Quaternary ammonium salt derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and provides a quaternary ammonium salt derivative, and a preparation method therefor and a use thereof. The structure of the quaternary ammonium salt derivative is as shown in formula I. The compound of the present invention has an excellent differential blocking effect on sensory and motor nerves, high safety during use, and a long duration of action. Thus, the compound of the present invention has wide application prospects in the preparation of local anesthetic drugs for sensory-motor dissociation.

Description

A quaternary ammonium salt derivative, its preparation method and application Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a quaternary ammonium salt derivative, its preparation method, and its application, wherein the quaternary ammonium salt derivative contains a bridged ring structure. Background Technology

[0002] Local anesthetics (DAs) are a class of drugs that reversibly block the generation and conduction of nerve impulses. When DAs are injected into or applied near nerve tissue, they can cause temporary inhibition of sensory, motor, and autonomic nerve functions, either simultaneously or separately, at the site of nerve innervation. DAs are the cornerstone of local anesthesia for surgical procedures and the treatment of acute and chronic pain, and have been used clinically for over a century.

[0003] Currently used local anesthetics generally exhibit the characteristic of simultaneous sensory and motor nerve blockade, a feature that imposes numerous limitations in clinical practice. In labor analgesia, motor nerve blockade can lead to maternal muscle weakness, significantly prolonging labor and increasing the cesarean section rate. In postoperative analgesia, motor dysfunction can delay patient recovery, especially for patients requiring early mobilization. Although bupivacaine and ropivacaine show some differential blocking properties at low concentrations, significant limitations remain: 1) insufficient duration of blockade; 2) bupivacaine can still cause muscle weakness in some patients. Currently, no local anesthetics under development have achieved separate sensory and motor nerve blockade.

[0004] Therefore, there is an urgent need to design a new compound that, when producing local anesthesia, can have a sensory blockade time that is significantly longer than that of motor blockade, or even produce no motor blockade, thereby achieving sensory-motor dissociation blockade. Summary of the Invention

[0005] The purpose of this invention is to provide a quaternary ammonium salt derivative containing a bridged ring structure, its preparation method, and its application.

[0006] This invention provides compounds of Formula I, or their stereoisomers, or their pharmaceutically acceptable salts, or their solvates, or their crystal forms, or their prodrugs, or their metabolites, or their deuterated derivatives:

[0007] in, for

[0008] At least one of R1, R2, R3, and R4 is selected from At the same time, R1, R2, R3, R4, R m2 At least one of them is selected from The remaining groups are each independently selected from hydrogen, hydroxyl, halogen, amino, nitro, cyano, unsubstituted, or with one or more R groups. c The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; R c Each independently selected from C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 Alkyne, halogen, hydroxyl, deuterium, amino, nitro, cyano;

[0009] X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl;

[0010] X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl;

[0011] n is selected from 0, 1, or 2;

[0012] X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl;

[0013] X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl;

[0014] X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl;

[0015] R a Selected from C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group;

[0016] The M ring is selected from 5-8 quinary aromatic rings and 5-8 heterocyclic aromatic rings;

[0017] e1 is selected from 0, 1, 2, 3, 4, or 5; e2 is selected from 0, 1, 2, or 3;

[0018] R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of 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, C 2-10 alkenyl, C 2-10 Alkyne, halogen, hydroxyl, deuterium, amino, nitro, cyano;

[0019] R5, R6, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl group, unsubstituted or surrounded by one or more R groups. g The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; R g 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;

[0020] It is a monovalent anion.

[0021] Furthermore, the structure of the compound is shown in Formula II:

[0022] in, for

[0023] X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0024] X2 is selected from NR f2 O, S; R f2Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0025] The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings;

[0026] e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5;

[0027] R1, R2, R4, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-10 alkenyl; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0028] n is selected from 0, 1, or 2;

[0029] X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0030] X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0031] X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0032] R a Selected from C 1-8 alkyl;

[0033] R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0034] It is a monovalent anion.

[0035] Furthermore, the structure of the compound is shown in formula II-1, II-2, II-3 or II-4:

[0036] in, for

[0037] X1 is selected from O and S, and X2 is selected from O, S, and NR. f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0038] X3 is selected from O and S, and X4 is selected from O, S, and NR. f4 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0039] R a Selected from C 1-5 alkyl;

[0040] R2 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R2 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0041] R4 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R4 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0042] R2 and R4 are not both hydrogen;

[0043] R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0044] R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0045] R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups.c3 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy;

[0046] R c3 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0047] e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl;

[0048] e1 is selected from 0, 1, or 2; R m1 Each independently selected from C 1-5 alkyl;

[0049] e2 is selected from 1, 2, or 3;

[0050] It is a monovalent anion.

[0051] Furthermore, the compound is selected from one of the following compounds:

[0052] Furthermore, the structure of the compound is shown in Formula III:

[0053] in, for

[0054] X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0055] X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0056] The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings;

[0057] e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5;

[0058] R3, R2, R4, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. cThe following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0059] n is selected from 0, 1, or 2;

[0060] X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0061] X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0062] X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0063] R a Selected from C 1-8 alkyl;

[0064] R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0065] It is a monovalent anion.

[0066] Furthermore, the structure of the compound is shown in Formula III-1, Formula III-2, Formula III-3, or Formula III-4:

[0067] in, for

[0068] X1 is selected from O and S;

[0069] X2 is selected from O, S, NR f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0070] n is selected from 0, 1, or 2;

[0071] X3 is selected from O and S;

[0072] X4 is selected from None, O, S, NR f3 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0073] X5 is selected from None, O, S, NR f3 ;R f5 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0074] X4 and X5 are not both absent;

[0075] R a Selected from C 1-5 alkyl;

[0076] R2 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R2 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0077] R4 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R4 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0078] R2 and R4 are not both hydrogen;

[0079] R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups. c3 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c3 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0080] e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl;

[0081] e1 is selected from 0, 1, or 2; Rm1 Each independently selected from C 1-5 alkyl;

[0082] e2 is selected from 1, 2, or 3;

[0083] It is a monovalent anion.

[0084] Furthermore, the compound is selected from one of the following compounds:

[0085] Furthermore, the structure of the compound is shown in Formula IV:

[0086] in, for

[0087] X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0088] X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0089] The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings;

[0090] e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5;

[0091] R is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R. y The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R y Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0092] R1, R3, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0093] n is selected from 0, 1, or 2;

[0094] X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0095] X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0096] X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl;

[0097] R a Selected from C 1-8 alkyl;

[0098] R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups;

[0099] It is a monovalent anion.

[0100] Furthermore, the structure of the compound is shown in Formula IV-1, Formula IV-2, or Formula IV-3:

[0101] in, for

[0102] X1 is selected from O and S;

[0103] X2 is selected from O, S, NR f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0104] n is selected from 0, 1, or 2;

[0105] X3 is selected from O and S;

[0106] X4 is selected from None, O, S, NRf3 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0107] X5 is selected from None, O, S, NR f3 ;R f5 Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0108] X4 and X5 are not both absent;

[0109] R a Selected from C 1-5 alkyl;

[0110] R is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R. y The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R y Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0111] R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0112] R3 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R3 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups;

[0113] e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl;

[0114] e1 is selected from 0, 1, or 2; R m1 Each independently selected from C 1-5 alkyl;

[0115] e2 is selected from 1, 2, or 3;

[0116] It is a monovalent anion.

[0117] Furthermore, the compound is selected from one of the following compounds:

[0118] Furthermore, the monovalent anion described in this invention is a monovalent acid radical ion.

[0119] Furthermore, the monovalent anion described in this invention is a monovalent halide ion.

[0120] The present invention also provides a pharmaceutical composition comprising, wherein the pharmaceutical composition is an active ingredient of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its crystal form, its prodrug, its metabolite or its deuterated derivative thereof, and pharmaceutically acceptable excipients.

[0121] The present invention also provides the use of the above-mentioned compounds, their stereoisomers, their pharmaceutically acceptable salts, their solvates, their crystal forms, their prodrugs, their metabolites or their deuterated derivatives in the preparation of medicaments having analgesic and / or anesthetic effects.

[0122] Furthermore, the drug is a drug with long-acting analgesic and / or long-acting local anesthetic effects.

[0123] Furthermore, the drug is a sensorimotor dissociative drug with analgesic and / or anesthetic effects.

[0124] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0125] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～10 Alkyl groups refer to straight-chain or branched alkyl groups containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1～10 Alkoxy groups refer to straight-chain or branched alkoxy groups containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 2-10 Alkenyl refers to a straight-chain or branched alkenyl group containing 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 2-10 Alkyne refers to a straight-chain or branched alkynyl group containing 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and so on.

[0126] "Aryl" or "aromatic ring" refers to a monocyclic group consisting entirely of carbon atoms with a conjugated π-electron system, such as a phenyl group. The aryl group does not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent compound must be on a carbon atom of a ring with a conjugated π-electron system.

[0127] "Heteroaryl" or "heteroary ring" refers to a heteroaryl group containing one or more heteroatoms. The heteroatoms referred to here include, but are not limited to, oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazoleyl, tetrazolyl, etc.

[0128] A 5-8 membered aromatic ring refers to an aromatic ring containing 5, 6, 7, or 8 ring atoms, while a 5-8 membered heteroaromatic ring refers to a heteroaromatic ring containing 5, 6, 7, or 8 ring atoms.

[0129] Halogens are fluorine, chlorine, bromine or iodine.

[0130] The compounds of this invention exhibit excellent sensory and motor nerve dissociation blocking effects, good safety profile, and long duration of action. These compounds show broad application prospects in the preparation of local anesthetic drugs for sensory-motor dissociation.

[0131] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0132] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0133] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0134] Example 1. Synthesis of compound 1-1-1-1

[0135] 1. Synthesis of S2

[0136] S1 (500 mg, 3.0 mmol) was dissolved in methanol (40 mL), and then Pd / C (100 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was monitored by LCMS until complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound S2 (500 mg, yield: 99%). ESI[M+H] + =169.4[M+H] + .

[0137] 2. Synthesis of S3

[0138] S2 (500 mg, 2.96 mmol) was dissolved in acetone (20 mL), and the system was cooled to 0°C in an ice bath. Jones' reagent (2 M in H2SO4, 5.3 mL, 10.55 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred overnight at 60°C. After the reaction was complete as monitored by LCMS, the reaction mixture was cooled to room temperature, and isopropanol (20 mL) was added. The mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to give crude product S3 (800 mg, yield: 100%). ESI [M+H] + =184.4[M+H] + .

[0139] 3. Synthesis of S4

[0140] The crude product S3 was dissolved in methanol (20 mL), and an equivalent amount of concentrated hydrochloric acid was added. The mixture was stirred at 70 °C for three days. Two-thirds of the solvent was removed by rotary evaporation. The residue was cooled to 0 °C, and the pH was adjusted to 7 with saturated sodium bicarbonate. ～ 8. Slowly add ethylenediamine (355 mg, 5.92 mmol), stirring for 15 minutes after addition. Extract with diethyl ether, combine the organic phases, dry over anhydrous magnesium sulfate, filter, evaporate to dryness, and purify the residue by column chromatography to give compound S4 (300 mg, yield: 51%). ESI [M+H] + =197.4[M+H] + .

[0141] 4. Synthesis of A-2

[0142] Add A-1 (2.0 g, 16.53 mmol) to a 250 mL single-necked flask, dissolve in THF (80 mL), then add pyridine (2.61 g, 33.06 mmol). Cool the system to 0 °C, then add bromoacetyl bromide (3.34 g, 16.53 mmol) dropwise. After the addition is complete, stir the mixture overnight at room temperature. After the reaction is complete, filter to remove the solid, pour into ice water, and extract with dichloromethane (3 × 60 mL). Wash the organic phase with saturated brine (60 mL), dry to anhydrous Na₂SO₄, filter, and remove the solvent under reduced pressure to obtain the crude product. Purify by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to give white solid A-1 (2.1 g, yield: 53%). ESI [M+H] + =242.4[M+H] + .

[0143] 5. Synthesis of 1-1-1-1

[0144] S4 (200 mg, 1.02 mmol) was dissolved in acetonitrile (10 mL), and A-2 (246 mg, 1.02 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-1-1-1 (150.26 mg, yield: 34%). ESI [M] + =359.2 [M] + .

[0145] 1 H NMR (400MHz, DMSO-d6) δ: 10.04 (s, 1H), 7.13-7.08 (m, 3H), 4.97 (t, J = 9.6Hz, 1H), 4.62(d,J=15.6Hz,1H),4.41(d,J=15.6Hz,1H),4.09(t,J=10.8Hz,1H),3.85-3.77 (m,4H),3.70(t,J=10.0Hz,1H),3.58(t,J=9.6Hz,1H),2.26(t,J=9.2Hz,1H),2.1 7-2.02(m,10H),1.99(t,J=13.6Hz,1H),1.49-1.40(m,2H),0.87(t,J=7.6Hz,3H).

[0146] Example 2. Synthesis of compound 1-1-2-1

[0147] 1. S6 Synthesis

[0148] S5 (1.0 g, 5.99 mmol) was dissolved in methanol (120 mL), and then Pd / C (200 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound S6 (1.0 g, yield: 99%). ESI [M+H] + =169.4[M+H] + .

[0149] 2. Synthesis of S7

[0150] In a 250 mL single-necked flask, 1.71 g of potassium permanganate (2.34 g, 14.79 mmol) solid was added and dissolved in 105 mL of water. 6.2 mL of 0.5 M potassium hydroxide solution was slowly added. The system was cooled to 0 °C in an ice bath. The hydrogenation product S6 (1.0 g, 5.92 mmol) from the previous step was dissolved in 10 mL of water and slowly added to the potassium permanganate solution. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 28 h. After the reaction was complete as monitored by LCMS, 8.4 mL of isopropanol was added, and the mixture was stirred for 30 minutes. The reaction solution was filtered, and the filter cake was washed with 20 mL of water and 20 mL of isopropanol to obtain a colorless, transparent solution. The pH was adjusted to 7 using 6 N hydrochloric acid, and the solution was concentrated under reduced pressure to obtain a pale yellow solid. This solid was thoroughly slurried with 30 mL of dichloromethane:methanol (2:1, v / v) and concentrated under reduced pressure to obtain S7 (750 mg, yield: 69%). ESI[M+H] + =184.4[M+H] + .

[0151] 3. S8 Synthesis

[0152] The crude product S7 (420 mg, 2.30 mmol) was dissolved in methanol (20 mL), and an equivalent amount of concentrated hydrochloric acid was added. The mixture was stirred at 70 °C for three days. Two-thirds of the solvent was removed by rotary evaporation. The residue was cooled to 0 °C and the pH was adjusted to 7 with saturated sodium bicarbonate. ～ 8. Extract three times with dichloromethane, combine the organic phases, dry to anhydrous magnesium sulfate, filter, evaporate to dryness, and purify the residue by column chromatography (dichloromethane / methanol = 20 / 1) to give compound S8 (220 mg, yield: 49%). ESI [M+H] + =197.4[M+H] + .

[0153] 4. Synthesis of 1-1-2-1

[0154] S8 (220 mg, 1.12 mmol) was dissolved in acetonitrile (15 mL), and A-2 (271 mg, 1.12 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-1-2-1 (316.59 mg, yield: 65%). ESI [M] + =359.2 [M] + .

[0155] 1H NMR(400MHz,DMSO-d6)δ:10.06(s,1H),7.15-7.08(m,3H),4.95-4.93(m,1H),4.51-4.03(m,2H),4.08-4.01(m,2H),3.81(s,3H),3. 73-7.60(m,2H),2.49-2.43(m,1H),2.18(s,6H),2.13(d,J=6.0Hz,2H),2.08-1.99(m,3H),1.52-1.44(m,2H),0.86(t,J=7.2Hz,3H).

[0156] Example 3. Synthesis of compound 1-1-2-2

[0157] 1. Preparation of compound S10

[0158] S9 (2.00 g, 12.11 mmol) was added to a 100 mL single-necked flask, dissolved in tetrahydrofuran (60 mL), and then pyridine (1.92 g, 24.21 mmol) was added. The system was cooled to 0 °C, and then bromoacetyl bromide (2.69 g, 13.32 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for one hour. After the reaction was monitored by LCMS until complete, the solvent was removed under reduced pressure to obtain the crude product. The solid was filtered off, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 10 / 1) to obtain a white solid S10 (2.20 g, yield: 64%). ESI [M+H] + =286.0[M+H] + .

[0159] 2. Synthesis of S8

[0160] The synthesis of S8 is described in Example 2.

[0161] 3. Synthesis of 1-1-2-2

[0162] S8 (210 mg, 1.07 mmol) was dissolved in acetonitrile (10 mL), and then S10 (305 mg, 1.07 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-1-2-2 (274.76 mg, yield: 53%). ESI [M] + =403.3 [M] + .

[0163] 1H NMR(400MHz, DMSO-d6)δ:10.35(s,1H),7.64(dd,J=8.0,1.2Hz,1H),7.52(t,J=6.8Hz,1H),7.33 (t,J=8.0Hz,1H),4.90(q,J=7.2Hz,1H),4.50(d,J=15.2Hz,1H),4.34(d,J=15.6Hz,1H),4.10-4. 08(m,1H),4.04-3.99(m,1H),3.82(s,3H)3.79(s,3H),3.72-3.69(m,1H),3.60-3.59(m,1H),2.4 9(s,1H),2.24(s,3H),2.08(s,2H),2.03-1.98(m,3H),1.51-1.46(m,2H),0.88(t,J=7.6Hz,3H).

[0164] Example 4. Synthesis of compound 1-1-3-2

[0165] 1. Synthesis of S10

[0166] The synthesis of S10 is described in Example 3.

[0167] 2. Synthesis of compound 1-2-3-2

[0168] S10 (400 mg, 1.40 mmol) was added to a 50 mL single-necked flask, dissolved in 10 mL of MeCN, followed by S1 (233 mg, 1.40 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. Ethyl acetate (20 mL) was added to the reaction mixture, stirred for 10 minutes, filtered, and the solid was washed with n-hexane (3 × 20 mL) and dried to give a white solid 1-2-3-2 (500 mg, 79% yield). ESI[M] + =373.5 [M] + .

[0169] 3. Synthesis of compound 1-1-3-2

[0170] Add 1-2-1-2 (500 mg, 1.10 mmol) to a reaction flask, then transfer it to a 50 mL single-necked flask. Dissolve the dissolved product in MeOH (20 mL), then add Pd / C (100 mg). Stir the system at room temperature for 2 h under H2 atmosphere. After the reaction is complete, filter to remove Pd / C, and distill under reduced pressure to obtain the crude product. Slurry the crude product with ethyl acetate, filter, collect the filter cake, and dry to obtain compound 1-1-3-2 (208.42 mg, yield 46%). ESI[M] + =375.8 [M] + .

[0171] 1 H NMR (400MHz, DMSO-d6), δ: 10.23 (s, 1H), 7.62 (d, J = 7.6Hz, 1H), 7.52 (d, J = 7.2Hz, 1H),7.32(t,J=7.6Hz,1H),5.67(t,J=4.4Hz,1H),4.26(q,J=5.6Hz,2H),4.07(t, J=10Hz,1H),3.92(t,J=10Hz,2H),3.79(s,3H),3.74(d,J=10Hz,2H),3.63~3.50( m,2H),2.25(s,3H),2.04~1.83(m,6H),1.44~1.36(m,2H),0.86(t,J=7.2Hz,3H).

[0172] Example 5. Synthesis of compound 1-1-4-2

[0173] 1. Synthesis of S10

[0174] The synthesis of S10 is described in Example 3.

[0175] 2. Preparation of compound 1-2-4-2

[0176] S5 (257 mg, 1.54 mmol) was dissolved in MeCN (20 mL), and S10 (440 mg, 1.54 mmol) was added at room temperature. The mixture was heated to 45 °C and stirred overnight. After the reaction was completed as monitored by LCMS, the solvent was removed from the reaction solution under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–10%) to give a white solid compound 1-2-4-2 (700 mg, 100% yield). ESI [M] + =373.3 [M] + .

[0177] 3. Preparation of compound 1-1-4-2

[0178] 1-2-2-2 (700 mg, 1.54 mmol) was dissolved in MeOH (20 mL), and Pd / C (10% wt, 70 mg) was added at room temperature. The reaction mixture was purged with hydrogen three times and stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH / CH2Cl2 (v / v) = 0–5%) to give a white solid compound 1-1-4-2 (500 mg, yield 71%). ESI [M] + =375.3 [M] + .

[0179] 1 H NMR(400MHz, DMSO-d6)δ:10.19(s,1H),7.62(d,J=8.0Hz,1H),7.52(d,J=6.8Hz,1H),7 .32(t,J=7.6Hz,1H),5.66(t,J=4.8Hz,1H),4.39(d,J=16.0Hz,1H),4.26(d,J=16.0Hz, 1H),4.15-4.01(m,1H),3.92-3.70(m,7H),3.69-3.51(m,2H),2.25(s,3H),2.19-2.05( m,1H),2.04-1.75(m,4H),1.65-1.53(m,1H),1.53-1.37(m,2H),0.87(t,J=7.6Hz,3H).

[0180] Example 6. Synthesis of compound 1-1-3-3

[0181] 1. Synthesis of compound S12

[0182] S11 (589 mg, 2.82 mmol) was added to a 100 mL single-necked flask, dissolved in 30 mL of THF, and then pyridine (668 mg, 8.46 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (560 mg, 2.82 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for three hours. After the reaction was complete, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 10 / 1) to give a white solid S12 (400 mg, yield: 43%). (ESI [M+H]) + =330.1[M+H]+

[0183] 2. Synthesis of compound 1-2-3-3

[0184] S12 (330 mg, 1.0 mmol) was added to a 50 mL single-necked flask, dissolved in 10 mL of MeCN, and then S1 (167 mg, 1.0 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and ethyl acetate (20 mL) was added to the reaction system. The mixture was stirred for 10 minutes, filtered, and the solid was washed with n-hexane (3 × 20 mL) and dried to give a white solid 1-2-3-3 (340 mg, 68% yield). ESI[M] + =417.3 [M] + .

[0185] 3. Synthesis of compound 1-1-3-3

[0186] Add 1-2-3-3 (340 mg, 0.68 mmol) to a reaction flask, then transfer it to a 50 mL single-necked flask, dissolve it in MeOH (20 mL), and then add Pd / C (68 mg). Stir the system at room temperature for 2 h under H2 atmosphere. After the reaction is complete, filter to remove Pd / C, distill under reduced pressure to obtain the crude product, slurry with ethyl acetate, filter, collect the filter cake, and dry to obtain compound 1-1-1-3 (127.06 mg, yield 37%). ESI [M] + =419.2 [M] + .

[0187] 1 H NMR (400MHz, DMSO-d6), δ: 10.66 (s, 1H), 7.99 (d, J = 7.6Hz, 2H), 7.51 (t, J = 7.6Hz, 1H), 5.67 (s, 1H), 4.26 (q, J = 4.8Hz, 2H), 4.02 (t, J = 11.2Hz, 1H),3.90(d,J=10.4Hz,2H),3.83(s,6H),3.76~3.67(m,2H),3.60~3.3 3(m,2H),2.05~1.83(m,6H),1.46~1.39(m,2H),0.86(t,J=7.2Hz,3H).

[0188] Example 7. Synthesis of compound 1-1-4-3

[0189] 1. Synthesis of S12

[0190] The synthesis of S12 is described in Example 6.

[0191] 2. Synthesis of 1-2-4-3

[0192] S12 (400 mg, 121 mmol) was added to a 50 mL single-necked flask, dissolved in 10 mL of MeCN, and then S5 (204 mg, 1.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and ethyl acetate (20 mL) was added to the reaction system. The mixture was stirred for 10 minutes, filtered, and the solid was washed with n-hexane (3 × 20 mL) and dried to give a white solid 1-2-4-3 (400 mg, 66% yield). ESI[M] + =417.3 [M] + .

[0193] 3. Synthesis of 1-1-4-3

[0194] Add 1-2-2-3 (400 mg, 0.8 mmol) to a reaction flask, then transfer it to a 50 mL single-necked flask, dissolve it in MeOH (20 mL), and then add Pd / C (80 mg). Stir the system at room temperature for 2 h under H2 atmosphere. After the reaction is complete, filter to remove Pd / C, distill under reduced pressure to obtain the crude product, slurry with ethyl acetate, filter, collect the filter cake, and dry to obtain compound 1-1-4-3 (221.64 mg, yield 55%). ESI [M] + =419.2 [M] + .

[0195] 1 H NMR (400MHz, DMSO-d6), δ: 10.65 (s, 1H), 8.00 (t, J = 3.6Hz, 2H), 7.51 (t, J = 8.0Hz, 1H), 5.67 (t ,J=4.8Hz,1H),4.42(d,J=16.0Hz,1H),4.24(d,J=15.6Hz,1H),4.06~4.01(m,1H),3.86(s,1H) ,3.83(s,6H),3.82~3.79(m,3H),3.64~3.61(m,1H),3.55~3.51(m,1H),3.12(t,J=10.8Hz,1H) ,2.00(s,2H),1.97~1.85(m,2H),1.65~1.60(m,1H),1.50~1.42(m,2H),0.88(t,J=7.2Hz,3H).

[0196] Example 8. Synthesis of compound 1-1-5-1

[0197] 1. Synthesis of S3

[0198] The synthesis of S3 is described in Example 1.

[0199] 2. Synthesis of S14

[0200] In a 5 mL single-necked flask, S3 (50 mg, 0.27 mmol) solid was added and dissolved in 1 mL of anhydrous dichloromethane. 77 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.5 equiv.), triethylamine (37 mL, 1.0 equiv.), and 55 mg of 1-hydroxybenzotriazole (HOBT, 1.5 equiv.) were added under ice bath conditions. After stirring for 20 min, S13 (33 mg, 1.0 equiv.) was added to the reaction mixture. The mixture was heated to room temperature, and the reaction progress was monitored by TLC. After 12 h, the mixture was evaporated to dryness and separated by column chromatography to obtain S14 (39 mg, yield 73%).

[0201] 3. Synthesis of S15

[0202] S14 (39 mg) was dissolved in 2 mL of methanol, and 6 mg of Pd / C (5%, w / w, 0.01 equiv.) was added. After purging the gas three times with a triple-layer hydrogen balloon, the reaction was carried out at room temperature. The reaction progress was monitored by TLC. After 48 h, Pd / C was removed by filtration, and the filter cake was thoroughly washed with methanol. The filtrate was collected, evaporated to dryness, and separated by column chromatography to obtain the target product S15 (23 mg, yield 85%).

[0203] 4. Synthesis of 1-1-5-1

[0204] Add A-2 (150 mg, 0.62 mmol) to a 50 mL single-necked flask, dissolve in MeCN (10 mL), then add S15 (122 mg, 0.62 mmol), and stir overnight at room temperature. After the reaction is complete, remove the solvent under reduced pressure, add ethyl acetate (20 mL) to the reaction system, stir for 10 minutes, filter, wash the solid with n-hexane (3 × 20 mL), and dry to give a white solid 1-1-5-1 (184.41 mg, yield 67%), ESI[M]. + =358.3 [M] + .

[0205] 1 H NMR(400MHz, DMSO-d6)δ:9.95(d,J=6.4Hz,1H),8.51(t,J=4.4Hz,1H),7.13~7.06(m ,3H),4.67(t,J=9.6Hz,1H),4.55(d,J=16Hz,1H),4.48(d,J=16.4Hz,1H),4.26(t,J =10.8Hz,1H),4.07(t,J=10.4Hz,1H),3.75~3.61(m,2H),2.63(d,J=4.4Hz,3H),2.1 4(s,1H),2.11(s,6H),2.06~1.91(m,5H),1.48~1.39(m,2H),0.87(t,J=7.2Hz,3H).

[0206] Example 9. Synthesis of compound 1-1-3-4

[0207] 1. Synthesis of S17

[0208] S16 (1.87 g, 8.94 mmol) was added to a 250 mL single-necked flask, dissolved in THF (50 mL), followed by pyridine (1.41 g, 17.88 mmol). The system was cooled to 0 °C, and bromoacetyl bromide (1.81 g, 8.94 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with dichloromethane (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to give a pale yellow solid S17 (1.5 g, yield: 52%). ESI [M+H] + =329.9[M+H] + .

[0209] 2. Synthesis of 1-2-3-4

[0210] S17 (385 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and then S1 (195 mg, 1.17 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give a white solid compound 1-2-3-4 (320 mg, yield: 66%). ESI [M] + =417.2 [M] + .

[0211] 3. Synthesis of 1-1-3-4

[0212] Compound 1-2-3-4 (284 mg, 0.682 mmol) was dissolved in methanol (20 mL), and then Pd / C (55 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to obtain compound 1-1-3-4 (200.40 mg, yield: 70%). ESI [M] + =419.2 [M] + .

[0213] 1H NMR(400MHz, DMSO-d6)δ:10.84(s,1H),,8.43(s,1H),7.99(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,1H),5.61(t,J=5.2Hz,1H),4.34(s,2H),4.11(t,J=10 .8Hz,1H),4.00(s1H),3.90(s,3H),3.88(s,3H),3.80-3.68(m,3H),3.58- 3.50(m,3H),2.04-1.86(m,6H),1.46-1.40(m,2H),0.86(t,J=7.2Hz,3H).

[0214] Example 10. Synthesis of compound 1-1-4-4

[0215] 1. Synthesis of S17

[0216] The synthesis of S17 is described in Example 9.

[0217] 2. Synthesis of 1-2-4-4

[0218] S17 (385 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and then S5 (195 mg, 1.17 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give a white solid compound 1-2-4-4 (370 mg, yield: 76%). ESI [M] + =417.3 [M] + .

[0219] 3. Synthesis of 1-1-4-4

[0220] 1-2-4-4 (284 mg, 0.682 mmol) was dissolved in methanol (20 mL), and then Pd / C (55 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate, filtered, and the filter cake was collected and lyophilized with water to give a white solid compound 1-1-4-4 (200.4 mg, yield: 70%). ESI [M] + =419.2 [M] + .

[0221] 1H NMR (400MHz, DMSO-d6) δ: 10.83 (s, 1H),, 8.47 (d, J = 1.2Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.8 5(dd,J=8.0,1.6Hz,1H),5.64(t,J=5.6Hz,1H),4.48-4.42(m,2H),4.11(t,J=10.8Hz,1H) ,4.00(s1H),3.90(s,3H),3.88(s,3H),3.80-3.72(m,3H),3.70-3.59(m,2H),3.55-3.52( m,1H),2.33(t,J=1.6Hz,1H),2.00-1.89(m,4H),1.55-1.44(m,3H),0.88(t,J=7.6Hz,3H).

[0222] Example 11. Synthesis of compound 1-1-3-5

[0223] 1. Synthesis of S19

[0224] S18 (1.6 g, 8.94 mmol) was added to a 250 mL single-necked flask, dissolved in THF (50 mL), followed by pyridine (1.41 g, 17.88 mmol). The system was cooled to 0 °C, and bromoacetyl bromide (1.81 g, 8.94 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with dichloromethane (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to give a white solid S19 (1.5 g, yield: 56%). ESI [M+H] + =300.4[M+H] + .

[0225] 2. Synthesis of 1-2-3-5

[0226] S19 (350 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and then S1 (195 mg, 1.17 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-2-3-5 (320 mg, yield: 58%). ESI [M] + =387.4 [M] + .

[0227] 3. Synthesis of 1-1-3-5

[0228] 1-2-3-5 (320 mg, 0.682 mmol) was dissolved in methanol (20 mL), and then Pd / C (64 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to obtain compound 1-1-3-5 (228.14 mg, yield: 71%). ESI [M] + =389.4 [M] + .

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),7.71(s,2H),5.67(t,J=5.2Hz,1H),4.43(t,J=17.6Hz,2H),4.14(t,J=11.2Hz,1H),3.99( d,J=8.4Hz,1H),3.89-3.73(m,6H),3.65-3.51(m,2H),2.24(s,6H),2.01-1.87(m,6H),1.46-1.38(m,2H),0.86(t,J=7.2Hz,3H).

[0230] Example 12. Synthesis of compound 1-1-4-5

[0231] 1. Synthesis of S19

[0232] The synthesis of S19 is described in Example 11.

[0233] 2. Preparation of 1-2-4-5

[0234] S19 (350 mg, 1.17 mmol) was dissolved in acetonitrile (10 mL), and then S5 (195 mg, 1.17 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-2-4-5 (370 mg, yield: 68%). ESI [M] + =387.4 [M] + .

[0235] 3. Synthesis of 1-1-4-5

[0236] 1-2-4-5 (370 mg, 0.789 mmol) was dissolved in methanol (20 mL), and then Pd / C (64 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to obtain compound 1-1-4-5 (313.69 mg, yield: 84%). ESI [M] + =389.4 [M] + .

[0237] 1 H NMR (400MHz, DMSO-d6) δ: 10.19 (s, 1H), 7.71 (s, 2H), 5.67 (t, J = 5.2Hz, 1H), 4.45(dd,J=16.0,26.8Hz,2H),4.12(t,J=6.0Hz,1H),3.91-3.81(m,6H),3.7 9-3.70(m,2H),3.59-3.56(m,1H),2.23(s,6H),2.14(t,J=10.8Hz,1H),2.0 0-1.89(m,4H),1.56-1.51(m,1H),1.49-1.42(m,2H),0.86(t,J=7.2Hz,3H).

[0238] Example 13. Synthesis of compound 1-1-3-6

[0239] 1. Synthesis of S21

[0240] S20 (589 mg, 2.82 mmol) was added to a 100 mL single-necked flask, dissolved in 30 mL of THF, followed by the addition of pyridine (668 mg, 8.46 mmol). The system was cooled to 0 °C, and bromoacetyl bromide (560 mg, 2.82 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for three hours. After the reaction was complete, the solid was removed by filtration, and the solvent was removed by vacuum distillation to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 to 10 / 1) to give a white solid, S21 (400 mg, yield: 43%). (ESI [M+H]) + =330.1[M+H] +

[0241] 2. Synthesis of 1-2-3-6

[0242] S21 (330 mg, 1.0 mmol) was added to a 50 mL single-necked flask, dissolved in MeCN (10 mL), and then S1 (167 mg, 1.0 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. Ethyl acetate (20 mL) was added to the reaction system, and the mixture was stirred for 10 minutes. The mixture was filtered, and the solid was washed with n-hexane (3 × 20 mL) and dried to give a white solid 1-2-3-6 (340 mg, 68% yield). ESI[M] + =417.3 [M] + .

[0243] 3. Synthesis of 1-1-3-6

[0244] 1-2-3-6 (340 mg, 0.68 mmol) was added to a reaction flask, then transferred to a 50 mL single-necked flask and dissolved in MeOH (20 mL). Pd / C (68 mg) was then added, and the system was stirred at room temperature for 2 h under H2 atmosphere. After the reaction was complete, Pd / C was removed by filtration, and the crude product was obtained by vacuum distillation. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and dried to obtain compound 1-1-3-6 (177.15 mg, yield 52%). ESI[M]+ = 419.2[M]+.

[0245] 1 H NMR (400MHz, DMSO-d6), δ11.01(s,1H),8.47(s,2H),8.22(s,1H),5.62(t,J=4.4Hz,1H),4.32(s,2H),4.16(d,J=6Hz,1H),4.14(s ,1H),3.90(s,6H),3.79~3.69(m,3H),3.61~3.51(m,2H),2.04~1.82(m,6H),1.42(dd,J=6.8,12.0Hz,2H),0.87(t,J=7.2Hz,3H).

[0246] Example 14. Synthesis of compound 1-1-4-6

[0247] 1. Synthesis of S21

[0248] The synthesis of S21 is described in Example 13.

[0249] 2. Synthesis of 1-2-4-6

[0250] S21 (400 mg, 1.21 mmol) was added to a 50 mL single-necked flask, dissolved in MeCN (10 mL), followed by S5 (202 mg, 1.21 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure. Ethyl acetate (20 mL) was added to the reaction mixture, which was stirred for 10 minutes. The mixture was then filtered, and the solid was washed with n-hexane (3 × 20 mL) and dried to give a white solid 1-2-4-6 (400 mg, 79% yield). ESI[M] + =417.3 [M] + .

[0251] 3. Synthesis of 1-1-4-6

[0252] 1-2-4-6 (400 mg, 0.96 mmol) was added to a reaction flask, then transferred to a 50 mL single-necked flask and dissolved in methanol (20 mL). Pd / C (80 mg) was then added, and the system was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, Pd / C was removed by filtration, and the crude product was obtained by vacuum distillation. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and dried to give compound 1-1-4-6 (177.15 mg, yield 52%). ESI[M] + =419.2 [M] + .

[0253] 1 H NMR (400MHz, DMSO-d6), δ10.94(s,1H),8.46(d,J=4.4Hz,2H),8.22(t,J=1.6Hz,1H),5.64(t,J=5.2Hz,1H),4.32(s,2H),4.16(d,J=6.0Hz,1H ), 3.90 (s, 6H), 3.87 ~ 3.59 (m, 6H), 2.16 (t, J = 12.8Hz, 1H), 2.00 ~ 1.96 (m, 2H), 1.89 (d, J = 6.4Hz, 2H), 1.52 ~ 1.46 (m, 3H), 0.88 (t, J = 7.2Hz, 3H).

[0254] Example 15. Synthesis of compound 1-1-5-4

[0255] 1. Synthesis of S15

[0256] The synthesis of S15 is described in Example 8.

[0257] 2. Synthesis of S17

[0258] The synthesis of S17 is described in Example 9.

[0259] 3. Synthesis of 1-1-5-4

[0260] S15 (130 mg, 0.663 mmol) was dissolved in acetonitrile (5 mL), and then S17 (219 mg, 0.663 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-5-4 (156.04 mg, yield: 44.7%). ESI [M] + = 446.4 [M] + .

[0261] 1 H NMR (400MHz, DMSO-d6) δ: 10.85 (s, 1H), 8.48 (q, J = 4.4Hz, 1H), 8.32 (dd, J = 1.6, 6.8Hz, 1H) ,7.98(d,J=8.0Hz,1H),7.86(dd,J=1.6,8.4Hz,1H),4.56(t,J=9.2Hz,1H),4.47(d,J=15.6 Hz,1H),4.35(d,J=15.6Hz,1H),4.08(q,J=10.8Hz,2H),3.90(s,3H),3.87(s,3H),3.81-3. 66(m,2H),2.65-2.59(m,3H),2.14-1.90(m,6H),1.50-1.40(m,2H),0.88(t,J=7.2Hz,3H).

[0262] Example 16. Synthesis of compound 1-1-5-5

[0263] 1. Synthesis of S19

[0264] The synthesis of S19 is described in Example 11.

[0265] 2. Preparation of S15

[0266] The synthesis of S15 is described in Example 8.

[0267] 3. Preparation of 1-1-5-5

[0268] S15 (140 mg, 0.714 mmol) was dissolved in acetonitrile (5 mL), and then S19 (214 mg, 0.714 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a pale yellow solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-5-5 (210.7 mg, yield: 59.5%). ESI [M] + =416.4 [M] + .

[0269] 1 H NMR (400MHz, DMSO-d6) δ: 10.18 (s, 1H), 8.48 (q, J = 4.4Hz, 1H), 7.70 (s, 2H), 4.66 (t,J=9.6Hz,1H),4.58(d,J=16.4Hz,1H),4.48(d,J=16.4Hz,1H),4.24(t,J=10. 8Hz,1H),4.07(t,J=9.6Hz,1H),3.84(s,3H),3.75-3.63(m,2H),2.65(t,J=6.4H z,3H),2.19(m,6H),2.14-1.91(m,6H),1.48-1.40(m,2H),0.88(t,J=7.2Hz,3H).

[0270] Example 17. Synthesis of compound 1-2-3-1

[0271] 1. Synthesis of S22

[0272] In a 250 mL single-necked flask, potassium permanganate (2.34 g, 14.79 mmol) solid was added and dissolved in 105 mL of water. 20 mL of 2N sulfuric acid solution was slowly added, and the system was cooled to 0°C in an ice bath. S1 (1.0 g, 5.92 mmol) was dissolved in 10 mL of water and slowly added to the potassium permanganate solution. After the addition was complete, the mixture was brought to room temperature and reacted for 28 hours. After the reaction was complete as monitored by LCMS, isopropanol (8.4 mL) was added, and the mixture was stirred for 30 minutes. The reaction solution was filtered, and the filter cake was washed with 20 mL of water and 20 mL of isopropanol to obtain a colorless and transparent solution. The pH was adjusted to 7 using 6N hydrochloric acid, and the solution was concentrated under reduced pressure to obtain a pale yellow solid. This solid was thoroughly slurried with 30 mL of dichloromethane:methanol (2:1, v / v) and concentrated under reduced pressure to obtain S22 (700 mg, yield: 63%). ESI[M+H] + =186.4[M+H] + .

[0273] 2. Synthesis of S23

[0274] S22 (420 mg, 2.27 mmol) was dissolved in methanol (20 mL), and an equivalent amount of concentrated hydrochloric acid was added. The mixture was stirred at 70 °C for three days. Two-thirds of the solvent was removed by rotary evaporation. The residue was cooled to 0 °C and the pH was adjusted to 7 with saturated sodium bicarbonate. ～ 8. Extract with diethyl ether, combine the organic phases, dry to anhydrous magnesium sulfate, filter, evaporate to dryness, and purify the residue by column chromatography to give compound S23 (260 mg, yield: 58%). ESI [M+H] + =200.4[M+H] + .

[0275] 3. Preparation of A-2

[0276] The synthesis of A-2 is described in Example 1.

[0277] 4. Preparation of 1-2-3-1

[0278] S12 (240 mg, 1.21 mmol) was dissolved in acetonitrile (10 mL), and A-2 (293 mg, 1.21 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-2-3-1 (234.28 mg, yield: 44%). ESI [M] + =361.3 [M] + .

[0279] 1 H NMR(400MHz, DMSO-d6)δ:9.97(s,1H),7.14-7.08(m,3H),5.66(t,J=4.8Hz,1H),4.45(s,2H),4.25-4.13(m,2H),4.02(d,J=6.8Hz,1H),3.9 2-3.77(m,3H),3.70(s,3H),3.69-3.61(m,1H),3.24(t,J=9.2Hz,1H),2.46(s,1H),2.17(s,6H),2.06-1.96(m,3H),1.69(t,J=9.2Hz,1H).

[0280] Example 18. Synthesis of compound 1-1-6-1

[0281] 1. Preparation of S7

[0282] The synthesis of S7 is described in Example 2.

[0283] 2. Preparation of S24

[0284] Dissolve S7 (700 mg, 3.83 mmol) in dichloromethane (20 mL), cool the system to 0 °C in an ice bath, add DMF (28 mg, 0.38 mmol), and then slowly add oxaloyl chloride (973 mg, 7.66 mmol). After the addition is complete, stir the reaction at 0 °C for one hour; concentrate at 10 °C to remove the solvent, and use the residue for later use. Methylamine (2.0N in THF, 19.1mL, 38.3mmol) and triethylamine (1.16g, 11.49mmol) were dissolved in dichloromethane (20mL). The system was cooled to 0°C in an ice bath. The remaining product was then dissolved in dichloromethane (5mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (20mL) of water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound S24 (370mg, yield: 49.3%). ESI [M+H] + =197.4[M+H] + .

[0285] 3. Preparation of A-2

[0286] The synthesis of A-2 is described in Example 1.

[0287] 4. Synthesis of 1-1-6-1

[0288] S24 (243 mg, 1.24 mmol) was dissolved in acetonitrile (5 mL), and A-2 (300 mg, 1.24 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain an off-white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-1 (384.16 mg, yield: 70.7%). ESI [M] + =358.3 [M] + .

[0289] 1H NMR (400MHz, DMSO-d6) δ: 9.96 (s, 1H), 8.52 (d, J = 4.4Hz, 1H), 7.13-7.05 (m, 3 H),4.70(t,J=9.6Hz,1H),4.59-4.40(m,3H),3.88-3.80(m,2H),3.56(t,J=2. 8Hz,1H),2.65(d,J=4.8Hz,3H),2.34(t,J=2.4Hz,1H),2.20-2.02(m,9H),1. 96-1.91(m,1H),1.81-1.74(m,1H),1.52-1.46(m,2H),0.88(t,J=7.2Hz,3H).

[0290] Example 19. Synthesis of compound 1-1-1-2

[0291] 1. Preparation of S4

[0292] The synthesis of S4 is described in Example 1.

[0293] 2. Preparation of S10

[0294] The synthesis of S10 is described in Example 3.

[0295] 3. Preparation of 1-1-1-2

[0296] S4 (210 mg, 1.07 mmol) was dissolved in acetonitrile (15 mL), and then S10 (305 mg, 1.07 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-1-1-2 (237.10 mg, yield: 46%). ESI [M] + = 403.4 [M] + .

[0297] 1H NMR(400MHz, DMSO-d6)δ:10.34(d,J=8.8Hz,1H),7.63(dd,J=1.2,7.6Hz,1H),7.53(t,J=0.8Hz,1H),7. 33(t,J=7.6Hz,1H),4.90(t,J=9.6Hz,1H),4.62(d,J=15.6Hz,1H),4.33(d,J=15.6Hz,1H),4.06(t,J=11 .6Hz,1H),3.87-3.81(m,1H),3.79(s,3H),3.78(s,3H),3.76-3.71(m,1H),3.62-3.57(m,1H),2.29-2. 24(m,1H),2.22(s,3H),2.16-2.05(m,4H),2.02-1.94(m,1H),1.48-1.39(m,2H),0.88(t,J=7.2Hz,3H).

[0298] Example 20. Synthesis of compound 1-1-6-5

[0299] 1. Preparation of S24

[0300] The synthesis of S24 is described in Example 18.

[0301] 2. Preparation of S19

[0302] The synthesis of S19 is described in Example 11.

[0303] 3. Preparation of 1-1-1-2

[0304] S24 (282 mg, 1.44 mmol) was dissolved in acetonitrile (5 mL), and then S19 (430 mg, 1.44 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give an off-white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-5 (315.74 mg, yield: 44.3%). ESI [M] + = 446.4 [M] + .

[0305] 1H NMR (400MHz, DMSO-d6) δ: 10.20 (s, 1H), 8.52 (d, J = 4.4Hz, 1H), 7.70 (s, 2H), 4.70 (t, J=9.6Hz,1H),4.59-4.45(m,3H),3.85(t,J=7.6Hz,5H),3.56(t,J=2.8Hz,1H),2.65( d,J=4.8Hz,3H),2.34(t,J=2.4Hz,1H),2.19(s,6H),2.13(s,1H),2.07-2.03(m,2H) ,1.93(d,J=7.6Hz,1H),1.81-1.76(m,1H),1.52-1.49(m,2H),0.88(t,J=7.2Hz,3H).

[0306] Example 21. Synthesis of compound 1-1-5-2

[0307] 1. Preparation of S15

[0308] The synthesis of S15 is described in Example 8.

[0309] 2. Preparation of S10

[0310] The synthesis of S10 is described in Example 3.

[0311] 3. Preparation of 1-1-5-2

[0312] S15 (210 mg, 1.07 mmol) was dissolved in acetonitrile (5 mL), and then S15 (305 mg, 1.07 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1 to 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-5-2 (195.70 mg, yield: 38%). ESI [M] + =402.3 [M] + .

[0313] 1H NMR(400MHz, DMSO-d6)δ:10.22(s,1H),8.45(t,J=4.0Hz,1H),7.63(d,J=7.6Hz,1H ),7.52(d,J=6.8Hz,1H),7.33(t,J=8.0Hz,1H),4.61(t,J=9.2Hz,1H),4.51(d,J=16 .0Hz,1H),4.27(d,J=16.0Hz,1H),4.12-4.05(m,2H),3.82-3.71(m,5H),2.65(t,J =7.2Hz,3H),2.20(s,3H),2.12-1.91(m,6H),1.49-1.42(m,2H),0.90-0.86(m,3H).

[0314] Example 22. Synthesis of compound 1-1-6-2

[0315] 1. Preparation of S24

[0316] The synthesis of S24 is described in Example 18.

[0317] 2. Preparation of S10

[0318] The synthesis of S10 is described in Example 3.

[0319] 3. Preparation of 1-1-6-2

[0320] S24 (275 mg, 1.40 mmol) was dissolved in acetonitrile (20 mL), and then S10 (400 mg, 1.40 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give an off-white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-2 (365.82 mg, yield: 54.14%). ESI [M] + =402.4 [M] + .

[0321] 1H NMR (400MHz, DMSO-d6) δ: 10.26 (s, 1H), 8.49 (d, J = 4.8Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.50 (d, J = 7.2Hz ,1H),7.33(t,J=8.0Hz,1H),4.67(t,J=9.2Hz,1H),4.54-4.46(m,2H),4.28(d,J=16.0Hz,1H),3.95(q, J=10.8Hz,1H),3.79(s,3H),3.71-3.66(m,2H),2.65(d,J=4.4Hz,3H),2.34(t,J=5.6Hz,1H),2.22(s,3 H),2.12-2.03(m,3H),1.92-1.90(m,1H),2.34(t,J=8.8Hz,1H),1.51-1.46(m,2H),0.91-0.87(m,3H).

[0322] Example 23. Synthesis of compound 1-1-5-3

[0323] 1. Preparation of S15

[0324] The synthesis of S15 is described in Example 8.

[0325] 2. Preparation of S12

[0326] The synthesis of S12 is described in Example 6.

[0327] 3. Preparation of 1-1-5-3

[0328] S15 (220 mg, 1.1 mmol) was dissolved in acetonitrile (20 mL), and then S12 (368 mg, 1.12 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1 to 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-5-3 (262.74 mg, yield: 44.58%). ESI [M] + =446.2 [M] + .

[0329] 1H NMR (400MHz, DMSO-d6) δ: 10.64 (s, 1H), 8.39 (d, J = 4.4Hz, 1H), 8.00 (d, J = 7.6Hz, 2H) ,7.52(t,J=8.0Hz,1H),4.59(t,J=9.2Hz,1H),4.51(d,J=16.0Hz,1H),4.25(d,J=16. 0Hz,1H),4.07(t,J=9.6Hz,1H),3.97(t,J=11.2Hz,1H),3.84(m,6H),3.80-3.74(m, 2H),2.67-2.63(m,3H),2.12-1.92(m,6H),1.47-1.42(m,2H),0.88(t,J=7.6Hz,3H).

[0330] Example 24. Synthesis of compound 1-1-6-3

[0331] 1. Preparation of S24

[0332] The synthesis of S24 is described in Example 18.

[0333] 2. Preparation of S12

[0334] The synthesis of S12 is described in Example 6.

[0335] 3. Preparation of 1-1-6-3

[0336] S24 (178 mg, 0.91 mmol) was dissolved in acetonitrile (5 mL), and then S12 (300 mg, 0.91 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give an off-white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-3 (374.54 mg, yield: 78.2%). ESI [M] + =446.2 [M] + .

[0337] 1H NMR (400MHz, DMSO-d6) δ: 10.65 (s, 1H), 8.43 (d, J = 4.4Hz, 1H), 8.00 (d, J = 7.6Hz, 2H), 7.52(t,J=8.0Hz,1H),4.66(t,J=9.4Hz,1H),4.54-4.40(m,2H),4.26-4.20(m,1H),3. 98-3.92(m,1H),3.84(s,6H),3.66-3.51(m,2H),2.65(d,J=4.8Hz,3H),2.40-2.35(m ,1H),2.18-2.02(m,3H),1.96-1.81(m,2H),1.54-1.45(m,2H),0.89(t,J=7.2Hz,3H).

[0338] Example 25. Synthesis of compound 1-1-6-4

[0339] 1. Preparation of S24

[0340] The synthesis of S24 is described in Example 18.

[0341] 2. Preparation of S17

[0342] The synthesis of S17 is described in Example 9.

[0343] 3. Preparation of 1-1-6-4

[0344] S24 (178 mg, 0.91 mmol) was dissolved in acetonitrile (5 mL), and then S17 (300 mg, 0.91 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to give an off-white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-4 (349.99 mg, yield: 66.5%). ESI [M] + =446.2 [M] + .

[0345] 1H NMR(400MHz,DMSO-d6)δ:10.85(s,1H),8.44(br,1H),8.31(s,1H),7.98(d,J=8.4H z,1H),7.87(d,J=8.4Hz,1H),4.63-4.61(m,1H),4.49-4.45(m,2H),4.36-4.30(m, 1H),3.98-3.85(m,7H),3.66-3.62(m,2H),2.64(d,J=4.8Hz,3H),2.40-2.35(m,1H ),2.18-2.02(m,3H),1.96-1.75(m,2H),1.54-1.47(m,2H),0.90(t,J=7.2Hz,3H).

[0346] Example 26. Synthesis of compound 1-1-5-7

[0347] 1. Preparation of S26

[0348] S25 (5.0 g, 28.22 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (200 mL). Pyridine (4.46 g, 56.44 mmol) was then added, and the system was cooled to 0°C in an ice bath. Bromoacetyl bromide (5.69 g, 28.22 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was monitored by LCMS until complete, the solvent was removed under reduced pressure. The crude product was slurried with petroleum ether to give a white solid compound S26 (3.3 g, yield: 39%). ESI [M+H] + =298.2[M+H] + .

[0349] 2. Preparation of S15

[0350] The synthesis of S15 is described in Example 8.

[0351] 3. Preparation of 1-1-5-7

[0352] S26 (297 mg, 1.00 mmol) was added to the reaction flask and dissolved in acetonitrile (15 mL). S15 (196 mg, 1.00 mmol) was then added, and the reaction mixture was allowed to react overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-10:1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give C-1-1-5-7 (213.80 mg, yield 51.6%). ESI [M] + =414.4 [M] + .

[0353] 1 H NMR (400MHz, DMSO-d6) δ: 9.87 (s, 1H), 8.48-8.47 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7. 6Hz,2H),4.72-4.64(m,2H),4.46(d,J=16.4Hz,1H),4.18(t,J=11.2Hz,1H),4.06(t,J=10.0H z,1H),3.74-3.64(m,2H),2.98-2.92(m,1H),2.88-2.81(m,1H),2.66(d,J=4.8Hz,3H),2.20- 2.13(m,1H),2.06-1.91(m,5H),1.47-1.41(m,2H),1.14-1.10(m,12H),0.88(t,J=7.6Hz,3H).

[0354] Example 27. Synthesis of compound 1-1-6-7

[0355] 1. Preparation of S24

[0356] The synthesis of S24 is described in Example 18.

[0357] 2. Preparation of S26

[0358] The synthesis of S26 is described in Example 26.

[0359] 3. Preparation of 1-1-6-7

[0360] S26 (300 mg, 1.02 mmol) was added to the reaction flask and dissolved in acetonitrile (10 mL). S24 (200 mg, 1.02 mmol) was then added, and the reaction mixture was allowed to react overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-10:1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-7 (365.47 mg, yield: 72%). ESI [M] + =414.3 [M] + .

[0361] 1H NMR (400MHz, DMSO-d6) δ9.89-9.87(m,1H),8.49(d,J=4.4Hz,1H),7.29(t,J=8.0Hz,1H),7.18(d,J=8.0Hz,2 H),4.75(t,J=9.6Hz,1H),4.65(d,J=6.4Hz,1H),4.50-4.40(m,2H),3.90-3.77(m,2H),3.56(t,J=10.8Hz,1 H),2.99-2.92(m,1H),2.89-2.83(m,1H),2.67(d,J=4.4Hz,3H),2.39-2.33(m,1H),2.13(s,1H),2.10-2.04 (m,2H),1.94-1.89(m,1H),1.80-1.75(m,1H),1.54-1.44(m,2H),1.14-1.10(m,12H),0.88(t,J=7.2Hz,3H).

[0362] Example 28. Synthesis of compound 1-1-3-8

[0363] 1. Preparation of S26

[0364] S25 (1.0 g, 6.10 mmol) was added to a 100 mL single-necked flask, dissolved in tetrahydrofuran (30 mL), and then pyridine (964 mg, 12.20 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (1.23 g, 6.10 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with dichloromethane (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 20 / 1) to give a pale yellow solid S26 (1.2 g, yield: 69%). ESI [M+H] + =285.4[M+H] + .

[0365] 2. Preparation of S27

[0366] S1 (247 mg, 1.48 mmol) was dissolved in acetonitrile (20 mL), and then S26 (420 mg, 1.48 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give a white solid compound S27 (360 mg, yield: 54%). ESI [M] + =372.3 [M] + .

[0367] 3. Preparation of 1-1-3-8

[0368] S27 (320 mg, 0.708 mmol) was dissolved in methanol (20 mL), and then Pd / C (64 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was pulped with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give compound 1-1-3-8 (179.20 mg, yield: 56%). ESI [M] + =374.3 [M] + .

[0369] 1 H NMR (400MHz, DMSO-d6) δ: 10.11 (s, 1H), 8.19 (d, J = 4.4Hz, 1H), 7.36 (t, J = 6.0H z,1H),7.32-7.24(m,2H).5.64(t,J=5.2Hz,1H),4.19(dd,J=25.2,15.6Hz,2H ),4.00-3.93(m,3H),3.88-3.69(m,2H),3.62-3.51(m,2H),2.70(d,J=4.8Hz, 3H), 2.21 (s, 3H), 2.01-1.84 (m, 6H), 1.46-1.39 (m, 2H), 0.86 (t, J = 7.2Hz, 3H).

[0370] Example 29. Synthesis of compound 1-1-5-9

[0371] 1. Preparation of S29

[0372] S28 (2.0 g, 13.42 mmol) was added to a 250 mL single-necked flask, dissolved in tetrahydrofuran (80 mL), followed by pyridine (2.12 g, 26.85 mmol). The system was cooled to 0 °C, and bromoacetyl bromide (3.25 g, 16.10 mmol) was slowly added. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 20 / 1) to give a white solid S29 (2.1 g, yield: 58%). ESI [M+H] + =286.4[M+H] + .

[0373] 2. Preparation of S15

[0374] The synthesis of S15 is described in Example 8.

[0375] 3. Preparation of 1-1-5-9

[0376] S15 (250 mg, 1.28 mmol) was dissolved in acetonitrile (20 mL), and then S29 (343 mg, 1.28 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-5-9 (314.87 mg, yield: 53%). ESI [M] + =386.4 [M] + .

[0377] 1 H NMR (400MHz, DMSO-d6) δ: 9.92 (s, 1H), 8.51 (d, J = 3.2Hz, 1H), 7.22-7.16 (m, 2H), 7.09 (dd, J = 6. 4,2.0Hz,1H),4.71(t,J=9.2Hz,1H),4.61(d,J=16.4Hz,1H),4.47(d,J=16.4Hz,1H),4.22(t,J =11.2Hz,1H),3.56(dd,J=11.6,3.6Hz,1H),3.77-3.64(m,2H),2.96(s,1H),2.64(d,J=4.4Hz, 3H),2.20-1.88(m,9H),1.48-1.40(m,2H),1.11(dd,J=6.8,2.8Hz,6H),0.88(t,J=7.2Hz,3H).

[0378] Example 30. Synthesis of compound 1-1-6-9

[0379] 1. Preparation of S24

[0380] The synthesis of S24 is described in Example 18.

[0381] 2. Preparation of S29

[0382] The synthesis of S29 is described in Example 29.

[0383] 3. Preparation of 1-1-6-9

[0384] S24 (250 mg, 1.28 mmol) was dissolved in acetonitrile (20 mL), and then S29 (343 mg, 1.28 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 = 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-1-6-9 (314.41 mg, yield: 55%). ESI [M] + =386.4 [M] + .

[0385] 1 H NMR(400MHz, DMSO-d6)δ:9.93(s,1H),8.51(d,J=4.0Hz,1H),7.21-7.17(m,2H),7.08(dd,J=6.8,1.2Hz,1H ),4.73(t,J=8.8Hz,1H),4.60(d,J=16.4Hz,1H),4.44(d,J=12.0Hz,2H),3.86(d,J=9.6Hz,2H),3.56(t,J=1 0.8Hz,1H),2.95(s,1H),2.65(d,J=4.0Hz,3H),2.35(d,J=12.4Hz,1H),2.10-2.04(m,6H),1.92(q,J=8.4H z,1H),2.65(dd,J=12.8,9.2Hz,1H),1.54-1.43(m,2H),1.11(dd,J=6.8,2.0Hz,6H),0.88(t,J=7.2Hz,3H).

[0386] Example 31. Synthesis of compound 1-1-5-10

[0387] 1. Preparation of S31

[0388] Add S30 (500 mg, 3.03 mmol) and isopropanol (30 mL) to a round-bottom flask. Add concentrated sulfuric acid (1 mL) while stirring at room temperature. Stir overnight at 90 °C under a nitrogen atmosphere. After the reaction is complete, quench with saturated sodium bicarbonate aqueous solution. Extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain crude product, and purify by silica gel column chromatography to obtain compound S31 (pale yellow solid, 350 mg, yield 56%).

[0389] 2. Preparation of S32

[0390] S31 (350 mg, 1.69 mmol), pyridine (267 mg, 3.38 mmol), and tetrahydrofuran (20 mL) were added to a round-bottom flask. Bromoacetyl bromide (303 mg, 2.53 mmol) was slowly added dropwise with stirring at 0 °C. Stirring continued after the addition was complete, and the mixture was allowed to return to room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound S32 (white solid, 500 mg, 90% yield).

[0391] 3. Preparation of S15

[0392] The synthesis of S15 is described in Example 8.

[0393] 4. Preparation of 1-1-5-10

[0394] S32 (500 mg, 1.52 mmol), S15 (299 mg, 1.52 mmol), and acetonitrile (10 mL) were added to a round-bottom flask. The mixture was stirred overnight at 50 °C. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography to give compound 1-1-5-10 (white solid, 295.62 mg, yield 37%). ESI [M] + =444.3.

[0395] 1 H NMR (400MHz, DMSO-d6) δ: 10.21 (s, 1H), 8.53 (q, J = 4.8Hz, 1H), 7.67 (s, 2H), 5.20-5. 05(m,1H),4.67(t,J=9.6Hz,1H),4.62-4.45(m,2H),4.24(t,J=10.8Hz,1H),4.01-4. 11(m,1H),3.80-3.60(m,2H),2.64(d,J=4.4Hz,3H),2.18(s,6H),2.16-2.10(m,1H) ,2.09-1.89(m,5H),1.53-1.38(m,2H),1.31(d,J=6.4Hz,6H),0.88(t,J=7.2Hz,3H).

[0396] Example 32. Synthesis of compound 1-1-6-10

[0397] 1. Preparation of S32

[0398] The synthesis of S32 is described in Example 31.

[0399] 2. Preparation of S24

[0400] The synthesis of S24 is described in Example 18.

[0401] 3. Preparation of 1-1-6-10

[0402] S32 (500 mg, 1.52 mmol), S24 (299 mg, 1.52 mmol), and acetonitrile (10 mL) were added to a round-bottom flask. The mixture was stirred overnight at 50 °C. After the reaction was complete, the compound 1-1-6-10 was purified by silica gel column chromatography (white solid, 313.24 mg, yield 39%). ESI [M] + =444.4 [M] + .

[0403] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.55(q,J=4.8Hz,1H),7.67(s,2H),5.20-5.05(m,1H),4.75-4.40(m,4H),3.90-3.50(m,3H),2.6 5(d,J=4.4Hz,3H),2.30-2.25(m,1H),2.19(s,6H),2.17-1.75(m,5H),1.55-1.45(m,2H),1.31(d,J=6.0Hz,6H),0.88(t,J=7.2Hz,3H).

[0404] Example 33. Synthesis of compound 1-1-5-11

[0405] 1. Preparation of S33

[0406] S30 (2.0 g, 12.12 mmol) was added to a 250 mL single-necked flask, dissolved in 60 mL of n-propanol, and then 2 mL of concentrated sulfuric acid was added. The reaction was allowed to proceed overnight at 90 °C. After the reaction was complete as monitored by LCMS, the solvent was removed under reduced pressure. The crude product was diluted with dichloromethane and poured into water (80 mL), then extracted with dichloromethane (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 ≈ 20 / 1) to give a white solid S33 (2.1 g, yield: 84%). ESI [M+H] + =208.4[M+H] + .

[0407] 2. Preparation of S34

[0408] S33 (600 mg, 2.90 mmol) was added to a 100 mL single-necked flask, dissolved in 20 mL of THF, followed by the addition of pyridine (458 mg, 5.80 mmol). The system was cooled to 0 °C, and bromoacetyl bromide (644 mg, 3.19 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 20 / 1) to give a white solid S34 (900 mg, yield: 95%). ESI [M+H] + =328.4[M+H] + .

[0409] 3. Preparation of S15

[0410] The synthesis of S15 is described in Example 8.

[0411] 4. Preparation of 1-1-5-11

[0412] S15 (250 mg, 1.28 mmol) was dissolved in acetonitrile (20 mL), and then S34 (417 mg, 1.28 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-5-11 (388.35 mg, yield: 58%). ESI [M] + =444.4 [M] + .

[0413] 1 HNMR(400MHz,DMSO-d6)δ:10.20(s,1H),8.54-8.51(m,1H),7.70(s,2H),4.67( t,J=9.6Hz,1H),4.61-4.48(m,2H),4.27-4.20(m,3H),4.06(t,J=10.0Hz,1H), 3.76-3.64(m,2H),2.65(t,J=6.4Hz,3H),2.19(s,6H),2.15-1.91(m,6H),1.76 -1.67(m,2H),1.48-1.40(m,2H),0.96(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H).

[0414] Example 34. Synthesis of compound 1-1-6-11

[0415] 1. Preparation of S34

[0416] The synthesis of S34 is described in Example 33.

[0417] 2. Preparation of S24

[0418] The synthesis of S24 is described in Example 18.

[0419] 3. Preparation of 1-1-6-11

[0420] S34 (500 mg, 1.52 mmol), S24 (299 mg, 1.52 mmol), and acetonitrile (10 mL) were added to a round-bottom flask. The mixture was stirred overnight at 50 °C. After the reaction was complete, the compound 1-1-6-11 was purified by silica gel column chromatography (white solid, 386.23 mg, yield 48%). ESI [M] + =444.3 [M] + .

[0421] 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.55-8.48 (m, 1H), 7.70 (s, 2H), 4.72-4.40 (m, 4H), 4.22 (t, J = 6.6Hz, 2H) 3.90-3.50 (m, 3H), 2.6 6(d,J=4.4Hz,3H),2.30-2.25(m,1H),2.19(s,6H),2.17-1.50(m,7H),1.55-1.45(m,2H),0.96(t,J=7.6Hz,3H),0.88(t,J=7.2Hz,3H).

[0422] Example 35. Synthesis of compound 1-1-5-12

[0423] 1. Preparation of S35

[0424] S30 (5.0 g, 30.0 mmol), dissolved in methylaminetetrahydrofuran solution (2N, 150 mL, 300.0 mmol) and DMF (100 mL), was added to a reaction flask. Then, DIPEA (20.4 g, 150.0 mmol) and HATU (17.0 g, 45 mmol) were added. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was monitored by LCMS to ensure complete reaction, the solvent was removed by vacuum distillation. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound S35 (2.5 g, yield: 47%).

[0425] 2. Preparation of S36

[0426] S35 (2.5 g, 15.2 mmol) was added to a reaction flask and dissolved in tetrahydrofuran (100 mL). Pyridine (2.4 g, 30.4 mmol) was then added, and the system was cooled to 0°C in an ice bath. Bromoacetyl bromide (3.36 g, 16.7 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was monitored by LCMS until complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 30 / 1) to give compound S36 (1.0 g, yield: 33%).

[0427] 3. Preparation of S15

[0428] The synthesis of S15 is described in Example 8.

[0429] 4. Preparation of 1-1-5-12

[0430] S15 (250 mg, 1.3 mmol) was dissolved in acetonitrile (5 mL), and then S36 (400 mg, 1.45 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane:methanol (100:1-20:1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give a white solid compound 1-1-5-12 (317.88 mg, yield: 49%). ESI [M] + =415.3 [M] + .

[0431] 1 H NMR(400MHz, DMSO-d6)δ:10.13(s,1H),8.54(dd,J=4.4,9.2Hz,1H),8.39(dd,J=4.8 ,8.8Hz,1H),7.56(s,2H),4.71-4.66(m,1H),4.60-4.48(m,2H),4.24(t,J=11.2Hz, 1H), 4.06 (t, J = 10.0Hz, 1H), 3.78-3.66 (m, 2H), 2.75 (d, J = 4.4Hz, 3H), 2.65 (d, J = 6. 4Hz,3H),2.16(s,6H),2.12-1.91(m,6H),1.48-1.40(m,2H),0.88(t,J=6.4Hz,3H).

[0432] Example 36. Synthesis of compound 1-1-5-13

[0433] 1. Preparation of S38

[0434] S37 (2.1 g, 8.64 mmol), pinacol isopropenylborate (1.6 g, 9.51 mmol), Cs₂CO₃ (8.45 g, 25.92 mmol), and Pd(dppf)Cl₂ (316 mg, 0.432 mmol) were added to a 100 mL single-necked flask, dissolved in DOX (40 mL) and water (4 mL). The reaction was carried out overnight at 90 °C. After the reaction was monitored by LCMS until complete, the solvent was removed by vacuum distillation. The crude product was diluted with dichloromethane, poured into water (40 mL), and extracted with dichloromethane (3 × 40 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 2 / 1) to give a white solid S38 (1.1 g, yield: 62%). ESI[M+H] + =206.4[M+H] + .

[0435] 2. Preparation of S39

[0436] S38 (1.1 g, 5.37 mmol) was dissolved in methanol (60 mL), and then Pt / C (220 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound S39 (1.0 g, yield: 91%). ESI [M+H] + =208.4[M+H] + .

[0437] 3. Preparation of S40

[0438] S39 (1.0 g, 4.83 mmol) was added to a 100 mL single-necked flask, dissolved in tetrahydrofuran (30 mL), and then pyridine (764 mg, 9.66 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (1.07 g, 5.31 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 20 / 1) to give a white solid S40 (1.0 g, yield: 63%). ESI [M+H] + =328.4[M+H] + .

[0439] 4. Preparation of S15

[0440] The synthesis of S15 is described in Example 8.

[0441] 5. Preparation of 1-1-5-13

[0442] S15 (475 mg, 2.43 mmol) was dissolved in acetonitrile (20 mL), and then S40 (950 mg, 2.91 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain a white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-5-13 (358.68 mg, yield: 24%). ESI [M] + =444.4 [M] + .

[0443] 1 H NMR(400MHz,DMSO-d6)δ:10.17(s,1H),8.51(d,J=4.4Hz,1H),7.73(dd,J=13.2,1.6Hz,2H), 4.70(t,J=9.2Hz,1H),4.64(d,J=16.4Hz,1H),4.52(t,J=16.4Hz,1H),4.21(t,J=11.2Hz,1H) ,4.06(t,J=11.6Hz,1H),3.85(s,3H),3.75-3.65(m,2H),3.01(s,1H),2.64(d,J=4.4Hz,3H), 2.17(s,4H),2.06-1.92(m,5H),1.47-1.41(m,2H),1.15-1.13(m,6H),0.88(t,J=7.2Hz,3H).

[0444] Example 37. Synthesis of compound 1-1-5-14

[0445] 1. Preparation of S41

[0446] S25 (2.1 g, 11.86 mmol) was added to a 100 mL single-necked flask, followed by saturated sodium bicarbonate (30 mL), diethyl ether (30 mL), and then iodine (3.6 g, 14.23 mmol). The reaction was allowed to proceed at room temperature for 5 hours after the addition was complete. The reaction was monitored by LCMS until completion. Saturated sodium thiosulfate solution (30 mL) was added, and the mixture was stirred for half an hour. Extraction was performed with diethyl ether (3 × 40 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 the crude product. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 2 / 1) to give a white solid S41 (2.5 g, yield: 69.4%). ESI [M+H] + =304.4[M+H]+ .

[0447] 2. Preparation of S42

[0448] S41 (2.5 g, 8.25 mmol), DPPP (267 mg, 0.825 mmol), Et3N (8.45 g, 24.75 mmol), and Pd(OAc)2 (371 mg, 1.65 mmol) were added to a 100 mL single-necked flask, dissolved in DMF (20 mL) and methanol (20 mL), and the mixture was purged three times with carbon monoxide. The reaction was carried out overnight at 80 °C under carbon monoxide conditions. After the reaction was completed as monitored by LCMS, the mixture was poured into water (40 mL) and extracted with dichloromethane (3 × 40 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 2 / 1) to give a white solid S42 (1.1 g, yield: 56.7%). ESI[M+H] + =236.4[M+H] + .

[0449] 3. Preparation of S43

[0450] S42 (1.1 g, 4.66 mmol) was added to a 100 mL single-necked flask, dissolved in tetrahydrofuran (30 mL), and then pyridine (736 mg, 9.32 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (1.04 g, 5.13 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 ≈ 20 / 1) to give a white solid S43 (1.2 g, yield: 72.3%). ESI [M+H] + =357.4[M+H] + .

[0451] 4. Preparation of S15

[0452] The synthesis of S15 is described in Example 8.

[0453] 5. Preparation of 1-1-5-14

[0454] S15 (231 mg, 1.18 mmol) was dissolved in acetonitrile (10 mL), and then S43 (420 mg, 1.18 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-5-15 (320.24 mg, yield: 49%). ESI [M] + =472.4 [M] + .

[0455] 1 H NMR (400MHz, DMSO-d6) δ: 10.16 (s, 1H), 8.51 (d, J = 4.4Hz, 1H), 7.75 (s, 2H), 4.74-7.67 (m, 2H ),4.54(d,J=16.8Hz,1H),4.16(t,J=11.2Hz,1H),4.06(t,J=11.6Hz,1H),3.86(s,3H),3.75- 3.67(m,2H),3.02(t,J=5.6Hz,1H),2.90(t,J=6.0Hz,1H),2.66(d,J=4.0Hz,3H),2.19-2.13 (m,1H),2.06-1.91(m,5H),1.48-1.39(m,2H),1.13(d,J=6.4Hz,12H),0.88(t,J=7.6Hz,3H).

[0456] Example 38. Synthesis of compound 1-1-5-15

[0457] 1. Preparation of S45

[0458] S44 (1.1 g, 6.67 mmol) was added to a 100 mL single-necked flask, dissolved in tetrahydrofuran (30 mL), and then pyridine (1.05 g, 13.33 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (1.48 g, 7.34 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 ≈ 20 / 1) to give a white solid S45 (900 mg, yield: 47.4%). ESI [M+H] + =286.4[M+H] + .

[0459] 2. Preparation of S15

[0460] The synthesis of S15 is described in Example 8.

[0461] 3. Preparation of 1-1-5-15

[0462] S15 (289 mg, 1.47 mmol) was dissolved in acetonitrile (10 mL), and then S45 (420 mg, 1.47 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-5-15 (352.12 mg, yield: 49.6%). ESI [M] + =402.4 [M] + .

[0463] 1 H NMR(400MHz, DMSO-d6)δ:10.18(s,1H),8.58(dd,J=8.8,4.0Hz,1H),7.86(s,1H),7.80(d d,J=8.0,1.6Hz,1H),7.59(d,J=8.4Hz,1H),4.59(t,J=9.6Hz,1H),4.45(q,J=15.6Hz,2H) ,4.24(t,J=11.2Hz,1H),4.08(t,J=10.0Hz,1H),3.84(s,3H),3.80-3.66(m,2H),2.62(d ,J=4.4Hz,3H),2.27(s,3H),2.13-1.92(m,6H),1.47-1.42(m,2H),0.88(t,J=7.2Hz,3H).

[0464] Example 39. Synthesis of compound 1-3-5-5

[0465] 1. Preparation of S46

[0466] In a 500 mL single-necked flask, S1 (5.01 g, 30.0 mmol) solid was added and dissolved in 150 mL of acetonitrile and 150 mL of 0.67 M NaH2PO4 aqueous solution. Then, 20% NaClO2 aqueous solution (27.0 g, 60.0 mmol), 7.5% NaClO aqueous solution (3.0 g, 3.0 mmol), and TEMPO (468 mg, 3.0 mmol) were added sequentially. The reaction was allowed to proceed at room temperature for 48 hours. After the reaction was complete as monitored by LCMS, saturated sodium thiosulfate (30 mL) was added, and the mixture was stirred for 30 minutes. Impurities were removed by extraction with dichloromethane. The aqueous phase was adjusted to pH 4 with 2N hydrochloric acid and concentrated under reduced pressure to obtain a pale yellow solid. This solid was eluted thoroughly with dichloromethane / methanol at a ratio of 5:1 (400 mL). The eluent was concentrated under reduced pressure to obtain a pale yellow solid S46 (3.0 g, yield: 56%). + =182.4[M+H] + .

[0467] 2. Preparation of S47

[0468] The crude product S46 (694 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 mixture was stirred at 0 °C for one hour. The solvent was removed by concentration at 10 °C, and the residue was used for later use. Methylamine (2.0N in THF, 19.1mL, 38.3mmol) and triethylamine (1.16g, 11.49mmol) were dissolved in dichloromethane (20mL). The system was cooled to 0°C in an ice bath. The remaining product was then dissolved in dichloromethane (5mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (20mL) of water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 1) to give compound S47 (390mg, yield: 52.5%). ESI [M+H] + =195.3[M+H] + .

[0469] 3. Preparation of S19

[0470] The synthesis of S19 is described in Example 11.

[0471] 4. Preparation of 1-3-5-5

[0472] S47 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S19 (300 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1 to 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-3-5-5 (~240 mg, yield: 55%). ESI [M] + =414.4 [M] + .

[0473] 1 H NMR (400MHz, DMSO-d6) δ: 10.20 (s, 1H), 8.54 (dd, J = 4.0, 8.8Hz, 1H), 7.70 ( s,2H),5.97-5.88(m,1H),5.24-5.20(m,2H),4.70(t,J=11.2Hz,1H),4.63- 4.52(m,2H),4.38-4.26(m,2H),3.84(s,3H),3.80-3.67(m,2H),2.94-2.8 8(m,1H),2.64(d,J=4.4Hz,3H),2.19-2.09(m,9H),1.94(t,J=11.2Hz,2H).

[0474] Example 40. Synthesis of compound 1-1-4-16

[0475] 1. Preparation of S49

[0476] S48 (4.58 g, 20.00 mmol) was added to a 250 mL single-necked flask and dissolved in DOX / H2O (100 / 10 mL). Then, pinacol isopropenylborate (4.03 g, 24.00 mmol), cesium carbonate (13.00 g, 40.00 mmol), and Pd(dppf)Cl2 (0.73 g, 1.00 mmol) were added sequentially. The mixture was stirred overnight at 90 °C. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with dichloromethane (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 5 / 1) to give a pale yellow oil, S49 (3.01 g, yield: 78.53%). ESI [M+H] + =192.1.

[0477] 2. Preparation of S50

[0478] S49 (3.01 g, 15.76 mmol) was dissolved in methanol (200 mL), and then Pt / C (0.30 g) was added. The mixture was purged three times with hydrogen, and the reaction was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 100 / 1~10 / 1) to obtain a pale yellow oily S50 (2.05 g, yield: 67.21%). ESI [M+H] + =194.2.

[0479] 3. Preparation of S51

[0480] S50 (2.05 g, 10.62 mmol) was added to a 250 mL single-necked flask, dissolved in tetrahydrofuran (100 mL), and then pyridine (1.68 g, 21.24 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (2.35 g, 11.68 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with ethyl acetate (3 × 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 5 / 1) to give a white solid S51 (1.50 g, yield: 45.45%). ESI [M+H] + =314.2.

[0481] 4. Preparation of S52

[0482] S52 (0.47 g, 1.50 mmol) was dissolved in acetonitrile (30 mL), and then S5 (0.25 g, 1.50 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give a white solid compound S52 (0.45 g, yield: 74.95%). ESI [M] + =401.3.

[0483] 5. Preparation of 1-1-4-16

[0484] S52 (0.45 g, 1.12 mmol) was dissolved in methanol (20 mL), and then Pd / C (45.00 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH = 100 / 1 to 10 / 1) to give a white solid. This solid was then lyophilized with pure water to give a white solid compound 1-1-4-16 (0.31 g, yield: 68.89%). ESI [M] + =403.4.

[0485] 1 H NMR(400MHz, DMSO-d6)δ:10.22(s,1H),7.65-7.61(m,2H),7.41(t,J=7.6Hz,1H), 5.64(t,J=4.8Hz,1H),4.50-4.27(m,2H),4.13(d,J=4.8Hz,1H),3.87-3.79(m,7H) ,3.71-3.62(m,2H),3.21-3.3.18(m,1H),2.17-2.11(m,1H),2.00-1.87(m,4H),1 .65-1.56(m,1H),1.48-1.44(m,2H),1.15(t,J=7.6Hz,6H),0.87(t,J=7.6Hz,3H).

[0486] Example 41. Synthesis of compound 1-1-4-17

[0487] 1. Preparation of S53

[0488] S9 (4.95 g, 30.00 mmol) was dissolved in methanol / water (100 / 40 mL), and then lithium hydroxide monohydrate (3.78 g, 90.00 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LCMS, the pH was adjusted to 4 with citric acid aqueous solution. The crude product, concentrated under reduced pressure, was purified by silica gel column chromatography (DCM: MeOH = 100 / 1 to 10 / 1) to give a pale yellow oily compound S53 (4.02 g, yield: 88.30%). ESI [M] + =151.2.

[0489] 2. Preparation of S54

[0490] S53 (4.02 g, 26.62 mmol) was dissolved in isopropanol / concentrated sulfuric acid (100 / 100 mL), and after three nitrogen purgings, the mixture was stirred at 100 °C for 3 days. After the reaction was complete as monitored by LCMS, the solution was poured into ice water and extracted with ethyl acetate (3 × 100 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100 / 1 to 3 / 1) to give colorless oily S54 (2.10 g, yield: 40.86%). ESI [M] + =194.2.

[0491] 3. Preparation of S55

[0492] S54 (0.96 g, 5.00 mmol) was added to a 250 mL single-necked flask, dissolved in tetrahydrofuran (50 mL), and then pyridine (0.79 g, 10.00 mmol) was added. The system was cooled to 0 °C, and bromoacetyl bromide (1.11 g, 5.50 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solid was removed by filtration, and the mixture was poured into ice water and extracted with dichloromethane (3 × 50 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100 / 1 to 3 / 1) to give a white solid S55 (0.81 g, yield: 51.28%). ESI [M+H] + =314.3.

[0493] 4. Preparation of S56

[0494] S55 (0.47 g, 1.50 mmol) was dissolved in acetonitrile (30 mL), and then S5 (0.25 g, 1.50 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was then slurried with ethyl acetate, filtered, and the filter cake was collected and evaporated to dryness to give a white solid compound S56 (0.41 g, yield: 66.67%). ESI [M] + =401.3.

[0495] 5. Preparation of 1-1-4-17

[0496] S56 (402 mg, 1.00 mmol) was dissolved in methanol (20 mL), and then Pd / C (41 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH = 100 / 1 to 10 / 1) to give a white solid. This solid was then lyophilized with pure water to give a white solid compound 1-1-4-17 (301.98 mg, yield: 74.69%). ESI [M] + =403.1.

[0497] 1H NMR(400MHz, DMSO-d6)δ:10.20(s,1H),7.58(t,J=6.8Hz,1H),7.50(d,J=7.2Hz,1H),7.3 1(t,J=7.6Hz,1H),5.66(t,J=4.8Hz,1H),5.07-5.01(m,1H),4.40-4.22(m,2H),4.06-4.0 3(m,1H),3.88-3.80(m,4H),3.68-3.62(m,2H),2.26(s,3H),2.14-2.08(m,1H),1.99-1.8 5(m,4H),1.63-1.58(m,1H),1.48-1.41(m,2H),1.31-1.29(m,6H),0.87(t,J=7.6Hz,3H).

[0498] Example 42. Synthesis of compound 1-1-7-5

[0499] 1. Preparation of S3

[0500] The synthesis of S3 is described in Example 1.

[0501] 2. Preparation of S57

[0502] Dissolve S3 (700 mg, 3.83 mmol) in dichloromethane (20 mL), cool the system to 0 °C in an ice bath, add DMF (28 mg, 0.38 mmol), and then slowly add oxaloyl chloride (973 mg, 7.66 mmol). After the addition is complete, stir the reaction at 0 °C for one hour; concentrate at 10 °C to remove the solvent, and use the residue for later use. Propylamine (678 mg, 11.49 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. The remaining product was then dissolved in dichloromethane (5 mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (20 mL) of water, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol ≈ 20 / 1) to give compound S57 (430 mg, yield: 50.1%). ESI [M+H] + =225.4[M+H] + .

[0503] 3. Preparation of S19

[0504] The synthesis of S19 is described in Example 11.

[0505] 4. Preparation of 1-1-7-5

[0506] S57 (375 mg, 1.67 mmol) was dissolved in acetonitrile (20 mL), and then S19 (500 mg, 1.67 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain a white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-7-5 (325.18 mg, yield: 37%). ESI [M] + =444.4 [M] + .

[0507] 1 H NMR(400MHz, DMSO-d6)δ:10.19(s,1H),8.50(t,J=5.2Hz,1H),7.70(s,2H),4.69(t,J=9.6 Hz,1H),4.62(d,J=16.0Hz,1H),4.48(d,J=16.0Hz,1H),4.19(t,J=11.2Hz,1H),4.06(t,J =11.6Hz,1H),3.84(s,3H),3.76-3.62(m,2H),3.23-3.14(m,1H),2.96-2.89(m,1H),2.19 (s,7H),2.07-2.01(m,3H),1.93(t,J=10.4Hz,2H),1.47-1.38(m,4H),0.89-0.82(m,6H).

[0508] Example 43. Synthesis of compound 1-1-7-4

[0509] 1. Preparation of S57

[0510] The synthesis of S57 is described in Example 40.

[0511] 2. Preparation of S17

[0512] The synthesis of S17 is described in Example 9.

[0513] 3. Preparation of 1-1-7-4

[0514] S57 (340 mg, 1.52 mmol) was dissolved in acetonitrile (20 mL), and then S17 (500 mg, 1.52 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-1-7-4 (319.6 mg, yield: 38.1%). ESI [M] + =474.4 [M] + .

[0515] 1 H NMR (400MHz, DMSO-d6) δ: 10.86 (s, 1H), 8.52 (t, J = 6.0Hz, 1H), 8.36 (d, J = 1.2Hz, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.86(dd,J=8.4,1.6Hz,1H),4.64(t,J=9.2Hz,1H),4.52(d,J=16.0Hz,1H),4.41(d,J=16.0Hz,1H),4.17(t,J =10.0Hz,1H),4.07(t,J=10.0Hz,1H),3.88(d,J=9.2Hz,6H),3.79-3.67(m,2H),3.10-3.06(m,1H),2.98-2.9 3(m,1H),2.14-1.92(m,6H),1.46-1.42(m,2H),1.46-1.42(m,2H),0.88(t,J=7.2Hz,3H),0.75-0.69(m,3H).

[0516] Example 44. Synthesis of compound 1-3-5-4

[0517] 1. Preparation of S47

[0518] The synthesis of S47 is described in Example 39.

[0519] 2. Preparation of S17

[0520] The synthesis of S17 is described in Example 9.

[0521] 3. Preparation of 1-3-5-4

[0522] S47 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S17 (330 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-3-5-4 (320.33 mg, yield: 72%). ESI [M] + =444.3 [M] + .

[0523] 1 H NMR(400MHz, DMSO-d6)δ:10.87(s,1H),8.51(t,J=4.8Hz,1H),8.32(d,J=1.6Hz,1H),7.97 (d,J=8.0Hz,1H),7.87(dd,J=8.4,2.0Hz,1H),5.97-5.88(m,1H),5.25-5.20(m,2H),4.63- 4.58(m,1H),4.53-4.33(m,3H),4.13(t,J=8.8Hz,1H),3.90(s,3H),3.87(s,3H),3.83-3. 74(m,2H),2.94-2.92(m,1H),2.62(t,J=4.4Hz,3H),2.13-2.10(m,3H),2.00-1.95(m,2H).

[0524] Example 45. Synthesis of compound 1-3-6-4

[0525] 1. Preparation of S58

[0526] In a 500 mL single-necked flask, S5 (5.01 g, 30.0 mmol) solid was added and dissolved in 150 mL of acetonitrile and 150 mL of 0.67 M NaH2PO4 aqueous solution. Then, 20% NaClO2 aqueous solution (27.0 g, 60.0 mmol), 7.5% NaClO aqueous solution (3.0 g, 3.0 mmol), and TEMPO (468 mg, 3.0 mmol) were added sequentially. The reaction was allowed to proceed at room temperature for 48 hours. After the reaction was complete as monitored by LCMS, saturated sodium thiosulfate (30 mL) was added, and the mixture was stirred for 30 minutes. Impurities were removed by extraction with dichloromethane. The aqueous phase was adjusted to pH 4 with 2N hydrochloric acid and concentrated under reduced pressure to obtain a pale yellow solid. This solid was eluted thoroughly with dichloromethane / methanol at a ratio of 5:1 (400 mL). The eluent was concentrated under reduced pressure to obtain a pale yellow solid S58 (2.8 g, yield: 50%).

[0527] 2. Preparation of S59

[0528] The crude product S58 (694 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 mixture was stirred at 0 °C for one hour. The solvent was removed by concentration at 10 °C, and the residue was used for later use. Methylamine (2.0N in THF, 19.1mL, 38.3mmol) and triethylamine (1.16g, 11.49mmol) were dissolved in dichloromethane (20mL). The system was cooled to 0°C in an ice bath. The remaining product was then dissolved in dichloromethane (5mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (20mL) water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 1) to obtain a pale yellow oily compound S59 (380mg, yield: 51%).

[0529] 3. Preparation of S17

[0530] The synthesis of S17 is described in Example 9.

[0531] 4. Preparation of 1-3-6-4

[0532] S59 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S17 (330 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and freeze-dried at low temperature to obtain a white solid 1-3-6-4 (217.45 mg, yield: 49%). ESI [M] + =444.3 [M] + .

[0533] 1H NMR(400MHz, DMSO-d6)δ:10.88(s,1H),8.55(t,J=4.4Hz,1H),8.30(d,J=1.6Hz,1H),7.98(d,J=4.4Hz ,1H),7.88(dd,J=1.6Hz,8.0Hz,1H),6.03-5.95(m,1H),5.33-5.25(m,2H),4.62-4.36(m,4H),3.98(d ,J=7.6Hz,2H),3.76-3.71(m,2H),3.90(s,3H),3.87(s,3H),3.67(d,J=3.6Hz,1H),2.97(d,J=4.4Hz, 1H),2.63(d,J=4.4Hz,3H),2.32(d,J=9.2Hz,1H),2.19(s,1H),2.08-2.01(m,2H),1.86-1.81(m,1H).

[0534] Example 46. Synthesis of compound 1-3-6-5

[0535] 1. Preparation of S19

[0536] The synthesis of S19 is described in Example 11.

[0537] 2. Preparation of S59

[0538] The synthesis of S59 is described in Example 45.

[0539] 3. Preparation of 1-3-6-5

[0540] S59 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S19 (300 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-3-6-5 (213.43 mg, yield: 52%). ESI [M] + =414.3 [M] + .

[0541] 1H NMR (400MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.60 (dd, J = 3.6, 8.8Hz, 1H), 7.71 (s, 2H),6.02-5.93(m,1H),5.31-5.24(m,2H),4.70-4.49(m,4H),4.22-4.19(m, 1H),3.96-3.90(m,1H),3.84(s,3H),3.63-3.58(m,1H),2.96(s,1H),2.64(d ,J=4.4Hz,3H),2.35-2.30(m,1H),2.19-2.01(m,9H),1.81(t,J=11.2Hz,1H).

[0542] Example 47. Synthesis of compound 1-3-3-7

[0543] 1. Preparation of S10

[0544] The synthesis of S10 is described in Example 3.

[0545] 2. Preparation of 1-3-3-7

[0546] S1 (200 mg, 1.20 mmol) was added to a 50 mL single-necked flask, dissolved in acetonitrile (10 mL), followed by S10 (341 mg, 1.20 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 20 / 1), concentrated under reduced pressure, dissolved in water, and lyophilized at low temperature to give a white solid 1-3-3-7 (312.42 mg, yield 57.5%). ESI [M] + =373.5 [M] + .

[0547] 1 H NMR (400MHz, DMSO-d6), δ: 10.27 (s, 1H), 7.62 (t, J = 6.8Hz, 1H), 7.52 (d, J = 6.8Hz, 1H) ,7.32(t,J=7.6Hz,1H),5.96-5.87(m,1H),5.70(t,J=4.8Hz,1H),5.22(t,J=8.8Hz,2H ),4.38-4.29(m,2H),4.13-4.10(m,1H),4.00(t,J=9.2Hz,1H),3.95-3.90(m,1H),3.8 7-3.72(m,6H),3.69-3.61(m,1H),2.85-2.87(m,1H),2.27(s,3H),2.03-1.86(m,5H).

[0548] Example 48. Synthesis of compound 1-3-5-9

[0549] 1. Preparation of S29

[0550] The synthesis of S29 is described in Example 29.

[0551] 2. Preparation of S59

[0552] The synthesis of S47 is described in Example 39.

[0553] 3. Preparation of 1-3-5-9

[0554] S47 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S29 (270 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to obtain a white solid 1-3-5-9 (202.49 mg, yield: 44%). ESI [M] + =384.4 [M] + .

[0555] 1 H NMR(400MHz,DMSO-d6)δ:9.93(s,1H),8.53(br,1H),7.23-7.16(m,2H),7.10- 7.08(m,1H),5.97-5.88(m,1H),5.25-5.20(m,2H),4.77-4.49(m,3H),4.38-4 .24(m,2H),3.80-3.69(m,2H),2.95-2.89(m,2H),2.64(d,J=4.4Hz,3H),2.21 -2.10(m,6H),1.99-1.91(m,2H),1.11(d,J=6.8Hz,3H),1.11(d,J=6.8Hz,3H).

[0556] Example 49. Synthesis of compound 1-3-8-4

[0557] 1. Preparation of S58

[0558] The synthesis of S58 is described in Example 45.

[0559] 2. Preparation of S60

[0560] Dissolve S58 (1.4 g, 7.73 mmol) in dichloromethane (40 mL), cool the system to 0 °C in an ice bath, add DMF (113 mg, 1.55 mmol), and then slowly add oxaloyl chloride (1.96 g, 15.46 mmol). After the addition is complete, stir the reaction at 0 °C for one hour; concentrate at 10 °C to remove the solvent, and use the residue for later use. Propylamine (1.4 g, 23.19 mmol) and triethylamine (3.9 g, 38.65 mmol) were dissolved in dichloromethane (40 mL). The system was cooled to 0°C in an ice bath. The remaining product was then dissolved in dichloromethane (20 mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (60 mL) of water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solution was purified by column chromatography (dichloromethane / methanol ≈ 20 / 1) to give compound S60 (630 mg, yield: 36.6%). ESI [M+H] + =223.4[M+H] + .

[0561] 3. Preparation of S17

[0562] The synthesis of S17 is described in Example 9.

[0563] 4. Preparation of 1-3-8-4

[0564] S60 (37 mg, 0.167 mmol) was dissolved in acetonitrile (20 mL), and then S17 (50 mg, 0.167 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-3-8-4 (150 mg, yield: 35%). ESI [M] + =472.4 [M] + .

[0565] 1H NMR(400MHz, DMSO-d6)δ:10.91(s,1H),8.61(t,J=5.6Hz,1H),8.33(d,J=1.2Hz,1H),7.97(d,J=8.0Hz,1 H),7.87(dd,J=8.0,1.6Hz,1H),6.07-5.98(m,1H),5.34-5.26(m,2H),4.66(t,J=9.6Hz,1H),4.64-4.43 (m,3H),4.07-3.97(m,2H),3.90(s,3H),3.87(s,3H),3.70-3.65(m,1H),3.11-2.96(m,3H),2.34(t,J=1 1.6Hz,1H),2.20(s,1H),2.09-2.01(m,2H),1.85-1.79(m,1H),1.40-1.31(m,2H),0.75(t,J=7.2Hz,3H).

[0566] Example 50. Synthesis of compound 1-3-8-5

[0567] 1. Preparation of S60

[0568] The synthesis of S60 is described in Example 49.

[0569] 2. Preparation of S19

[0570] The synthesis of S19 is described in Example 11.

[0571] 3. Preparation of 1-3-8-5

[0572] S60 (200 mg, 0.90 mmol) was dissolved in acetonitrile (20 mL), and then S19 (269 mg, 0.90 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LCMS, the product was concentrated under reduced pressure, and the crude product was purified by normal column chromatography [dichloromethane:methanol (100 / 1 ≈ 20 / 1)] to obtain an off-white solid. This solid was dissolved in deionized water and lyophilized at low temperature to give 1-3-8-5 (130 mg, yield: 41.6%). ESI [M] + =442.4 [M] + .

[0573] 1H NMR (400MHz, DMSO-d6) δ: 10.22 (s, 1H), 8.57 (t, J = 5.2Hz, 1H), 7.71 (s, 2H), 6.02-5.94 (m, 1H), 5. 31-5.24(m,2H),4.72-4.62(m,2H),4.51(d,J=16.0Hz,2H),4.17(d,J=12.8Hz,1H),3.92(d,J=10 .4Hz,1H),3.84(s,3H),3.62-3.56(m,1H),3.22-3.16(m,1H),2.97-2.90(m,2H),2.39-2.33(m,1 H),2.19(s,7H),2.09-2.01(m,2H),1.82-1.77(m,1H),1.46-1.38(m,2H),0.85(t,J=7.6Hz,3H).

[0574] Example 51. Synthesis of compound 1-3-7-4

[0575] 1. Preparation of S46

[0576] The synthesis of S46 is described in Example 39.

[0577] 2. Preparation of S61

[0578] The crude product S46 (694 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 mixture was stirred at 0 °C for one hour. The solvent was removed by concentration at 10 °C, and the residue was used for later use. Propylamine (2.26 g, 38.3 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. The remaining product was then dissolved in dichloromethane (5 mL) and slowly added to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS, the reaction solution was poured into (20 mL) of water and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 1) to give compound S61 (445 mg, yield: 52.4%). ESI [M+H] + =223.3[M+H] + .

[0579] 3. Preparation of S17

[0580] The synthesis of S17 is described in Example 9.

[0581] 4. Preparation of 1-3-7-4

[0582] S61 (222 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S17 (330 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was complete as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane to methanol (100 / 1 to 20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to give 1-3-7-4 (200 mg, yield: 35%). ESI [M] + =472.3 [M] + .

[0583] 1 H NMR(400MHz, DMSO-d6)δ:10.88(s,1H),8.54(t,J=5.6Hz,1H),8.37(d,J=1.6Hz,1H),7.98(d,J=8.0 Hz,1H),7.87(dd,J=8.4,2.0Hz,1H),5.97-5.88(m,1H),5.25-5.20(m,2H),4.70-4.65(m,1H),4.58- 4.34(m,3H),4.21(t,J=10.8Hz,1H),3.90(s,3H),3.88(s,3H),3.85-3.70(m,2H),3.11-3.04(m,1H) ,3.00-2.90(m,2H),2.19-2.11(m,3H),1.98-1.92(m,2H),1.37-1.27(m,2H),0.71(t,J=7.2Hz,3H).

[0584] Example 52. Synthesis of compound 1-3-7-5

[0585] 1. Preparation of S61

[0586] The synthesis of S61 is described in Example 51.

[0587] 2. Preparation of S19

[0588] The synthesis of S19 is described in Example 11.

[0589] 3. Preparation of 1-3-7-5

[0590] S61 (222 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S19 (300 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was complete as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~20 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to obtain a white solid 1-3-7-5 (200 mg, yield: 40%). ESI [M] + =442.4 [M] + .

[0591] 1 H NMR (400MHz, DMSO-d6) δ: 10.23 (s, 1H), 8.53 (t, J = 5.6Hz, 1H), 7.70 (s, 2H), 5.9 6-5.88(m,1H),5.25-5.19(m,2H),4.77-4.52(m,3H),4.35(t,J=10.0Hz,1H),4. 22(t,J=11.2Hz,1H),3.84-3.71(m,5H),3.21-3.16(m,1H),2.97-2.91(m,2H), 2.24-2.10(m,9H),1.95-1.90(m,2H),1.45-1.38(m,2H),0.83(t,J=7.2Hz,3H).

[0592] Example 53. Synthesis of compound 1-3-7-5

[0593] 1. Preparation of S10

[0594] The synthesis of S10 is described in Example 3.

[0595] 2. Preparation of 1-3-7-5

[0596] S5 (257 mg, 1.54 mmol) was dissolved in acetonitrile (20 mL), and S10 (440 mg, 1.54 mmol) was added at room temperature. The mixture was heated to 45 °C and stirred overnight. After the reaction was completed as monitored by LCMS, the solvent was removed from the reaction solution under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0–10%) to give a white solid compound 1-3-7-5 (318.54 mg, yield 53%). ESI [M] + =373.3.

[0597] 1H NMR(400MHz, DMSO-d6)δ:10.22(s,1H),7.62(d,J=8.0Hz,1H),7.52(d,J=6.8Hz,1H),7.32(t,J= 7.6Hz,1H),6.08-5.93(m,1H),5.66(t,J=4.8Hz,1H),5.27-5.19(m,2H),4.39(d,J=16.0Hz,1H), 4.26 (d, J = 16.0 Hz, 1H), 4.08-3.96 (m, 2H), 3.92-3.78 (m, 7H), 3.69-3.62 (m, 1H), 2.88-2.70 (m, 1H), 2.26 (s, 3H), 2.12-2.07 (m, 2H), 1.97-1.94 (m, 2H), 1.67-1.62 (m, 1H). Example 54. Synthesis of compound 0-0-0-1

[0598] 1. Preparation of S47

[0599] The synthesis of S47 is described in Example 39.

[0600] 2. Preparation of S32

[0601] The synthesis of S32 is described in Example 31.

[0602] 3. Preparation of 1-3-5-4

[0603] S47 (194 mg, 1.0 mmol) was dissolved in acetonitrile (15 mL), and then S32 (328 mg, 1.0 mmol) was added. The mixture was stirred at 50 °C for 3 days. After the reaction was complete as monitored by LCMS, the product was concentrated under reduced pressure. The crude product was purified by normal column chromatography [dichloromethane: methanol (100 / 1~10 / 1)] to obtain a white solid. This solid was then dissolved in deionized water and lyophilized at low temperature to obtain a white solid 0-0-0-1 (310.44 mg, yield: 70%). ESI [M] + =442.4 [M] + .

[0604] 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.54(dd,J=4.0Hz,8.8Hz,1H),7.67(s,2H),5.97-5.88(m,1H),5.24-5.09(m,3H),4.73-4.52(m,3H),4.38 -4.25(m,2H),3.82-3.69(m,2H),2.93(d,J=7.6Hz,1H),2.64(d,J=4.8H z,3H),2.19-2.09(m,9H),1.95(t,J=11.2Hz,2H),1.31(d,J=6.0Hz,6H).

[0605] Example 55. Synthesis of compound 0-0-0-2

[0606] 1. Preparation of 1-3-8-5

[0607] The synthesis of 1-3-8-5 is described in Example 50.

[0608] 2. Preparation of 0-0-0-2

[0609] 1-3-8-5 (240 mg, 0.460 mmol) was dissolved in methanol (20 mL), and then Pd / C (48 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 20 / 1). After concentration under reduced pressure, the product was dissolved in water and freeze-dried at low temperature to give a white solid 0-0-0-2 (177.55 mg, yield: 73.7%). ESI [M] + =444.4 [M] + .

[0610] 1H NMR(400MHz, DMSO-d6)δ:10.25(s,1H),8.54(t,J=5.2Hz,1H),7.70(s,2H),4.73(t,J=9.2Hz,1H ),4.62(d,J=16.0Hz,1H),4.51-4.71(m,2H),3.93-3.80(m,5H),3.59(t,J=10.0Hz,1H),3.22-3. 16(m,1H),2.98-2.92(m,1H),2.42-2.36(m,1H),2.20(s,6H),2.14(s,1H),2.10-2.04(m,2H),1. 92(d,J=7.6Hz,1H),1.79-1.74(m,1H),1.56-1.48(m,2H),1.46-1.39(m,2H),0.90-0.84(m,6H).

[0611] Example 56. Synthesis of compound 0-0-0-3

[0612] 1. Preparation of 1-3-8-4

[0613] The synthesis of 1-3-8-4 is described in Example 49.

[0614] 2. Preparation of 0-0-0-3

[0615] 1-3-8-4 (280 mg, 0.507 mmol) was dissolved in methanol (20 mL), and then Pd / C (56 mg) was added. The mixture was purged three times with hydrogen, and the reaction was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was complete as monitored by LCMS, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1 to 20 / 1). After concentration under reduced pressure, the product was dissolved in water and freeze-dried at low temperature to give a white solid 0-0-0-3 (206.40 mg, yield: 73.5%). ESI [M] + =474.2 [M] + .

[0616] 1H NMR(400MHz, DMSO-d6)δ:10.89(s,1H),8.54(t,J=5.2Hz,1H),8.33(d,J=1.2Hz,1H),7.97(d,J=8.0Hz,1H),7.86(d d,J=8.4,1.6Hz,1H),4.69(t,J=9.6Hz,1H),4.54-4.47(m,2H),4.39(d,J=16.0Hz,1H),3.94-3.88(m,7H),3.72(d,J =12.4Hz,1H),3.64(t,J=10.4Hz,1H),3.11-2.98(m,2H),2.38-2.32(m,1H),2.14(s,1H),2.11-2.05(m,2H),1.96- 1.88(m,1H),1.81-1.76(m,1H),1.58-1.51(m,2H),1.40-1.32(m,2H),0.91(t,J=7.6Hz,3H),0.75(t,J=7.2Hz,3H).

[0617] The remaining compounds of the present invention were prepared by referring to the synthesis methods of the above embodiments and combining them with conventional methods in the art.

[0618] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0619] Experimental Example 1: Pharmacological Study on the Selective Blocking Effect of the Compounds of the Present Invention on Sensory Nerves

[0620] 1.1 Experimental methods: A rat sciatic nerve block model was used.

[0621] Anesthesia was induced and maintained using isoflurane inhalation. Rats were immobilized in a right lateral decubitus position. Hair was shaved from the left ischial tuberosity to the greater trochanter of the femur, extending at least 2 cm laterally to the endpoint. The skin at the shaved area was disinfected with iodine-alcohol swabs. Wearing sterile gloves, the operator inserted a 1 mL syringe perpendicularly to the skin at the midpoint of the line connecting the two bony landmarks. After the needle tip reached the bony structure, the syringe was securely fixed, and 0.4 ml (0.05 ml / s) of the positive control drug ropivacaine or the compound was slowly injected. Measurements were taken at 10 min, 30 min, 1 h, and 2 h post-injection, and then every 2 h until 8 h, followed by 24 h (if less than 24 h had passed, a 14 h follow-up measurement was required), and then every 4 h until recovery. The following behavioral observations were conducted on the rats by the experimental personnel, who were unaware of the treatments received by the rats.

[0622] A. Thermal pain threshold (modified hot plate test)

[0623] The sensory blocking effect of the drug was evaluated using a modified hot plate test. Rats were properly held so that the sole of the hind limb on the injection side was in contact with a metal plate maintained at a constant temperature of 55°C, and timing was started simultaneously. The time interval from the rat's contact with the hot plate to its withdrawal of the leg due to heat pain was recorded as the paw withdrawal latency (PWL). If the rat did not withdraw its paw after 12 seconds (cutoff value), it was manually removed from the hot plate to avoid burns.

[0624] If MPE ≥ 50%, it is defined as effective thermal pain blockade; otherwise, it is ineffective.

[0625] The time interval between the injection and the first effective measurement point of thermal pain blockade is the onset time of thermal pain blockade; the time interval between the injection and the first point when the thermal pain threshold changes from effective to ineffective is the failure time of thermal pain blockade; the difference between the two is the duration of thermal pain blockade.

[0626] B. Motor function (hindlimb pedaling test)

[0627] The motor blocking effect of the drug was evaluated by the Postural Extensor Thrust (PET) test. The rat was lifted vertically and its hind limb on the injection side was placed on an electronic balance. The hind limb muscle strength at this point was represented by the numerical value displayed on the balance. When the limb was completely paralyzed, the reading was the limb's own weight, approximately 10–20 g.

[0628] If MPE ≥ 50%, the exercise blockade is defined as effective; otherwise, it is ineffective.

[0629] The time interval between the injection and the first measurement point when motor function disappears is the onset time of motor blockade; the time interval between the injection and the first time when motor function recovers is the failure time of motor blockade; the difference between the two is the duration of motor blockade.

[0630] Experimental rats will receive injections of gradient concentrations of the drug, with an initial dose of 1% (w / v). If effective, doses of 0.5%, 0.25%, and 0.1% will be tested until ineffective; if ineffective, doses of 1.5%, 2%, and 2.5% will be tested until effective or significant adverse reactions occur. Local and systemic toxicity will be closely monitored throughout the experiment. The final effective concentration (C0.05) for sensorimotor nerve dissociation blockade without local or systemic adverse reactions will be determined. min ).

[0631] 1.2 Experimental Results

[0632] As shown in Table 1, at a certain concentration, the sensory blockade time induced by the compound of the present invention in the rat sciatic nerve blockade experiment was significantly longer than that of motor blockade, showing obvious sensory blockade selectivity compared with ropivacaine hydrochloride, and there were no local or systemic adverse reactions at this concentration.

[0633] Table 1. Pharmacodynamic evaluation of the compounds of the present invention in rat sciatic nerve block

[0634] Example 2: Safety evaluation of topical administration of the compound of the present invention

[0635] 2.1 Experimental Methods

[0636] Samples were collected from the sciatic nerve of rats on day 14 after administration of propofol. Rats were euthanized under isoflurane anesthesia by cardiac injection of propofol (or air). The muscles, connective tissue, and nerve at the administration site were exposed, and gross anatomical scoring was performed. The nerve and surrounding muscle tissue were then placed in a fixation bottle containing 10% neutral formaldehyde solution. After processing, the specimens were cut into 4 μm thick sections, stained with hematoxylin and eosin (HE), and compared with pathological sections from the positive control group.

[0637] 2.2 Experimental Results

[0638] Gross anatomical and pathological section comparisons revealed no significant differences between the compound of this invention and the control group in terms of gross anatomical findings (skin, nerves at the injection site and surrounding tissues) and pathological sections (local inflammatory cell infiltration, myocytotoxicity, and nerve axon demyelination). This indicates that the compound exhibits good local tissue safety while providing a long-lasting local anesthetic effect.

[0639] This invention provides a local anesthetic drug capable of producing sensory-motor nerve dissociation blockade, i.e., the duration of sensory blockade is significantly longer than that of motor blockade, and has low systemic and local tissue toxicity. Therefore, the compound of this invention has broad application prospects in the preparation of local analgesics, providing a new option for the clinical preparation of drugs with analgesic effects.

Claims

1. The compound represented by Formula I, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its crystal form, or its prodrug, or its metabolite, or its deuterated derivative: in, for At least one of R1, R2, R3, and R4 is selected from At the same time, R1, R2, R3, R4, R m2 At least one of them is selected from The remaining groups are each independently selected from hydrogen, hydroxyl, halogen, amino, nitro, cyano, unsubstituted, or with one or more R groups. c The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; R c Each independently selected from C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 Alkyne, halogen, hydroxyl, deuterium, amino, nitro, cyano; X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl; X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl; n is selected from 0, 1, or 2; X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl; X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl; X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 Alkynyl, 5-8 aryl, 5-8 heteroaryl; R a Selected from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group; The M ring is selected from 5-8 quinary aromatic rings and 5-8 heterocyclic aromatic rings; e1 is selected from 0, 1, 2, 3, 4, or 5; e2 is selected from 0, 1, 2, or 3; R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of 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, C 2-10 alkenyl, C 2-10 Alkyne, halogen, hydroxyl, deuterium, amino, nitro, cyano; R5, R6, R7, and R8 are each independently selected from hydrogen, halogen, hydroxyl group, unsubstituted or surrounded by one or more R groups. g The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkenyl, C 2-10 alkynyl group; R g 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: in, for X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings; e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5; R1, R2, R4, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy, C 2-10 alkenyl; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; n is selected from 0, 1, or 2; X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; R a Selected from C 1-8 alkyl; R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; 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, II-2, II-3 or II-4: in, for X1 is selected from O and S, and X2 is selected from O, S, and NR. f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl; X3 is selected from O and S, and X4 is selected from O, S, and NR. f4 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl; R a Selected from C 1-5 alkyl; R2 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R2 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R4 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R4 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R2 and R4 are not both hydrogen; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups. c3 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c3 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl; e1 is selected from 0, 1, or 2; R m1 Each independently selected from C 1-5 alkyl; e2 is selected from 1, 2, or 3; 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 2, characterized in that: The compound is selected from one of the following compounds:

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 1, characterized in that: The structure of the compound is shown in Formula III: in, for X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings; e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5; R3, R2, R4, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; n is selected from 0, 1, or 2; X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; R a Selected from C 1-8 alkyl; R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; It is a monovalent anion.

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 5, characterized in that: The structure of the compound is shown in formula III-1, III-2, III-3 or III-4: in, for X1 is selected from O and S; X2 is selected from O, S, NR f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl; n is selected from 0, 1, or 2; X3 is selected from O and S; X4 is selected from None, O, S, NR f3 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl; X5 is selected from None, O, S, NR f3 ;R f5 Selected from hydrogen, C 1-5 Alkyl, phenyl; X4 and X5 are not both absent; R a Selected from C 1-5 alkyl; R2 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R2 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R4 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R4 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R2 and R4 are not both hydrogen; R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups. c3 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c3 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl; e1 is selected from 0, 1, or 2; R m1 Each independently selected from C 1-5 alkyl; e2 is selected from 1, 2, or 3; 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 5, characterized in that: The compound is selected from one of the following compounds:

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 1, characterized in that: The structure of the compound is shown in Formula IV: in, for X1 is selected from NR f1 O, S; R f1 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X2 is selected from NR f2 O, S; R f2 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; The M ring is selected from benzene rings and 5-6 membered heteroaromatic rings; e1 is selected from 0, 1, 2, 3, 4 or 5; e2 is selected from 0, 1, 2 or 3; the sum of e1 and e2 is not greater than 5; R is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R. y The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R y Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; R1, R3, R m2 At least one of them is selected from The remaining ones are each independently selected from hydrogen, hydroxyl, unsubstituted, or converted by one or more R groups. c The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R c Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; n is selected from 0, 1, or 2; X3 is selected from NR f3 O, S; R f3 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X4 is selected from none, NR f4 O, S; R f4 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; X5 is selected from none, NR f5 O, S; R f5 Selected from hydrogen, C 1-8 Alkyl, phenyl, 5-6 membered heteroaryl; R a Selected from C 1-8 alkyl; R m1 Each is independently selected from hydrogen, hydroxyl, unsubstituted or composed of one or more R groups. d The following groups are substituted: C 1-8 Alkyl, C 1-8 Alkoxy; R d Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, halogens, and hydroxyl groups; It is a monovalent anion.

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 8, characterized in that: The structure of the compound is shown in formula IV-1, IV-2 or IV-3: in, for X1 is selected from O and S; X2 is selected from O, S, NR f2 ;R f2 Selected from hydrogen, C 1-5 Alkyl, phenyl; n is selected from 0, 1, or 2; X3 is selected from O and S; X4 is selected from None, O, S, NR f3 ;R f4 Selected from hydrogen, C 1-5 Alkyl, phenyl; X5 is selected from None, O, S, NR f3 ;R f5 Selected from hydrogen, C 1-5 Alkyl, phenyl; X4 and X5 are not both absent; R a Selected from C 1-5 alkyl; R is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R. y The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R y Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R1 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R1 groups. c1 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c1 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; R3 is selected from hydrogen, hydroxyl group, unsubstituted or surrounded by one or more R3 groups. c2 The following groups are substituted: C 1-5 Alkyl, C 1-5 Alkoxy; R c2 Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, halogens, and hydroxyl groups; e is selected from 1, 2, 3, 4, or 5; R m Each independently selected from C 1-5 alkyl; e1 is selected from 0, 1, or 2; R m1 Each independently selected from C 1-5 alkyl; e2 is selected from 1, 2, or 3; 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 8, characterized in that: The compound is selected from one of the following compounds:

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-10, its stereoisomers, its pharmaceutically acceptable salts, its solvates, its crystal forms, its prodrugs, its metabolites or their deuterated derivatives as active ingredients.

12. Use of the compound of any one of claims 1-10, 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.

13. The use according to claim 12, characterized in that: The drug is a drug with long-acting analgesic and / or long-acting local anesthetic effects.

14. The use according to claim 12 or 13, characterized in that: The drug is a sensorimotor dissociative drug with analgesic and / or anesthetic effects.

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