-1-sulfonyl chloride 33b

[0584] At room temperature, thiourea (1.5 g, 19.85 mmol) was added to a solution of 1-bromo-2-(2-bromoethoxy)ethane 33a (2.5 mL, 19.85 mmol) in ethanol (30 mL). The reaction mixture was refluxed and stirred for 30 minutes under nitrogen protection. The reaction mixture was evaporated to dryness to give a crude product, which was dissolved in 7 mL of acetonitrile. Then, a solution of N-chlorosuccinimide (10.6 g, 80 mmol), acetonitrile (25 mL), and 2M hydrochloric acid (6.5 mL) was added dropwise at -10 °C. The reaction mixture was stirred at -10 °C for 30 minutes. The solvent was evaporated to dryness, filtered, and the filter cake was washed with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1). The filtrates were combined and evaporated to dryness to give 33b (5.0 g, yield: 100%), a yellow liquid crude product, which was used directly for the next step.

[0585] 1 H NMR (400MHz, CDCl3): δ4.00 (t, =5.6Hz, 2H), 4.12 (t, J =5.6Hz, 2H), 3.88, (t, J =5.9Hz, 2H), 3.50 (t, J =5.9Hz, 2H).

[0586] Step 2: 2-(2-bromoethoxy)ethane-1-sulfonamide 33c

[0587] 10 mL of ammonia solution was slowly added dropwise at 0 °C to a mixed solution of 2-(2-bromoethoxy)ethane-1-sulfonyl chloride 33b (5 g, 19.85 mmol) and dioxane, and stirred at the same temperature for 30 minutes. The reaction solution was then slowly heated to 22 °C and stirred for 1 hour. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to obtain 33c (1.2 g, yield: 26%), which was a colorless oily liquid.

[0588] 1 H NMR (500MHz, DMSO-d6): δ6.78 (bs, 2H), 3.81 (t, J=6.5Hz, 2H), 3.75 (t, J=6.0Hz, 2H), 3.60 (t, J=6.0Hz, 2H), 3.27 (t, J=6.5Hz, 2H).

[0589] Step 3: 2-(2-(3-methoxy-2-nitrophenoxy)ethoxy)ethane-1-sulfonamide 33d

[0590] At room temperature, 2-(2-bromoethoxy)ethane-1-sulfonamide 33c (485 mg, 2.01 mmol) and potassium carbonate (552 mg, 4 mmol) were sequentially added to 3-methoxy-2-nitrophenol (338 mg, 2.0 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was then heated to 80 °C and stirred at this temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (80 mL) and ethyl acetate (50 mL). The aqueous phase was then separated, and the organic phase was washed once with water (50 mL) and once with saturated brine (50 mL). The aqueous phases were combined and extracted once with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 50%-60%) to give 33d (600 mg, yield: 94%) as a yellow solid.

[0591] LCMS: RT=1.44min, m / z=321.0[M+1] + .

[0592] Step 4: 2-(2-(2-amino-3-methoxyphenoxy)ethoxy)ethane-1-sulfonamide 33e

[0593] At room temperature, palladium on carbon (44 mg, 20%) was added to a methanol (5 mL) solution of 2-(2-(3-methoxy-2-nitrophenoxy)ethoxy)ethane-1-sulfonamide 33d (224 mg, 0.7 mmol). The reaction mixture was purged three times with a hydrogen balloon and reacted at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed twice with 30 mL of methanol. The filtrates were combined and evaporated to dryness to give 33e (180 mg, yield: 92%) as a yellow solid.

[0594] LCMS: RT=0.89min, m / z=291.0[M+1] + .

[0595] Step 5: 2-(2-(2-isothiocyano-3-methoxyphenoxy)ethoxy)ethane-1-sulfonamide 33f

[0596] At room temperature, 1,1-thiocarbonylbis-2(1H)-pyridine (158 mg, 0.68 mmol) was added to a solution of 2-(2-(2-amino-3-methoxyphenoxy)ethoxy)ethane-1-sulfonamide 33e (180 mg, 0.62 mmol) in 10 mL of dichloromethane. The reaction mixture was reacted at room temperature for 16 hours under nitrogen protection. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (eluent: dichloromethane; methanol = 20:1) to give 33f (180 mg, yield: 87%) as a colorless oil.

[0597] LCMS: RT=1.22min, m / z=333.1[M+1] + .

[0598] Step 6: (Z)-6-ethoxy-N'-(14-methoxy-4,4-dioxide-5,6,8,9-tetrahydro-3H-benzo[k][1,4]dioxa[7]thia[8,10]diazacyclododecane-2-yl)pyridinyl hydrazine 33g

[0599] 2-(2-(2-isothiocyano-3-methoxyphenoxy)ethoxy)ethane-1-sulfonamide 33f (180 mg, 0.54 mmol) was dissolved in acetonitrile (10 mL) at room temperature, followed by the addition of cesium carbonate (356 mg, 1.08 mmol) and stirring overnight at room temperature. The reaction mixture was cooled to 0 °C in an ice-water bath, and 6-ethoxypyridinyl hydrazine (107 mg, 0.59 mmol) and silver nitrate (275 mg, 1.62 mmol) were added sequentially to the reaction mixture, which was then stirred at 0 °C for 10 min. The reaction mixture was directly evaporated to dryness, wet-processed, and purified by silica gel column chromatography (dichloromethane:methanol = 10%) to give 33 g (127 mg, yield: 49%) as a white solid.

[0600] LCMS: RT=1.73min, m / z=480.3[M+H] + .

[0601] Step 7: 1-(6-ethoxypyridin-2-yl)-15-methoxy-6,7,9,10-tetrahydro-4H-benzo[k][1,2,4]triazolo[3,4-i][1,4]dioxa[7]thio[8,10]diazacyclododecane 5,5-dioxide compound 33

[0602] At room temperature, methanesulfonic acid (125 mg, 1.3 mmol) was added to a solution of (Z)-6-ethoxy-N'-(14-methoxy-4,4-dioxide-5,6,8,9-tetrahydro-3H-benzo[k][1,4]dioxa[7]thia[8,10]diazacyclododecane-2-yl)pyridinyl hydrazine 33 g (127 mg, 0.26 mmol) in 1,4-dioxane (10 mL). The reaction mixture was then placed in an oil bath preheated to 90 °C and reacted at this temperature for 2 hours. The reaction mixture was evaporated to dryness, and the crude product was purified by high performance liquid chromatography to give compound 33 (50 mg, yield: 42%) as a white solid.

[0603] High performance liquid chromatography method: Column: Boston Prep C18 10μm 21.2×250mm; Mobile phase: water (0.1% TFA) B: acetonitr; Gradient: 30%-55% in 10min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 8.3; Wavelength (nm): 214 / 254;

[0604] LCMS: RT=1.55min, m / z=462.1[M+1] + ;

[0605] 1 H NMR (400MHz, CDCl3): δ7.62-7.57 (m, 2H), 7.32 (t, J=8.4Hz, 1H), 6.68-6.62 (m, 3H), 4.77-4.32 (m, 1H), 4.21- 4.16 (m, 1H), 4.08-4.02 (m, 1H), 74-3.68 (m, 5H), 3.44-3.35 (m, 4H), 3.19-3.13 (m, 1H), 1.07 (t, J=7.2Hz, 3H).

[0606] Example 34: 1-(6-ethoxypyridin-2-yl)-15-fluoro-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 34

[0607] Following the same procedure as in Example 26, 3-fluoro-2-nitrophenol was used instead of 3-bromo-2-nitrophenol as the raw material to prepare target compound 34 (45.6 mg), which was a racemic mixture.

[0608] High performance liquid chromatography method: Column: Boston Prep C18 10μm 21.2×250mm; Mobile phase: water (10mM NH4HCO3)B: acetonitrile; Gradient: 18-48% in 8min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 9.3; Wavelength (nm): 214 / 254;

[0609] LCMS: RT=1.38min, m / z=463.0[M+1] + ;

[0610] 1 H NMR (400MHz, MeOH-d4): δ7.69-7.65 (m, 2H), 7.49-7.43 (m, 1H), 7.15 (d, J=8.8Hz, 1H), 6.95 (t, J=8.8Hz, 1H), 6.66-6.63 (m, 1H), 4.90 (d, J =15.6Hz, 1H), 4.44 (d, J = 15.6Hz, 1H), 3.76-3.71 (m, 1H), 3.56-3.52 (m, 1H), 3.46-3.41 (m, 3H), 3.12-3.07 (m, 1H), 1.07 (t, J = 7.2Hz, 3H).

[0611] Example 35: 1-(6-ethoxypyridin-2-yl)-14-methoxy-7,8-dihydro-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1]thio[2,4,7,9]tetraazacycloundecyl-9(10H)-one 5,5-dioxide compound 35

[0612] Step 1: 2-Isothiocyanate-1-methoxy-3-nitrobenzene 35b

[0613] At room temperature, 2.55 g (11 mmol) of 1,1-thiocarbonylbis-2(1H)-pyridine was added to a solution of 1.68 g (10 mmol) of 2-methoxy-6-nitroaniline in dichloromethane (40 mL), and the reaction mixture was reacted at room temperature for 48 hours under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give 2-isothiocyanate-1-methoxy-3-nitrobenzene 35b (360 mg, yield: 18%) as a colorless oil.

[0614] LCMS: RT=1.91min, m / z=211.0[M+H] + .

[0615] Step 2: Black solid pure product (E)-(2-(N-(2-(6-ethoxypyridinyl)hydrazino)((2-methoxy-6-nitrophenyl)imino)methyl)aminosulfonyl)ethyl)tert-butyl carbamate 35f

[0616] At room temperature, 2-isothiocyanate-1-methoxy-3-nitrobenzene 35b (310 mg, 1.48 mmol) was dissolved in 20 mL of acetonitrile solution, followed by the addition of tert-butyl (2-aminosulfonylethyl)carbamate (497 mg, 2.22 mmol) and cesium carbonate (965 mg, 2.96 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C in an ice-water bath, and 6-ethoxypyridyl hydrazide (295 mg, 1.63 mmol) and silver nitrate (755 mg, 4.44 mmol) were added sequentially to the reaction mixture, which was then stirred at 0 °C for 10 minutes. The reaction mixture was concentrated to dryness under reduced pressure, wet-loaded, and purified by silica gel column chromatography (dichloromethane:methanol = 10%) to give (E)-(2-(N-(2-(6-ethoxypyridinyl)hydrazino)((2-methoxy-6-nitrophenyl)imino)methyl)aminosulfonyl)ethyl)carbamate 35f (800 mg, yield: 93%).

[0617] LCMS: RT=1.66min, m / z=482.1[M-Boc+H] + .

[0618] Step 3: 35g of 2-amino-N-(5-(6-ethoxypyridin-2-yl)-4-(2-methoxy-6-nitrophenyl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide

[0619] At room temperature, methanesulfonic acid (397 mg, 4.14 mmol) was added to a solution of (E)-(2-(N-(2-(6-ethoxypyridinyl)hydrazino)((2-methoxy-6-nitrophenyl)imino)methyl)aminosulfonyl)ethyl)carbamate tert-butyl 35f (800 mg, 1.38 mmol) in 1,4-dioxane (20 mL), and the reaction mixture was then placed in an oil bath preheated to 90 °C and reacted at this temperature for 16 hours. The reaction solution was concentrated to dryness under reduced pressure. The crude product was adjusted to pH 9 with saturated sodium bicarbonate and extracted four times with a mixed solution of dichloromethane, methanol and tetrahydrofuran (300 mL, 10:1:1). The organic phases were combined, dried over sodium sulfate pentahydrate, filtered, and concentrated to dryness under reduced pressure to give 35 g (600 mg, yield: 93%) of 2-amino-N-(5-(6-ethoxypyridin-2-yl)-4-(2-methoxy-6-nitrophenyl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide.

[0620] LCMS: RT=1.47min, m / z=464.1[M+1] + .

[0621] Step 4: 2-Amino-N-(4-(2-amino-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide for 35 hours

[0622] At room temperature, palladium on carbon (92 mg) was added to 35 g (463 mg, 1.0 mmol) of 2-amino-N-(5-(6-ethoxypyridin-2-yl)-4-(2-methoxy-6-nitrophenyl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide in 10 mL of methanol. The reaction mixture was purged three times with a hydrogen balloon and reacted at room temperature for 1 hour. The reaction solution was filtered, and the filter cake was washed three times with methanol (30 mL). The filtrate was concentrated to dryness under reduced pressure to give 2-amino-N-(4-(2-amino-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide 35h (400 mg, yield: 92%).

[0623] LCMS: RT=1.43min, m / z=434.3[M+1] + .

[0624] Step 5: 1-(6-ethoxypyridin-2-yl)-14-methoxy-7,8-dihydro-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1]thio[2,4,7,9]tetraazacycloundecyl-9(10H)-one 5,5-dioxide compound 35

[0625] Under ice bath conditions, a solution of bis(chloromethyl) carbonate (308 mg, 1.04 mmol) in dichloromethane was added dropwise to a reaction mixture of 2-amino-N-(4-(2-amino-6-methoxyphenyl)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)ethane-1-sulfonamide 35h (300 mg, 0.69 mmol) and triethylamine (209 mg, 2.07 mmol) in dichloromethane (10 mL). The reaction mixture was reacted at room temperature for 16 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted three times with a mixed solvent of dichloromethane and methanol (100 mL, 10:1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by high performance liquid chromatography (column: Boston Prep C18 10μm 21.2×250mm; mobile phase: A: water (10mmol NH4HCO3) B: acetonitrile; gradient: 10%-35% B in 10min, stop at 16min; flow rate: 30ml / min) to give 1-(6-ethoxypyridin-2-yl)-14-methoxy-7,8-dihydro-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1]thiazo[2,4,7,9]tetraazacycloundeca-9(10H)-one 5,5-dioxide compound 35 (15mg, yield: 5%), as a white solid.

[0626] LCMS: RT=1.36min, m / z=460.2[M+1] + .

[0627] 1 H NMR (400MHz, DMSO-d6): 13.60 (s, 1H), 7.89-7.86 (m, 1H), 7.98-7.75 (m, 2H), 7.62 (d, J=7.6Hz, 1H), 7.50-7.46 (m, 1H), 7.20- 1.16 (m, 1H), 6.92-6.74 (m, 2H), 3.74 (s, 3H), 3.55-3.41 (m, 2H), 3.29-3.23 (m, 2H), 3.09-2.95 (m, 2H), 1.00 (t, J=7.2Hz, 3H).

[0628] Example 36: (S)-1-(6-ethoxypyridin-2-yl)-15-(1-hydroxyethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 36A; (R)-1-(6-ethoxypyridin-2-yl)-15-(1-hydroxyethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 36B

[0629] Step 1: At room temperature, 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxaldehyde 5,5-dioxide compound 30B (20 mg, 0.0424 mmol) was dissolved in (5 mL) tetrahydrofuran, and then cooled to 0 °C. Methyl magnesium bromide (3.0 M, 0.1 mL) was added to the reaction mixture and stirred overnight at room temperature. Dilute hydrochloric acid aqueous solution (2 M, 1 mL) was added to the reaction mixture, and the aqueous phase was extracted three times with a mixed solvent of dichloromethane and tetrahydrofuran (10:1, 100 mL). The organic phase was then dried, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to give (S)-1-(6-ethoxypyridin-2-yl)-15-(1-hydroxyethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 36A (3.1 mg, yield: 14). Compound 36B (6.5 mg, yield: 31.4%) and (R)-1-(6-ethoxypyridin-2-yl)-15-(1-hydroxyethyl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 36B (6.5 mg, yield: 31.4%) were both white solids.

[0630] Compound 36A:

[0631] LCMS: RT=1.38min, m / z=489.1[M+1] + .

[0632] 1H NMR (400MHz, MeOD): 7.72-7.67 (m, 2H), 7.53 (t, J=8Hz, 1H), 7.35-7.29 (m, 2H), 6.71 (d, J=7.2Hz, 1H), 5.01 (d, J=15.2Hz, 1H), 4.56- 4.55 (m, 1H), 4.43 (d, J=15.2Hz, 1H), 3.79-3.76 (m, 1H), 3.47-3.42 (m, 3H), 3.30-3.22 (m, 2H), 1.37-1.33 (m, 3H), 1.06-1.02 (m, 3H).

[0633] Compound 36B:

[0634] LCMS: RT=1.42min, m / z=489.2[M+1] + .

[0635] 1 H NMR (400MHz, MeOD): 7.74-7.72 (m, 2H), 7.57-7.53 (m, 1H), 7.38-7.32 (m, 2H), 6.75-6.71 (m, 1H), 4.96 (d, J=14.8Hz, 1H) , 4.60-4.56 (m, 1H), 4.43 (d, J=14.8Hz, 1H), 3.79-3.73 (m, 1H), 3.47-3.41 (m, 2H), 3.39-3.23 (m, 3H), 1.06-0.90 (m, 6H).

[0636] High performance liquid chromatography method: Column: Boston Prep C18 10μm 21.2×250mm; Mobile phase: A: water (0.2% FA) B: acetonitrile; Gradient: 25%-55% B in 8min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 8.3 (compound 36A) / 9.5 (compound 36B); Wavelength (nm): 214 / 254.

[0637] Example 37: 15-(difluoromethyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide compound 37

[0638] At room temperature, 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxaldehyde 5,5-dioxide compound 30B (20 mg, 0.0424 mmol) was dissolved in (5 mL) dichloromethane solution and cooled to 0 °C in an ice-water bath. Then, diethylaminosulfur trifluoride (0.0341 mg, 0.212 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was quenched in ice water, and the reaction solution was extracted with a mixed solvent of dichloromethane and tetrahydrofuran (10:1, 30 mL). The organic phase was then concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography to give compound 37 (3.8 mg, yield: 18.2%) of 15-(difluoromethyl)-1-(6-ethoxypyridin-2-yl)-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-9(10H)-one 5,5-dioxide, as a white solid.

[0639] LCMS: RT=1.40, m / z=495.0[M+1] + .

[0640] 1 H NMR (400MHz, MeOD): 7.74-7.61 (m, 4H), 7.42 (d, J=7.6Hz, 1H), 6.81-6.54 (m, 2H), 4.99 (d, J=6.8Hz, 1H), 4.49 (d, J=14.4Hz, 1H), 3.75-3.69 (m, 1H), 3.52-3.45 (m, 1H), 3.30-3.23 (m, 4H), 1.03 (t, J=7.2Hz, 3H).

[0641] High-performance liquid chromatography (HPLC) method: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (0.2% FA), B: ACN

[0642] Gradient: 35%-65% B in 10 min, stop at 16 min; Flow rate: 30 ml / min; Retention time (min): 9.5; Wavelength (nm): 214 / 254.

[0643] Example 38: (Z)-16-chloro-1-(6-ethoxypyridin-2-yl)-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa([7]thio[4,6]diazacyclotridecane 5,5-dioxide Compound 38

[0644] Following the same procedure as in Example 2, 2-amino-3-chlorophenol was used instead of 2-amino-3-methoxyphenol as the raw material, and 4-bromobut-1-ene was used instead of 3-bromoprop-1-ene as the reagent to prepare target compound 38 (15.4 mg), which is a specific cis compound.

[0645] LCMS: RT=1.54, m / z=476.2[M+1] + .

[0646] 1 H NMR (400MHz, MeOD): 7.71-7.63 (m, 2H), 7.43-7.39 (m, 1H), 7.12-7.07 (m, 2H), 6.69 (d, J=8Hz, 1H), 5.54-5.4 2 (m, 2H), 4.16-4.12 (m, 2H), 3.48-3.36 (m, 3H), 3.16-3.10 (m, 1H), 2.52-2.29 (m, 4H), 1.07 (t, J=7.2Hz, 3H).

[0647] Example 39: 1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,8,9,10,11-hexahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotridecane 5,5-dioxide Compound 39

[0648] At room temperature, (Z)-1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotetane 5,5-dioxide compound 19B (15 mg, 0.0318 mmol) was dissolved in 5 mL of ethanol solution, and then palladium on carbon (65%, 5 mg) was added to the reaction mixture. The air in the reaction flask was purged by a hydrogen balloon, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered directly and the filter cake was washed three times with dichloromethane (3 mL). The filtrate was concentrated to dryness under reduced pressure to give 1-(6-ethoxypyridin-2-yl)-16-methoxy-6,7,8,9,10,11-hexahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotetane 5,5-dioxide compound 39 (11.4 mg, yield: 75.7%) as a white solid.

[0649] LCMS: RT=1.81min, m / z=474.1[M+1] + .

[0650] 1 H NMR (400MHz, MeOD): 7.71-7.67 (m, 1H), 7.60 (d, J=6.8Hz, 1H), 7.38 (t, J=8.4Hz, 1H), 6.76-6.69 (m, 3H), 4.17-4.12 (m, 1H), 4.02-3.96 (m, 1H), 3. 66(s, 3H), 3.50-3.34(m, 3H), 3.05-2.99(m, 1H), 2.04-1.86(m, 2H), 1.7 8-1.57(m, 4H), 1.36-1.32(m, 1H), 1.23-1.20(m, 1H), 1.08-1.04(m, 3H).

[0651] Example 40: 1-(6-ethoxypyridin-2-yl)-9-oxo-7,8,9,10-tetrahydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclododecane-15-carboxamide 5,5-dioxide Compound 40

[0652] Following the same procedure as in Example 26, 3-cyano-2-nitrophenol was used instead of 3-bromo-2-nitrophenol as the raw material. During the high-performance liquid chromatography purification process, the cyano group was hydrolyzed into an amide group to prepare the target compound 40 (5.6 mg), which was a racemic mixture.

[0653] LCMS: RT=1.39min, m / z=488.1[M+1] + .

[0654] 1 H NMR (500MHz, d6-DMSO): 8.56 (s, 1H), 7.94-7.87 (m, 1H), 7.80-7.78 (m, 1H), 7.73-7.56 (m, 2H), 7.36-7.31 (m, 1H), 7.18-7.12 (m, 1H), 6.92 (d, J=8.0Hz, 1H), 4.77 (s, 2H), 4.56-4.47 (m, 2H), 3.60-3.55 (m, 2H), 2.98-2.94 (m, 2H), 1.37 (t, J=7.0Hz, 3H).

[0655] Example 41: (Z)-1-(6-ethoxypyridin-2-yl)-16-fluoro-6,7,10,11-tetrahydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6]diazacyclotridecene 5,5-dioxide Compound 41

[0656] Following the same procedure as in Example 2, 2-amino-3-chlorofluorophenol was used instead of 2-amino-3-methoxyphenol as the raw material, and 4-bromobut-1-ene was used instead of 3-bromoprop-1-ene as the reagent to prepare target compound 41 (13.1 mg), which is a specific cis compound.

[0657] LCMS: RT=1.67min, m / z=460.2[M+1] + .

[0658] 1 H NMR (500MHz, MeOD): 7.73-7.70 (m, 1H), 7.65-7.63 (m, 1H), 7.49-7.44 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 6.88-6.84 (m, 1H), 6.74-6. 73 (m, 1H), 5.54-5.45 (m, 2H), 4.22-4.13 (m, 2H), 3.50-3.40 (m, 2H), 3.22-3.16 (m, 2H), 2.51-2.27 (m, 4H), 1.08 (t, J=7.0Hz, 3H).

[0659] Example 42: (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazohexacyclic dodecene 5,5-dioxide compound 42A; (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazohexacyclic dodecene 5,5-dioxide compound 42B; (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide compound 42C; (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide compound 42D

[0660] Step 1: (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazohexacyclic dodecene 5,5-dioxide compound 42A; compound (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7 ,10-Tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide compound 42B; 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide 42b

[0661] The compound 42a, a 5,5-dioxide of 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide (prepared according to the same procedure as in Example 2, using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-carbazide instead of 6-ethoxypyridinyl hydrazide as the starting material), was chirally resolved to obtain three isomers: (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[b][1,2,4]triazol[b][1,2,4]oxosulfurdiazazolide 5,5-dioxide. Compound 42A of azido[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide, compound (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide, and compound 42B of 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide, and compound 42b of azido[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide.

[0662] Chiral resolution conditions: Instrument: SFC-80; Chiral column: DAICEL CHIRALPAK IBN-10 25*250mm, 10µm; Column temperature: 35℃; Mobile phase: CO2 / [MeOH]=50 / 50; Flow rate: 45ml / min; Column pressure: 100bar; Detection wavelength: 215nm; Cycle time: 5.08min; Sample volume: 150mg sample dissolved in 15mL methanol / acetonitrile; Injection volume: 3.0mL per injection.

[0663] Compound 42A: (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiaza-hexacyclic dodecene 5,5-dioxide. Compound 42A (2.66 mg, yield: 1.77%) is a white solid.

[0664] LCMS: RT=1.268min, m / z=443.3[M+1] + .

[0665] Retention time of chiral column: RT = 2.512 min;

[0666] 1 H NMR (400MHz, DMSO-d6): 13.07 (s, 1H), 7.57 (t, J=8.4Hz, 1H), 6.92 (dd, J=5.6Hz, 8.4Hz, 2H), 6.80 (s, 1H), 5.80-5.69 (m, 2H), 4.56-4.47 (m, 2H), 4.07-4.02 (m, 2H), 3.73 (s, 3H), 3.17-3.10 (m, 1H), 2.85-2.51 (m, 5H), 2.33-2.24 (m, 2H).

[0667] Compound 42B: (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazahexacyclic dodecene 5,5-dioxide. Compound 42B (10.29 mg, yield 6.86%) is a white solid.

[0668] LCMS: RT=1.311min, m / z=443.3[M+1] + .

[0669] Retention time of chiral column: RT = 2.942 min;

[0670] 1 H NMR (400MHz, DMSO-d6): 12.83 (s, 1H), 7.56 (t, J=8.4Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.96 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 5.59-5.52 (m, 1 H), 5.42-5.34 (m, 1H), 4.51-4.37 (m, 2H), 4.03 (d, J=7.2Hz, 2H), 3.78 (s, 3H), 3.10-2.98 (m, 2H), 2.79-2.51 (m, 4H), 2.40-2.26 (m, 2H).

[0671] Compound 42b: 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide 42b (80 mg, yield: 53%), is a white solid.

[0672] Step 2: (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazohexacyclic dodecene 5,5-dioxide compound 42C; (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazol[4,3-d][1,7,4,6]oxosulfurdiazazohexacyclic dodecene 5,5-dioxide compound 42D

[0673] The compound 42b, consisting of 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide, was chirally resolved to yield two isomers: (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7, Compound 42C of 10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide and compound (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide and compound 42D.

[0674] Chiral resolution conditions: Instrument: SFC-80; Chiral column (S,S)-Whelk-O-1 25*250mm, 10µm; Column temperature: 35℃; Mobile phase: CO2 / [MeOH / ACN]=50 / 50; Flow rate: 45ml / min; Column pressure: 100bar; Detection wavelength: 215nm; Cycle time: 6.5min; Sample volume: 80mg sample dissolved in 10mL methanol; Injection volume: 3.0mL per injection.

[0675] Compound 42C: (E)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazahexacyclic dodecene 5,5-dioxide. Compound 42C (11.93 mg, yield: 14.91%) is a white solid.

[0676] LCMS: RT=1.296min, m / z=443.2[M+1]+ .

[0677] Retention time of chiral column: RT = 1.499 min;

[0678] 1 H NMR (400MHz, DMSO-d6): 12.82 (s, 1H), 7.56 (t, J=8.4Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 5.59-5.52 (m, 1H), 5.42- 5.34 (m, 1H), 4.51-4.37 (m, 2H), 4.03 (t, J=7.2Hz, 2H), 3.78 (s, 3H), 3.1 1-2.98(m, 2H), 2.79-2.72(m, 1H), 2.67-2.59(m, 2H), 2.50-2.26(m, 3H).

[0679] Compound 42D: (Z)-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-15-methoxy-4,6,7,10-tetrahydrobenzo[b][1,2,4]triazolo[4,3-d][1,7,4,6]oxosulfurdiazazolide 5,5-dioxide. Compound 42D (2.02 mg, yield: 2.53%) is a white solid.

[0680] LCMS: RT=1.263min, m / z=443.3[M+1] + .

[0681] Retention time of chiral column: RT = 1.811 min;

[0682] 1 H NMR (400MHz, DMSO-d6): 13.06 (s, 1H), 7.57 (t, J=8.4Hz, 1H), 6.92 (dd, J=5.2Hz, 8.4Hz, 2H), 6.80 (s, 1H), 5.80-5.69 (m, 2H), 4.56-4.47 (m, 2H), 4.08-4.01 (m, 2H), 3.73 (s, 3H), 3.17-3.09 (m, 1H), 2.85-2.63 (m, 5H), 2.33-2.24 (m, 2H).

[0683] Example 43: (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide Compound 43A; (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide

[0684] Step 1: Ethyl 2-(2-amino-3-methoxyphenoxy)acetic acid 43b

[0685] 2-Amino-3-methoxyphenol 43a (4.0 g, 28.75 mmol) was dissolved in N,N-dimethylformamide (40 mL) at room temperature. The solution was cooled to -20 °C under nitrogen protection, and sodium hydride (1.2 g, 28.75 mmol, 60 wt%) was added. The reaction was continued at -20 °C for 0.5 h, followed by the addition of ethyl bromoacetate (4.3 g, 25.87 mmol). The reaction mixture was then reacted at -20 °C for 2 h under nitrogen protection. The reaction was confirmed to be complete by LCMS. The reaction mixture was cooled to room temperature, and saturated ammonium chloride (10 mL) was added. The mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain ethyl 2-(2-amino-3-methoxyphenoxy)acetic acid 43b (4.0 g, crude), a brown solid.

[0686] LCMS: m / z = 226.2[M+H] + ;

[0687] Step 2: Ethyl 2-(2-isothiocyano-3-methoxyphenoxy)acetate 43c

[0688] Ethyl 2-(2-amino-3-methoxyphenoxy)acetate 43b (4.0 g, 17.76 mmol) was dissolved in dichloromethane (100 mL) at room temperature, and 1,1′-thiocarbonylbis(pyridin-2(1H)-one) (4.0 g, 19.53 mmol) was added. The mixture was exchanged with nitrogen three times, and the reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction was confirmed to be complete by LCMS. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8%) to give ethyl 2-(2-isothiocyano-3-methoxyphenoxy)acetate 43c (2.5 g, yield: 52.7%) as a yellow oil.

[0689] LCMS: m / z = 268.1 [M+H] + ;

[0690] Step 3: Ethyl 2-(2-((((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)(2-(6-ethoxymethylpyridinyl)hydrazine)methylene)amino)-3-methoxyphenoxy)acetate 43e

[0691] At room temperature, ethyl 2-(2-isothiocyano-3-methoxyphenoxy)acetate 43c (650 mg, 2.43 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of benzyl N-(1-methyl-2-aminosulfonyl-ethyl)carbamate 43d (43d was prepared according to the method reported in the Journal of Medicinal Chemistry, 2009, vol. 52, #7, pp. 1922-1934) (695 mg, 2.55 mmol) and cesium carbonate (1.6 g, 4.86 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen protection after three nitrogen purgings. The reaction was monitored by LCMS until completion. The reaction mixture was then cooled to 0 °C in an ice-water bath, and silver nitrate (826 mg, 4.86 mmol) and 6-ethoxypyridinecarbamoyl hydrazine (462 mg, 2.55 mmol) were added sequentially. The reaction mixture was then stirred at room temperature for 2 hours after three nitrogen purgings. The reaction was detected by LCMS. The system was filtered with diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to give ethyl 2-(2-((((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)(2-(6-ethoxymethylpyridinyl)hydrazino)methylene)amino)-3-methoxyphenoxy)acetate 43e (1.2 g, yield 72.0%), which was a yellow oil.

[0692] LCMS: m / z = 687.4 [M+H] + ;

[0693] Step 4: Ethyl 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetate 43f

[0694] At room temperature, ethyl 2-(2-((((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)(2-(6-ethoxymethylpyridinyl)hydrazino)methylene)amino)-3-methoxyphenoxy)acetate 43e (1.2 g, 1.75 mmol) was dissolved in anhydrous 1,4-dioxane (20 mL), and methanesulfonic acid (503 mg, 5.24 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction was completed by LCMS, and the solvent was distilled under reduced pressure to obtain the crude product, which was dispersed in water (20 mL) and ethyl acetate (15 mL). The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (15 mL). The combined organic phases were washed twice with saturated brine (15 mL), dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to give ethyl 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetate 43f (780 mg, yield 67.0%), as a red oil.

[0695] LCMS: m / z = 669.2 [M+H] + ;

[0696] Step 5: 43g of 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid

[0697] At room temperature, 43f (780 mg, 1.17 mmol) of ethyl 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonamide)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid was dissolved in 5 mL of ethanol and 5 mL of water, and sodium hydroxide (466 mg, 11.66 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was completed by LCMS, and the pH of the reaction mixture was adjusted to less than 5 with 1 N hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL). The combined organic phases were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, 43 g (450 mg, yield 60.0%) of 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonylamino)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid, as a white solid. The crude product was used directly in the next step without further purification.

[0698] LCMS: m / z: 641.5 [M+H] + .

[0699] 1H-NMR (400MHz, DMSO-d6) δ13.32 (s, 1H), 12.95 (s, 1H), 7.76 (t, J=7.8Hz, 1H), 7.54 (d, J=7. 4Hz, 1H), 7.39-7.32 (m, 6H), 7.21-7.15 (m, 1H), 6.79 (dd, J=13.7, 8.2Hz, 2H), 6.64 (d, J=8.8 Hz, 1H), 4.99 (s, 2H), 4.6-4.48 (m, 2H), 3.95-3.86 (m, 1H), 3.67 (d, J=3.8Hz, 3H), 3.42-3.37 (m, 2H), 3.19-3.12 (m, 1H), 2.94 (t, J=7.0Hz, 1H), 1.15-1.10 (m, 3H), 1.00 (t, J=7.0Hz, 3H).

[0700] Step 6: 2-(2-(3-((2-aminopropyl)sulfonamide)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid for 43 hours

[0701] At room temperature, 43 g (450 mg, 0.70 mmol) of 2-(2-(3-((2-((((benzyloxy)carbonyl)amino)propyl)sulfonamide)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid was dissolved in anhydrous methanol (4 mL) and palladium on carbon (80 mg, 10 wt%) was added. The reaction mixture was purged three times with hydrogen and reacted at 25 °C for 2 hours under hydrogen protection. The reaction was confirmed to be complete by LCMS. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, 2-(2-(3-(((2-aminopropyl)sulfonamide)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid 43h (230 mg, yield: 64.0%), as a colorless oil.

[0702] LCMS: m / z: 507.3 [M+H] + .

[0703] Step 7: (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 43A; (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 43B

[0704] At room temperature, 2-(2-(3-((2-aminopropyl)sulfonamide)-5-(6-ethoxypyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-methoxyphenoxy)acetic acid (43 h, 200 mg, 0.39 mmol), N,N-diisopropylethylamine (459 mg, 3.55 mmol), and 1-propylphosphoric anhydride (1 mL, 50 wt%) were added sequentially to ethyl acetate (3 mL), and the reaction mixture was reacted at 60 °C for 16 h. The reaction was detected as complete by LCMS. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (4 mL). The organic phase was washed three times with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacron. Dodecain-9(10H)-one 5,5-dioxide compound 43A (51.70 mg, yield: 15.93%, white solid) and (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrylane dodecain-9(10H)-one 5,5-dioxide compound 43B (51.70 mg, yield: 23.77%, white solid).

[0705] Compound 43A:

[0706] High performance liquid chromatography preparation conditions: Column: YMC-Actus Triart C18, 150*20mm, 5um; Mobile phase: A: water (0.1% FA), B: acetonitrile; Gradient: 30-50% in 6.5min and 7.8min, stop at 8min; Flow rate: 20ml / min.

[0707] LCMS: RT=1.682min, m / z=489.3[M+H] + ;

[0708] 1H-NMR (400MHz, DMSO-D6) δ13.35 (s, 1H), 8.15-8.10 (m, 1H), 7.78 (t, J=7.8Hz, 1H), 7.61 (d, J=7 .4Hz, 1H), 7.40 (t, J=8.5Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 6.79 (dd, J=12.8, 8.4Hz, 2H), 4.70 (d, J =14.0Hz, 1H), 4.43 (d, J = 14.3Hz, 1H), 3.99 (q, J = 7.8Hz, 1H), 3.61 (s, 3H), 3.48 (dd, J = 14.5, 9.8 Hz, 1H), 3.40-3.33 (m, 3H), 2.99 (d, J=15.1Hz, 1H), 1.13 (d, J=6.6Hz, 3H), 1.00 (t, J=7.0Hz, 3H).

[0709] Compound 43B:

[0710] LCMS: RT=1.723min, m / z=489.3[M+H] + ;

[0711] 1H-NMR (400MHz, DMSO-D6) δ13.67 (s, 1H), 8.45 (s, 1H), 7.79 (t, J=7.8Hz, 1H), 7.60 (d , J=7.4Hz, 1H), 7.45 (t, J=8.4Hz, 1H), 7.09 (d, J=8.2Hz, 1H), 6.82 (dd, J=17.7, 8.4Hz , 2H), 5.01 (d, J=15.4Hz, 1H), 4.36 (d, J=15.4Hz, 1H), 4.00-3.94 (m, 1H), 3.63 (s, 3H) , 3.43-3.33 (m, 2H), 3.26-3.18 (m, 2H), 1.19 (d, J=6.6Hz, 3H), 1.01 (t, J=7.1Hz, 3H).

[0712] Example 44: 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclodidecyne-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 44

[0713] Following the same procedure as in Example 43, compound 44 (51.70 mg, yield: 35.7%) was prepared by replacing benzyl N-(1-methyl-2-aminosulfonyl-ethyl)carbamate 43d with N-(1-cyclopropyl-2-aminosulfonyl-ethyl)carbamate as the starting material, and was a white solid.

[0714] LCMS: m / z = 501.3 [M+H] + ;

[0715] 1H-NMR (400MHz, DMSO-d6) δ8.32 (s, 1H), 7.77 (t, J=7.8Hz, 1H), 7.61 (d, J=7.4Hz, 1H), 7.42 (t, J=8.4Hz, 1H), 6.98 (d, J=8.5Hz, 1H), 6.83 (d, J=8.5Hz, 1H), 6.75 (d, J=8.2Hz, 1 H), 4.55 (d, J=13.2Hz, 1H), 4.28 (d, J=12.9Hz, 1H), 3.63 (s, 3H), 3.45 (d, J=14.8Hz, 1H ), 3.39-3.33 (m, 2H), 3.00 (d, J=14.6Hz, 1H), 0.99 (t, J=7.1Hz, 3H), 0.88-0.76 (m, 4H).

[0716] Example 45: (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 45A; (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 45B

[0717] (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 43A (25 mg) was obtained by chiral preparative column chromatography to give (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4] Triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 45A (11.1 mg); (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 45B (11.1 mg). Compounds 45A and 45B are a pair of rotational isomers.

[0718] Chiral separation preparation conditions: Equipment: SFC-150 (Waters); Chiral column: AD 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH(0.2% NH3 (7M in MeOH)]=50 / 50; Flow rate: 100mL / min; Outlet pressure: 100bar; Wavelength: 214nM; Injection volume: 3mL; Sample: 25mg mixture dissolved in 30mL dichloromethane / methanol (1:2) solvent.

[0719] Compound 45A:

[0720] Retention time in chiral column: 0.863 min.

[0721] LCMS: m / z = 489.3 [M+H] + ;

[0722] 1H NMR (400MHz, CD3OD) δ7.76-7.59 (m, 2H), 7.42 (t, J=8.5Hz, 1H), 6.98 (d, J=8.7Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 6.70 (d, J=8.2Hz, 1H), 4.82 (d, J=14.5H z, 1H), 4.53 (d, J=14.5Hz, 1H), 4.21 (s, 1H), 3.64 (s, 3H), 3.57-3.46 (m, 2H ), 3.36 (m, 1H), 3.16 (m, 1H), 1.31 (d, J = 6.8Hz, 3H), 1.06 (t, J = 7.1Hz, 3H).

[0723] Compound 45B:

[0724] Retention time in chiral column: 2.246 min.

[0725] LCMS: RT=1.441min, m / z=489.3[M+H]+;

[0726] 1 H NMR (400MHz, CD3OD) δ7.76-7.59 (m, 2H), 7.43 (t, J=8.5Hz, 1H), 6.99 (d, J=8.6Hz, 1H), 6.78 (d, J=8.4Hz, 1H), 6.71 (d, J=8.1Hz, 1H), 4.83 (d, J=14.5Hz, 1H), 4.53(d, J=14.5Hz, 1H), 4.27-4.18(m, 1H), 3.64(s, 3H), 3.57-3.43(m, 2H), 3.37(m, 1H), 3.18(m, 1H), 1.31(d, J=6.8Hz, 3H), 1.06(t, J=7.0Hz, 3H).

[0727] Example 46: (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 46A; (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 46B

[0728] (R)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 43B (40 mg) was obtained by chiral preparative column chromatography. Triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 46A (17.1 mg); (S)-1-(6-ethoxypyridin-2-yl)-15-methoxy-7-methyl-7,8-dihydro-4H,6H-benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triacrondodecano-9(10H)-one 5,5-dioxide compound 46B (16.1 mg). Compounds 46A and 46B are a pair of rotational isomers of compound 43B.

[0729] Chiral separation preparation conditions: Equipment: SFC-150 (Waters); Chiral column: IG 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=45 / 55; Flow rate: 120mL / min; Outlet pressure: 100bar; Wavelength: 214nM; Injection volume: 4mL; Sample: 45mg mixture dissolved in 60mL dichloromethane / methanol (1:2) solvent.

[0730] Compound 46A:

[0731] Retention time in chiral column: 1.178 min.

[0732] LCMS: m / z = 489.3[M+H]+;

[0733] 1H NMR (400MHz, CD3OD) δ7.71 (t, J=7.8Hz, 1H), 7.64 (d, J=7.3Hz, 1H), 7.46 (t, J=8 .5Hz, 1H), 6.98 (d, J=8.5Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.71 (d, J=8.2Hz, 1H), 4.98 (d, J=15.5Hz, 1H), 4.47 (d, J=15.6Hz, 1H), 4.23 (d, J=6.4Hz, 1H), 3.68 (s, 3H), 3.54-3.34(m, 3H), 3.28(s, 1H), 1.31-1.28(m, 3H), 1.06(t, J=7.1Hz, 3H).

[0734] Compound 46B:

[0735] Retention time in chiral column: 2.067 min.

[0736] LCMS: m / z = 489.3[M+H]+;

[0737] 1 H NMR (400MHz, CD3OD) δ7.71 (t, J=7.8Hz, 1H), 7.64 (dd, J=7.5, 0.9Hz, 1H), 7.46 (t, J= 8.5Hz, 1H), 6.98 (d, J=8.5Hz, 1H), 6.83 (d, J=8.5Hz, 1H), 6.71 (d, J=8.1Hz, 1H), 4.9 8 (d, J=15.6Hz, 1H), 4.47 (d, J=15.5Hz, 1H), 4.23 (q, J=6.1Hz, 1H), 3.68 (s, 3H), 3.5 4-3.34 (m, 3H), 3.28 (d, J=5.3Hz, 1H), 1.30 (d, J=6.8Hz, 3H), 1.06 (t, J=7.1Hz, 3H).

[0738] Example 47: 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclodidecyn-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 47A; 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclodidecyn-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 47B

[0739] 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclodidecyn-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 44 (56 mg) was isolated by chiral preparative column chromatography to give 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][ 1]Oza[7]thia[4,6,10]triazacyclodidecyn-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 47A (20.1 mg); 1-(6-ethoxypyridin-2-yl)-15-methoxy-4H,6H,8H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1]oxa[7]thia[4,6,10]triazacyclodidecyn-7,1′-cyclopropane]-9(10H)-one 5,5-dioxide compound 47B (20.0 mg). Compounds 47A and 47B are a pair of rotational isomers.

[0740] Chiral column separation conditions: Equipment: SFC-150 (Waters); Chiral column: OZ 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=50 / 50; Flow rate: 120mL / min; Outlet pressure: 100bar; Wavelength: 214nM; Injection volume: 4mL; Sample: 45mg mixture dissolved in 60mL dichloromethane / methanol (1:2) solvent.

[0741] Compound 47A:

[0742] LCMS: RT=m / z=501.3[M+H]+;

[0743] Retention time in chiral column: 1.115 min.

[0744] 1 H NMR (400MHz, CD3OD) δ7.74-7.60 (m, 2H), 7.43 (t, J=8.5Hz, 1H), 6.96 (d, J=8.5Hz, 1H), 6.81 (d, J=8.5Hz, 1H), 6.69 (d, J=8.1Hz, 1H), 4.69 (d, J=13.7Hz, 1H), 4.45 (d, J=13.7Hz, 1H), 3.68 (s, 3H), 3.52-3.34 (m, 3H), 3.34-3.32 (m, 1H), 1.05 (t, J=7.1Hz, 3H), 1.02-0.81 (m, 4H).

[0745] Compound 47B:

[0746] Retention time in chiral column: 3.221 min.

[0747] LCMS: m / z = 501.3[M+H]+;

[0748] 1 H NMR (400MHz, CD3OD) δ7.74-7.61 (m, 2H), 7.44 (t, J=8.5Hz, 1H), 6.96 (d, J=8.5Hz, 1H), 6.81 (d, J=8.4Hz, 1H), 6.70 (d, J=8.1Hz, 1H), 4.70 (d, J=13.7Hz, 1H), 4.45 (d, J=13.8Hz, 1H), 3.68 (s, 3H), 3.55-3.35 (m, 3H), 3.35-3.32 (m, 1H), 1.06 (t, J=7.1Hz, 3H), 1.03-0.80 (m, 4H).

[0749] Bioactivity test

[0750] Test Example 1: cAMP Activity Assay

[0751] Upon binding of ligands or drug molecules to the APJ receptor, the corresponding G protein-coupled signaling pathway is activated. APJ activation inhibits the production of foscoline-stimulated cyclic AMP (cAMP) in cells in a pertussis-sensitive manner. In addition, APJ activation leads to the recruitment of β-repressor proteins, resulting in receptor internalization and activation of extracellular regulated kinases (ERKs). This invention uses a cAMP assay to evaluate the bioactivity of small molecule drugs for APJ binding. The specific experimental procedure is as follows:

[0752] 1) Detection buffer: 1×stimulation buffer (supplier: Cisbio, product number 62AM4PEJ, lot number 29F), 500μM IBMX (supplier: Sigma, product number I5879, lot number STBF6061V), ddH2O;

[0753] 2) Compound preparation: The test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 mM. The solution was then diluted to a working concentration of 0.2 mM. The compound was serially diluted 4-fold using an Echo pipetting system according to the microplate layout scheme. 50 nL of each solution was added to a 384 cell plate in duplicate wells to a final concentration of 1 μM. The plate was then centrifuged at 1000 rpm for 1 min.

[0754] 3) Following the microplate layout protocol, use the Echo pipetting system to transfer 50 nL of Forskolin (supplier MCE, product number HY-15371) (final concentration is 1.5 μM) into a 384 cell plate;

[0755] 4) Cell Plating: Digest cells with preheated trypsin for 2 minutes, then stop digestion with culture medium. Collect the cell suspension in a 15 mL centrifuge tube, centrifuge at 1000 rpm for 5 min, discard the supernatant, wash the cells twice with HBSS buffer (supplier: Invitrogen, product number 14025, batch number 2003842), resuspend the cells with assay buffer, adjust the cell density to 1.5E+06 cells / mL, and add 10 μL to each well of a 384 cell plate (15,000 cells). Centrifuge at 1000 rpm for 1 min, and incubate the cell plate at 23°C for 60 min.

[0756] 5) Preparation of standard curve: The cAMP standard was serially diluted 4-fold with detection buffer to a total of 10 concentration points, with the highest concentration being 32 μM. 10 μL was added to each well according to the microplate layout scheme.

[0757] 6) Preparation of detection reagents: Dilute Anti cAMP and cAMP tracer (supplier VKEY-BIO, product number 210922D01) to 1× with lysis buffer to obtain detection reagents. Add 10 μL of detection reagents to each well according to the microplate layout scheme, centrifuge at 1000 rpm for 1 min, and incubate the cell plate in a 23℃ incubator for 60 min.

[0758] 7) Read the board on Envision.

[0759] Results analysis:

[0760] 1) Use Microsoft Excel to calculate the percentage of activity. For agonists, use the formula %Effect = 100 × (1 - (Sample Raw Value - Low Control Average) / (High Control Average - Low Control Average)).

[0761] 2) Using GraphPad Prism7 data analysis software, for agonists, the Dose-response-Stimulation-log[agonist] vs. response-variable slope mode was selected for fitting analysis to obtain the EC50 of each tested sample. 50 value.

[0762] Test Example 2: β-Arrestin Activity Assay

[0763] 1. Method:

[0764] This study used the HEK293T-APJ-βArrestin2 stable cell line and, through interaction with different concentrations of test compounds, utilized... The Live Cell Substrates kit uses the NanoBiT method to detect changes in fluorescence intensity to study the ability of test substances to recruit β-arrestin 2 to human APJ receptors and to calculate the corresponding concentration-effect curves.

[0765] 2. Determination of the inhibitory activity of the test substance on APJ receptors

[0766] 1) On day 1, HEK293T-APJ-βArrestin2 cells were cultured to 80% confluence, and cells were collected by trypsin digestion. After counting, they were seeded into 384-well plates (CAT#3764) at 15,000 cells / well / 20μL in Opti-MEM + 4% FBS medium and incubated overnight.

[0767] 2) On the second day, the positive drug and the test compound were serially diluted with DMSO.

[0768] 3) According to According to the Live Cell Substrates instructions, dilute the substrate 20 times and add it to the well at a rate of 5 μL / well, then shake well.

[0769] 4) Use ECHO (acoustic pipetting system) to transfer the graded diluted compound (25 nL) into the corresponding wells of a 384-well plate and incubate in the dark for 10 minutes.

[0770] 5) After incubation, read the Luminescence signal value using a microplate reader.

[0771] 6) Analyze the functional relationship between signal values ​​and compound concentrations, and use XLFIT or GraphPadPrism software for nonlinear regression method to perform curve fitting and EC50 analysis. 50 calculate.

[0772] 7) Data Analysis

[0773] The average value of the positive control group.

[0774] The mean value of the negative control (DMSO).

[0775] Control compound 1 was prepared according to the procedure in Example 263.0 of WO2016 / 187308; control compound 2 was prepared according to the procedure in Example 2 of WO2020 / 7301. Specific test results are shown in Table 1.

[0776] Table 1: EC50 of the compounds disclosed herein for cAMP and β-Arrestin 50 and selective results

[0777] Note: "-" indicates not tested. In the EC50 of β-Arrestin, 500 nM ≤ A, 100 ≤ B < 500 nM, and 10 ≤ C < 100 nM.

[0778] Experimental data show that some of the compounds in this invention have good agonistic activity against the APJ receptor, effectively inhibiting cAMP production and exhibiting weak recruitment ability for β-arrestin. They are excellent G protein-biased APJ receptor agonists, suggesting that the compounds in this invention have the potential for better therapeutic effects and can effectively avoid human side effects caused by poor selectivity.

[0779] Test Example 3: Pharmacokinetic Test

[0780] 1. Drug preparation

[0781] Weigh a certain amount of the drug and prepare a formulation for gavage and intravenous injection. The solvent for both gavage and intravenous injection is 10% DMA + 10% Solutol HS15 + 80% Saline.

[0782] 2. Administration

[0783] ICR mice were fasted for 12 hours before administration, but had free access to water. The intravenous dose was 1 mg / kg, and the gavage dose was 2 mg / kg. They were allowed to resume eating 4 hours after administration.

[0784] 3. Sampling

[0785] At 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 8 and 24 h after gavage administration, 30 mL of whole blood was collected from the submandibular vein of mice and placed in anticoagulant centrifuge tubes containing EDTA-K2. The centrifuge tubes were centrifuged at 5000 rpm and 4℃ for 5 min, and the separated plasma was stored at -80℃ for analysis.

[0786] 4. Measurement

[0787] Take 10 mL of plasma sample and add 200 mL of MeOH / Acetonitrile (1:1, v / v) containing internal standards (50 nM terfenadine and 500 nM tolbutamide) for protein precipitation (vortex for 10 min, then centrifuge at 4000 rpm for 10 min). Transfer 100 mL of the supernatant to a 96-well plate and perform LC-MS / MS analysis.

[0788] 5. Pharmacokinetic Parameter Results

[0789] The pharmacokinetic parameters of the disclosed compound and its control compounds 1 and 2 are shown in Table 2 below.

[0790] Table 2: Pharmacokinetic parameters of some compounds of the present invention and control compounds 1 and 2

[0791] Compounds 2B, 2C, 19B, and 33 of this invention exhibited higher areas under the curve, highest plasma concentrations, and better oral bioavailability in mice compared to control compounds 1 and 2, demonstrating superior pharmacokinetic properties.

Claims

1. A compound as represented by Formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: ###0001### Formula (I) ​ wherein X 1 , X 2 , and X 3 are independently N or CR 3 ; R3is independently hydrogen, deuterium, halogen, R 3-1 , -N(R 3-1 )C(=O)R 3-1 , -N(R 3-1 )C(=O)OR 3-1 , -N(R 3-1 )C(=O)N(R 3-1 )2, -N(R 3-1 )C(=NR 3- 1 )N(R 3-1 )2, -NR 3-1 S(=O)2R 3-1 , -C(=O)R 3-1 , -C(=O)OR 3-1 , -C(=O)N(R 3-1 )2, -C(=O)N(R 3-1 )OR 3-1 , -C(=O)N(R 3-1 )C(=O)R 3-1 , -OR 3-1 , -SR 3-1 , -N(R 3-1 )2, -Si(R 3-1 )3, -S(=O)nR 3-1 , -S(=O)(=NR 3-1 )R 3-1 , -S(=O)2N(R 3-1 )2, -OC(=O)R 3-1 , -OC(=O)N(R 3-1 )2, -P(=O)(R 3-1 )2, -P(=O)(OR 3-1 )2, -OP(=O)(R 3-1 )2, or -OP(=O)(OR 3-1 )2; R 3-1 independently hydrogen, -CN, -NO2, -OH, -SH, -NH2, C1-C8alkyl, C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10aryl, or 5-10 membered heteroaryl; wherein said C1-C8alkyl, C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 3-1-1 ; and wherein in said 3-12 membered heterocycloalkyl and 3-12 membered heterocycloalkenyl, the heteroatoms or heteroatom groups are independently selected from one or more of N, O, S, S(=O), S(=O)2, and C(=O), and the number of heteroatoms is independently 1, 2, 3, 4, or 5. R 3-1-1 independently deuterium, halogen, -CN, -NO2, oxo (=0), -OH, -SH, -NH2, -C(=0)NH2, -0-(Ci-C6alkyl), -0-(Ci-C6haloalkyl), -NH(Ci-C6alkyl), -N(Ci-C6alkyl)2, -C(=0)(Ci-C6alkyl), -C(=0)NH2, -C(=0)NH(Ci-C6alkyl), -C(=0)N(Ci-C6alkyl)2, or -S(=0) n -(Ci-C6alkyl); n is 1 or 2; L 1 is a chemical bond, a is attached to ring A; L 11 H, Ci-C6-alkyl or Ci-C6-haloalkyl; L 12 Ci-C6-alkyl or Ci-C6-haloalkyl; L 2 L 21 L 22 L 23 -L 22 -L 23 ; L 21 is C l -C 10 alkylene, Ci-C 10 heteroalkylene, C2-C 10 alkenylene or C2-C 10 heteroalkenylene, said Ci-C 10 alkylene and Ci-C 10 heteroalkylene is optionally substituted with 1, 2 or 3 L 1a , said C2-C 10 alkenylene and C2-C 10 heteroalkenylene is optionally substituted with 1, 2 or 3 L 1b , said Ci-C 10 heteroalkylene is Ci-C 10 alkylene in which one or more -CH2- is independently replaced by -O-, -NRL 1c -, -C(=NRL 1c )-, -S-, -S(=O)-, -S(=O)2- or -C(=O)- resulting in a Ci-C 10 heteroalkylene; said C2-C 10 heteroalkenylene is C2-C 10 alkenylene in which one or more -CH2- is independently replaced by -O-, -NRL 1c -, -C(=NRL 1c )-, -S-, -S(=O)-, -S(=O)2- or -C(=O)- resulting in a C2-C 10 heteroalkenylene; L 22 independently C3-C 12 cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 cycloalkenylene, 4-12 membered heterocycloalkenylene, C6-C 10 arylene or 5-10 membered heteroarylene, said C3-C 12 cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 cycloalkenylene, 4-12 membered heterocycloalkenylene, C6-C 10 arylene and 5-10 membered heteroarylene are optionally substituted with 1, 2, or 3 L 1a atoms or atom groups selected from one or more of O, N, S, S(=0), S(=0)2, and C(=0), the number of heteroatoms being 1, 2, 3, 4, or 5; and in said 5-10 membered heteroarylene, the heteroatoms are selected from one or more of N, O, and S, the number of heteroatoms being 1, 2, 3, 4, or 5; L 23 independently C1-C4alkylene or C1-C4heteroalkylene, said C1-C4alkylene or C1-C4heteroalkylene being optionally substituted with 1, 2, or 3 L 1a substituents, said C1-C4heteroalkylene being C1-C4alkylene in which one or more -CH2- groups have been independently replaced with -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; L 1a independently hydrogen, deuterium, halogen, -CN, -NO2, C1-C6alkyl, -O-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(C1-C6alkyl), -C(=O)N(C1-C6alkyl)2, C6-C10aryl, and 5-10 membered heteroaryl, wherein said C1-C6alkyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 L 10 1a-1 independently hydrogen, deuterium, halogen, -CN, -NO2, C1-C6alkyl, -O-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(C1-C6alkyl), -C(=O)N(C1-C6alkyl)2, C6-C 10 1a-2 independently hydrogen, deuterium, halogen, -CN, -NO2, C1-C6alkyl, -O-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(C1-C6alkyl), -C(=O)N(C1-C6alkyl)2, C6-C10aryl, and 5-10 membered heteroaryl, wherein said C1-C6alkyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 L​​ L 1a-1 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 10 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 10 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 1a-2 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L L 1a-2 R2is as defined for R 3 ; L 1b independently halogen, -OH, -CN, C1-C6alkyl, C6-C 10 aryl or 5-10 membered heteroaryl, said C1-C6alkyl is optionally substituted with 1, 2, or 3 L 1a-1 substituents; said C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, or 3 L 1a-2 substituents; in said 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, O, and S, the number of heteroatoms being 1, 2, 3, 4, or 5; L 1c independently hydrogen, CN, -NO2, C1-C6alkyl, C1-C6haloalkyl, -0-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(C1-C6alkyl), C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C4-C 12 cycloalkenyl, 4-12 membered heterocycloalkenyl, -C(=O)N(C1-C6alkyl)2, C6-C 10 aryl or 5-10 membered heteroaryl; in said 3-12 membered heterocycloalkyl and 4-12 membered heterocycloalkenyl, the heteroatoms or heteroatom groups are independently selected from one or more of N, O, S, S(=O), S(=O)2and C(=O), the number of heteroatoms being independently 1, 2, 3, 4 or 5; in said 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, O and S, the number of heteroatoms being 1, 2, 3, 4 or 5; L 3 -C(R 3-1 )2-,-O-,-S-,-S(=O)-,-S(=O)2-,-C(=O)-or-NR 3-1 -; Ring A is a 5-10 quintile heteroaromatic ring, wherein the 5-10 quintile heteroaromatic ring is optionally surrounded by one, two, or three R atoms. A1 Replace, R A1 Independently, it can be deuterium, halogen, OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -S(=O)-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -O-(C1-C6 haloalkyl) or C1-C6 alkyl; in the 5-10 membered heteroaryl ring, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; R 1 is C 1-8 alkyl, -0-(Ci-C8alkyl), -Ci-C6alkylene-0-(Ci-C6alkyl), C4-C 12 cycloalkenyl, 4-12 membered heterocycloalkenyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C 1-8 alkyl, -0-(Ci-C8alkyl), -Ci-C6alkylene-0-(Ci-C6alkyl), C4-C 12 cycloalkenyl, 4-12 membered heterocycloalkenyl, C3-C 12 cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 R 1a substituted, the C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R 1b substituted; in the 3-12 membered heterocycloalkyl and 4-12 membered heterocycloalkenyl, the heteroatoms or heteroatom groups are independently selected from one or more of N, O, S, S(=0), and S(=0)2, and the number of heteroatoms is independently 1, 2, 3, 4, or 5; in the 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; R 1a independently halogen, -CN, C1-C6alkyl, -0-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or oxo (=0); R 1b independently deuterium, -F, -CI, -Br, -I, -CN, -N02, carboxyl, Ci-C6alkyl, Ci-C6haloalkyl, -S-(Ci-C6alkyl), -0-(Ci-C6alkyl), -0-(Ci-C6haloalkyl), -Ci-C6alkylene-0-(Ci-C6alkyl), -Ci-C6alkylene-0-(Ci-C6haloalkyl), -OH, -NH2, -NH(Ci-C6alkyl), -N(Ci-C6alkyl)2, -C(=0)-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, -C(=0)-0-(Ci-C6alkyl), -C(=0)NH2, -C(=0)NH(Ci-C6alkyl), -C(=0)N(Ci-C6alkyl)2, -S(=0)2-(Ci-C6alkyl), C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C4-C 12 cycloalkenyl, or 4-12 membered heterocycloalkenyl; in said 3-12 membered heterocycloalkyl and 4-12 membered heterocycloalkenyl, the heteroatoms or heteroatom groups are independently selected from one or more of N, O, S, S(=0) and S(=0)2, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; R 2 R is as defined for R 3 .

2. The compound of Formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1: X 1 , X 2 , and X 3 are independently N or CR 3 ; R 3 independently H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, or -S(=O)2-(C1-C6 alkyl); L 1 For a is attached to ring A; L 11 H or Ci-C6alkyl; L 12 Ci-C6-alkyl; L 2 L 21 L 22 L 23 L 22 L 23 ; L 21 alkylene, C1-C 10 heteroalkylene, C2-C 10 alkenylene, C2-C 10 heteroalkenylene, C2-C 10 alkynylene, C2-C 10 heteroalkynylene, C2-C 10 heteroalkylene optionally substituted with 1, 2, or 3 L 1a alkenylene, C2-C 10 heteroalkenylene, C2-C 10 heteroalkynylene, C2-C 1b alkynylene, C2-C 10 heteroalkynylene, C2-C 10 heteroalkylene, C1-C 10 heteroalkenylene, C2-C 10 heteroalkynylene, C2-C 10 heteroalkynylene, C2-C 10 heteroalkynylene, C2-C L 22 independently C3-C 12 cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 cycloalkenylene, 4-12 membered heterocycloalkenylene, C6-C 10 arylene or 5-10 membered heteroarylene, said C3-C 12 cycloalkylene, 3-12 membered heterocycloalkylene, C4-C 12 cycloalkenylene, 4-12 membered heterocycloalkenylene, C6-C 10 arylene and 5-10 membered heteroarylene are optionally substituted with 1, 2, or 3 L 1a ; in said 3-12 membered heterocycloalkylene and 4-12 membered heterocycloalkenylene, the heteroatoms are selected from one or more of -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, and -C(=O)-, and the number of heteroatoms is 1, 2, or 3; in said 5-10 membered heteroarylene, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; L 23 independently C1-C4alkylene or C1-C4heteroalkylene, said C1-C4alkylene or C1-C4heteroalkylene being optionally substituted with 1, 2, or 3 L 1a substituents, said C1-C4heteroalkylene being C1-C4alkylene in which one or more -CH2- groups have been independently replaced with -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; L 1a Independently, it can be deuterium, halogen, -CN, C1-C6 alkyl, -O-(C1-C6 alkyl), OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L 1a-1 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 10 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 10 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L 1a-2 independently halogen, C6-C10aryl, or 5-10 membered heteroaryl, said C6-C10aryl and 5-10 membered heteroaryl being optionally substituted with 1, 2, or 3 L L 1a-2 independently cyano, halogen, C1-C6alkoxy, or C1-C6alkyl; L 1b Independently halogen, -OH, -CN, C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 Substitution; in the 5-10 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L 3 is -O-, -S- or -NH-; Ring A is a 5-10 quintile heteroaromatic ring, wherein the 5-10 quintile heteroaromatic ring is optionally surrounded by one, two, or three R atoms. A1 Replace, R A1 Independently, it is a halogen, OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or C1-C6 alkyl; in the 5-10 membered heteroaryl ring, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 1 is C 1-8 alkyl, -O-(Ci-C8alkyl), -Ci-C6alkylene-O-(Ci-C6alkyl), C4-C 12 cycloalkenyl, 4-12 membered heterocycloalkenyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C 1-8 alkyl, -O-(Ci-C8alkyl), -Ci-C6alkylene-O-(Ci-C6alkyl), C4-C 12 cycloalkenyl, 4-12 membered heterocycloalkenyl, C3-C 12 cycloalkyl, and 3-12 membered heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 R 1a substituted; the C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R 1b substituted; in the 3-12 membered heterocycloalkyl and 4-12 membered heterocycloalkenyl, the heteroatoms are independently selected from one or more of N, O, S, S(=O), and S(=O)2, and the number of heteroatoms is independently 1, 2, or 3; in the 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. R 1a independently halogen, -CN, C1-C6alkyl, -0-(C1-C6alkyl), -OH, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or oxo (=0); R 1b independently deuterium, -F, -CI, -Br, -I, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -C1-C6 alkylene-O-(C1-C6 alkyl), -C1-C6 alkylene-O-(C1-C6 haloalkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, or -S(=O)2-(C1-C6 alkyl); R 2 H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O- (C1-C6 alkyl), -O-(C1-C6 haloalkyl), -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-(C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, or -S(=O)2-(C1-C6 alkyl).

3. The compound of formula (I) as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions: (1) each "halo" is independently F, Cl, Br, or I, for example F or Cl; (2) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, for example methyl or ethyl; (3) each "C1-C6 alkylene" is independently methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, or t-butylene; (4) each "C1-C6haloalkyl" is independently a C1-C6alkyl group as defined above substituted with 1, 2, or 3 halogen atoms; l -C6alkyl, and said halogen is F, Cl, Br, or I; (5) each "C2-C6 alkenyl" is independently C2-C4 alkenyl, for example, ethenyl, propenyl, or allyl; (6) each "C2-C6 alkynyl" is independently C2-C4 alkynyl, for example, ethynyl, propynyl, or propargyl; (7) each "C1-C6alkyl" is independently a straight or branched saturated carbon chain having one to six carbon atoms, e.g., -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, or -CH2CH2CH2CH2CH2CH3; 10 each "alkylene" is independently -(CH2)n-, n is 1-10, e.g., -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, or -(CH2)8-, (8) each "C1-C6alkyl" is independently a straight or branched saturated carbon chain having one to six carbon atoms; 10 each "heteroalkylene" is independently -(CH2)n- wherein 1 or more -CH2- are n independently replaced with -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-, and n is 1-10; for example, -(CH2)n- wherein 1, 2, or 3 -CH2- are independently replaced with -O-, -NH-, or -C(=O)-, and n is 3, 4, 5, 6, 7, or 8, further for example preferably (9) Each "C2-C" 10 "Alkenyl" groups are each independently C2-C 10 Straight-chain alkenyl groups, such as C4, C5, C6, C7, or C8 straight-chain alkenyl groups, wherein the number of -CH=CH- groups is one, and the configuration of -CH=CH- is the R configuration, the S configuration, or a mixture thereof, further for example... preferably (10) Each "C2-C 10 Each of the "heteroene groups" is independently C2-C. 10 One or more -CH2- groups in the hesene group are independently replaced by -O-, -NH-, or -S-, for example... (11) each "C3-C6cycloalkylene" is independently C4-C6monocycloalkylene, C6-C6 12 cycloalkylene, C6-C 12 cycloalkylene, C6-C 12 cycloalkylene, C6-C 12 cycloalkylene, such as cyclobutylene, cyclopentylene or cyclohexylene, further such as (12) each "3-12 membered heterocycloalkylene" is independently 4-7 membered monocyclic heterocycloalkylene, 6-12 membered annulated heterocycloalkylene, 6-12 membered bridged heterocycloalkylene, or 6-12 membered spirocyclic heterocycloalkylene, for example 4-7 membered monocyclic heterocycloalkylene having 1 or 2 heteroatoms which are -N- and / or -C(=0)-, further for example (13) each "C4-C7 cycloalkylene" is independently C4-C7 cycloalkylene, C4-C6 cycloalkylene, or C4-C5 cycloalkylene; 12 C6-C7 cycloalkenylene, C6-C6 cycloalkenylene, or C6-C5 cycloalkenylene; 12 C6-C7 cycloalkenylene, C6-C6 cycloalkenylene, or C6-C5 cycloalkenylene; 12 C6-C7 cycloalkenylene, C6-C6 cycloalkenylene, or C6-C5 cycloalkenylene; 12 C6-C7 cycloalkenylene, C6-C6 cycloalkenylene, or (14) each "4-12 membered heterocycloalkenylene" is independently 4-7 membered monocyclic heterocycloalkenylene, 6-12 membered annulated heterocycloalkenylene, 6-12 membered bridged heterocycloalkenylene, or 6-12 membered spirocyclic heterocycloalkenylene; (15) each "C6-Cio-aryl" is independently C6-Cio-aryl, for example phenyl; 10 each "arylene" is independently arylene or naphthylene, for example arylene, further for example (16) each "5-10 membered heteroarylene" is independently 5-6 membered monocyclic heteroarylene or 8-10 membered bicyclic heteroarylene; (17) each "C1-C4 alkylene" is independently C1-C4 straight chain alkylene, for example methylene, ethylene, or n-propylene; (18) each "C1-C4 heteroalkylene" is independently C1-C4 straight chain alkylene in which one or more -CH2- is independently replaced with -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; (19) Each "C6-C" 10 Each aryl group can be independently phenyl or naphthyl, for example, phenyl; (20) each "5-10 membered heteroaryl" is independently 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl, for example 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatoms which are N, further for example pyridyl or pyrimidinyl, preferably (21) each "5-10 membered heteroaromatic ring" is independently 5-6 membered monocyclic heteroaromatic ring or 8-10 membered bicyclic heteroaromatic ring, for example, 5-6 membered monocyclic heteroaromatic ring having 1, 2, or 3 N heteroatoms or 8-10 membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 N heteroatoms, further for example, triazolyl, imidazopyrazinyl, or imidazopyridazinyl; (22) each "C 1-8 alkyl" is each independently C 1-6 alkyl, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; (23) Each "C4-C 12 Each "cycloalkenyl" group can be independently a C4-C7 monocyclic cycloalkenyl or a C6-C cycloalkenyl. 12 cycloalkenyl, C6-C 12 Bridged ring cycloalkenyl or C6-C 12 Spirocyclic cycloalkenyl; (24) each "4-12 membered heterocycloalkenyl" is independently 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered annulated heterocycloalkenyl, 6-12 membered bridged heterocycloalkenyl, or 6-12 membered spirocyclic heterocycloalkenyl, for example (25) Each "C3-C" 12 Each cycloalkyl group is independently a C4-C7 monocyclic cycloalkyl group or a C6-C cycloalkyl group. 12 cycloalkyl, C6-C 12 Bridged cycloalkyl or C6-C 12 Spirocycloalkyl; (26) each "3-12 membered heterocycloalkyl" is independently 4-7 membered heterocycloalkyl, 6-12 membered annulated heterocycloalkyl, 6-12 membered bridged heterocycloalkyl, or 6-12 membered spirocyclic heterocycloalkyl; (27) each "C2-C8 alkenyl" is independently C2-C6 alkenyl, for example, ethenyl, propenyl, or allyl; each "C2-C8 alkynyl" is independently C2-C6 alkynyl, for example, ethynyl, propynyl, or propargyl; and (29) Each "C3-C" 12 Each "cycloalkenyl" group can be independently a C4-C7 monocyclic cycloalkenyl or a C6-C cycloalkenyl. 12 cycloalkenyl, C6-C 12 Bridged ring cycloalkenyl or C6-C 12 Spirocyclic cycloalkenyl; (30) each "3-12 membered heterocycloalkenyl" is independently 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered annulated heterocycloalkenyl, 6-12 membered bridged heterocycloalkenyl, or 6-12 membered spirocyclic heterocycloalkenyl.

4. The compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 3, wherein one or more of the following conditions: (1) X 1 , X 2 , and X 3 are independently CR 3 , for example CH; (2) L 1 To For example preferably a is attached to ring A; (3) L 2 L 21 or L 23 -L 22 -L 23 ; L 21 For C1-C 10 Alkylene, C1-C 10 Heteroalkyl, C2-C 10 alkenyl or C2-C 10 Heteroenyl, the C1-C 10 Alkylene and C1-C 10 The heteroalkyl group is optionally surrounded by one, two, or three L-members. 1a Instead, the C2-C 10 alkenyl and C2-C 10 The hesylene group is optionally surrounded by one, two, or three L-members. 1b replace; L 1a independently OH, C1-C6alkyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C6alkyl is optionally substituted with 1, 2, or 3 L 1a-1 substituents; said C6-C 10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 L 1a-2 substituents; L 1a-1 Independently for C6-C 10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace; L 1a-2 independently halogen or Ci-C6alkyl; L 1b Independently C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace; L 22 independently C3-C 12 cycloalkylene, 3-12 membered heterocycloalkylene, C6-C 10 arylene, or 5-10 membered heteroarylene; L 23 independently C1-C4alkylene or C1-C4heteroalkylene; Preferably, L 2 is L 21 or L 23 -L 22 -L 23 ; L 21 C3-C8alkylene, C3-C8heteroalkylene, C3-C8alkenylene, or C3-C8heteroalkenylene, said C3-C8alkylene and C3-C8heteroalkylene optionally substituted with 1, 2, or 3 L 1a substituents, said C3-C8alkenylene and C3-C8heteroalkenylene optionally substituted with 1, 2, or 3 L 1b substituents; L 1a independently OH, C1-C6alkyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C6alkyl is optionally substituted with 1, 2, or 3 L 1a-1 substituted, said C6-C 10 aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 L 1a-2 substituted; L 1a-1 Independently for C6-C 10 Aryl or 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace; L 1a-2 independently halogen or Ci-C6alkyl; L 1b Independently C1-C6 alkyl, C6-C 10 Aryl or 5-10 heteroaryl, wherein the C1-C6 alkyl group is optionally surrounded by one, two or three L-membered groups. 1a-1 Instead, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one, two, or three L-membered molecules. 1a-2 replace; L 22 independently C3-C6cycloalkylene, 3-6 membered heterocycloalkylene, phenylene, or 5-6 membered heteroarylene; L 23 independently C1-C4alkylene or C1-C4heteroalkylene; (3) L 3 is -O-; (4) Ring A is a "1, 2, 3, or 4 heteroatoms of which are N" 5-6 membered monocyclic heteroaromatic ring, said 5-6 membered monocyclic heteroaromatic ring is optionally substituted with 1, 2, or 3 R A1 substituents; or an 8-10 membered bicyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms each independently N, O, or S, said 8-10 membered bicyclic heteroaromatic ring being optionally substituted with 1, 2, or 3 R A1 substituents; (5) R A1 independently halogen, -NH2, or Ci-C6alkyl; (6) R 1 is either scheme a or scheme b: Scheme a: 5-10 membered heteroaryl or 5-10 membered heterocycloalkenyl, said 5-10 membered heteroaryl or 5-10 membered heterocycloalkenyl optionally substituted by 1, 2, 3 or 4 R 1b substituents; Scheme b: 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R 1b substituents; (7) R 1b independently C l -C6alkyl or -O-(Ci-C6alkyl); (8) R 2 -O-(C1-C6alkyl), for example methoxy.

5. The compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 3, wherein one or more of the following conditions: (1) L 2 is either Scheme 1 or Scheme 2 below: Scheme 1: Scheme 2: wherein denotes that the double bond is in the Z configuration, the E configuration or a mixture thereof, for example the Z configuration, "*" denotes that the configuration of the carbon atom to which it is attached is the R configuration, the S configuration or a mixture thereof; b is connected to L 1 ; L 2 For example, the following Scheme I or Scheme II: Scheme I: Scheme II: wherein b is connected to L 1 ; (2) L 3 is -O- or -NH-; (3) R 2 halo, -O-(C1-C6alkyl), C2-C6alkenyl, or C1-C6alkyl optionally substituted with one or more R 3-1-1 substituents, said R 3-1-1 independently halo, -OH, oxo (=0), -SH, -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; R 2 for example methoxy, -F, -CI, -Br, -CH3, -CH2CH3, -CF3, 6. The compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 3, wherein one or more of the following conditions: (1) L 2 To wherein, denotes that the double bond is in the Z configuration, the E configuration or a mixture thereof, for example the Z configuration, "*" denotes that the configuration of the carbon atom to which it is attached is the R configuration, the S configuration or a mixture thereof; b is connected to L 1 ; For example: wherein b is connected to L 1 ; (2) Ring A is: G1： wherein c is attached to R and d is attached to L 1 or, G2： wherein the c-side is connected to R 1 and the d-side is connected to L 1 ​ For example: G11： wherein the c-side is connected to R 1 and the d-side is connected to L 1 or, G21： wherein the c-side is connected to R 1 and the d-side is connected to L 1 ​ Further for example: G11-1： wherein the c-side is connected to R 1 and the d-side is connected to L 1 or, G21-1： wherein the c-side is connected to R 1 and the d-side is connected to L 1 ​ (3) R 1 For preferably For example 7. The compound of formula (I) as described in at least one of claims 1-6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound as shown in formula (I) is a compound as shown in formula (I-1) or as shown in formula (I-2): wherein X 1 , X 2 , X 3 , L 1 , L 2 , L 3 , ring A, R 1 and R 2 are as defined in at least one of claims 1 to 6.

8. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound as shown in formula (I) is any one of the following compounds: wherein, in the above compound, denotes that the double bond is in the E configuration, the Z configuration or a mixture thereof, corresponding the compound of the structure denotes or a mixture thereof, e side and L 3 is connected; For example:

9. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (I) is any one of the following compounds: one stereoisomer having a retention time of 2.48 min under the following conditions: Chiral column: AS 20*250 mm, 10 um; Column temperature: 35 °C; Mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 65 / 35; Flow rate: 100 ml / min; one stereoisomer having a retention time of 3.09 min under the following conditions: Chiral column: AS 20*250 mm, 10 um; Column temperature: 35 °C; Mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 65 / 35; Flow rate: 100 ml / min; one stereoisomer having a retention time of 1.42 min under the following conditions: Chiral column: Column: IK 25*250 mm, 10 um; Column temperature: 25 °C; Mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 60 / 40; Flow rate: 100 ml / min; one stereoisomer having a retention time of 1.65 min under the following conditions: Chiral column: Column: IK 25*250 mm, 10 um; Column temperature: 25 °C; Mobile phase: CO2 / MeOH (0.2% v / v ammonia in methanol) = 60 / 40; Flow rate: 100 ml min; the first eluting compound under the following conditions: Chiral column: IG 25*250 mm, 10 um; Column temperature: room temperature; Mobile phase: CO2 / MeOH (0.2% v / v ammonia in methan ol) = 50 / 50; Flow rate: 120 ml / min; preferably, the retention time of the first eluting compound under the conditions is 1.71 min; the second eluting compound under the following conditions: Chiral column: IG 25*250 mm, lOum; Column temperature: room temperature; Mobile phase: CO2 / MeOH (0.2 % v / v ammonia in methanol) = 50 / 50; Flow rate: 120 ml / min; preferably, the retention of the second eluting compound under the conditions is 2.64 min; the first eluting compound under the following conditions: Chiral column (R,R) WHELK-O 125*250 mm, 10 um; Column temperature: room temperature; Mobile phase: CO2 / MEOH (0.2% v / v ammonia in methanol) = 70 / 30; Flow rate: 100 ml / min; preferably, the retention time of the first eluting compound under the conditions is 2.13 min; the second eluting compound under the following conditions: Chiral column (R,R) WHELK-O l25*250 mm, 10 um; Column temperature: room temperature; Mobile phase: CO 2 / MeOH (0.2% v / v ammonia in methanol) = 70 / 30; Flow r ate: 100 ml / min; preferably, the retention of the second eluting compound under the conditions is 3.18 min; the first eluting compound under the following conditions: Chiral column: AD 25*250mm, 10um (Daicel); Column temperature: 25°C; Mobile phase: CO2 / [EtOH (0.2% NH3 (7M in MeOH)] = 65 / 35; Flow rate: 120 ml / min; preferably the retention time of the first eluting compound under the stated conditions is 1.14 min; the second eluting compound under the following conditions: Chiral column: AD 25*250mm, 10um (Daicel); Column temperature: 25°C; Mobile phase: CO2 / [EtOH (0.2% NH3 (7M in MeOH)] = 65 / 35; Flow rate: 120 ml / min; preferably the retention time of the second eluting compound under the stated conditions is 3.14 min; the first eluting compound under the following conditions: Chiral column: OD 25*250mm, 10um (Daicel); Column temperature: 25°C; Mobile phase: CO2 / [MeOH (0.5% NH3 (7M in MeOH)] = 60 / 40; Flow rate: 100 ml / min; preferably the retention time of the first eluting compound under the stated conditions is 0.92 min; the second eluting compound under the following conditions: Chiral column: OD 25*250mm, lOum (Daicel); Column temperature: 25°C; Mobile phase: CO2 / MeOH (0.5% NH3 (7M in MeOH)] = 60 / 40; Flow rate: 100 ml / min; preferably the retention time of the second eluting compound under the stated conditions is 1.30 min; the first eluting compound under the following conditions: Chiral column: AD 25*250 mm, 10um (Daicel); Column temperature: room temperature; Mobile phase: CO2 / [MEOH (0.2% NH3 (7M in MeOH)] = 55 / 45; Flow rate: 120 ml / min; preferably the retention time of the first eluting compound is 1.03 min under the stated conditions; the second eluting compound under the following conditions: Chiral column: AD 25* 250mm, 10um (Daicel); Column temperature: room temperature; Mobile phase: CO 2 / [MEOH (0.2% NH3 (7M in MeOH] = 55 / 45; Flow rate: 120 ml / min; preferably the retention time of Mixture 1 and Mixture 2 retention time 1.54 min mixture: Column: Xtimate Prep C18 10 μm 21.2 x 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 32-62% B in 8 min, stop at 16 min Flow rate: 30 ml / min, said Mixture 1 is a mixture of 2, said mixture 2 being a mixture of Mixture 1 and Mixture 2 for the compound with a retention time of 1.74 min under the following conditions: Column: Xtimate Prep C18 10 pm 212 x 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 32-62% B in 8 min, stop at 16 min; Flow rate: 30 ml / min, said Mixture 1 being The mixture, wherein the mixture 2 is a mixture of Mixture 3 and Mixture 4 for the compound with a retention time of 1.51 min under the following conditions: Column: Xtimate Prep C18 10 μm 21.2 x 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 30-60% B in 8 min, stop at 16 min; Flow rate: 30 ml / min, said Mixture 3 is a mixture of 4, said mixture 4 being a mixture of Mixture 3 and Mixture 4 for the compound with a retention time of 1.60 min under the following conditions: Column: Xtimate Prep C18 10 μm 21.2 x 250 mm; Mobile phase: A: water (10 mmol NH4HCO3), B: acetonitrile; Gradient: 30-60% B in 8 min, stop at 16 min; Flow rate: 30 ml / min; Mixture 3 is a mixture of 4, said mixture 4 being a mixture of The mixture of enantiomers that eluted first in Mixture 1 and Mixture 2 under the following conditions: Boston Prep C18 10 μm 21.2 x 250 mm; mobile phase: A: water (0.2% FA), B: acetonitrile; gradient: 25% - 55% B in 8 min, stop at 16 min; flow rate: 30 ml / min, said Mixture 1 being The mixture, wherein the mixture 2 is a mixture of; preferably the retention time of the first eluting mixture is 8.3 min under the stated conditions; Mixture 1 and Mixture 2, a mixture of enantiomers eluting later under the following conditions: Boston Prep C18 10 μm 212 x 250 mm; mobile phase: A: water (0.2% FA), B: acetonitrile; gradient: 25% - 55% B in 8 min, stop at 16 min; flow rate: 30 ml / min, said Mixture 1 being The mixture, wherein the mixture 2 is a mixture of; preferably the retention time of the second eluting mixture is 9.5 min under the stated conditions; one rotational isomer of the compound of formula (I), said rotational isomer being in the trans configuration, With the relative spatial position of the substituents of the compound A is as follows retention time of 3.14 min under the conditions described; and The retention time for the compound was 2.512 mm under the following conditions: chiral column DAICEL CHIRALPAK IB N-10 25*250 mm, 10 um; column temperature: 35 °C; mobile phase: CO2 / [MeOH] = 50 / 50; flow rate: 45 ml / min; The compound with a retention time of 2.942 min under the following conditions: chiral column DAICEL CHIRALPAK IB N-10 2 5*250 mm, 10 um; column temperature: 35 °C; mobile phase: CO2 / [MeOH] = 50 / 50; flow rate: 45 ml / min; The compound with a retention time of 1.499 min under the following conditions: Chiral column (S,S)-Whelk-O-1 25* 250 mm, 10 um; column temperature: 35 °C; mobile phase: CO2 / [MeOH / ACN] = 50 / 50; flow rate: 45 ml / min; Compound with retention time of 1.811 min under the following conditions: Chiral column (S, S)-Whelk-O-1 25*250 mm, 10 um; column temperature: 35 °C; mobile phase: CO2 / [MeOH / ACN] = 50 / 50; flow rate: 45 ml / min; Compound eluting first under the following conditions: Column: YMC-Actus Triart C18, 150*20 mm, 5 um; mobile phase: A: water (0.1% FA), B: acetonitrile; gradient: 30-50% in 6.5 min and 7.8 min, stop at 8 min; flow rate: 20 ml / min; preferably the compound eluting first has a retention time of 1.682 min; Compound eluting last under the following conditions: Column: YMC-Actus Triart C18, 150 * 20 mm, 5 um; mobile phase: A: water (0.1% FA) B: acetonitrile; gradient: 30-50% in 6.5min and 7.8min, stop at 8min; flow rate: 20 ml / min; preferably the compound eluting last has a retention time of 1.723 min; one rotameric form of Compound A which is the first eluting compound when Compound A is separated under the following conditions: Chiral column: AD 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH (0 . 2% NH3(7M in MeOH)] = 50 / 50; Flow rate: 100 mL / min; preferably, the retention time of the first eluting compound is 0.863 min; said compound A is Compound eluting first under the following conditions: Column: YMC-Actus Triart Cl8, 150*20 mm, 5 um; mobile phase: A: water (0.l%FA), B: acetonitrile; gradient: 30-50% in 6. 5 min and 7.8 min, stop at 8 min; flow rate: 2O ml / min; preferably the compound eluting first has a retention time of 1.682 min; Compound eluting last under the following conditions: Column: YMC-Actus Triart C18, one rotational isomer of Compound A which is the later eluting compound when Compound A is separated under the following conditions: Chiral column: AD 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH (0.2% NH3(7M in MeOH)] = 50 / 50; Flow rate: 100 mL / min; preferably the retention time of the later eluting compound is 2.246 min; said Compound A is 150*20 mm, 5 um; mobile phase: A: water (0.1 % FA), B: acetonitrile; gradient: 30-50% in 6,5 min and 7.8 min, stop at 8 min; flow rate: 30 ml / min; preferably the compound eluting last has a retention time of 1.723 min; Compound eluting first under the following conditions: Column: YMC-Actus Triart C18, one rotational isomer of compound B which is the first eluting compound when compound B is separated on a chiral column: IG 25*250mm, 10um (Daieel); mobile phase: CO2 / [MeOH (0.2% NH3(7M in MeOH)] = 45 / 55: flow rate: 120 mL / min; preferably the retention time of the first eluting compound is 1.178 min; said compound B is 150* 20 mm, 5 um; mobile phase: A: water (0.1%FA), B: acetonitrile; gradient: 30-50% in 8 min, stop at 8 min; flow rate: 20 ml / min; preferably the first eluting compound has a retention time of 1.682 min; Compound eluting last under the following conditions: Column: YMC-Actus Triart C18, 150*20 mm, 5 urn; mobile phase: A: water (0.1%FA), B: acetonitril; gradient: 30-50% in 8 min, stop at 8 min; f ow rate: 20 ml / min; preferably the last eluting compound has a retention time of 1.723 min; one rotational isomer of compound B which is the later eluting compound when compound B is separated on a chiral column: IG 25*250mm, 10um (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3(7M in MeOH)] = 45 / 55; flow rate: 120 mL / min; preferably the later eluting compound has a retention time of 2.067 min; said compound B is Compound eluting later: Column: YMC-Actus Triart C18, 150*20mm, 5um; Mobile phase: A: water (0.1%FA), B: acetonitrile; Gradient: 30-50% in 6.5min and 7.8min, stop at 8min; Flow rate: 20ml / min; Preferably, the retention time of the compound eluting later is 1.723min; Compound eluting earlier: Chiral column: OZ 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH (0.2%NH3 (7M in MeOH)] = 50 / 50; Flow rate: 120mL / min; Preferably, the retention time of the compound eluting earlier is 1.115min; Compound eluting later: Chiral column: OZ 25*250mm, 10um (Daicel); Mobile phase: CO2 / [MeOH (0.2%NH3 (7M in MeOH)] = 50 / 50; Flow rate: 120mL / min; Preferably, the retention time of the compound eluting later is 3.221min.

10. A pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, according to at least one of claims 1 to 9, and a pharmaceutically acceptable excipient.

11. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate or a solvate of a pharmaceutically acceptable salt thereof, according to at least one claim of claims 1 to 9, or a pharmaceutical composition according to claim 10, for the preparation of an agonist of the APJ receptor.

12. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solventate thereof or a solvate of a pharmaceutically acceptable salt thereof, according to at claim of claims 1 to 9, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for a disease associated with the APJ receptor, preferably a cardiovascular disease or muscle atrophy, such as pulmonary hypertension or heart failure.

13. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solution thereof or a solvate of a pharmaceutically acceptable salt thereof, according to at least claim of claims 1 to 9, or a pharmaceutical composition according to claim 10, to increase muscle, or to prevent and / or treat a cardiovascular disease or muscle atrophy, such as pulmonary hypertension or heart failure.

14. A process for preparing a compound of formula (I) according to at least one of claims 1 to 9, which is process 1, process 2, process 3 or process 4: Scheme 1: Method 1 : which comprises the following steps: carrying out a cyclization reaction of a compound as shown in formula (IA) as shown below, in the presence of a solvent, under the action of a ruthenium carbene complex catalyst, to prepare a compound as shown in formula (I); wherein, X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , L 3 and ring A is as defined in at least one of claims 1 to 9; L 2 , L 2-1 and L 2-2 are defined as any one of the following schemes: Preferably, in process 1, the ruthenium carbene complex catalyst is Grubbs II catalyst; L 2 C2-C 10 alkenylene or C2-C 10 heteroalkenylene, said C2-C 10 alkenylene and C2-C 10 heteroalkenylene are optionally substituted with 1, 2, or 3 L 1b substituents; L 2-1 and L 2-2 is independently C2-C6alkenyl or C2-C6heteroalkenyl, said C2-C6alkenyl or C2-C6heteroalkenyl optionally substituted with 1, 2, or 3 L 1b substituents; L 1b of the application; and pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (II): In some Scheme 2: L 2 -C(=O)-C1-C4alkylene-; L 2m -C(=O)-C1-C4alkylene-; L 2m -C(=O)-C1-C4alkylene-; L 2m is H or C1-C6alkyl; L 2-1 -C1-C4alkylene-C3-C6cycloalkylene-NHL 2m or -C1-C4alkylene-NHL 2m , L 2-2 -C1-C4alkylene-COOH; or L is -C1-C4alkylene-C3-C6cycloalkylene-NH2 2-1 -C1-C4alkylene-C3-C6cycloalkylene-NH2 2-2 -C1-C4alkylene-C3-C6cycloalkylene-NH2 2m -C1-C4alkylene-C3-C6cycloalkylene-NH2 2m -C1-C4alkylene-C3-C6cycloalkylene-NH2 L 2m H or C1-C6 alkyl; ​ Preferably, in the method 1, the solvent is a halogenated hydrocarbon solvent, such as dichloromethane; Method 2: comprising the step of preparing a compound of formula (I) by subjecting a compound of formula (IB) to a reduction reaction as shown below in the presence of a reducing agent in a solvent; wherein X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , L 3 and ring A are as defined in at least one of claims 1 to 9; L 2' C2-C 10 alkenylene or C2-C 10 heteroalkenylene, said C2-C 10 alkenylene and C2-C 10 heteroalkenylene are optionally substituted with 1, 2, or 3 L 1b substituents; L 2 alkylene or C2-C 10 alkylene or C2-C 10 heteroalkylene, said C2-C 10 alkylene and C2-C 10 heteroalkylene is optionally substituted with 1, 2, or 3 L 1b substituents; L 1b of at least one of claims 1 to 9; Preferably, in the method 2, the reducing agent is Pd / C; Preferably, in the method 2, the solvent is an alcohol solvent, such as ethanol; Method 3: comprising the step of preparing a compound of formula (I) by condensation reaction of a compound of formula (IC) in a solvent in the presence of methanesulfonic acid; Preferably, the solvent is a cyclic ether solvent, such as 1,4-dioxane; Preferably, the temperature of the condensation reaction is 80-100°C, such as 90°C; Method 4: comprising the step of condensation reaction of a compound of formula (ID) with a compound of formula (IE) in a solvent to produce a compound of formula (I); wherein X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , L 3 and ring A are as defined in at least one of claims 1 to 9; L 2 -C(=O)-NHL 2m -C1-C6alkylene- ## one end of which is attached to L 1 ; L 2-2 -C1-C6alkylene-NRcRd 2m ; L 2m H or Ci-C6alkyl; R s1 and R s2 each independently is C1-C6 alkyl substituted with one or more halogen; Preferably, the compound of formula (IE) is Preferably, the solvent is a halogenated alkane solvent, such as dichloromethane.

15. A compound as shown in formula (IA): wherein, X 1 , X 2 , X 3 , R 1 , R 2 , L 1 , L 3 , L 2-1 , L 2-2 and ring A is as defined in claim 14; Preferably, the compound of formula (IA) is any one of the following compounds: wherein, for each of the corresponding structural denotes or mixtures thereof, e is L3 相 cis; the configuration of the carbon atom marked "*" is the R configuration, the S configuration or a mixture thereof; Further for example:

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