Quaternary ammonium salt compound containing bridged ring structure, and preparation method therefor and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry. Provided are a quaternary ammonium salt compound containing a bridged ring structure, and a preparation method therefor and the use thereof. The compound has a structure as shown in formula (I). The compound can not only produce a long-acting analgesic effect, but also has a low toxicity to systemic and local tissues, has a good safety and a long duration of action in use, and has broad application prospects in the preparation of drugs having long-acting analgesic and / or long-acting local anesthetic effects.

Description

Quaternary ammonium salt compound containing bridged ring structure and preparation method and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a quaternary ammonium salt compound containing a bridged ring structure and a preparation method and use thereof. BACKGROUND

[0002] Pain, especially chronic pain, has become a major challenge in the field of global public health. Epidemiological data shows that chronic pain affects more than 30% of the global population. In China, the total number of patients with chronic pain has exceeded 300 million, and continues to grow at a rate of 10-20 million cases per year. However, the current treatment rate of chronic pain patients in China is less than 60%, and less than 50% of patients can obtain effective analgesic treatment. This treatment gap not only seriously affects the daily activities and quality of life of patients, but also causes significant social and economic burden.

[0003] From the perspective of clinical needs, the analgesic drug market is showing a sustained growth trend. In 2019, the analgesic drug market size of public medical institutions in China reached 18.4 billion yuan. In the global market, the analgesic drug market size in 2022 was 38.6 billion US dollars, and is expected to continue to expand at a CAGR of 6.02% from 2023 to 2030. Common analgesic drugs mainly include opioid drugs, non-steroidal anti-inflammatory drugs (NSAIDs) and local anesthetics, etc. Among them, opioid drugs may cause adverse reactions such as respiratory depression and addiction; NSAIDs have a "ceiling effect" and may increase the risk of gastrointestinal ulcers and myocardial infarction.

[0004] Local anesthetics are a class of drugs that can reversibly block nerve conduction by various administration routes (including surface application, peripheral nerve ending / nerve trunk injection, epidural space or subarachnoid space injection, etc.) while maintaining the patient's conscious state. Its mechanism of action is to inhibit voltage-gated sodium channels, causing temporary sensory loss in specific innervation areas. Compared with systemic analgesic drugs, local anesthetics have significant advantages such as accurate analgesic effect and no addiction, and therefore play an important role in perioperative analgesia and postoperative pain management.

[0005] However, the current local anesthetics have significant limitations in clinical application, mainly in the mismatch between the duration of action and the postoperative pain period (the conventional formulation only maintains effective analgesia for 8-12 hours, while postoperative pain usually lasts for 48-72 hours), and the increased risk of local tissue toxicity with increasing dose and duration of administration. To break through these limitations, current research mainly focuses on two directions: one is to develop new local anesthetic compounds through molecular structure modification, such as QX-314, QX-OH and Neosaxitoxin quaternary ammonium derivatives, but their duration of action still cannot meet the clinical needs; the other is to use sustained-release delivery systems such as liposomes, polymer microspheres and other carrier technologies to prolong the release time of the drugs, among which bupivacaine liposomes as a representative formulation can prolong the duration of action to 72 hours, but clinical research data shows that it cannot significantly reduce the opioid drug use and the incidence of related adverse reactions in patients.

[0006] Therefore, it is of great clinical significance and broad application prospect to design a new local anesthetic compound that can produce long-acting analgesia. At the same time, the new compound can also be further prolonged by a sustained-release delivery system. SUMMARY

[0007] The purpose of the present application is to provide a quaternary ammonium salt compound containing a bridged ring structure and its preparation method and use. The compounds involved in the present application are all optically pure compounds derived from naturally occurring bridged ring amine structures.

[0008] The present application provides a compound represented by Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a crystal form thereof, a prodrug thereof, a metabolite thereof or a deuterated derivative thereof:

[0009] at least one of R1, R2, R3 and R4 is selected from the rest are each independently selected from hydrogen, hydroxyl, unsubstituted or substituted by one or more than two R b substituted C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl;

[0010] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy;

[0011] Y1 is selected from O, S, NH, Y2 is selected from O, S, NH, null, Y3 is selected from O, S, NH, R 11 is selected from C 1-10alkyl;

[0012] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 are each independently selected from C 1-10 alkyl, is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k is selected from the following groups, which are unsubstituted or substituted by one or more R x phenyl, 5-6 membered heteroaryl, R x are each independently selected from halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0013] R b is selected from C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0014] R2 and R4 are not simultaneously hydrogen;

[0015] is

[0016] X1 is selected from NH, O, S;

[0017] X2 is selected from NH, O, S;

[0018] R9 is selected from C 1-10 alkyl, 5-8 membered aromatic ring, 5-8 membered heteroaromatic ring, which are unsubstituted or substituted by one or more substituents; the substituents are each independently selected from halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy, 3-6 membered saturated cycloalkyl, C 1-10 alkyl;

[0019] R5, R6, R7, R8 are each independently selected from hydrogen, halogen, hydroxyl, the following groups, which are unsubstituted or substituted by one or more R d alkyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl; R deach independently selected from C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0020] is a monovalent anion.

[0021] Further, the structure of the compound is shown as Formula II:

[0022] R1is selected from hydroxyl, unsubstituted or substituted by one or more than two R b substituted by one or more than two R 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl;

[0023] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy;

[0024] Y1is selected from O, S, NH, Y2is selected from O, S, NH, null, Y3is selected from O, S, NH, R 11 is selected from C 1-10 alkyl;

[0025] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 each independently selected from C 1-10 alkyl, is a monovalent anion, K1is selected from O, S, NH, K2is selected from O, S, NH, R k is selected from C x alkyl, C x each independently selected from halogen, C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkoxy;

[0026] R b is selected from C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0027] R2, R4are each independently selected from the group consisting of hydrogen, hydroxyl, unsubstituted or substituted by one or more than one R c substituted by one or more than one R 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl; R2and R4are not simultaneously hydrogen;

[0028] wherein q is selected from 1, 2, 3 or 4, R 12 is selected from the group consisting of hydrogen, C 1-10 alkyl;

[0029] Z1is selected from O, S, NH, Z2is selected from O, S, NH, no, Z3is selected from O, S, NH, R 13 is selected from the group consisting of C 1-10 alkyl;

[0030] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 are each independently selected from the group consisting of C 1-10 alkyl, is a monovalent anion, L1is selected from O, S, NH, L2is selected from O, S, NH, R L is selected from the group consisting of unsubstituted or substituted by one or more than one R Y phenyl, 5-6 membered heteroaryl, R Y are each independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0031] R c is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0032] is

[0033] X1is selected from NH, O, S;

[0034] X2is selected from NH, O, S;

[0035] R9is selected from C 1-10alkyl, 5-8 membered aromatic ring, 5-8 membered heteroaromatic ring, each independently substituted with one or two or more substituents selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl-substituted C 1-10 alkyl;

[0036] is a monovalent anion.

[0037] Further, the structure of the compound is shown as formula II-1:

[0038] R1is selected from the group consisting of hydroxy, unsubstituted or substituted with one or two or more R b substituted C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl;

[0039] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl;

[0040] Y1is selected from O, S, NH, Y2is selected from O, S, NH, null, Y3is selected from O, S, NH, R 11 is selected from the group consisting of C 1-6 alkyl;

[0041] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 each independently selected from the group consisting of C 1-6 alkyl, is a monovalent anion, f is selected from 1, 2, 3 or 4, R f each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0042] R b is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy;

[0043] R2, R4each independently selected from the group consisting of hydrogen, hydroxy, unsubstituted or substituted by one or more R c substituted by one or more R 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl; R2and R4are not simultaneously hydrogen;

[0044] wherein q is selected from 1, 2, 3 or 4, R 12 selected from hydrogen, C 1-6 alkyl;

[0045] Z1is selected from O, S, NH, Z2is selected from O, S, NH, null, Z3is selected from O, S, NH, R 13 selected from C 1-6 alkyl;

[0046] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 each independently selected from C 1-6 alkyl, is a monovalent anion, g is selected from 1, 2, 3 or 4, R g each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0047] R c selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl;

[0048] is a monovalent anion.

[0049] A ring is selected from a phenyl ring, a 5-6 membered heteroaromatic ring;

[0050] m is selected from 1, 2, 3 or 4;

[0051] R a each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0052] is a monovalent anion.

[0053] Further, the structure of the compound is shown in formula II-2 or formula II-3:

[0054] R a1 R a2 R a3 Each is independently selected from hydrogen, C 1-3 alkyl;

[0055] Of R2 and R4, one is hydrogen and the other is selected from C. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group;

[0056] It is a monovalent anion.

[0057] Furthermore, the compound is one of the following compounds:

[0058] Furthermore, the structure of the compound is shown in Formula III:

[0059] R3 is selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group;

[0060] Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-10 alkyl;

[0061] Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-10 alkyl;

[0062] W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k Selected from those that have not been replaced or have been replaced by one or more R x Substituted groups include: phenyl, 5-6 membered heteroaryl, R xeach independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0063] R b selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0064] R2, R4are each independently selected from the group consisting of hydrogen, hydroxyl, unsubstituted or substituted by one or more R c substituted by one or more R 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl; R2and R4are not simultaneously hydrogen;

[0065] wherein q is selected from 1, 2, 3 or 4, R 12 selected from the group consisting of C 1-10 alkyl;

[0066] Z1is selected from O, S, NH, Z2is selected from O, S, NH, no, Z3is selected from O, S, NH, R 13 selected from the group consisting of C 1-10 alkyl;

[0067] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 each independently selected from the group consisting of C 1-10 alkyl, is a monovalent anion, L1is selected from O, S, NH, L2is selected from O, S, NH, R L selected from the group consisting of unsubstituted or substituted by one or more R Y phenyl, 5-6 membered heteroaryl, R Y each independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0068] R c selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10alkynyl, deuterium, amino, nitro, cyano;

[0069] For

[0070] X1is selected from NH, O, S;

[0071] X2is selected from NH, O, S;

[0072] R9is selected from C 1-10 alkyl, the following groups which are unsubstituted or substituted by one or more substituents selected independently from each other from halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0073] is a monovalent anion.

[0074] Further, the structure of the compound is shown as formula III-1:

[0075] R3is selected from hydrogen, hydroxyl, the following groups which are unsubstituted or substituted by one or two substituents R b alkyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl;

[0076] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from hydrogen, C 1-6 alkyl;

[0077] Y1is selected from O, S, NH, Y2is selected from O, S, NH, nothing, Y3is selected from O, S, NH, R 11 is selected from C 1-6 alkyl;

[0078] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 are each independently selected from C 1-6 alkyl, is a monovalent anion, f is selected from 1, 2, 3 or 4, R f are each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C1-6 alkoxy;

[0079] R b selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl;

[0080] R2, R4are each independently selected from hydrogen, hydroxyl, unsubstituted or substituted by one or more than one R c selected from C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl; R2and R4are not simultaneously hydrogen;

[0081] wherein q is selected from 1, 2, 3 or 4, R 12 selected from hydrogen, C 1-6 alkyl;

[0082] Z1is selected from O, S, NH, Z2is selected from O, S, NH, null, Z3is selected from O, S, NH, R 13 selected from C 1-6 alkyl;

[0083] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 are each independently selected from C 1-6 alkyl, is a monovalent anion, g is selected from 1, 2, 3 or 4, R g are each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0084] R c selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl;

[0085] is

[0086] A ring is selected from phenyl ring, 5-6 membered heteroaromatic ring;

[0087] m is selected from 1, 2, 3 or 4;

[0088] R a are each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0089] is a monovalent anion.

[0090] Further, the compound is one of the following compounds:

[0091] Further, the compound has a structure as shown in Formula IV:

[0092] R1is selected from the group consisting of hydroxy, unsubstituted or substituted by one or two or more R b alkyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl;

[0093] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from the group consisting of hydrogen, C 1-10 alkyl;

[0094] Y1is selected from O, S, NH, Y2is selected from O, S, NH, nothing, Y3is selected from O, S, NH, R 11 is selected from the group consisting of C 1-10 alkyl;

[0095] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 are each independently selected from the group consisting of C 1-10 alkyl, is a monovalent anion, K1is selected from O, S, NH, K2is selected from O, S, NH, R k is selected from the group consisting of unsubstituted or substituted by one or two or more R x phenyl, 5-6 membered heteroaryl, R x are each independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0096] R b is selected from the group consisting of C 1-10 alkyl, C1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0097] R3is selected from the group consisting of hydrogen, hydroxyl, unsubstituted or substituted by one or two or more R c substituted by one or two or more R 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl;

[0098] wherein q is selected from 1, 2, 3 or 4, R 12 is selected from the group consisting of hydrogen, C 1-10 alkyl;

[0099] Z1is selected from O, S, NH, Z2is selected from O, S, NH, no, Z3is selected from O, S, NH, R 13 is selected from the group consisting of C 1-10 alkyl;

[0100] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 are each independently selected from the group consisting of C 1-10 alkyl, is a monovalent anion, L1is selected from O, S, NH, L2is selected from O, S, NH, R L is selected from the group consisting of unsubstituted or substituted by one or two or more R Y phenyl, 5-6 membered heteroaryl, R Y are each independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0101] R c is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 alkynyl, deuterium, amino, nitro, cyano;

[0102] is

[0103] X1is selected from NH, O, S;

[0104] X2is selected from NH, O, S;

[0105] R9is selected from C 1-10 alkyl, 5-8 membered aromatic ring, 5-8 membered heteroaromatic ring, each of which is unsubstituted or substituted by one or more substituents each of which is independently selected from the group consisting of halogen, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, C 1-10 alkoxy, halogen-substituted C 1-10 alkoxy;

[0106] is a monovalent anion.

[0107] Further, the structure of the compound is shown in formula IV-1 :

[0108] R1is selected from the group consisting of hydroxy, unsubstituted or substituted by one or more R b alkyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl;

[0109] wherein p is selected from 1, 2, 3 or 4, R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl;

[0110] Y1is selected from O, S, NH, Y2is selected from O, S, NH, null, Y3is selected from O, S, NH, R 11 is selected from the group consisting of C 1-6 alkyl;

[0111] W is selected from O, S, CH2, e is selected from 1, 2, 3 or 4, R e1 , R e2 each independently selected from the group consisting of C 1-6 alkyl, is a monovalent anion, f is selected from 1, 2, 3 or 4, R f each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0112] R b is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy;

[0113] R3is selected from the group consisting of hydrogen, hydroxy, unsubstituted or substituted by one or more Rc substituted C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl;

[0114] wherein q is selected from 1, 2, 3 or 4, R 12 selected from hydrogen, C 1-6 alkyl;

[0115] Z1is selected from O, S, NH, Z2is selected from O, S, NH, null, Z3is selected from O, S, NH, R 13 selected from C 1-6 alkyl;

[0116] U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 , R h2 each independently selected from C 1-6 alkyl, is a monovalent anion, g is selected from 1, 2, 3 or 4, R g each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0117] R c selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl;

[0118] is

[0119] A ring is selected from phenyl ring, 5-6 membered heteroaromatic ring;

[0120] m is selected from 1, 2, 3 or 4;

[0121] R a each independently selected from hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy;

[0122] is a monovalent anion.

[0123] Further, the compound is one of the following compounds: Further, the compound is one of the following compounds:

[0124] Further, the monovalent anion according to the present application is a monovalent acid radical ion.

[0125] Further, the monovalent anion according to the present application is a monovalent halogen ion.

[0126] The present application also provides a pharmaceutical composition which is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the above-mentioned compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, crystal form thereof, prodrug thereof, metabolite thereof, or deuterated derivative thereof as an active ingredient.

[0127] The present application also provides the use of the above-mentioned compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, crystal form thereof, prodrug thereof, metabolite thereof, or deuterated derivative thereof in the manufacture of a medicament having an analgesic or / and anesthetic effect.

[0128] Further, the medicament is a medicament having a long-acting analgesic or / and a long-acting local anesthetic effect.

[0129] Definitions of terms used in connection with the present application: Unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description of the specification, unless a different meaning dictates from the context of usage; for terms not specifically defined herein, the meaning given such terms by one of ordinary skill in the art in light of the disclosure and context will control.

[0130] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a～b Alkyl denotes any alkyl group of from "a" to "b" carbon atoms. For example, C 1～10 Alkyl denotes any alkyl group of from "a" to "b" carbon atoms. For example, C 1～10 Alkyl denotes any alkyl group of from "a" to "b" carbon atoms. For example, C 2-10 Alkyl denotes any alkyl group of from "a" to "b" carbon atoms. For example, C 2-10 Alkyl denotes any alkyl group of from "a" to "b" carbon atoms. For example, C

[0131] "Aryl" or "aromatic ring" means a fully carbon monocyclic ring group having a conjugated pi electron system, such as phenyl. The aryl group contains no heteroatoms, such as nitrogen, oxygen, or sulfur, and the point of attachment of the parent molecule must be on a carbon atom on the ring having the conjugated pi electron system.

[0132] "Heteroaryl" or "heteroaromatic" refers to a heteroaromatic group containing one to several heteroatoms. Heteroatoms as used herein include, but are not limited to, oxygen, sulfur, nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.

[0133] 5-8 membered aromatic ring refers to an aromatic ring containing 5, 6, 7 or 8 ring atoms, and 5-8 membered heteroaromatic ring refers to a heteroaromatic ring containing 5, 6, 7 or 8 ring atoms.

[0134] Halogen is fluorine, chlorine, bromine or iodine.

[0135] The compound provided by the present application not only can produce long-acting analgesic effect, but also has little systemic and local tissue toxicity, and has wide application prospect in the preparation of drugs with long-acting analgesic or / and long-acting local anesthetic effect.

[0136] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and common means in the art, other various forms of modification, replacement or change can be made without departing from the above basic technical idea of the present application.

[0137] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0138] The raw materials and equipment used in the specific embodiments of the present application are known products, which are obtained by purchasing commercially available products.

[0139] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is carried out by using (Bruker Avance III 400 NMR) nuclear magnetic instrument, and the determination solvents are deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3), deuterated methanol (d4-MeOH), deuterated water (D2O), and the internal standard is tetramethylsilane (TMS).

[0140] The determination of LCMS is carried out by using (Agilent LCMS 1200-6120) (ESI), and the chromatographic column is Waters Xbridge Prep C 18OBD 10 μm 19*250 mm. Column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] to 5% [water + 10 mM ammonium bicarbonate] and 95% [CH3CN] in 1.6 min, hold for 1.4 min, gradient to 95% [water + 10 mM ammonium bicarbonate] and 5% [CH3CN] in 0.05 min, hold for 0.7 min.

[0141] (1) Medicinal materials and reagents

[0142] The thin layer chromatography silica gel plates used in thin layer chromatography (TLC) were manufactured by Qingdao Suike Separation Material Co., Ltd., with a specification of 50*200 mm and a thickness of 0.2-0.25 mm.

[0143] The silica gel used in column chromatography was 200-300 mesh silica gel manufactured by Weihai Rushan City Taiyang Drying Agent Co., Ltd.

[0144] (2) Main instruments

[0145] Electronic balance, FA2004, Shanghai Liangping Instrument and Meter Co., Ltd.

[0146] Temperature-controlled pressure-regulating magnetic stirrer, TY98-1, Shanghai Sile Instrument Co., Ltd.

[0147] Triple-purpose ultraviolet analyzer, ZF-2 type, Shanghai Anting Scientific Instrument Factory

[0148] Rotary evaporator, R201, Zhengzhou HuiCheng Electronic Technology Co., Ltd.

[0149] Liftable water bath, R201D, Zhengzhou HuiCheng Electronic Technology Co., Ltd.

[0150] Circulating water type vacuum pump (table type), SHB-III, Zhengzhou HuiCheng Electronic Technology Co., Ltd.

[0151] Circulating water type vacuum pump (mobile type), SHB-B95, Zhengzhou HuiCheng Electronic Technology Co., Ltd.

[0152] Low-temperature circulating pump, DLSB-5 / 20, Zhengzhou HuiCheng Electronic Technology Co., Ltd.

[0153] Rotary vane type vacuum pump (oil pump), 2XZ-4, Shanghai Vacuum Pump Factory

[0154] Example 1, Preparation of compound 1-1-1 of the present application

[0155] 1. Synthesis of A-1

[0156] A-0 (2.0 g, 16.53 mmol) was added to a 250 mL single-neck flask, dissolved in THF (80 mL), then pyridine (2.61 g, 33.06 mmol) was added, the system was cooled to 0 °C with ice, and bromoacetyl bromide (3.34 g, 16.53 mmol) was added dropwise, and the system was stirred at room temperature overnight after the addition was completed. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to obtain white solid A-1 (2.1 g, yield: 53%). ESI [M+H] + = 242.4 [M+H] + .

[0157] 2. Synthesis of S2

[0158] S1 (300 mg, 1.80 mmol) was dissolved in MeOH (100 mL), Pd / C (60 mg) was added, and hydrogen was replaced three times. The system was stirred under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow oily compound S2 as a crude product, which was directly used in the next step without purification (310 mg, yield: 100%). ESI [M+H] + = 170.4 [M+H] + .

[0159] 3. Synthesis of 1-1-1

[0160] S2 (310 mg, 1.83 mmol) was dissolved in dichloromethane (10 mL), and A-1 (442 mg, 1.83 mmol) was added. The system was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, it was concentrated under reduced pressure, and the crude product was slurried with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound 1-1-1 (208.17 mg, yield: 34%). ESI [M+H] + = 170.4 [M+H] + .

[0161] 1H NMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 7.14-7.08 (m, 3H), 5.67 (t, J = 5.2 Hz, 1H), 4.33 (s, 2H), 4.13 (t, J = 11.6 Hz, 1H), 3.97 (t, J = 8.8 Hz, 1H), 3.91-3.89 (m, 1H), 3.87-3.85 (m, 2H), 3.81-3.74 (m, 2H), 2.17 (s, 6H), 2.04-1.87 (m, 6H), 1.46-1.39 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). Example 2, Preparation of compound 1-1-2 of the present application

[0162] 1. Synthesis of A-1

[0163] Synthesis of A-1 is referred to Example 1.

[0164] 2. Synthesis of 1-1-2

[0165] S1 (300 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL) and A-1 (434 mg, 1.80 mmol) was added. The reaction was stirred at room temperature overnight. After monitoring the completion of the reaction by LCMS, the crude product was washed with ethyl acetate, filtered, the filter cake was collected and dried under vacuum to obtain compound 1-1-2 (151.12 mg, yield: 37%).

[0166] 1 H NMR (400 MHz, DMSO-d6) δ: 9.93 (s, 1H), 7.14-7.08 (m, 3H), 5.95-5.87 (m, 1H), 5.70 (t, J = 4.8 Hz, 1H), 5.22 (t, J = 8.4 Hz, 2H), 4.35 (s, 2H), 4.19-4.15 (m, 1H), 4.02 (t, J = 8.8 Hz, 1H), 3.91-3.75 (m, 4H), 3.66-3.59 (m, 1H), 2.86-2.80 (m, 1H), 2.17 (s, 6H), 2.02-1.96 (m, 3H), 1.91 (d, J = 9.2 Hz, 2H).

[0167] Example 3, Preparation of compound 1-1-3 of the present application

[0168] 1. Synthesis of compound B1

[0169] Take 1.2g S1 in 100mL single-mouth flask, add 40mL anhydrous dichloromethane to dissolve, cool to 0°C. Dissolve 0.3mL liquid bromine in 10mL anhydrous dichloromethane, slowly add to the above reaction liquid (10 minutes to add). Slowly warm to room temperature for 2h, TLC detection reaction. After the reaction raw material disappears, add 20mL saturated sodium thiosulfate solution to the reaction system, shake and separate, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain B1 crude product directly for the next step reaction.

[0170] 2. Synthesis of compound S4

[0171] Take B1 crude product in the above step and 147.6mg tetrabutylammonium iodide, dissolve in 40mL tetrahydrofuran in a 100mL single-mouth flask, warm to 45°C, add 2.4g powdered potassium hydroxide solid in two portions (1h interval), keep 45°C for 2h, TLC detection reaction. After the starting material disappears, take a pad with diatomite sand core funnel, filter the reaction liquid, wash the filter cake with 5x 40mL tetrahydrofuran, concentrate the filtrate to obtain the crude product, purify by column chromatography to obtain the target product 581mg, yield 48%.

[0172] 3. Synthesis of compound B2

[0173] In a 25mL Schlenk tube, add Pd(PPh3)2Cl2(0.07mmol, 48.5mg,), CuI(0.14mmol, 15.8mg), 1-bromopropene(Z / E, mixture, 4.55mmol, 546mg), replace nitrogen three times, dissolve S4(3.5mmol, 581mg) in 7mL anhydrous tetrahydrofuran, and add to the above Schlenk tube. Keep 45°C for 10h, TLC detection reaction, dry the reaction liquid after the starting material disappears, obtain the crude product, purify by column chromatography to obtain B2(287mg, yield 40%).

[0174] 4. Synthesis of compound S3

[0175] In a 25mL single-mouth flask, add Pd / C(10%, w / w, 0.014mmol, 15mg, 0.01equiv.), 287mg B2, dissolve with 15mL methanol, configure a double-layer hydrogen balloon to replace hydrogen three times, react at room temperature for 72h. Take a dry sand core funnel, lay 0.5cm diatomite in it, filter the reaction liquid, dry, and separate by column chromatography to obtain S3, yield 86%.

[0176] 5. Synthesis of A-1

[0177] The synthesis of A-1 refers to Example 1.

[0178] 6. Synthesis of compound 1-1-3

[0179] A-1 (138 mg, 0.57 mmol) was dissolved in acetonitrile (6 mL) and S3 (120 mg, 0.57 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure. The crude product was slurried with ethyl acetate, filtered, and the filter cake was collected and dried to give compound 1-1-3 (110 mg, yield: 43%). ESI [M] + = 373.2 [M] + .

[0180] 1 HNMR (400 MHz, DMSO-d6) δ: 9.95 (s, 1H), 7.14-7.08 (m, 3H), 5.67 (t, J = 5.6 Hz, 1H), 4.32 (s, 2H), 4.12 (t, J = 11.2 Hz, 1H), 3.95 (d, J = 8.8 Hz, 1H), 3.91-3.86 (m, 1H), 3.81-3.73 (m, 2H), 3.62-3.51 (m, 2H), 2.16 (s, 6H), 2.05-1.87 (m, 6H), 1.39 (s, 2H), 1.32-1.22 (m, 6H), 0.86 (t, J = 6.4 Hz, 3H).

[0181] Example 4, Preparation of compound 1-1-5 of the present application

[0182] 1. Synthesis of A-1

[0183] The synthesis of A-1 was performed according to Example 1.

[0184] 2. Synthesis of S-4

[0185] The synthesis of S-4 was performed according to Example 3.

[0186] 3. Synthesis of 1-1-5

[0187] S4 (150 mg, 0.91 mmol) was dissolved in acetonitrile (10 mL) and A-1 (220 mg, 0.91 mmol) was added at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) and recrystallization with ethyl acetate to give compound 1-1-5 (220 mg, yield 59%) as a white solid. ESI [M] + = 327.3.

[0188] 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.15-7.06 (m, 3H), 5.75 (t, J = 4.8 Hz, 1H), 4.37 (s, 2H), 4.21-4.02 (m, 2H), 3.98-3.80 (m, 4H), 3.63-3.50 (m, 1H), 3.31 (d, J = 2.4 Hz, 1H), 3.27-3.18 (m, 1H), 2.23-2.11 (m, 7H), 2.11-2.05 (m, 1H), 2.05-1.92 (m, 3H).

[0189] Example 5, Preparation of compound 1-2-2 of the present application

[0190] 1. Synthesis of A-1

[0191] The synthesis of A-1 is referred to Example 1.

[0192] 2. Synthesis of 1-2-2

[0193] S6 (500 mg, 2.99 mmol) was dissolved in dichloromethane (15 mL), A-1 (724 mg, 2.99 mmol) was added at room temperature. Stirring at room temperature overnight, after the reaction was monitored by LCMS to be complete, the reaction was evaporated under reduced pressure to remove the solvent to obtain the crude product, the crude product was purified by recrystallization with ethyl acetate to obtain compound 1-2-2 (400 mg, yield 33%). ESI [M] + = 329.2.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H), 7.13-7.07 (m, 3H), 6.01-5.92 (m, 1H), 5.66 (t, J = 4.8 Hz, 1H), 5.26-5.19 (m, 2H), 4.48-4.38 (m, 2H), 4.12-4.07 (m, 2H), 3.93-3.76 (m, 4H), 3.62-3.59 (m, 1H), 2.87 (d, J = 5.2 Hz, 1H), 2.16 (m, 6H), 2.14-2.07 (m, 2H), 1.96 (s, 2H), 1.63-1.58 (m, 1H).

[0195] Example 6, Preparation of compound 1-2-1 of the present application

[0196] 1. Synthesis of 1-2-2

[0197] The synthesis of 1-2-2 is referred to Example 5.

[0198] 2, Synthesis of 1-2-1

[0199] Dissolve 1-2-2 (400 mg, 0.98 mmol) in methanol (20 mL), add Pd / C (10% wt, 100 mg) at room temperature. Replace the reaction solution with hydrogen three times, stir overnight at room temperature. After monitoring the reaction completion by LCMS, filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (MeOH / CH2Cl2(v / v) = 0-5%) to obtain compound 1-2-1 (210 mg, yield 52%). ESI [M] + = 331.3.

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.15-7.05 (m, 3H), 5.67 (t, J = 4.8 Hz, 1H), 4.46-4.26 (m, 2H), 4.18-4.03 (m, 1H), 3.92-3.66 (m, 5H), 3.62-3.48 (m, 1H), 2.20-2.06 (m, 7H), 2.04-1.94 (m, 2H), 1.94-1.80 (m, 2H), 1.61-1.50 (m, 1H), 1.49-1.37 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0201] Example 7, Preparation of compound 2-1-1 of the application

[0202] 1, Synthesis of S9

[0203] Put S8 (2.0 g, 14.81 mmol) into a 100 mL single-neck flask, dissolve with THF (80 mL), then add pyridine (2.34 g, 29.62 mmol), cool the system to 0°C with an ice bath, slowly drop acetyl bromide (3.0 g, 14.81 mmol), stir the reaction at room temperature overnight. After the reaction is complete, filter out the solid, pour into ice water, extract with ethyl acetate (3 x 80 mL). Wash the organic phase with saturated brine (80 mL), dry with anhydrous Na2SO4, filter and evaporate the solvent under reduced pressure to obtain the crude product, which is purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1-20 / 1) to obtain white solid S9 (2.3 g, yield: 61%). ESI [M+H] + = 256.4 [M+H] + .

[0204] 2, Synthesis of S10

[0205] S1 (320 mg, 1.92 mmol) was dissolved in acetonitrile (10 mL), then S9 (490 mg, 1.92 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was monitored to be complete by LCMS, the reaction mixture was concentrated under reduced pressure. The crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried under vacuum to give compound S10 (380 mg, yield: 47%). ESI [M] + = 343.3 [M] + .

[0206] 3. Synthesis of 2-1-1

[0207] S10 (320 mg, 0.76 mmol) was dissolved in methanol (20 mL), then Pd / C (64 mg) was added, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was monitored to be complete by LCMS, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried under vacuum to give compound 2-1-1 (186.02 mg, yield: 58%). ESI [M] + = 345.2 [M] + .

[0208] 1 H NMR (400 MHz, DMSO-d6) d: 9.85 (s, 1H), 6.90 (s, 2H), 5.57 (d, J = 4.8 Hz, 1H), 4.30 (s, 2H), 4.12 (q, J = 11.2 Hz, 1H), 3.96 (s, 1H), 3.90-3.86 (m, 1H), 3.80-3.73 (m, 2H), 3.62-3.50 (m, 2H), 2.22 (s, 3H), 2.19 (s, 6H), 2.01-1.89 (m, 6H), 1.46-1.38 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0209] Example 8, Preparation of compound 3-2-1 of the present application

[0210] 1. Synthesis of S12

[0211] Sll (1 g, 6.70 mmol) was added into a 100 mL single-neck flask, dissolved in tetrahydrofuran (40 mL), then pyridine (1.06 g, 13.40 mmol) was added, the system was cooled to 0 °C with ice, bromoacetyl bromide (2.03 g, 10.05 mmol) was added dropwise, and the system was stirred at room temperature overnight after the addition was completed. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 10 / 1 ～ 5 / 1), to obtain white solid S12 (1.67 g, yield: 93%). ESI [M+H] + = 270.1 [M+H] + .

[0212] 2. Synthesis of S13

[0213] S12 (400 mg, 1.48 mmol) was dissolved in acetonitrile (6 mL), then S6 (225 mg, 1.34 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound S13 (500 mg, yield: 95%). ESI [M] + = 357.2 [M] + .

[0214] 3. Synthesis of 3-2-1

[0215] S13 (500 mg, 1.14 mmol) was dissolved in methanol (15 mL), then Pd / C (50 mg) was added, and the system was replaced with hydrogen three times, and stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the system was filtered with diatomite, and the filtrate was concentrated under reduced pressure. The crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound 3-2-1 (127.80 mg, yield: 26%). ESI [M] + = 359.4 [M] + .

[0216] 1H NMR (400 MHz, DMSO-d6) δ: 9.90 (s, 1H), 7.20 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 5.66 (t, J = 4.8 Hz, 1H), 4.42 (dd, J = 16, 40.0 Hz, 2H), 4.13 (d, J = 4.8 Hz, 1H), 3.89 - 3.76 (m, 4H), 3.71 - 3.67 (m, 2H), 3.62 - 3.55 (m, 1H), 2.55 - 2.45 (m, 4H), 2.16 - 2.10 (m, 1H), 2.00 - 1.87 (m, 4H), 1.60 - 1.56 (m, 1H), 1.49 - 1.41 (m, 2H), 1.10 (t, J = 7.6 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H).

[0217] Example 9, Preparation of the compound 4-2-1 of the present application

[0218] 1. Synthesis of S15

[0219] S14 (1 g, 6.70 mmol) was added into a 100 mL single-neck flask, dissolved in tetrahydrofuran (40 mL), then pyridine (1.06 g, 13.40 mmol) was added, the system was cooled to 0 °C with ice, bromoacetyl bromide (2.03 g, 10.05 mmol) was added dropwise, and the system was stirred at room temperature overnight after the addition was completed. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 10 / 1 ～ 5 / 1), to obtain white solid S15 (1.67 g, yield: 93%). ESI [M+H] + = 270.1 [M+H] + .

[0220] 2. Synthesis of S16

[0221] S15 (400 mg, 1.48 mmol) was dissolved in acetonitrile (6 mL), then S6 (225 mg, 1.34 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed, the crude product was obtained by concentrating under reduced pressure, then the product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound S16 (500 mg, yield: 95%). ESI [M] + = 357.2 [M] + .

[0222] 3. Synthesis of 4-2-1

[0223] S16 (500 mg, 1.14 mmol) was dissolved in methanol (15 mL), then Pd / C (50 mg) was added, and the reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried under vacuum to obtain compound 4-2-1 (221 mg, yield: 54%). ESI [M] + = 359.4 [M] + .

[0224] 1 H NMR (400 MHz, DMSO-d6) δ: 9.88 (s, 1H), 7.20 (m, 2H), 7.09 (m, 1H), 5.66 (t, J = 4.4 Hz, 1H), 4.42 (dd, J = 16.0, 38.8 Hz, 2H), 4.11 (s, 1H), 3.89-3.76 (m, 4H), 3.69-3.55 (m, 2H), 3.05 (s, 1H), 2.15 (m, 4H), 2.00-1.87 (m, 4H), 1.60-1.55 (m, 1H), 1.49-1.41 (m, 2H), 1.17-1.12 (m, 6H), 0.88-0.84 (m, 3H).

[0225] Example 10, Preparation of compound 5-1-1 of the present application

[0226] 1. Synthesis of S18

[0227] S17 (650 mg, 3.67 mmol) was added to a 100 mL single-neck flask, dissolved in THF (20 mL), pyridine (580 mg, 7.34 mmol) was added, the system was cooled to 0°C with ice, and bromoacetyl bromide (741 mg, 3.67 mmol) was added dropwise. The reaction was stirred at room temperature overnight after completion. After the reaction was completed, the solid was removed by filtration, poured into ice water, extracted with ethyl acetate (3 x 20 mL), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered under suction, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ～ 20 / 1) to obtain white solid S18 (650 mg, yield: 60%). ESI [M+H] + = 298.4 [M+H] + .

[0228] 2. Synthesis of S19

[0229] S1 (197 mg, 1.18 mmol) was dissolved in acetonitrile (6 mL), and S18 (350 mg, 1.18 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, it was concentrated under reduced pressure. The crude product was slurried with ethyl acetate, filtered, the filter cake was collected, and dried under vacuum to obtain compound S19 (360 mg, yield: 66%). ESI [M] + = 386.4 [M] + .

[0230] 3, Synthesis of 5-1-1

[0231] S19 (340 mg, 0.31 mmol) was dissolved in methanol (10 mL), and Pd / C (68 mg) was added. The reaction was stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, it was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was slurried with ethyl acetate, filtered, the filter cake was collected, and dried under vacuum to obtain compound 5-1-1 (155.43 mg, yield: 46%). ESI [M] + = 388.4 [M] + .

[0232] 1 H NMR (400 MHz, DMSO-d6) δ: 9.91 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 5.68 (t, J = 4.8 Hz, 1H), 4.38 (q, J = 16.4 Hz, 2H), 11.2 (t, J = 11.2 Hz, 1H), 4.02-3.96 (m, 1H), 3.91-3.87 (m, 1H), 3.79-3.71 (m, 2H), 3.61-3.53 (m, 2H), 3.08-2.96 (m, 2H), 2.02-1.88 (m, 6H), 1.47-1.39 (m, 2H), 1.19-1.10 (m, 12H), 0.86 (t, J = 7.2 Hz, 3H).

[0233] Example 11, Preparation of compound 26-1-1-0 of the present application

[0234] 1, Synthesis of S21

[0235] S20 (2.0 g, 21.51 mmol) was added to a 100 mL single-neck flask, dissolved in THF (60 mL), then pyridine (3.40 g, 43.02 mmol) was added, the system was cooled to 0 °C with ice, and bromoacetyl bromide (4.3 g, 21.51 mmol) was added dropwise, and the system was stirred at room temperature overnight after the addition was completed. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1-20 / 1) to obtain white solid S21 (2.0 g, yield: 43%). ESI [M+H] + = 214.4 [M+H] + .

[0236] 2. Synthesis of S22

[0237] S1 (320 mg, 1.50 mmol) was dissolved in acetonitrile (10 mL), and S21 (251 mg, 1.50 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound S22 (300 mg, yield: 66%). ESI [M] + = 301.4 [M] + .

[0238] 3. Synthesis of 26-1-1-0

[0239] S22 (300 mg, 0.79 mmol) was dissolved in methanol (30 mL), and Pd / C (60 mg) was added, and the system was replaced with hydrogen three times, and the system was stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the system was filtered with diatomite, and the filtrate was concentrated under reduced pressure, and the crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound 26-1-1-0 (208.01 mg, yield: 69%). ESI [M] + = 303.4 [M] + .

[0240] 1H NMR (400 MHz, DMSO-d6) δ: 10.60 (s, 1H), 7.59 (t, J = 1.2 Hz, 2H), 7.19 (q, J = 2.0 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 5.63 (t, J = 5.2 Hz, 1H), 4.24 (t, J = 16.4 Hz, 1H), 4.12 (t, J = 11.6 Hz, 1H), 3.97 (t, J = 8.8 Hz, 1H), 3.85-3.71 (m, 3H), 3.63-3.49 (m, 2H), 2.05-1.88 (m, 6H), 1.48-1.36 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0241] Example 12, Preparation of compound 2-1-1-1 of the present application

[0242] 1. Synthesis of S23

[0243] S1 (1.3 g, 7.78 mmol) was dissolved in methanol (160 mL), then Pd / C (260 mg) was added, and the reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound S23 (1.3 g, yield: 99%).

[0244] 2. Synthesis of S24

[0245] In a 500 mL single-neck flask, potassium permanganate (3.04 g, 19.23 mmol) was added as a solid and dissolved in 270 mL of water. A 0.5 M potassium hydroxide solution (8.0 mL) was slowly added, and the system was cooled to 0°C in an ice bath. The hydrogenation product S23 (1.3 g, 7.69 mmol) from the previous step was dissolved in 10 mL of water and slowly added to the potassium permanganate solution. After the addition was completed, the reaction was allowed to warm to room temperature and was stirred for 28 hours. After the reaction was completed by LCMS monitoring, isopropyl alcohol (11 mL) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, and the filter cake was washed with 20 mL of water and 20 mL of isopropyl alcohol to obtain a colorless transparent solution. The pH was adjusted to 7 using 6N hydrochloric acid, and the reaction mixture was concentrated under reduced pressure to obtain a light yellow solid. The solid was thoroughly slurried in dichloromethane:methanol (2:1, V / V) (60 mL), and the slurry was concentrated under reduced pressure to obtain S24 (1.0 g, yield: 71%).

[0246] 3. Synthesis of S25

[0247] The above crude product S24 (700 mg, 3.83 mmol) was dissolved in dichloromethane (20 mL), the system was cooled to 0 °C in an ice bath, DMF (28 mg, 0.38 mmol) was added, and then oxalyl chloride (973 mg, 7.66 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at 0 °C for one hour. The solvent was removed by concentration at 10 °C, and the residue was used as is. A0 (463 mg, 3.83 mmol) and triethylamine (1.16 g, 11.49 mmol) were dissolved in dichloromethane (20 mL), the system was cooled to 0 °C in an ice bath, and then the above residue was dissolved in dichloromethane (5 mL) and slowly added to the reaction system. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the reaction solution was poured into water (20 mL), extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by column chromatography (dichloromethane:methanol = 20:1) gave S25 (210 mg, yield: 15%).

[0248] 4. Synthesis of S26

[0249] S25 (210 mg, 0.734 mmol) was dissolved in acetonitrile (5 mL), and then methyl bromoacetate (562 mg, 3.67 mmol) was added. The reaction was stirred at 80 °C overnight. After the reaction was complete, as monitored by LCMS, the crude product was concentrated under reduced pressure, and then purified by normal phase column [dichloromethane:methanol (100:1-20:1)] to give S26 (230 mg, yield: 71%) as a light yellow solid. ESI [M+H] + = 359.4 [M] + .

[0250] 5. Synthesis of 2-1-1-1

[0251] S26 (230 mg, 0.524 mmol) was added to a reaction flask, dissolved in methanol (10 mL), and purged with a nitrogen balloon three times. The system was cooled to 0 °C in an ice bath, and then LiBH4 (2.0 N in THF, 0.53 mL, 1.05 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the system was cooled to 0 °C, and then 0.5 N HBr aq. (0.5 mL) was slowly added to quench the reaction. The solvent was removed by evaporation under reduced pressure, and the crude product was purified by normal phase column [dichloromethane:methanol (100:1-20:1)] to give a light yellow solid. The solid was thoroughly slurried in ethyl acetate (10 mL), filtered, and concentrated to give 2-1-1-1 (202.24 mg, yield: 94%). ESI [M+H] + = 331.3 [M] + .

[0252] 1HNMR (400 MHz, DMSO-d6) δ: 9.99 (s, 1H), 7.14-7.09 (m, 3H), 5.44 (t, J = 4.8 Hz, 1H), 4.53 (t, J = 9.6 Hz, 1H), 3.97-3.84 (m, 4H), 3.74 (t, J = 11.2 Hz, 1H), 3.65-3.54 (m, 2H), 3.45-3.40 (m, 1H), 3.34 (t, J = 3.6 Hz, 1H), 2.16 (s, 6H), 2.12-2.07 (m, 2H), 2.02-1.94 (m, 3H), 1.45-1.39 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0253] Example 13, Preparation of compound 2-1-2-1 of the present application

[0254] 1. Synthesis of S27

[0255] S6 (1.0 g, 5.99 mmol) was dissolved in methanol (120 mL), Pd / C (200 mg) was added, and the reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound S27 (1.0 g, yield: 99%).

[0256] 2. Synthesis of S28

[0257] In a 500 mL single-neck flask, potassium permanganate (2.34 g, 14.79 mmol) was added as a solid and dissolved using 210 mL of water. 6.2 mL of a 0.5 M potassium hydroxide solution was slowly added, and the system was cooled to 0°C in an ice bath. The hydrogenation product S27 (1.0 g, 5.92 mmol) from the previous step was dissolved in 10 mL of water and slowly added to the above potassium permanganate solution. After the addition was completed, the reaction was allowed to proceed at room temperature for 28 hours. After the reaction was completed by LCMS monitoring, isopropyl alcohol (8.5 mL) was added, and the reaction was stirred for 30 minutes. The reaction was filtered, and the filter cake was washed with 20 mL of water and 20 mL of isopropyl alcohol to obtain a colorless transparent solution. The pH was adjusted to 7 using 6N hydrochloric acid, and the solution was concentrated under reduced pressure to obtain a light yellow solid. The solid was thoroughly slurried in 40 mL of dichloromethane:methanol (2:1, V / V), and concentrated under reduced pressure to obtain S28 (750 mg, yield: 69.4%).

[0258] 3. Synthesis of S29

[0259] The above crude product S28 (750 mg, 4.10 mmol) was dissolved in dichloromethane (20 mL), the system was cooled to 0 °C in an ice bath, DMF (30 mg, 0.41 mmol) was added, and then oxalyl chloride (1.04 g, 8.20 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at 0 °C for one hour. The solvent was removed by concentration at 10 °C, and the residue was used as is. A0 (496 mg, 4.10 mmol) and triethylamine (1.24 g, 12.3 mmol) were dissolved in dichloromethane (20 mL), the system was cooled to 0 °C in an ice bath, and then the above residue was dissolved in dichloromethane (10 mL) and slowly added to the reaction system. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the reaction solution was poured into water (20 mL), extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by column chromatography (dichloromethane:methanol = 20:1) yielded compound S29 (180 mg, yield: 16%).

[0260] 4. Synthesis of S30

[0261] S29 (180 mg, 0.629 mmol) was dissolved in acetonitrile (5 mL), and then methyl bromoacetate (481 mg, 3.15 mmol) was added. The reaction was stirred at 80 °C overnight. After the reaction was complete, as monitored by LCMS, the crude product was concentrated under reduced pressure, and then purified by normal phase column [dichloromethane:methanol (100:1-20:1)] to yield S30 as a light yellow solid (200 mg, yield: 72.4%).

[0262] 5. Synthesis of 2-1-2-1

[0263] Compound S30 (200 mg, 0.456 mmol) was purified by column chromatography (dichloromethane:methanol = 20:1) and added to a reaction flask, dissolved in methanol (10 mL), and replaced with a nitrogen balloon three times. The system was cooled to 0 °C in an ice bath, and then LiBH4 (2. N in THF, 0.46 mL, 0.911 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the system was cooled to 0 °C, and then 0.5 N HBr aq. (0.5 mL) was slowly added to quench the reaction. The solvent was removed by evaporation under reduced pressure, and then the crude product was purified by normal phase column [dichloromethane:methanol (100:1-20:1)] to yield a light yellow solid. The solid was thoroughly slurried in ethyl acetate (10 mL), filtered, and concentrated to yield 2-1-2-1 (184.43 mg, yield: 98%). ESI [M+H] = 331.3 [M] + = 331.3 [M] + .

[0264] 1HNMR (400 MHz, DMSO-d6) δ: 9.92 (s, 1H), 7.14-7.09 (m, 3H), 5.44 (t, J = 4.8 Hz, 1H), 4.56 (t, J = 9.2 Hz, 1H), 4.35 (d, J = 2.4 Hz, 1H), 3.92 (dd, J = 5.2, 1.0 Hz, 2H), 3.77 (dd, J = 10.4, 12.4 Hz, 1H), 3.63-3.59 (m, 1H), 3.53-3.52 (m, 1H), 3.42-3.35 (m, 2H), 2.51 (s, 1H), 2.17 (s, 7H), 2.05-2.00 (m, 2H), 1.98-1.91 (m, 2H), 1.55-1.49 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0265] Example 14, Preparation of compound 1-1-11 of the present application

[0266] 1. Synthesis of S31

[0267] S1 (1.5 g, 8.99 mmol) was dissolved in 40 mL of 2N sulfuric acid solution, the system was cooled to 0°C in ice bath, 1.71 g of potassium permanganate (3.55 g, 22.48 mmol) solid was dissolved in 100 mL of water and slowly added to the above sulfuric acid solution. After the addition was completed, the system was allowed to warm to room temperature and reacted for 28 h. After the reaction was completed by LCMS monitoring, isopropyl alcohol (13 mL) was added, stirred for 30 min, the reaction solution was filtered, the filter cake was washed with 20 mL of water and 20 mL of isopropyl alcohol to obtain a colorless transparent solution. The pH was adjusted to 6 using 6N hydrochloric acid, and concentrated under reduced pressure to obtain a light yellow solid. The light yellow solid was concentrated under reduced pressure to obtain S31 (1.0 g, yield: 60%). ESI [M+H]+= 186.4 [M+H]+.

[0268] 2. Synthesis of S32

[0269] S31 (1.0 g, 5.41 mmol) was dissolved in methanol (30 mL) and slowly added with thionyl chloride (3.2 g, 27.05 mmol). The reaction was stirred at 70°C for two hours, the solvent was removed by rotary evaporation, the residue was diluted with dichloromethane (30 mL), poured into ice water, the pH was adjusted to 7-8 with saturated sodium bicarbonate, extracted with dichloromethane four times (30 x 4), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to obtain compound S32 (710 mg, yield: 66%). ESI [M+H]+= 200.4 [M+H] + = 200.4 [M+H] + .

[0270] 3. Synthesis of S33

[0271] Into a 50 mL single necked flask, S32 (300 mg, 1.51 mmol) and THF (10 mL) were added, purged with nitrogen balloon for three times, cooled to 0 °C under nitrogen atmosphere. Lithium aluminum hydride (2.5 N in THF, 3.02 mmol, 1.2 mL) was added dropwise slowly, stirred at room temperature for one hour. After the reaction was completed, water (0.2 mL), 15% NaOH (0.2 mL) and water (0.6 mL) were added slowly, stirred at room temperature for 20 minutes, dried over anhydrous magnesium sulfate, filtered, the solvent was removed under reduced pressure to give a crude product, purified by normal phase column [dichloromethane: methanol (100:1-20:1)], to give S33 (150 mg, yield: 58%) as yellow oil. ESI [M+H] + = 172.4 [M+H] + .

[0272] 4. Synthesis of A-1

[0273] Synthesis of A-1 was referred to Example 1.

[0274] 5. Synthesis of 1-1-11

[0275] S33 (150 mg, 0.877 mmol) was dissolved in acetonitrile (10 mL), then A-1 (212 mg, 0.877 mmol) was added, stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, concentrated under reduced pressure to give a crude product, purified by normal phase column [dichloromethane: methanol (100:1-20:1)], slurried with ethyl acetate, filtered, the filter cake was collected, dissolved with water, and lyophilized at low temperature to give 1-1-11 (79.10 mg, yield: 22%). ESI [M] + = 333.2 [M] + .

[0276] 1 H NMR (400 MHz, DMSO-d6) δ: 9.96 (s, 1H), 7.14-7.08 (m, 3H), 5.67 (t, J = 5.2 Hz, 1H), 4.85 (t, J = 5.2 Hz, 1H), 3.37 (q, J = 16.0 Hz, 2H), 4.15 (t, J = 11.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 3.91-3.86 (m, 1H), 3.80-3.59 (m, 4H), 3.46 (t, J = 6.8 Hz, 2H), 2.24-2.17 (m, 7H), 2.07 (s, 1H), 2.04-1.83 (m, 4H).

[0277] Example 15, Preparation of the compound 1-2-11 of the present application

[0278] 1. Synthesis of S34

[0279] In a 250 mL single neck flask, add 1.71 g of potassium permanganate (2.34 g, 14.79 mmol) solid, dissolve with 105 mL of water, slowly add 20 mL of 2N sulfuric acid solution, cool the system to 0°C in ice bath, dissolve S6 (1.0 g, 5.92 mmol) in 10 mL of water, slowly add the above potassium permanganate solution, after addition, let it warm up to room temperature for 28 h. After the reaction is complete by LCMS monitoring, add isopropyl alcohol (8.4 mL), stir for 30 min, filter the reaction solution, wash the filter cake with 20 mL of water, 20 mL of isopropyl alcohol, get a colorless transparent solution, adjust the pH to 7 with 6N hydrochloric acid, concentrate under reduced pressure to get a light yellow solid, fully slurry the solid with 30 mL of dichloromethane:methanol (2:1, V / V), concentrate under reduced pressure to get S34 (700 mg, yield: 63%). ESI [M+H] = 186.4 + + .

[0280] 2. Synthesis of S35

[0281] Dissolve S34 (420 mg, 2.27 mmol) in methanol (20 mL), slowly drop in thionyl chloride (420 mg, 2.27 mmol), stir the reaction at 70°C for two hours, rotary evaporate the solvent, dilute the residue with dichloromethane (20 mL), pour into ice water, adjust the pH to 7-8 with saturated sodium bicarbonate, add dichloromethane extraction four times (30 x 4), combine the organic phase, dry with anhydrous magnesium sulfate, filter, rotary evaporate, the residue, column purification (DCM / MeOH = 20 / 1) to get compound S35 (260 mg, yield: 58%). ESI [M+H] = 200.4 + + .

[0282] 3. Synthesis of S36

[0283] Into a reaction flask, add S35 (2.0 g, 20 mmol) and THF (50 mL), replace three times with a nitrogen balloon, cool to 0°C under nitrogen environment. Slowly drop in lithium aluminum hydride ((2.5N in THF, 16 mL), stir at room temperature for one hour. After the reaction is complete, slowly add water (2 mL), 15% NaOH (2 mL) and water (6 mL), stir at room temperature for 20 min, dry with anhydrous magnesium sulfate, filter, evaporate the solvent under reduced pressure to get a crude product, normal phase column purification [dichloromethane:methanol (100:1-20:1)], get yellow oil S36 (1.6 g, yield: 78%). ESI [M+H] = 181.2 + + ​​​.

[0284] 4. Synthesis of 1-2-11

[0285] S36 (240 mg, 1.21 mmol) was dissolved in acetonitrile (10 mL), and A-1 (293 mg, 1.21 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was monitored to be complete by LCMS, the solvent was removed under reduced pressure. The crude product was slurried with ethyl acetate, filtered, and the filter cake was collected and dried under vacuum to give compound 1-2-11 (234.28 mg, yield: 44%). ESI [M+H] + = 361.3 [M] + .

[0286] 1 H NMR (400 MHz, DMSO-d6) δ: 9.97 (s, 1H), 7.14-7.08 (m, 3H), 5.66 (t, J = 4.8 Hz, 1H), 4.45 (s, 2H), 4.25-4.13 (m, 2H), 4.02 (d, J = 6.8 Hz, 1H), 3.92-3.77 (m, 3H), 3.70 (s, 3H), 3.69-3.61 (m, 1H), 3.24 (t, J = 9.2 Hz, 1H), 2.46 (s, 1H), 2.17 (s, 6H), 2.06-1.96 (m, 3H), 1.69 (t, J = 9.2 Hz, 1H).

[0287] Example 16, Preparation of compound 4-1-1 of the present application

[0288] 1. Synthesis of S38

[0289] S37 (5.0 g, 33.55 mmol) was added to a reaction flask, dissolved in tetrahydrofuran (200 mL), and pyridine (5.31 g, 67.11 mmol) was added. The system was cooled to 0 °C with an ice bath, and bromoacetyl bromide (8.1 g, 33.55 mmol) was slowly added dropwise. After the addition was complete, the reaction was stirred at room temperature for 1 hour. After the reaction was monitored to be complete by LCMS, the solvent was removed under reduced pressure. The crude product was slurried with petroleum ether to give white solid compound S38 (3.2 g, yield: 35%). ESI [M+H] + = 270.2 [M+H] + .

[0290] 2. Synthesis of S39

[0291] S38 (1.0 g, 3.72 mmol) was dissolved in acetonitrile (20 mL), and S1 (3.72 mg, 3.72 mmol) was added. After the addition was completed, the mixture was stirred at room temperature for 16 hours. After the reaction was completed by LCMS, the reaction solution was poured into water (50 mL), and extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurry with ethyl acetate to obtain compound S39 (1.1 g, yield: 82.9%). ESI [M] + = 357.4 [M] + .

[0292] 3, Synthesis of 4-1-1

[0293] S39 (800 mg, 2.24 mmol) was dissolved in methanol (20 mL), and Pd / C (80 mg) was added. After hydrogen replacement was performed three times, the mixture was stirred at room temperature for 2 hours under hydrogen. After the reaction was completed by LCMS, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The white solid was obtained by slurry with ethyl acetate, and then freeze-dried with deionized water to obtain compound 4-1-1 (514.23 mg, yield: 63.9%). ESI [M] + = 359.4 [M] + .

[0294] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.23-7.18 (m, 2H), 7.11-7.09 (m, 1H), 5.67 (t, J = 4.8 Hz, 1H), 4.37 (s, 2H), 4.18-4.09 (m, 1H), 3.98 (d, J = 8.4 Hz, 1H), 3.92-3.87 (m, 1H), 3.79-3.74 (m, 2H), 3.65-3.52 (m, 2H), 3.06 (s, 1H), 2.16 (m, 3H), 2.02-1.87 (m, 6H), 1.47-1.39 (m, 2H), 1.12 (s, 6H), 0.86 (t, J = 7.2 Hz, 3H).

[0295] Example 17, Preparation of Compound 6-1-1 of the Present Invention

[0296] 1, Synthesis of S41

[0297] S40 (1.21 g, 8.94 mmol) was added to a 250 mL single-neck flask, dissolved in THF (50 mL), pyridine (1.41 g, 17.88 mmol) was added, the system was cooled to 0°C with ice, and bromoacetyl bromide (1.81 g, 8.94 mmol) was added dropwise. After completion of the reaction, the solid was removed by filtration, poured into ice water, and extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ~ 5 / 1) to obtain white solid S41 (1.5 g, yield: 66%). ESI [M+H] + = 256.2.

[0298] 2. Synthesis of S42

[0299] S41 (600 mg, 2.34 mmol) was dissolved in acetonitrile (10 mL), and S1 (390 mg, 2.34 mmol) was added. After stirring at room temperature overnight, the reaction was monitored by LCMS. After completion of the reaction, the crude product was obtained by filtering the cake obtained by washing with ethyl acetate, and the white solid compound S42 (500 mg, yield: 62%) was obtained by drying under reduced pressure. ESI [M] + = 343.3.

[0300] 3. Synthesis of 6-1-1

[0301] S42 (500 mg, 1.46 mmol) was dissolved in methanol (20 mL), and Pd / C (100 mg) was added. After three times of hydrogen replacement, the reaction was stirred at room temperature under hydrogen for 2 hours. After completion of the reaction, which was monitored by LCMS, the filtrate was filtered through celite, and the filtrate was concentrated under reduced pressure. The white solid obtained by silica gel column chromatography (DCM: MeOH = 100 / 1 ~ 10 / 1) was further filtered by washing with ethyl acetate, and the white solid compound 6-1-1 (320.23 mg, yield: 63%) was obtained by collecting the filter cake and concentrating under reduced pressure. ESI [M] + = 345.3.

[0302] 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.19-7.10 (m, 3H), 5.67 (d, J = 4.8 Hz, 1H), 4.34 (s, 2H), 4.12 (d, J = 11.2 Hz, 1H), 3.98-3.87 (m, 2H), 3.80-3.74 (m, 2H), 3.64-3.52 (m, 2H), 2.55-2.45 (m, 2H), 2.16 (s, 3H), 2.04-1.85 (m, 6H), 1.48-1.37 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).

[0303] Example 18, Preparation of the compound 16-1-1 of the application

[0304] 1. Synthesis of S44

[0305] To a round-bottom flask was added S43 (1000 mg, 8.2 mmol), pyridine (978 mg, 12.4 mmol) and tetrahydrofuran (50 mL), bromoacetyl bromide (1999 mg, 9.9 mmol) was added dropwise slowly under ice bath, the mixture was slowly recovered to room temperature and stirred for 3 hours, after the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate (50 mL) and washed with deionized water, the aqueous layer was separated, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, the residue was added with n-hexane to make a slurry, and the compound S44 (off-white solid, 1200 mg, yield 60%) was obtained by filtration.

[0306] 2. Synthesis of S45

[0307] To a round-bottom flask was added S44 (500 mg, 2.1 mmol), S1 (345 mg, 2.1 mmol) and acetonitrile (10 mL), and stirred at room temperature overnight, after the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0~80:20) to obtain compound S45 (white solid, 600 mg, yield 71%).

[0308] 3. Synthesis of 16-1-1

[0309] To a round bottom flask was added S45 (600 mg, 0.39 mmol) and methanol (10 mL), and Pd / C (60 mg) was added under stirring, the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere, after the reaction was completed, the mixture was filtered and the filter cake was washed with methanol, the filtrate was collected and concentrated under reduced pressure, then purified by silica gel column chromatography (DCM:MeOH = 100:0 ~ 80:20) to obtain compound 16-1-1 (white solid, 475.57 mg, yield 79%). ESI [M] + = 331.3.

[0310] 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.21 (s, 2H), 6.77 (s, 1H), 5.61 (t, J = 5.0 Hz, 1H), 4.22 (s, 2H), 4.11 (t, J = 11.0 Hz, 1H), 4.04-3.90 (m, 1H), 3.85-3.71 (m, 3H), 3.60-3.49 (m, 2H), 2.24 (s, 6H,), 2.07-1.87 (m, 6H), 1.44-1.39 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0311] Example 19, Preparation of compound 6-2-1 of the present application

[0312] 1. Synthesis of S41

[0313] The synthesis of S41 is referred to Example 17.

[0314] 2. Synthesis of S46

[0315] S41 (300 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and S6 (195 mg, 1.17 mmol) was added and stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, it was concentrated under reduced pressure, and the crude product was washed with ethyl acetate to collect the filter cake, and dried to obtain a white solid compound S46 (300 mg, yield: 75%). ESI [M] + = 343.2.

[0316] 3. Synthesis of 6-2-1

[0317] S46 (300 mg, 0.87 mmol) was dissolved in methanol (20 mL), and Pd / C (60 mg) was added, and the reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (DCM:MeOH = 100 / 1 ~ 10 / 1) to obtain a white solid. Further, the white solid was filtered by slurry with ethyl acetate, and the filter cake was collected and concentrated under reduced pressure to obtain white solid compound 6-2-1 (161.17 mg, yield: 54%). ESI [M] + = 345.3.

[0318] 1 H NMR (400 MHz, DMSO-d6) δ: 9.97 (s, 1H), 7.19-7.09 (m, 3H), 5.67 (d, J = 4.0 Hz, 1H), 4.51-4.39 (m, 2H), 4.11 (d, J = 3.6 Hz, 1H), 3.92-3.81 (m, 4H), 3.70-3.59 (m, 2H), 2.55-2.45 (m, 2H), 2.15-2.10 (m, 4H), 2.00-1.90 (m, 4H), 1.61-1.57 (m, 1H), 1.47-1.43 (m, 2H), 1.10 (t, J = 7.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).

[0319] Example 20, Preparation of compound 1-2-3 of the present application

[0320] 1. Synthesis of S47

[0321] S6 (6.6 mmol, 1.1 g) was weighed into a 100 mL single-necked round-bottom flask, and 20 mL of N,N-dimethylformamide (DMF) was added to dissolve it. To the mixture, 4-dimethylaminopyridine (DMAP, 1.32 mmol, 161 mg), triethylamine (13.2 mmol, 1.34 g), and finally tert-butyldimethylsilyl chloride (9.9 mmol, 1.5 g) were added. The reaction mixture was stirred at room temperature overnight, and TLC was used to detect that the reaction was complete. Water was added to the reaction mixture, and ethyl acetate was used to extract it. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain TBS-protected product S47.

[0322] 2. Synthesis of S48

[0323] S47 (1.43 g, 5.1 mmol) was weighed into a 100 mL single neck flask, dissolved in 40 mL of anhydrous dichloromethane and cooled to 0 °C. 0.3 mL of bromine (1.8 g, 11.2 mmol) was dissolved in 10 mL of anhydrous dichloromethane and added slowly to the above reaction. The reaction was slowly warmed to room temperature and allowed to react for 2 h, monitored by TLC. After the starting material was consumed, 20 mL of saturated sodium thiosulfate solution was added to the reaction and shaken. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude S48 which was used directly in the next step.

[0324] 3. Synthesis of S49

[0325] The crude S48 and tetrabutylammonium iodide (185 mg, 0.51 mmol) were dissolved in 40 mL of tetrahydrofuran in a 100 mL single neck flask and warmed to 45 °C. Solid potassium hydroxide (3.4 g, 61.2 mmol) was added in two portions and the reaction was allowed to proceed for 2 h at 45 °C. The reaction was monitored by TLC. After the starting material was consumed, the reaction was filtered through a sintered glass funnel packed with 1 cm of celite. The filtrate was concentrated to give the crude product which was purified by column chromatography to give the desired product S49 (896 mg, 63% yield).

[0326] 4. Synthesis of S50

[0327] Pd(PPh3)2Cl2(0.014 mmol, 10 mg), CuI (0.028 mmol, 5.33 mg), 1-bromopropene (Z / E, mixture, 0.72 mmol, 87 mg) were added to a 25 mL Schlenk tube and the reaction was purged with nitrogen three times. S49 (0.72 mmol, 200 mg) was dissolved in 3 mL of anhydrous tetrahydrofuran and added to the above Schlenk tube. The reaction was allowed to proceed for 10 h at 45 °C. The reaction was monitored by TLC. After the starting material was consumed, the reaction was concentrated to give the crude product which was purified by column chromatography to give the desired product S50 (95 mg, 43% yield).

[0328] 5. Synthesis of S51

[0329] Pd / C (10%, w / w, 0.014 mmol, 15 mg) was added to a 25 mL single neck flask and a double layer of hydrogen balloon was attached to the flask. The reaction was purged with hydrogen three times and allowed to react for 2-3 days at room temperature. The reaction was monitored by TLC. After the reaction was complete, the reaction was filtered through a glass frit funnel packed with 1 cm of celite. The filtrate was concentrated to give the desired product S51 (451 mg, 95% yield).

[0330] 6. Synthesis of S52

[0331] A 250 mL dry single neck flask was charged with S51 (451 mg), dissolved in 30 mL of methanol, trifluoroacetic acid was added at room temperature and the reaction was allowed to proceed overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent and excess trifluoroacetic acid was removed by rotary evaporation. Then 30 mL of dichloromethane was added and the pH was adjusted to 13-14 using 4 M sodium hydroxide. The organic layer was extracted using DCM and the combined organic layer was concentrated under reduced pressure and dried under vacuum to obtain the product S52 (310 mg).

[0332] 7. Synthesis of 1-2-3

[0333] A 50 mL single neck flask was charged with A1 (137 mg, 0.56 mmol), dissolved in 20 mL of MeCN, S52 (120 mg, 0.56 mmol) and K2CO3 (77 mg, 0.56 mmol) were added and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the solid was removed by filtration and the solvent was removed by evaporation under reduced pressure. The crude product was purified by column chromatography [eluent: dichloromethane-methanol (100:1-20:1)] to obtain the product 1-2-3 (45.77 mg, 18% yield), ESI [M+H] = 373.3 [M] + = 373.3 [M] + .

[0334] 1 H NMR (400 MHz, DMSO-d6), δ 9.86 (s, 1H), 7.13-7.07 (m, 3H), 5.66 (t, J = 5.2 Hz, 1H), 4.36 (q, J = 20 Hz, 2H), 4.11 (d, J = 5.2 Hz, 1H), 3.89-3.68 (m, 5H), 3.59-3.52 (m, 1H), 2.17 (s, 6H), 2.15-2.04 (m, 1H), 1.96 (s, 1H), 1.89-1.88 (m, 2H), 1.57-1.53 (m, 1H), 1.43-1.39 (m, 2H), 1.29-1.23 (m, 7H), 0.86 (t, J = 6.4 Hz, 3H).

[0335] Example 21, Preparation of compound 2-2-1 of the present application

[0336] 1. Synthesis of S9

[0337] Synthesis of S9 was carried out as per example 7.

[0338] 2. Synthesis of S53

[0339] S6 (300 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), then S9 (195 mg, 1.17 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was monitored to be complete by LCMS, the crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried under vacuum to give compound S53 (400 mg, yield: 80%). ESI [M] + = 343.4 [M] + .

[0340] 3, Synthesis of 2-2-1

[0341] S53 (260 mg, 0.62 mmol) was dissolved in methanol (10 mL), then Pd / C (52 mg) was added, hydrogen was replaced for three times, the reaction was stirred at room temperature for 2 hours under hydrogen. After the reaction was monitored to be complete by LCMS, the crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried under vacuum to give compound 2-2-1 (228 mg, yield: 87%). ESI [M] + = 345.4 [M] + .

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 6.89 (s, 2H), 5.66 (t, J = 4.8 Hz, 1H), 4.37 (dd, J = 15.6, 31.6 Hz, 2H), 4.09 (d, J = 4.8 Hz, 1H), 3.89 - 3.76 (m, 4H), 3.72 - 3.67 (m, 2H), 3.61 - 3.54 (m, 1H), 2.22 (s, 3H), 2.20 - 2.16 (m, 1H), 2.11 (s, 6H), 1.99 - 1.86 (m, 4H), 1.59 - 1.55 (m, 1H), 1.49 - 1.41 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0343] Example 22, Preparation of compound 3-1-1 of the present application

[0344] 1, Synthesis of S12

[0345] The synthesis of S12 refers to Example 8.

[0346] 2, Synthesis of S54

[0347] S12 (316 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and A1 (195 mg, 1.17 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS, the crude product was filtered by acetic ether, and the filter cake was collected and dried to obtain a white solid compound S54 (300 mg, yield: 74%). ESI [M] + = 357.3.

[0348] 3, Synthesis of 3-1-1

[0349] S54 (500 mg, 1.4 mmol) was dissolved in methanol (20 mL), and Pd / C (100 mg) was added. Hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours under hydrogen. After the reaction was completed by LCMS, the reaction mixture was filtered by celite, and the filtrate was concentrated under reduced pressure. The white solid was purified by silica gel column (DCM:MeOH = 100 / 1 ~ 10 / 1), and further filtered by acetic ether to collect the filter cake and concentrate under reduced pressure to obtain a white solid compound 3-1-1 (306.12 mg, yield: 60%). ESI [M] + = 359.4.

[0350] 1 H NMR (400 MHz, DMSO-d6) δ: 9.92 (s, 1H), 7.25-7.12 (m, 3H), 5.68 (t, J = 4.8 Hz, 1H), 4.35 (s, 2H), 4.11 (d, J = 4.8 Hz, 1H), 3.98-3.87 (m, 2H), 3.80-3.73 (m, 2H), 3.62-3.55 (m, 2H), 2.51-2.47 (m, 4H), 2.02-1.88 (m, 6H), 1.45-1.41 (m, 2H), 1.11 (t, J = 7.6 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H).

[0351] Example 23, Preparation of the compound 5-2-1 of the present application

[0352] 1, Synthesis of S18

[0353] The synthesis of S18 is described in Example 10.

[0354] 2, Synthesis of S55

[0355] S6 (281 mg, 1.68 mmol) was dissolved in acetonitrile (10 mL), and S18 (500 mg, 1.68 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1) to obtain white solid S55 (480 mg, yield: 61.3%). ESI [M] + = 386.4 [M] + .

[0356] 3, Synthesis of 5-2-1

[0357] S55 (420 mg, 0.903 mmol) was dissolved in methanol (20 mL), and Pd / C (84 mg) was added. The reaction was stirred at room temperature for 2 hours under hydrogen gas. After the reaction was completed by LCMS, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1) to obtain white solid 5-2-1 (311.02 mg, yield: 73.7%). ESI [M] + = 388.4 [M] + .

[0358] 1 H NMR (400 MHz, DMSO-d6) δ: 9.83 (s, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 5.62 (t, J = 4.4 Hz, 1H), 4.51-4.35 (m, 2H), 4.13 (d, J = 4.4 Hz, 1H), 3.89-3.76 (m, 4H), 3.67-3.57 (m, 2H), 3.05-3.00 (m, 2H), 2.18-2.12 (m, 1H), 2.00-1.88 (m, 4H), 1.62-1.57 (m, 1H), 1.49-1.41 (m, 2H), 1.12 (d, J = 6.8 Hz, 12H), 0.86 (t, J = 7.2 Hz, 3H).

[0359] Example 24, Preparation of the compound 25-1-1 of the present application

[0360] 1, Synthesis of S57

[0361] S56 (1.0 g, 8.93 mmol) was added to a 250 mL single-neck flask, dissolved in THF (40 mL), pyridine (1.41 g, 17.86 mmol) was added, the system was cooled to 0°C with ice, bromoacetyl bromide (1.98 g, 9.82 mmol) was added dropwise, and the system was stirred at room temperature for one hour. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ~ 20 / 1) to obtain a yellow solid S57 (1.2 g, yield: 60%). ESI [M+H] + = 233.2 [M+H] + .

[0362] 2. Synthesis of S58

[0363] S57 (500 mg, 2.16 mmol) was dissolved in acetonitrile (10 mL), S1 (360 mg, 2.16 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed, the solvent was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 ~ 20 / 1) to obtain a white solid S58 (510 mg, yield: 59.2%). ESI [M] + = 320.2 [M] + .

[0364] 3. Synthesis of 25-1-1

[0365] S58 (450 mg, 1.125 mmol) was dissolved in methanol (30 mL), Pd / C (90 mg) was added, and the system was replaced with hydrogen three times, and stirred at room temperature under hydrogen for 2 hours. After the reaction was completed, the system was filtered with diatomite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 ~ 20 / 1), concentrated under reduced pressure, dissolved in water, and lyophilized at low temperature to obtain a white solid 25-1-1 (340.41 mg, yield: 70%). ESI [M] + = 322.2 [M] + .

[0366] 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 10.04 (s, 1H), 5.63 (t, J = 4.8 Hz, 1H), 2.34-4.24 (m, 2H), 4.13 (t, J = 11.6 Hz, 1H), 3.96 (t, J = 8.8 Hz, 1H), 3.79 (t, J = 4.4 Hz, 2H), 3.71 (t, J = 11.6 Hz, 1H), 3.59-3.48 (m, 2H), 2.28 (s, 3H), 2.12 (s, 3H), 2.01-1.83 (m, 6H), 1.44-1.37 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0367] Example 25, Preparation of the compound 25-2-1 of the present application

[0368] 1. Synthesis of S57

[0369] The synthesis of S57 is referred to Example 24.

[0370] 2. Synthesis of S59

[0371] S57 (500 mg, 2.16 mmol) was dissolved in acetonitrile (10 mL), then S6 (360 mg, 2.16 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1) to obtain white solid S59 (480 mg, yield: 55.7%). ESI [M] + = 320.2 [M] + .

[0372] 3. Synthesis of 25-2-1

[0373] S59 (420 mg, 1.05 mmol) was dissolved in methanol (20 mL), then Pd / C (84 mg) was added, and hydrogen was replaced for three times. The reaction was stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1), and then concentrated under reduced pressure. The white solid 25-2-1 (314.32 mg, yield: 74.2%) was obtained by dissolving in water and freeze-drying at low temperature. ESI [M] + = 322.2 [M] + .

[0374] 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 5.64 (t, J = 4.8 Hz, 1H), 4.33 (s, 2H), 4.07 (d, J = 6.0 Hz, 1H), 3.90-3.78 (m, 3H), 3.71-3.67 (m, 2H), 3.55 (t, J = 6.8 Hz, 1H), 2.28 (s, 3H), 2.17-2.11 (m, 4H), 1.99-1.88 (m, 4H), 1.52-1.42 (m, 3H), 0.86 (t, J = 7.2 Hz, 3H).

[0375] Example 26, Preparation of compound 0-0-1 of the present application

[0376] 1. Synthesis of A-1-0

[0377] A-0 (1.1 g, 9.09 mmol) was added into a 250 mL single-neck flask, dissolved in THF (50 mL), then pyridine (1.44 g, 18.18 mmol) was added, the system was cooled to 0 °C with ice, bromoacetyl bromide (2.0 g, 10.0 mmol) was added dropwise, and the system was stirred at room temperature for 2 hours after the reaction was completed. The solid was removed by filtration, poured into ice water, and extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered under suction, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ~ 20 / 1) to obtain white solid A-1-0 (1.2 g, yield: 67%). ESI [M+H] + = 198.4 [M+H] + .

[0378] 2. Synthesis of S60

[0379] S6 (440 mg, 2.64 mmol) was dissolved in acetonitrile (10 mL), then A-1-0 (520 mg, 2.64 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure, then washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound S60 (700 mg, yield: 72.6%). ESI [M] + = 329.4 [M] + .

[0380] 3. Synthesis of S61

[0381] S60 (540 mg, 1.48 mmol) was dissolved in MeOH (30 mL), Pd / C (108 mg) was added, hydrogen was replaced for three times, the system was stirred under hydrogen environment for 2 hours. After the reaction was monitored to be complete by LCMS, it was concentrated under reduced pressure, the crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried to obtain compound S61 (500 mg, yield: 92%). ESI [M] + = 331.4 [M] + .

[0382] 4, Synthesis of 0-0-1

[0383] S61 (350 mg, 0.95 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (452 mg, 3.8 mmol) was slowly added dropwise, and stirred at 40°C overnight after addition. After the reaction was monitored to be complete by LCMS, it was concentrated under reduced pressure, the crude product was slurried with ethyl acetate, filtered, the filter cake was collected and dried to obtain compound 0-0-1 (225.16 mg, yield: 60%). ESI [M+H] + = 349.4 [M] + .

[0384] 1 H NMR (400 MHz, DMSO-d6) δ: 10.50 (s, 1H), 7.18-7.08 (m, 3H), 4.51 (dd, J = 23.2, 15.2 Hz, 2H), 4.37 (dd, J = 10.8, 4.0 Hz, 1H), 4.31-4.27 (m, 1H), 4.10-4.02 (m, 2H), 3.64 (t, J = 2.8 Hz, 2H), 3.53 (dd, J = 12.0, 7.2 Hz, 1H), 2.31 (q, J = 9.2 Hz, 1H), 2.18 (s, 6H), 2.07-2.04 (m, 3H), 1.91 (t, J = 2.4 Hz, 1H), 1.74 (d, J = 14.0 Hz, 1H), 1.49-1.41 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0385] Example 27, Preparation of compound 0-0-2 of the application

[0386] 1, Synthesis of 1-2-1

[0387] The synthesis of 1-2-1 refers to Example 6.

[0388] 2, Synthesis of S62

[0389] To a reaction flask was added S62 (200 mg, 0.49 mmol) and 1,4-dioxane (10 mL) was added, then lithium bromide (85 mg, 0.98 mmol) was added, and the reaction was stirred at 120 °C for three hours. After the reaction was completed by LCMS, the reaction was poured into (20 mL) water, and extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, rotary evaporated, and the crude product was obtained by column (dichloromethane / methanol = 10 / 1), then the white solid was obtained by further slurry in ethyl acetate, and then dissolved in deionized water and lyophilized at low temperature to obtain 0-0-2 (272.67 mg, yield: 77%). ESI [M] + = 393.4 [M] + .

[0390] 3, Synthesis of 0-0-2

[0391] To a reaction flask was added S62 (200 mg, 0.49 mmol) and 1,4-dioxane (10 mL) was added, then lithium bromide (85 mg, 0.98 mmol) was added, and the reaction was stirred at 120 °C for three hours. After the reaction was completed by LCMS, the reaction was poured into (20 mL) water, and extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, rotary evaporated, and the crude product was obtained by column (dichloromethane / methanol = 10 / 1), then the white solid was obtained by further slurry in ethyl acetate, and then dissolved in deionized water and lyophilized at low temperature to obtain 0-0-2 (272.67 mg, yield: 77%). ESI [M] + = 393.4 [M] + .

[0392] 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.15-7.09 (m, 3H), 4.47 (d, J = 15.6 Hz, 1H), 4.39-4.35 (m, 2H), 4.15-4.12 (m, 1H), 4.02-3.97 (m, 1H), 3.90 (t, J = 10.4 Hz, 1H), 3.63-3.59 (m, 2H), 3.52-3.47 (m, 1H), 2.33-2.30 (m, 1H), 2.18 (s, 6H), 2.07-2.00 (m, 3H), 1.91 (s, 1H), 1.74 (d, J = 13.6 Hz, 1H), 1.47-1.42 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0393] Example 28, Preparation of the compound 0-0-3 of the application

[0394] 1, Synthesis of S63

[0395] S1 (700 mg, 4.19 mmol) was added into a 100 mL single-neck flask, dissolved in THF (20 mL), the system was cooled to 0 °C with ice bath, sodium hydride (419 mg, 10.48 mmol) was slowly added, and the reaction was stirred at 70 °C for two hours. The system was cooled to 0 °C with ice bath, and bromopropane (2.6 g, 20.95 mmol) dissolved in THF (10 mL) was slowly added dropwise into the above reaction system. After the addition was completed, the reaction was stirred at room temperature overnight. The reaction liquid was slowly poured into ice water, and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain S63, which was directly used in the next step. ESI [M+H] + = 210.4 [M+H] + .

[0396] 2, Synthesis of A-1

[0397] The synthesis of A-1 was carried out according to Example 1.

[0398] 3, Synthesis of S64

[0399] S63 (700 mg, 3.35 mmol) was dissolved in acetonitrile (30 mL), and A-1 (810 mg, 3.35 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure, and then washed with ethyl acetate. The filter cake was collected and dried to obtain compound S64 (320 mg, yield: 21.3%) as a white solid. ESI [M] + = 371.3 [M] + .

[0400] 4, Synthesis of 0-0-3

[0401] S64 (280 mg, 0.621 mmol) was dissolved in methanol (20 mL), and Pd / C (56 mg) was added. The system was replaced with hydrogen three times, and the reaction was stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the filter cake was collected and dried to obtain compound 0-0-3 (230.74 mg, yield: 81%) as a white solid. ESI [M] + = 373.3 [M] + .

[0402] 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 7.13-7.10 (m, 3H), 4.29 (q, J = 15.6 Hz, 2H), 4.08 (d, J = 8.8 Hz, 2H), 3.84-3.74 (m, 3H), 3.62 (q, J = 9.6 Hz, 1H), 3.54-3.38 (m, 3H), 2.18 (m, 6H), 2.04-1.87 (m, 6H), 1.61-1.56 (m, 2H), 1.44-1.40 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).

[0403] Example 29, Preparation of the compound 0-0-4 of the present application

[0404] 1. Synthesis of S65

[0405] S1 (700 mg, 4.19 mmol) was added into a 100 mL single-neck flask, dissolved in THF (20 mL), the system was cooled to 0 °C with ice bath, sodium hydride (419 mg, 10.48 mmol) was slowly added, and the system was stirred at 70 °C for two hours after the addition. The system was cooled to 0 °C with ice bath, and 2-bromoethyl methyl ether (2.91 g, 20.95 mmol) dissolved in THF (10 mL) was slowly added dropwise into the above reaction system, and the system was stirred at room temperature overnight after the addition. The reaction liquid was slowly poured into ice water, and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed by reduced pressure evaporation to obtain S65 which was directly used in the next step. ESI [M+H] + = 226.4 [M+H] + .

[0406] 2. Synthesis of A-1

[0407] The synthesis of A-1 was carried out according to Example 1.

[0408] 3. Synthesis of S66

[0409] S65 (700 mg, 3.35 mmol) was dissolved in acetonitrile (30 mL), and A-1 (810 mg, 3.35 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the system was concentrated by reduced pressure evaporation, and the crude product was washed with ethyl acetate, filtered, and the filter cake was collected and dried to obtain the white solid compound S66 (290 mg, yield: 20%). ESI [M] + = 387.3 [M] + .

[0410] 4. Synthesis of 0-0-4

[0411] S66 (260 mg, 0.557 mmol) was dissolved in methanol (10 mL), then Pd / C (52 mg) was added, hydrogen was replaced for three times, and the reaction was stirred at room temperature under hydrogen for 2 hours. After the reaction was monitored to be complete by LCMS, diatomite was filtered, the filtrate was concentrated under reduced pressure, and the crude product was slurried with ethyl acetate, filtered, and the filter cake was collected, dissolved with deionized water, and lyophilized at low temperature to obtain compound 0-0-4 (170.73 mg, yield: 66%). ESI [M] + = 389.3 [M] + .

[0412] 1 H NMR (400 MHz, DMSO-d6) δ: 10.01 (s, 1H), 7.14-7.09 (m, 3H), 4.28 (q, J = 15.6 Hz, 2H), 4.09-4.04 (m, 2H), 3.84 (t, J = 9.6 Hz, 3H), 3.68-3.58 (m, 3H), 3.53-3.46 (m, 3H), 3.29 (s, 3H), 2.17 (s, 6H), 2.03-1.90 (m, 6H), 1.45-1.40 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0413] Example 31, Preparation of compound 0-0-6 of the present application

[0414] Compound 0-0-6 is the same structure as compound S16, and the synthesis is referred to Example 10.

[0415] 1 H NMR (400 MHz, DMSO-d6) δ: 10.01 (s, 1H), 7.14-7.09 (m, 3H), 4.28 (q, J = 15.6 Hz, 2H), 4.09-4.04 (m, 2H), 3.84 (t, J = 9.6 Hz, 3H), 3.68-3.58 (m, 3H), 3.53-3.46 (m, 3H), 3.29 (s, 3H), 2.17 (s, 6H), 2.03-1.90 (m, 6H), 1.45-1.40 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0416] Example 32, Preparation of compound 0-0-7 of the present application

[0417] 1. Synthesis of S71

[0418] To a round-bottom flask was added S70 (2000 mg, 8.0 mmol), Pd(dppf)Cl2(1165 mg, 1.6 mmol), cyclohexylboronic acid (2739 mg, 31.9 mmol), potassium phosphate (6771 mg, 31.9 mmol), toluene (80 mL) and water (20 mL), the mixture was stirred at 100 °C under nitrogen atmosphere overnight, after the reaction was completed, the mixture was allowed to return to room temperature, water was added, and the organic phase was extracted with ethyl acetate three times, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (PE:EA = 100:0 ~ 80:80) to obtain the target compound S71 (pale yellow oil, 500 mg, yield 36%).

[0419] 2. Synthesis of S72

[0420] To a round-bottom flask was added S71 (500 mg, 2.9 mmol), pyridine (456 mg, 5.8 mmol) and THF (40 mL), bromoacetyl bromide (879 mg, 4.3 mmol) was slowly added dropwise under ice bath, the mixture was slowly returned to room temperature and stirred for 3 hours, after the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was dissolved in ethyl acetate and washed with deionized water, the aqueous layer was separated, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, the residue was added with n-hexane to make a slurry, and filtered to obtain compound S72 (off-white solid, 700 mg, yield 82%).

[0421] 3. Synthesis of S2

[0422] S2 was synthesized according to Example 10.

[0423] 4. Synthesis of 0-0-7

[0424] To a round-bottom flask was added S72 (383 mg, 1.3 mmol), S2 (200 mg, 1.2 mmol) and MeCN (10 mL), and stirred at room temperature overnight, after the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 ~ 80:20) to obtain compound 0-0-7 (beige solid, 348.91 mg, yield 64%). ESI [M] + = 383.4.

[0425] 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 2H), 5.64 (t, J = 4.8 Hz, 1H), 4.40-4.35 (m, 2H), 4.16-4.08 (m, 1H), 4.00-3.88 (m, 2H), 3.80-3.73 (m, 2H) 3.62-3.52 (m, 2H), 2.03-1.81 (m, 8H), 1.45-1.38 (m, 2H), 0.89-0.83 (m, 7H), 0.60-0.55 (m, 4H).

[0426] Example 33, Preparation of compound 0-0-8 of the application

[0427] 1. Synthesis of S74

[0428] Into a round bottom flask was added S73 (2500 mg, 11.7 mmol), Pd(dppf)Cl2 (853 mg, 1.2 mmol), borane (1867923-49-6, 3398 mg, 17.5 mmol), potassium phosphate (7430 mg, 35.0 mmol), toluene (80 mL) and water (20 mL), the mixture was stirred at 90 °C under nitrogen atmosphere overnight, after the reaction was completed, the mixture was allowed to return to room temperature, water was added, and extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum, the crude product was purified by silica gel column chromatography (PE:EA = 100:0~20:80) to obtain the target compound S74 (pale yellow oil, 2000 mg, yield 85%).

[0429] 2. Preparation of compound S75

[0430] Into a 100 mL simple kettle was added S74 (1000 mg, 5.0 mmol), catalyst (325146-81-4, 100 mg) and dichloromethane (40 mL), pressurized to a hydrogen pressure of 2.0 MPa, stirred at room temperature overnight, after the reaction was completed, transferred to a round bottom flask, and the solvent was removed by reduced pressure concentration, the residue was purified by silica gel column chromatography (PE:EA = 100:0~30:70) to obtain compound S75 (pale yellow oil, 600 mg, yield 59%).

[0431] 3. Preparation of compound S76

[0432] Into a round-bottom flask was added S75 (600 mg, 3.0 mmol), pyridine (467 mg, 5.9 mmol) and tetrahydrofuran (50 mL), bromoacetyl bromide (909 mg, 4.5 mmol) was added dropwise slowly under ice bath, the mixture was slowly recovered to room temperature and stirred for 3 hours, after the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate (50 mL) and washed with deionized water, the aqueous layer was separated, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent, the residue was added with n-hexane to make a slurry, and then filtered to obtain compound S76 (off-white solid, 800 mg, yield 82%).

[0433] 4. Synthesis of S2

[0434] S2 was synthesized according to Example 10.

[0435] 5. Preparation of compound 0-0-8

[0436] Into a round-bottom flask was added S76 (500 mg, 1.5 mmol), S2 (260 mg, 1.5 mmol) and MeCN (10 mL), and stirred at room temperature overnight, after the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0~80:20) to obtain compound 0-0-8 (white solid, 440.57 mg, yield 58%). ESI [M] + = 413.4.

[0437] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.32-7.27 (m, 2H), 7.20-7.16 (m, 1H), 5.66 (t, J = 4.4 Hz, 1H), 4.35 (s, 2H), 4.07-3.53 (m, 7H), 3.05-2.96 (m, 1H), 2.14-1.93 (m, 7H), 1.45-1.39 (m, 2H), 1.15-1.00 (m, 10H), 0.86 (t, J = 7.4 Hz, 3H), 0.50 (br, 1H), 0.27-0.00 (m, 3H).

[0438] Example 34, Preparation of compound 0-0-9 of the application

[0439] 1. Synthesis of S74

[0440] S74 was synthesized according to Example 33.

[0441] 2. Synthesis of S77

[0442] Into a 100 mL simple reactor, S74 (1000 mg, 5.0 mmol), catalyst (261948-85-0, 100 mg) and dichloromethane (40 mL) were added, and the pressure was increased to 2.0 MPa. After stirring at room temperature overnight, the reaction was completed, and the reaction mixture was transferred to a round-bottom flask and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE:EA = 100:0 ~ 30:70) to obtain compound S77 (pale yellow oil, 600 mg, yield 59%).

[0443] 3. Preparation of compound S78

[0444] Into a round-bottom flask, S77 (600 mg, 3.0 mmol), pyridine (467 mg, 5.9 mmol), and tetrahydrofuran (50 mL) were added, and bromoacetyl bromide (909 mg, 4.5 mmol) was slowly added dropwise while being cooled in an ice bath. After the mixture was slowly returned to room temperature and stirred for 3 hours, the reaction was completed, and the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was collected and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (50 mL) and washed with deionized water. The aqueous layer was separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was slurried with n-hexane, and compound S78 (off-white solid, 800 mg, yield 82%) was obtained by filtration.

[0445] 4. Synthesis of S2

[0446] S2 was synthesized according to Example 10.

[0447] 5. Preparation of compound 0-0-9

[0448] Into a round-bottom flask, S78 (500 mg, 1.5 mmol), S2 (260 mg, 1.5 mmol), and MeCN (10 mL) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 ~ 80:20) to obtain compound 0-0-9 (white solid, 369.76 mg, yield 50%). ESI [M] + = 413.4.

[0449] 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.32-7.27 (m, 2H), 7.20-7.16 (m, 1H), 5.66 (t, J = 4.4 Hz, 1H), 4.35 (s, 2H), 4.07-3.53 (m, 7H), 3.05-2.96 (m, 1H), 2.14-1.93 (m, 7H), 1.45-1.39 (m, 2H), 1.15-1.00 (m, 10H), 0.86 (t, J = 7.4 Hz, 3H), 0.50 (br, 1H), 0.27-0.00 (m, 3H).

[0450] Example 35, Preparation of compound 0-1-0 of the application

[0451] 1. Synthesis of S80

[0452] To a round-bottom flask was added S70 (1.0 g, 4.0 mmol), S79 (1.7 g, 8.8 mmol), Pd(dppf)Cl2(587 mg, 0.8 mmol), K2CO3(2.8 g, 20.1 mmol) and DOX / H2O (V1:V2=5:1, 30 mL), stirred at 100 °C overnight under nitrogen atmosphere, after the reaction was completed, quenched with water, extracted with ethyl acetate (50 mL x 3), combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, purified by silica gel column chromatography (PE:EtOAc=99:1) to obtain compound S80 (light yellow oil, 600 mg, yield 66%).

[0453] 2. Preparation of compound S81

[0454] To a round-bottom flask was added S80 (600 mg, 2.7 mmol) and MeOH (20 mL), and Pd / C (60 mg) was added under stirring, the mixture was stirred at 60 °C overnight under hydrogen atmosphere, after the reaction was completed, the mixture was allowed to return to room temperature, filtered and the filter cake was washed with methanol, the filtrate was collected and concentrated under reduced pressure to obtain compound S81 (light yellow oil, 550 mg, yield 90%).

[0455] 3. Preparation of compound S82

[0456] Into a round-bottom flask was added S81 (550 mg, 2.4 mmol), pyridine (570 mg, 7.2 mmol) and THF (40 mL), bromoacetyl bromide (576 mg, 2.9 mmol) was added dropwise slowly under ice-bath, the mixture was slowly recovered to room temperature and stirred for 3 h, after the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate (50 mL) and washed with deionized water, the aqueous layer was separated, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, the residue was added with n-hexane to make a slurry, and compound S82 (off-white solid, 500 mg, yield 60%) was obtained by filtration.

[0457] 4. Preparation of compound S83

[0458] Into a round-bottom flask was added S83 (200 mg, 0.57 mmol), S1 (105 mg, 0.63 mmol) and MeCN (10 mL), and stirred at room temperature overnight, after the reaction was completed, the solvent was removed under reduced pressure, the residue was added with ethyl acetate to make a slurry, and compound S83 (white solid, 200 mg, yield 68%) was obtained by filtration.

[0459] 5. Preparation of compound 0-1-0

[0460] Into a round-bottom flask was added S83 (200 mg, 0.39 mmol) and MeOH (10 mL), and Pd / C (20 mg) was added under stirring, the mixture was stirred at room temperature under hydrogen atmosphere for 2 h, after the reaction was completed, the mixture was filtered and the filter cake was washed with methanol, the filtrate was collected and concentrated under reduced pressure, added with ethyl acetate to make a slurry, filtered, the filter cake was dissolved in a small amount of methanol, and then freeze-dried with pure water to obtain compound 0-1-0 (white solid, 138.79 mg, yield 69%). ESI [M] + = 439.3.

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.29-7.21 (m, 1H), 7.19-7.14 (m, 2H), 5.72 (s, 1H), 4.38 (s, 2H), 4.12 (t, J = 10.8 Hz, 1H), 4.04-3.96 (m, 1H), 3.94-3.85 (m, 1H), 3.79-3.67 (m, 2H), 3.65-3.52 (m, 2H), 3.13-2.97 (m, 2H), 2.03-1.81 (m, 10H), 1.75 (br, 4H), 1.61 (br, 4H), 1.54-1.38 (m, 6H), 0.86 (t, J = 7.2 Hz, 3H).

[0462] Example 36, Preparation of compound 0-1-1 of the application

[0463] 1. Synthesis of S84

[0464] S1 (1.0 g, 5.99 mmol) was dissolved in 100 mL single-neck flask with DMF (30 mL), the system was cooled to 0 °C with ice bath, sodium hydride (288 mg, 7.19 mmol) was slowly added, and the reaction was stirred at room temperature for two hours. The system was cooled to 0 °C with ice bath, and TBDPSCl (1.98 g, 7.19 mmol) dissolved in DMF (10 mL) was slowly added dropwise into the above reaction system, and the reaction was stirred at room temperature overnight. The reaction solution was slowly poured into ice water, and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ~ 20 / 1) to obtain a light yellow solid S84 (1.8 g, yield: 74%). ESI [M+H] + = 406.4 [M+H] + .

[0465] 2. Synthesis of S85

[0466] S84 (1.8 g, 4.44 mmol) was dissolved in THF (30 mL), and the system was cooled to 0 °C with ice bath, and boro-hydride dimethyl sulfide (22.2 mL, 22.2 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 3 hours. The reaction system was cooled to 0 °C, and ethanol (2.0 g, 44.4 mmol), NaOH solution (5 M, 9 mL, 44.4 mmol), H2O2 (1.5 g, 44.4 mmol) were slowly added dropwise in sequence, and the reaction was stirred at 70 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was extracted with ethyl acetate (3 x 30 mL), and the organic phase was combined and washed with sodium thiosulfate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1 ~ 5 / 1) to obtain a light yellow solid S85 (1.3 g, yield: 70%). ESI [M] + = 424.3 [M+H] + .

[0467] 3. Synthesis of S86

[0468] S85 (1.3 g, 3.07 mmol) was dissolved in methanol (20 mL), and con. HBr (10 mL) was added, and the reaction was stirred at 60 °C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and the crude product was dissolved in water, extracted with dichloromethane (3 x 20 mL), and the aqueous phase was concentrated and dried with oil pump to obtain compound S86 (570 mg, yield: 70%). ESI [M]+ = 186.3 [M] + .

[0469] 4. Synthesis of A-1

[0470] Synthesis of A-1 is referred to Example 1.

[0471] 5. Synthesis of 0-1-1

[0472] S86 (500 mg, 1.89 mmol) was dissolved in DMF (15 mL), then A-1 (457 mg, 1.89 mmol), K2CO3 (261 mg, 1.89 mmol) were added and stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure, and then purified by normal column [dichloromethane:methanol = (100 / 1 ~ 5 / 1)] to obtain a white solid, which was dissolved in deionized water and lyophilized at low temperature to obtain 0-1-1 (426.26 mg, yield: 53%). ESI [M] + = 347.3 [M] + .

[0473] 1 HNMR (400 MHz, DMSO-d6) δ: 10.02 (s, 1H), 7.14-7.07 (m, 3H), 5.67 (t, J = 4.8 Hz, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.38 (s, 2H), 4.13 (t, J = 10.8 Hz, 1H), 3.93 (t, J = 12.4 Hz, 2H), 3.78 (t, J = 10.4 Hz, 2H), 3.66-3.59 (m, 2H), 3.45-3.41 (m, 2H), 2.17 (m, 7H), 2.00-1.88 (m, 5H), 1.61-1.54 (m, 2H).

[0474] Example 37, Preparation of the compound 0-1-2 of the present application

[0475] 1. Synthesis of A-1-0

[0476] Synthesis of A-1-0 is referred to Example 25.

[0477] 2. Synthesis of S87

[0478] A-1-0 (396 mg, 2.0 mmol) was dissolved in acetonitrile (20 mL), then S1 (334 mg, 2.0 mmol) was added and stirred at 0°C overnight. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure, and then purified by normal column [dichloromethane:methanol (100 / 1 ~ 20 / 1)] to obtain a white solid S87 (420 mg, yield: 57%).

[0479] 3. Synthesis of 0-1-2

[0480] S87 (366 mg, 1.0 mmol) was dissolved in methanol (20 mL), then Pd / C (50 mg) was added, and the reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase column [dichloromethane:methanol (100 / 1 ~ 20 / 1)], and then freeze-dried with water to obtain compound 0-1-2 (305.48 mg, yield: 83%) as a white solid. ESI [M] + = 331.3 [M] + .

[0481] 1 H NMR (400 MHz, DMSO-d6) d: 10.37 (s, 1H), 7.11-7.07 (m, 3H), 5.82 (t, J = 4.8 Hz, 1H), 4.52-4.38 (m, 2H), 4.12 (t, J = 10.8 Hz, 1H), 3.97-3.92 (m, 2H), 3.77-3.72 (m, 2H), 3.63-3.57 (m, 2H), 2.18 (s, 6H), 2.00-1.86 (m, 6H), 1.45-1.41 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0482] Example 38, Preparation of compound 0-1-3 of the present application

[0483] Compound 0-1-3 has the same structure as compound S60, and the synthesis is referred to Example 25.

[0484] ESI [M] + = 331.4 [M] + .

[0485] 1 H NMR (400 MHz, DMSO-d6) d: 10.37 (s, 1H), 7.11-7.07 (m, 3H), 5.82 (t, J = 4.8 Hz, 1H), 4.52-4.38 (m, 2H), 4.12 (t, J = 10.8 Hz, 1H), 3.97-3.92 (m, 2H), 3.77-3.72 (m, 2H), 3.63-3.57 (m, 2H), 2.18 (s, 6H), 2.00-1.86 (m, 6H), 1.45-1.41 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0486] Example 39, Preparation of compound 0-1-4 of the present application

[0487] 1. Synthesis of 0-1-2

[0488] Synthesis of 0-1-2 is referred to Example 37.

[0489] 2. Synthesis of 0-1-4

[0490] 0-1-2 (350 mg, 0.95 mmol) was dissolved in dichloromethane (20 mL), and then thionyl chloride (452 mg, 3.8 mmol) was slowly added dropwise. After the addition was completed, the reaction was stirred at 40°C overnight. After the reaction was completed by LCMS monitoring, the crude product was concentrated under reduced pressure, and then purified by silica gel column (dichloromethane:methanol = 100 / 1-20 / 1). After being concentrated under reduced pressure, water was added to dissolve it, and then it was lyophilized at low temperature to obtain compound 0-1-4 (312.42 mg, yield: 84.7%). ESI [M] + = 349.4 [M] + .

[0491] 1 H NMR (400 MHz, DMSO-d6) δ: 10.52 (s, 1H), 7.14-7.08 (m, 3H), 4.55-4.40 (m, 2H), 4.28-4.23 (m, 1H), 4.17 (d, J = 6.4 Hz, 2H), 4.04 (t, J = 11.6 Hz, 1H), 3.83-3.69 (m, 2H), 3.34-3.29 (m, 1H), 2.18-2.13 (m, 7H), 2.09-1.91 (m, 4), 1.80 (d, J = 9.2 Hz, 1H), 1.53-1.38 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0492] Example 40, Preparation of compound 0-1-5 of the present application

[0493] 1. Synthesis of S88

[0494] S17 (1000 mg, 5.64 mmol) was added to a 100 mL single-neck flask, dissolved in tetrahydrofuran (50 mL), pyridine (891 mg, 11.28 mmol) was added, the system was cooled to 0°C with ice, chloroacetyl chloride (956 mg, 8.46 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered under suction, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 100 / 1～ 20 / 1), white solid S88 (1200 mg, yield: 84%) was obtained. ESI [M+H] + = 254.2 [M+H] + .

[0495] 2. Synthesis of S89

[0496] S1 (658 mg, 3.94 mmol) was dissolved in acetonitrile (6 mL), and then S88 (1000 mg, 3.94 mmol) was added. The reaction was stirred at 70°C for 4 days. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography to obtain compound S89 (400 mg, yield: 24%). ESI [M] + = 385.4 [M] + .

[0497] 3. Synthesis of 0-1-5

[0498] S89 (400 mg, 0.95 mmol) was dissolved in methanol (10 mL), and then Pd / C (100 mg) was added. The reaction was stirred under hydrogen for 2 hours at room temperature. After the reaction was completed by LCMS monitoring, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 0-1-5 (261.15 mg, yield: 65%). ESI [M] + = 387.4 [M] + .

[0499] 1 H NMR (400 MHz, DMSO-d6) δ: 10.23 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 2H), 5.82 (t, J = 4.8 Hz, 1H), 4.52-4.41 (m, 2H), 4.12-4.06 (m, 1H), 3.97-3.92 (m, 2H), 3.76-3.71 (m, 2H), 3.63-3.56 (m, 2H), 3.09-2.98 (m, 2H), 2.02-1.86 (m, 6H), 1.47-1.39 (m, 2H), 1.19-1.10 (m, 12H), 0.86 (t, J = 7.2 Hz, 3H).

[0500] Example 41, Preparation of compound 0-1-6 of the present application

[0501] 1. Synthesis of 1-1-1

[0502] The synthesis of 1-1-1 was performed according to Example 1.

[0503] 2. Synthesis of S90

[0504] To a reaction flask was added S90 (760 mg, 1.55 mmol) and 1,4-dioxane (20 mL) was added to dissolve the compound, then lithium bromide (270 mg, 3.10 mmol) was added, the reaction was stirred at 120 °C for 3 hours, after the reaction was completed by LCMS, the reaction was poured into (30 mL) water, extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, rotary evaporated to dryness, the crude product was obtained by column (dichloromethane / methanol = 10 / 1), then the crude product was further washed with ethyl acetate to obtain a white solid, then dissolved in deionized water and freeze-dried to obtain 0-1-6 (456.75 mg, yield: 77%). ESI [M] + = 409.3 [M] + .

[0505] 3, Synthesis of 0-1-6

[0506] To a reaction flask was added S90 (760 mg, 1.55 mmol) and 1,4-dioxane (20 mL) was added to dissolve the compound, then lithium bromide (270 mg, 3.10 mmol) was added, the reaction was stirred at 120 °C for 3 hours, after the reaction was completed by LCMS, the reaction was poured into (30 mL) water, extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, rotary evaporated to dryness, the crude product was obtained by column (dichloromethane / methanol = 10 / 1), then the crude product was further washed with ethyl acetate to obtain a white solid, then dissolved in deionized water and freeze-dried to obtain 0-1-6 (456.75 mg, yield: 77%). ESI [M] + = 393.4 [M] + .

[0507] 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.15-7.08 (m, 3H), 4.55-4.38 (m, 2H), 4.31-4.25 (m, 1H), 4.03 (t, J = 10.0 Hz, 2H), 3.95-3.91 (m, 1H), 3.76-3.68 (m, 2H), 3.28 (d, J = 10.4 Hz, 1H), 2.24-2.18 (m, 7H), 2.09-1.89 (m, 4H), 1.78-1.72 (m, 1H), 1.54-1.39 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0508] Example 42, Preparation of compound 0-1-7 of the application

[0509] 1, Synthesis of S92

[0510] S91 (10.0 g, 35.97 mmol) was added to a 250 mL single-neck flask, dissolved in DMSO (180 mL), and then S91-0 (15.5 g, 107.91 mmol), potassium carbonate (9.9 g, 71.94 mmol) were added. After the addition was completed, the reaction was carried out at 80°C for 16 hours. After the reaction was completed, the solid was removed by filtration, poured into water (400 mL), and extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ~ 20 / 1) to obtain a light yellow oil S92 (3.0 g, yield: 50%). ESI [M+H] + = 169.2 [M+H] + .

[0511] 2. Synthesis of S93

[0512] S92 (3.0 g, 17.86 mmol) was added to a reaction flask, dissolved in ethanol / water (60 mL / 20 mL), and sodium hydroxide (1.5 g, 35.72 mmol) was dissolved in (4 mL) and added to the above reaction solution. The reaction was stirred at 80°C for two hours. After the reaction was completed by LCMS monitoring, the remaining material was concentrated under reduced pressure, dissolved in water (50 mL), and the pH was adjusted to 3 with 1M HCl. White precipitates were separated, filtered, and the filter cake was washed with deionized water three times. The filter cake was collected and dried to obtain a white solid S93 (1.7 g, yield: 68%). ESI [M+H] + = 141.2 [M+H] + .

[0513] 3. Synthesis of S94

[0514] S93 (1.7 g, 12.14 mmol) was added to a reaction flask, dissolved in tert-butanol (60 mL), and triethylamine (1.2 g, 12.14 mmol) and DPPA (3.3 g, 12.14 mmol) were added to the reaction system. The reaction was stirred at 80°C overnight. After the reaction was completed by LCMS monitoring, the reaction was cooled to room temperature, water (80 mL) was added to the reaction system, extracted with ethyl acetate (3 x 50 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 10%) to obtain a light yellow solid S94 (1.5 g, yield: 58.6%). ESI [M+H] + = 212.2 [M+H] + .

[0515] 4. Synthesis of S95

[0516] To a reaction flask was added S94 (1.5 g, 7.11 mmol), 1 N hydrochloric acid in dioxane (50 mL) was added, and the reaction was stirred at room temperature for 4 hours. After the reaction was completed by LCMS monitoring, the solvent was removed under reduced pressure to obtain a light brown solid S95 (900 mg, yield: 90%). ESI [M+H] + = 112.3.

[0517] 5. Synthesis of S96

[0518] S95 (900 mg, 6.16 mmol) was added to a 250 mL single-neck flask, dissolved in tetrahydrofuran (30 mL), pyridine (1.46 g, 18.49 mmol) was added, the system was cooled to 0°C with ice, bromoacetyl bromide (1.37 g, 6.78 mmol) was added dropwise, and the system was stirred at room temperature for one hour. After the reaction was completed, the solid was removed by filtration, poured into ice water, and extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to obtain a light yellow solid S96 (540 mg, yield: 38.0%). ESI [M+H] + = 232.2 [M+H] + .

[0519] 6. Synthesis of S97

[0520] S1 (202 mg, 1.21 mmol) was dissolved in acetonitrile (10 mL), S96 (280 mg, 1.21 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the solvent was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 20 / 1) to obtain a white solid S97 (420 mg, yield: 86.8%). ESI [M] + = 319.2 [M] + .

[0521] 7. Synthesis of 0-1-7

[0522] S97 (380 mg, 0.952 mmol) was dissolved in methanol (10 mL), Pd / C (76 mg) was added, the system was replaced with hydrogen three times, and the reaction was stirred at room temperature under hydrogen for 2 hours. After the reaction was completed by LCMS monitoring, the system was filtered through diatomite, the filtrate was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 20 / 1), and the white solid 0-1-7 (338.05 mg, yield: 88.5%) was obtained by dissolving in water and freeze-drying at low temperature. ESI [M] + = 321.2 [M] + .

[0523] 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 5.63 (t, J = 4.8 Hz, 1H), 4.29-4.21 (m, 2H), 4.12 (t, J = 11.6 Hz, 1H), 3.92 (d, J = 9.2 Hz, 1H), 3.86-3.81 (m, 1H), 3.79-3.69 (m, 2H), 3.57-3.49 (m, 2H), 2.12 (s, 3H), 2.01-1.83 (m, 6H), 1.83 (s, 3H), 1.46-1.38 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0524] Example 43, Preparation of the compound 0-1-8 of the present application

[0525] 1. Synthesis of S96

[0526] The synthesis of S96 is referred to Example 41.

[0527] 2. Synthesis of S98

[0528] S6 (188 mg, 1.13 mmol) was dissolved in acetonitrile (10 mL), and S96 (260 mg, 1.13 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed by LCMS monitoring, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1) to obtain white solid S98 (340 mg, yield: 75.7%). ESI [M] + = 319.2 [M] + .

[0529] 3. Synthesis of 0-1-8

[0530] S98 (320 mg, 0.802 mmol) was dissolved in methanol (10 mL), and Pd / C (64 mg) was added. Hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours under hydrogen. After the reaction was completed by LCMS monitoring, the crude product was purified by silica gel column (dichloromethane:methanol = 100 / 1 ~ 20 / 1), and then concentrated under reduced pressure. The white solid 0-1-8 (283.15 mg, yield: 87.9%) was obtained by dissolving in water and freeze-drying at low temperature. ESI [M] + = 321.2 [M] + .

[0531] 1H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H), 7.27 (t, J = 0.8 Hz, 1H), 5.62 (t, J = 5.2 Hz, 1H), 4.36-4.27 (m, 2H), 4.02 (d, J = 4.8 Hz, 1H), 3.88-3.65 (m, 5H), 3.57-3.54 (m, 1H), 2.16-2.12 (m, 4H), 1.99-1.83 (m, 7H), 1.58-1.53 (m, 1H), 1.49-1.42 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0532] The remaining compounds of the present application were prepared according to the synthetic methods described in the above examples, in combination with methods conventional in the art.

[0533] The beneficial effects of the present application are demonstrated below by specific test examples.

[0534] Test Example 1, Study on the Local Analgesic Effect of the Compound of the Present Invention

[0535] 1.1 Experimental Method: The long-acting local anesthetic effect of the compound was evaluated using a rat sciatic nerve block model.

[0536] Isoflurane inhalation was used to induce and maintain anesthesia, and the rats were fixed in a right lateral position. The left sciatic tubercle to the greater trochanter of the femur line on both sides of the periphery and the end point at least 2 cm of hair was shaved with an electric shaver. The skin at the hair removal site was disinfected with an iodine alcohol cotton swab. The operator wore sterile gloves, and at the midpoint of the line connecting the two bony landmarks, a 1 mL syringe was inserted vertically into the skin, and the needle tip reached the bony structure. The syringe was fixed properly, and 0.4 mL of positive control drug ropivacaine or compound (0.05 ml / s) was slowly injected. At 10 min, 30 min, 1 h, 2 h, every 2 h after 2 h to 8 h, then every 4 h to 24 h (if not more than 24 h, need to make up 14 h), and then every 4 h, until recovery. The rats were observed as follows, and the observers were unaware of the treatment received by the rats.

[0537] Thermal pain threshold (modified hot plate test)

[0538] The sensory block effect of the drug was evaluated by a modified hot plate test. The rat was properly gripped, and the foot of the injected hind limb was contacted with a metal plate with a constant temperature of 55°C, and the timing was started at the same time. The time interval from contacting the hot plate to the rat's leg withdrawal due to heat pain was recorded, which was the paw withdrawal latency (PWL). If the rat did not withdraw the paw for more than 12 s (cutoff value), it was manually removed from the hot plate to avoid burns.

[0539] If MPE≥50% is defined as effective; otherwise, ineffective.

[0540] The time interval between the end of injection and the first measurement point of effective thermal analgesia is the onset time of thermal analgesia; the time interval between the end of injection and the first measurement point of ineffective thermal analgesia is the failure time of thermal analgesia; the difference between the two is the maintenance time of thermal analgesia.

[0541] Motor function (Postural Extensor Thrust, PET)

[0542] The motor block effect of the drug is evaluated by Postural Extensor Thrust (PET). The rat is vertically lifted and the injected hind limb is made to step on the electronic sky platform, at which time the hind limb muscle strength of the rat is indicated by the value displayed by the limb stepping platform. When the limb is completely paralyzed, the reading is the weight of the limb itself, about 10-20 g.

[0543] If MPE≥50% is defined as effective; otherwise, ineffective.

[0544] The time interval between the end of injection and the first measurement point of ineffective motor function is the onset time of motor block; the time interval between the end of injection and the first measurement point of recovery of motor function is the failure time of motor block; the difference between the two is the maintenance time of motor block.

[0545] All compounds will be subjected to a dose escalation test scheme for pharmacodynamic evaluation. The experimental rats will receive injections of drugs at gradient concentrations, with the initial dose set at 1% (w / v), and then the dose is increased in a 2-fold concentration gradient. Local and systemic toxic reactions will be closely monitored during the test, and if significant adverse reactions are observed, the concentration will be adjusted by 2-fold reduction immediately. The final maximum concentration effective dose without local and systemic adverse reactions is determined.

[0546] 1.2 Experimental results

[0547] As shown in Table 1, the time of sensory and motor nerve block of the compound of the present application in rat sciatic nerve block is significantly longer than that of ropivacaine hydrochloride injection, and there is no local and systemic adverse reaction at this concentration.

[0548] Table 1. Pharmacodynamic evaluation of the compound of the present application in rat sciatic nerve block

[0549] Test Example 2, safety evaluation of local administration of the compound of the present application

[0550] 2.1 Experimental method

[0551] The rats were executed by heart injection of propofol (or air) under isoflurane anesthesia on the 14th day after administration of the sciatic nerve of the rats. The muscle, connective tissue and nerve of the administration site were exposed and subjected to gross anatomy scoring. Then the nerve and the muscle tissue around it were placed in a fixing bottle containing 10% neutral formaldehyde solution. After treatment, the specimen was cut into 4 μm thick sections, which were subjected to HE staining and compared with the pathological sections of the positive control group.

[0552] 2.2 Experimental results

[0553] It was found by comparison of the gross anatomy and pathological sections that, at the experimental concentration, the compound of the present application had no obvious difference in the gross anatomy of the skin, the nerve at the injection site and the tissue around it, and the local inflammatory cell infiltration, muscle cell toxicity and nerve axon demyelination of the pathological sections compared with the control group. It was indicated that the compound had good local tissue safety while exerting long-acting local analgesia.

[0554] The present application provides a compound capable of producing long-acting local analgesia and having little systemic and local tissue toxicity. Therefore, the compound of the present application has a broad application prospect in the preparation of local analgesic drugs, and provides a new choice for the preparation of drugs with analgesic effect in clinic.

Claims

1. The compound represented by Formula I, its stereoisomers, its pharmaceutically acceptable salts, its solvates, its crystal forms, its prodrugs, its metabolites, or its deuterated derivatives: At least one of R1, R2, R3, and R4 is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, Not replaced or replaced by one or more R b The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; in, p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-10 Alkyl, C 1-10 Alkoxy; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-10 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k Selected from those that have not been replaced or have been replaced by one or more R x Substituted groups include: phenyl, 5-6 membered heteroaryl, R x Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R b Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; R2 and R4 are not both hydrogen; for X1 is selected from NH, O, and S; X2 is selected from NH, O, and S; R9 is selected from C 1-10 Alkyl groups, unsubstituted or substituted with one or more substituents, including: 5-8 membered aromatic rings, 5-8 membered heteroaromatic rings; each substituent is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl substituted C 1-10 alkyl; R5, R6, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl group, unsubstituted or surrounded by one or more R groups. d The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; R d Each independently selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; It is a monovalent anion.

2. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that: The structure of the compound is shown in Formula II: R1 is selected from hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-10 Alkyl, C 1-10 Alkoxy; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-10 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k Selected from those that have not been replaced or have been replaced by one or more R x Substituted groups include: phenyl, 5-6 membered heteroaryl, R x Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R b Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; R2 and R4 are each independently selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 Alkyne group; R2 and R4 are not both hydrogen; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-10 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-10 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, L1 is selected from O, S, NH, L2 is selected from O, S, NH, R L Selected from those that have not been replaced or have been replaced by one or more R Y Substituted groups include: phenyl, 5-6 membered heteroaryl, R Y Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R c Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; for X1 is selected from NH, O, and S; X2 is selected from NH, O, and S; R9 is selected from C 1-10 Alkyl groups, unsubstituted or substituted with one or more substituents, including: 5-8 membered aromatic rings, 5-8 membered heteroaromatic rings; each substituent is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated cycloalkyl substituted C 1-10 alkyl; It is a monovalent anion.

3. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that: The structure of the compound is shown in Formula II-1: R1 is selected from hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-6 alkyl; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-6 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, f is selected from 1, 2, 3 or 4, R f Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R b Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; R2 and R4 are each independently selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 Alkyne group; R2 and R4 are not both hydrogen; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-6 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-6 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, g is selected from 1, 2, 3 or 4, R g Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R c Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; for Ring A is selected from benzene rings or 5-6 membered heteroaromatic rings; m is selected from 1, 2, 3, or 4; R a Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; It is a monovalent anion.

4. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 3, characterized in that: The structure of the compound is shown in Formula II-2 or Formula II-3: R a1 R a2 R a3 Each is independently selected from hydrogen, C 1-3 alkyl; Of R2 and R4, one is hydrogen and the other is selected from C. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group; It is a monovalent anion.

5. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that: The compound is one of the following compounds:

6. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that: The structure of the compound is shown in Formula III: R3 is selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-10 alkyl; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-10 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k Selected from those that have not been replaced or have been replaced by one or more R x Substituted groups include: phenyl, 5-6 membered heteroaryl, R x Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R b Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; R2 and R4 are each independently selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 Alkyne group; R2 and R4 are not both hydrogen; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-10 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-10 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, L1 is selected from O, S, NH, L2 is selected from O, S, NH, R L Selected from those that have not been replaced or have been replaced by one or more R Y Substituted groups include: phenyl, 5-6 membered heteroaryl, R Y Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R c Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; for X1 is selected from NH, O, and S; X2 is selected from NH, O, and S; R9 is selected from C 1-10 Alkyl groups, unsubstituted or substituted with one or more substituents, including: 5-8 membered aromatic rings, 5-8 membered heteroaromatic rings; each substituent is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; It is a monovalent anion.

7. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 6, characterized in that: The structure of the compound is shown in Formula III-1: R3 is selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-6 alkyl; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-6 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, f is selected from 1, 2, 3 or 4, R f Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R b Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; R2 and R4 are each independently selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 Alkyne group; R2 and R4 are not both hydrogen; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-6 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-6 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, g is selected from 1, 2, 3 or 4, R g Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R c Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; for Ring A is selected from benzene rings or 5-6 membered heteroaromatic rings; m is selected from 1, 2, 3, or 4; R a Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; It is a monovalent anion.

8. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 6, characterized in that: The compound is one of the following compounds:

9. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that: The structure of the compound is shown in Formula IV: R1 is selected from hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-10 alkyl; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-10 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, K1 is selected from O, S, NH, K2 is selected from O, S, NH, R k Selected from those that have not been replaced or have been replaced by one or more R x Substituted groups include: phenyl, 5-6 membered heteroaryl, R x Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R b Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; R3 is selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-10 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-10 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-10 alkyl, It is a monovalent anion, L1 is selected from O, S, NH, L2 is selected from O, S, NH, R L Selected from those that have not been replaced or have been replaced by one or more R Y Substituted groups include: phenyl, 5-6 membered heteroaryl, R Y Each is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; R c Selected from C 1-10 Alkyl, C 1-10 Alkoxy, halogen, hydroxyl, C 2-10 alkenyl, C 2-10 Alkynyl, deuterium, amino, nitro, cyano; for X1 is selected from NH, O, and S; X2 is selected from NH, O, and S; R9 is selected from C 1-10 Alkyl groups, unsubstituted or substituted with one or more substituents, including: 5-8 membered aromatic rings, 5-8 membered heteroaromatic rings; each substituent is independently selected from halogens, C 1-10 Alkyl, halogen-substituted C 1-10 Alkyl, C 1-10 alkoxy- or halogen-substituted C 1-10 Alkoxy; It is a monovalent anion.

10. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 9, characterized in that: The structure of the compound is shown in Formula IV-1: R1 is selected from hydroxyl group, Not replaced or replaced by one or more R b The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group; Where p is selected from 1, 2, 3, or 4, R 10 Selected from hydrogen, C 1-6 alkyl; Y1 is selected from O, S, NH; Y2 is selected from O, S, NH, and none; Y3 is selected from O, S, NH; R 11 Selected from C 1-6 alkyl; W is selected from O, S, CH2, e is selected from 1, 2, 3, or 4, R e1 R e2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, f is selected from 1, 2, 3 or 4, R f Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R b Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; R3 is selected from hydrogen, hydroxyl group, Not replaced or replaced by one or more R c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group; Where q is selected from 1, 2, 3, or 4, and R 12 Selected from hydrogen, C 1-6 alkyl; Z1 is selected from O, S, NH; Z2 is selected from O, S, NH, and none; Z3 is selected from O, S, NH; R 13 Selected from C 1-6 alkyl; U is selected from O, S, CH2, h is selected from 1, 2, 3 or 4, R h1 R h2 Each independently selected from C 1-6 alkyl, It is a monovalent anion, g is selected from 1, 2, 3 or 4, R g Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; R c Selected from C 1-6 Alkyl, C 1-6 Alkyl groups, halogens, and hydroxyl groups; for Ring A is selected from benzene rings or 5-6 membered heteroaromatic rings; m is selected from 1, 2, 3, or 4; R a Each is independently selected from hydrogen, halogen, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy; It is a monovalent anion.

11. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite, or its deuterated derivative according to claim 9, characterized in that: The compound is one of the following compounds:

12. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as an active ingredient, such as a compound of any one of claims 1-11, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite or its deuterated derivative.

13. Use of the compound of any one of claims 1-11, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite or its deuterated derivative in the preparation of a medicament having analgesic and / or anesthetic effects.

14. The use according to claim 13, characterized in that: The drug is a drug with long-acting analgesic and / or long-acting local anesthetic effects.

Images