Quinolone derivative of macrolide, preparation method therefor, and use thereof

Abstract

Provided are a compound represented by formula (I), a stereoisomer, tautomer, isotopic marker, nitrogen oxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition. The compound has good antibacterial and anti-inflammatory effects, can be used as an antibiotic, can treat infections caused by pathogenic microorganisms resistant to erythromycin and telithromycin, and simultaneously acts on two targets, i.e., ribosomes and topoisomerase.

Description

A quinolone derivative of a macrolide and a preparation method and application thereof

[0001] The present application claims the priority of the prior application with the patent application number 202410883573.7, the name of the invention being "A quinolone derivative of a macrolide and a preparation method and application thereof", filed on July 02, 2024 with the State Intellectual Property Office of China by the applicant, the content of the above-mentioned application being incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of chemical synthesis and pharmacy, in particular to a quinolone derivative of a macrolide and a preparation method and application thereof. BACKGROUND

[0003] Macrolide-lincosamide-streptogramin B (MLSB) has the same ribosome binding site and has cross-resistance. Among them, the fourteen-membered macrolide antibiotic erythromycin is a very important therapeutic drug for upper and lower respiratory tract infections, which is clinically used for the treatment of upper and lower respiratory tract infections or skin and soft tissue infections caused by pathogenic microorganisms such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, etc. The side effects are mild, and for half a century, it has provided a very efficient and safe drug route for humans, especially children. Since the main antibacterial mechanism is that the hydroxyl group and the tertiary amino group of 5-position desosamine act on the bases A2058 / A2059 of the ribosome 50S subunit nascent peptide release channel in the form of hydrogen bond, therefore, bacterial ribosome A2058 / A2059 base mutation, or mef gene-containing strains expressing methylase leading to N6 methylation of A2058 will all cause a sharp decrease in the affinity of erythromycin; in addition, mef gene-containing strains will be induced to express efflux pump protein by erythromycin containing cladinose, resulting in a decrease in the intracellular drug concentration below the antibacterial level and drug resistance.

[0004] The second-generation erythromycin clarithromycin and azithromycin appeared in the 1980s, although they have high resistance to (stomach) acid and good pharmacokinetic properties, but they have no antibacterial activity against erythromycin-resistant bacteria. The main reason is that the cladinose at the 3-position induces bacteria to produce drug resistance, resulting in modification of the key target A2058 or pumping out of the cell by the efflux pump.

[0005] As the third generation of erythromycin, ketolide TE802 only has activity against mef and erm induced resistant bacteria, but has no activity against constitutive erm resistant bacteria. Telithromycin is the only erythromycin derivative approved for the treatment of community-acquired bacterial pneumonia infection so far. It has excellent antibacterial activity against both induced and efflux resistant bacteria, and it acts on base pair A752 and U2609 of microbial ribosome, thus has good antibacterial activity against constitutive resistant Streptococcus pneumoniae and Streptococcus pyogenes. However, telithromycin still has no activity against constitutive resistant Staphylococcus aureus and resistant mycoplasma. After the marketing of telithromycin, it was found to have hepatotoxicity, and its use was strictly restricted. Other clinical research compounds were questioned for safety because they all have similar ketolide structures, and the research and development was stopped or terminated, resulting in only telithromycin being marketed for twenty years. The ketolide in clinical phase III, solithromycin, has the same antibacterial target as telithromycin, and its marketing application has been rejected.

[0006] Therefore, it is necessary to solve the problem of finding a new structural macrolide antibiotic that can treat infections caused by erythromycin-resistant and telithromycin-resistant pathogenic microorganisms. SUMMARY

[0007] To improve the above technical problems, the present application provides a compound as shown in formula (I), its stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug:

[0008] wherein X represents O or NH;

[0009] A represents O or NR;

[0010] R represents the following group unsubstituted or substituted with one, two or more R3: C 1-6 alkyl, -3-10 membered heterocyclyl-C 1-6 alkyl, -CH=NO-C 1-6 alkyl; when X represents NH, A represents NR, and R is selected from C 1-6 alkyl, C 1-6 alkyl end can be connected with X to form a ring;

[0011] Each R3 is the same or different, and is independently selected from H, halogen, OH, CN, NO2, NH2, COOH, -R4, -R4-R5;

[0012] R4, R5 represents C 6-10 aryl or 5-10 membered heteroaryl, said C 6-10aryl or 5-10 membered heteroaryl can be unsubstituted or substituted with one, two or more of the following groups: halogen, OH, CN, NO2, NH2, COOH;

[0013] Z represents CH2, NH or O;

[0014] Y represents C 2-6 alkynyl or 3-10 membered heterocyclyl containing one heteroatom selected from N, O or S;

[0015] D represents CH or N;

[0016] R1represents C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl can be unsubstituted or substituted with one, two or more of the following groups: halogen, OH, CN, NO2, NH2, COOH;

[0017] R2represents H, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0018] m is selected from an integer between 0 and 10; for example from an integer between 0 and 8, such as 1, 2, 3, 4 or 5;

[0019] n is selected from an integer between 0 and 10, for example from an integer between 0 and 6, such as 0, 1, 2 or 3;

[0020] and with the proviso that when Y represents C 2-6 alkynyl, A is not O.

[0021] According to some embodiments, A is selected from O or NR, R being selected from C 1-6 alkyl, -C 1-6 alkyl-NH2, -C 1-6 alkyl-R4-R5;

[0022] R4, R5are selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein at least one heteroatom is selected from N, for example 1, 2 or 3 heteroatoms are selected from N; for example R4, R5are phenyl, naphthyl, pyridyl, imidazolyl, triazol, benzoquinolyl, diazaphenanthryl, thiazolyl and the like.

[0023] According to some embodiments, A is selected from NR, R is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, -methyl-NH2, -ethyl-NH2, -propyl-NH2, -butyl-NH2, -propyl-imidazole-pyridine, -butyl-imidazole-pyridine, -butyl-triazole-pyridine, -butyl-triazole-aminobenzene, -pentyl-imidazole-pyridine; when X represents NH, A represents NR, R is selected from ethyl, propyl or butyl, the end of the ethyl, propyl or butyl can be linked to X to form a ring;

[0024] According to some embodiments, A is selected from NR, R is selected from methyl, ethyl, ethyl-NH2, when X represents NH, A represents NR, R is selected from ethyl, the end of the ethyl can be linked to X to form a ring;

[0025] According to some embodiments, Z represents CH2or O;

[0026] According to some embodiments, Y represents ethynyl, propynyl, pyrrolidinyl or piperidinyl;

[0027] According to some embodiments, Y represents ethynyl, (as ),

[0028] According to some embodiments, R1represents methyl, ethyl, cyclopropyl, fluorocyclopropyl;

[0029] According to some embodiments, R2represents H, halogen, for example selected from fluorine, preferably substituted at the 6-position;

[0030] According to some embodiments, m is selected from 2, 3, 4 or 5;

[0031] According to some embodiments, n is selected from 0 or 1 or 2.

[0032] According to some embodiments, the compound of formula (I) has the structure of formula (I-1):

[0033] wherein R’ represents -C 1-6 alkyl-, Z, Y, D, R1, R2, m, n have the definitions described above.

[0034] According to some embodiments, R’ is selected from -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH(CH3)-, -C(CH3)(CH3)CH(CH3)-, -C(CH3)(CH3)CH2-, -C(CH3)(CH3)C(CH3)(CH3)-.

[0035] According to some embodiments, the compound of formula (I) has the structure of formula (I-2):

[0036] wherein R, Z, Y, D, R1, R2, m, n have the definitions described above.

[0037] According to embodiments of the application, the compound of formula (I) has the structure of formula (II)

[0038] wherein X, A, Z, R1, R2, m, n have the definitions described above.

[0039] According to embodiments of the application, the compound of formula (I) has the structure of formula (II-1)

[0040] wherein R' represents -C 1-6 alkyl-, Z, R1, R2, m, n have the definitions described above.

[0041] According to embodiments of the application, the compound of formula (I) has the structure of formula (II-2)

[0042] wherein R, Z, R1, R2, m, n have the definitions described above.

[0043] According to embodiments of the application, the compound of formula (I) has the structure of formula (iii)

[0044] wherein X, A, Z, R1, R2, m, n have the definitions described above.

[0045] According to embodiments of the application, the compound of formula (I) has the structure of formula (III-1)

[0046] wherein R', Z, R1, R2, m, n have the definitions described above.

[0047] According to embodiments of the application, the compound of formula (I) has the structure of formula (III-2)

[0048] wherein R, Z, R1, R2, m, n have the definitions described above.

[0049] According to embodiments of the application, the compound of formula (I) is selected from the structures shown below:

[0050] According to an embodiment of the present application, the pharmaceutically acceptable salt includes a salt formed by the tertiary amino group on 5-dextrose amine or the nitrogen atom on the side chain heterocyclic ring with a pharmaceutically acceptable organic acid or inorganic acid. Preferably, the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or phosphoric acid; the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, malic acid or citric acid.

[0051] According to an embodiment of the present application, the pharmaceutically acceptable salt further includes a salt formed by the carboxyl group in the compound with a pharmaceutically acceptable organic base or inorganic base. Preferably, the inorganic base can be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, bicarbonate, disodium hydrogen phosphate, trisodium phosphate, diammonium hydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium metaphosphate, dilute aqueous ammonia solution, and the organic base can be one or more of meglumine, gluethisene, gluocinchridine, tromethamine, anhydrous or hexahydrate piperazine, morpholine, nicotinamide, 1,2-hexanediamine, tris-hydroxymethyl aminomethane, triethanolamine, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine, diisopropylamine, diethylamine, ethylenediamine, benzamide.

[0052] According to an embodiment of the present application, the prodrug has a structure shown in formula (IV) or formula (V):

[0053] wherein E represents a group of C 1-12 alkyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl; Rb is selected from halogen, C 1-12 alkyl or C 1-12 alkoxy; X, A, Z, Y, D, R1, R2, m, n have the definitions described above.

[0054] The present application also provides a preparation method of the compound of formula (I), comprising the following steps:

[0055] The intermediate M-1 is reacted to obtain compound M-2, and the compound M-2 is further reacted to prepare the compound of formula (I);

[0056] wherein X, A, Z, Y, D, R1, R2, m, n have the definitions described above, and G represents a hydroxyl protecting group.

[0057] The present application also provides an intermediate compound shown in formula M-1 or M-2:

[0058] wherein X, A, Z, Y, m, n have the definitions described above, and G represents a hydroxyl protecting group.

[0059] According to an embodiment of the present application, the method for preparing the compound of formula (II) comprises the following steps:

[0060] The intermediate M-1 is reacted with formula (W) to obtain compound M-2-1, and the compound M-2-1 is reacted with formula (V) and then the protecting group is removed to prepare the compound of formula (II);

[0061] wherein X, A, Z, m, n, R1, R2 have the definitions described above, and G represents a hydroxyl protecting group.

[0062] According to an embodiment of the present application, the method for preparing the compound of formula (III) comprises the following steps:

[0063] The intermediate M-1-2 is reacted with acetylene amine hydrochloride to obtain compound M-2-2, and the compound M-2-2 is reacted with formula (V-2) to prepare, and then the protecting group is removed to obtain the compound of formula (III);

[0064] wherein X, A, Z, m, n, R1, R2 have the definitions described above, and G represents a hydroxyl protecting group.

[0065] According to an embodiment of the present application, the above preparation method can be carried out in the presence of a solvent. For example, the solvent can be selected from at least one of the following: alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyether of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, and hydrocarbons that can be substituted with fluorine and chlorine atoms such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate; acetonitrile.

[0066] The present application also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound of formula (I), stereoisomers, tautomers, isotopically labeled, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof.

[0067] According to an embodiment of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0068] According to an embodiment of the present application, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0069] The present application also provides a use of the compound of Formula (I), stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition in the manufacture of a medicament, for example, in the manufacture of an antibacterial medicament.

[0070] According to an embodiment of the present application, the medicament is an anti-pathogenic microorganism medicament, such as an antibiotic.

[0071] According to an embodiment of the present application, the anti-pathogenic microorganism medicament is used to inhibit or kill at least one of the following pathogenic microorganisms: Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, Staphylococcus epidermidis, Moraxella catarrhalis, Mycoplasma or Chlamydia. According to a specific embodiment of the present application, the anti-pathogenic microorganism medicament is used to inhibit or kill at least one of the following strains of bacteria which are susceptible or of different resistance types to erythromycin: susceptible Streptococcus pneumoniae, constitutively resistant Streptococcus pneumoniae, efflux resistant Streptococcus pneumoniae, susceptible Staphylococcus aureus, inducibly resistant Staphylococcus aureus, constitutively resistant Staphylococcus aureus, susceptible Streptococcus pyogenes, efflux resistant Streptococcus pyogenes, inducibly resistant Streptococcus pyogenes, constitutively resistant Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis.

[0072] The present application also provides a compound of Formula (I), stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition for use as an anti-pathogenic microorganism medicament.

[0073] The present application also provides a use of the compound of Formula (I), stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as an antibiotic.

[0074] The present application also provides a method of treating a patient for a pathogenic microorganism, comprising administering to the patient a therapeutically effective amount of at least one of the compound of Formula (I), stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition.

[0075] According to an embodiment of the present application, the pathogenic microorganism can be at least one of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, Staphylococcus epidermidis, Moraxella catarrhalis, Mycoplasma or Chlamydia.

[0076] In some embodiments, the patient is a mammal, preferably a human. Beneficial effects

[0077] Provided herein are compounds represented by Formula (I), stereoisomers, tautomers, isotopically-labeled, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition, which have better antibacterial and anti-inflammatory effects, can be used as antibiotics, and can treat infections caused by pathogenic microorganisms resistant to erythromycin and telithromycin.

[0078] The compounds in the present application can also act on the ribosome and topoisomerase double targets simultaneously. BRIEF DESCRIPTION OF DRAWINGS

[0079] Figure 1 is the cytotoxicity of the compounds of the present application on HepG2 and 293T cell lines.

[0080] Definitions and explanations of terms

[0081] Unless otherwise indicated, the definitions and explanations of groups and terms in the present application specification and claims, including the definitions as examples, exemplary definitions, preferred definitions, definitions in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other. The group definitions and compound structures after such combination and integration should be understood as within the scope recorded in the present application specification and / or claims.

[0082] Unless otherwise indicated, the numerical ranges recorded in the present specification and claims correspond to at least each specific integer value in the numerical range. For example, the numerical range "0-10" corresponds to each integer value in the numerical range "0-10", i.e. 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0083] It should be understood that herein in describing one, two or more, "more" should mean greater than 2, for example an integer greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0084] Represented by a chemical bond used in the context of the present application.

[0085] The term "C1-12alkyl" denotes a straight or branched chain saturated hydrocarbon group having from 1 to 12 carbon atoms. For example, "C1-6alkyl" denotes a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The C1-6alkyl group includes C1-3alkyl, C3-6alkyl, and the like. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like or isomers thereof.

[0086] The term "C2-6alkynyl" is understood to mean a straight or branched chain hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, for example 2 or 3 carbon atoms ("C2-3alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl.

[0087] The term "C3-20cycloalkyl" is to be understood as meaning a saturated monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 20 carbon atoms, preferably "C3-10cycloalkyl". "C3-10cycloalkyl" means a saturated, monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) hydrocarbon ring or tricyclic cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Said C3-10cycloalkyl includes C3-8cycloalkyl, C3-5cycloalkyl, C6-8cycloalkyl, C3-4cycloalkyl, C5-6cycloalkyl, C6cycloalkyl and the like. Said C3-10cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as camphyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0088] The term "3-20 membered heterocyclyl" is understood to mean a saturated monocyclic, bicyclic hydrocarbon ring or bridged ring alkane containing 1-5 heteroatoms independently selected from N, O and S, a non-aromatic cyclic group having a total of 3-20 ring-forming atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: 3-membered rings such as aziridinyl, oxiridinyl; 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, for example, but not limited to, 5,5 membered rings such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or 5,6 membered bicyclic rings such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e. it can contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. When the 3-10 membered heterocyclyl group is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom of the 3-10 membered heterocyclyl group or through a heteroatom (e.g., N atom) of the 3-10 membered heterocyclyl ring. For example, when the 3-10 membered heterocyclyl group is selected from piperazinyl, tetrahydropyrrolyl, it can be attached to other groups through a nitrogen atom or a carbon atom of the piperazinyl group. Or when the 3-10 membered heterocyclyl group is selected from piperidinyl, it can be attached to other groups through a nitrogen atom of the piperidinyl ring or a carbon atom ortho, meta or para to the nitrogen atom of the piperidinyl ring.

[0089] The term "C6-20aryl" is to be understood as meaning an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. The term "C6-10aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C6-10aryl group is substituted, it can be mono- or polysubstituted. Furthermore, the substitution sites thereof are not limited, and, for example, can be ortho-, para- or meta-substitution.

[0090] The term "5-20 membered heteroaryl" is to be understood as including a monocyclic, bicyclic or tricyclic aromatic ring system, including aromatic or partially aromatic, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-10 membered heteroaryl" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, and of which the ring atoms contain 1 to 5 heteroatoms independently selected from N, O and S, the bicyclic and tricyclic aromatic ring systems can be fused, spiro or bridged. The heteroatoms in the 5-10 membered heteroaryl are preferably 1 to 3. In addition, the 5-10 membered heteroaryl can be benzo-fused in each case. The 5-10 membered heteroaryl includes 5-8 membered heteroaryl, 5-9 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, 6 membered heteroaryl, etc. Examples of heteroaryl include, but are not limited to: 5 membered rings, such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazolyl, imidazolyl, etc.; 6 membered rings, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclyl can be bicyclic, including but not limited to: 5,5 membered rings, such as tetrahydrocyclopentapyrazole; 5,6 membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzoisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuropyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6 membered rings, such as tetrahydroquinoline; 5,7 membered rings, such as tetrahydrocycloheptylthiazole, tetrahydrocycloheptylfuran. The heterocyclyl can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-10 membered heteroaryl is substituted, it can be mono- or polysubstituted. Furthermore, the substitution sites thereof are not limited, for example, the hydrogen attached to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to the heteroatom on the heteroaryl ring can be substituted.

[0091] The term "spiro" refers to a ring system in which two rings share one ring atom.

[0092] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0093] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0094] The term "halogen" designates fluorine, chlorine, bromine or iodine.

[0095] Crystallization often produces solvates of the compounds of the present application, and the term "solvate" as used herein, refers to a combination of one or more molecules of a compound of the present application with one or more molecules of solvent.

[0096] The solvent can be water, in which case the solvate is a hydrate. It can also be an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the present application can be true solvates, but in other cases, the compounds of the present application can only adventitiously retain water or a mixture of water and some other solvent in which the compounds of the present application were reacted or precipitated or crystallized. Solvates of the compounds of the present application are also within the scope of the present application.

[0097] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effects on the general health of the subject being treated.

[0098] The term "pharmaceutically acceptable" as used herein means a material (such as a carrier or diluent) which does not abrogate the biological activity of the compounds of the present application or otherwise cause an adverse effect to the subject to whom the composition is administered.

[0099] It will be appreciated by one skilled in the art that the compounds of the present application can exist in various pharmaceutically acceptable salt forms. If the compounds have a basic center, they can form acid addition salts; if the compounds have an acidic center, they can form base addition salts; if the compounds contain both an acidic center (e.g., carboxyl) and a basic center (e.g., amino), they can also form inner salts.

[0100] The term "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule between two positions. The compounds of the present application can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0101] Depending on their molecular structure, the compounds of the present application can be chiral and, therefore, exist as various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the present application encompass the isomers in which each chiral carbon is in the R or S configuration or a mixture thereof, a racemate. The compounds of the present application or intermediates thereto can be separated into the individual enantiomeric compounds by known chemical or physical methods, or used as a racemate. In the case of racemic amines, the diastereomeric amines are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acid, for example N-benzoyl proline or N-benzenesulfonyl proline, or the various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography is also advantageously performed with optically active stationary phases, for example dinitrobenzoylphenylglycine, cellulose trisporate or other carbohydrate derivatives or chiral derivatizing agents, fixed on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0102] In the present application, "pharmaceutical composition" means a formulation of a compound of the present application and a medium generally accepted for the delivery of biologically active compounds to mammals, such as humans. The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the active ingredient to the recipient.

[0103] In the present application, "pharmaceutically acceptable excipient" includes, but is not limited to, any ingredient that is acceptable for use in humans or animals in the relevant formulation to be administered, such as an adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor.

[0104] In the present application, the term "solvate" means a compound of the present application or a salt thereof, including stoichiometric or non-stoichiometric amounts of solvent when the solvent is water, then it is a hydrate.

[0105] In the present application, the term "prodrug" means a compound of the present application which can be converted under physiological conditions or by solvolysis to a compound of the present application which is biologically or pharmaceutically active. The prodrugs of the present application are prepared by modifying functional groups in such a way that their activity is not impaired but rather improved upon such conversion. Prodrugs include compounds of the present application wherein one or more hydroxyl or amino groups are linked to any moiety which is cleaved in vivo to form the free hydroxyl or amino group.

[0106] "Isotopologues" are all isotopes of atoms occurring in the compounds of the present application. Isotopologues include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present application are hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as but not limited to 2H, 3H, 13C, 14C, 15N, 180, 31P, 32P, 35S, 18F and 36C1, respectively. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non- isotopically labeled reagent. Such compounds are useful in, e.g., determination of biological activity. In the case of stable isotopes, such compounds have the potential to alter the biological, pharmacological, or pharmacokinetic properties of the molecule advantageously.

[0107] The terms "treatment" and other similar synonymous terms used herein include the following meanings:

[0108] (i) preventing a disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or has yet to be diagnosed as having the disease or condition;

[0109] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0110] (iii) relieving the disease or condition, i.e., causing the state of the disease or condition to regress; or

[0111] (iv) alleviating the symptoms of the disease or condition.

[0112] The term "patient" means any animal, including mammals, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0113] The term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder, or condition from occurring in an individual that is predisposed or does not yet exhibit symptoms of the disease pathology; (2) inhibiting the disease: for example, arresting the development of a disease, disorder, or condition (i.e., retarding the development of a pathology and / or symptoms); (3) relieving the disease: for example, causing the regression of a pathology and / or symptoms of a disease, disorder, or condition. DETAILED DESCRIPTION

[0114] The technical solutions of the present application will be further described below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0115] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0116] Side chain and aryl structures used herein:

[0117] The following examples are illustrative of the preparation of compounds 1-36 of the present application, the reaction scheme being:

[0118] Reaction conditions and reagents: a. benzoic anhydride, DMAP (4-dimethylaminopyridine), THF, N, N-dimethyl ethylenediamine, room temperature; b. CDI (carbonyldiimidazole), NaHMDS, THF / DMF = 1.5 / 1, room temperature; c. different amines (ethylenediamine, 40% aqueous methylamine or ethylamine), acetonitrile, room temperature; or when telithromycin side chain reagent W3 is used, telithromycin side chain reagent W3, DBU, THF / DMF = 1.5 / 1, 50 °C; d. when ethylenediamine is used in step c, the following conditions are used: acetic acid, ethanol 60 °C followed by 4 M HCl solution in ethanol, 45 °C; or benzyloxycarbonyl chloride (CbzCl), triethylamine, dichloromethane followed by 4 M HCl solution in ethanol, 45 °C; when methylamine, ethylamine, telithromycin side chain reagent W3 is used in step c, 4 M HCl solution in ethanol, 45 °C is used; e. CDI, DMAP, dichloromethane, room temperature; f. side chain (side chain Wl or side chain W2), DBU, DMF, room temperature; g. 12 M hydrochloric acid solution, ethanol; h. compound Vl, acetonitrile, 75 °C; i. when starting material 27-29, 31 is used, the following conditions are used: 1) ethanol, 2 N NaOH, room temperature; 2) refluxing in methanol; when 30 is used as starting material, the following conditions are used: 1) ethanol, 2 N NaOH, room temperature; 2) refluxing in methanol; 3) Pd / C, methanol, room temperature.

[0119] Preparation 1: synthesis of compound 1

[0120] Compound 1 (20.00 g, 26.74 mmol), DMAP (3.27 g, 26.74 mmol), benzoic anhydride (18.15 g, 80.22 mmol) were dissolved in 150 mL of dry tetrahydrofuran, triethylamine (11.12 mL, 80.22 mmol) was added and the reaction was stirred at room temperature. TLC was used to monitor the progress of the reaction. After about 48 h the reaction was complete, N, N-dimethylethylenediamine (5.84 mL, 53.48 mmol) was added dropwise under ice bath and after half an hour the reaction was concentrated by rotary evaporation. Then 200 mL of dichloromethane was added to the system and the organic phase was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and saturated brine solution, respectively. The organic phase was rotary evaporated to dryness and then compound 1 was recrystallized from dry ethanol to give 22.44 g (23.47 mmol, 87.8%) of compound 1 as white crystals.

[0121] Preparation 2: synthesis of compound 2

[0122] Compound 1 (10.00 g, 10.46 mmol), CDI (6.78 g, 41.83 mmol) were dissolved in a mixture of THF / DMF (42 mL / 15 mL), and 2 mol / L NaHMDS solution (8.37 mL, 16.73 mmol) was added dropwise with stirring. After the addition was completed, the mixture was stirred at room temperature for about 2 h. After the reaction was completed, 100 mL of ethyl acetate was added, and then washed with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic phase was dried to obtain compound 2 as a white solid 10.66 g (10.33 mmol, 98.8%).

[0123] Preparation Example 3: General synthesis method of compound 3-5

[0124] Compound 2 was dissolved in acetonitrile, and amine (ethylenediamine, 40% aqueous methylamine solution, or ethylamine) (10-20 eq) was added at room temperature, and stirred for 4-8 h. After the reaction was completed, ethyl acetate was added, and then washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively. The organic phase was dried to obtain the target compound 3-5.

[0125] Synthesis of compound 3

[0126] Using compound 2 (8.00 g, 7.75 mmol) and ethylenediamine (5.18 mL, 77.50 mmol) as raw materials, compound 3 (5.27 g, 5.14 mmol, 66.3%) was obtained according to the general synthesis method of the preparation example.

[0127] Synthesis of compound 4

[0128] Using compound 2 (26.44 g, 25.62 mmol) and 40% aqueous methylamine solution (20 mL, 256.19 mmol) as raw materials, compound 4 (19.36 g, 19.47 mmol, 76.0%) was obtained according to the general synthesis method of the preparation example.

[0129] Synthesis of compound 5

[0130] Using compound 2 (10.00 g, 9.69 mmol) and ethylamine (7 mL, 96.88 mmol) as raw materials, compound 5 (5.25 g, 5.21 mmol, 53.7%) was obtained according to the general synthesis method of the preparation example.

[0131] Preparation Example 4: Synthesis of compound 6

[0132] Compound 2 (3.85 g, 3.73 mmol) and telimycin side chain reagent W3 (0.80 g, 3.69 mmol) were dissolved in DMF / THF, DBU (0.52 mL, 3.73 mmol) was added, and the reaction was carried out at 50°C for 8 h. After the reaction was completed, ethyl acetate was added, and then the mixture was washed with water, saturated sodium bicarbonate, and saturated sodium chloride, respectively. The organic layer was dried to obtain compound 6 (3.60 g, 3.05 mmol, 81.7%).

[0133] Preparation Example 5: Synthesis of compound 7

[0134] Compound 3 (5.27 g, 5.14 mmol) was dissolved in ethanol (50 mL), and acetic acid (0.55 mL, 9.77 mmol) was added. After the reaction was completed, 2M hydrochloric acid solution was added, and the mixture was stirred at 40°C for 2 h on an oil bath. After the reaction was completed, water and methyl tert-butyl ether were added, and the water layer was added with ethyl acetate and adjusted to pH 10. The ethyl acetate layer was washed with water and saturated brine, respectively. The organic layer was dried and purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane: ethanol: ammonia water = 10 / 0.2 / 0.1) to obtain the target compound 7 (3.14 g, 4.72 mmol, 91.8%). HRMS (ESI) (M+H) + m / z 744.4409, calcd for C 40 H 62 N30 10 744.4430. 1H NMR (CDC13, 400 MHz) δ: 8.10-8.04 (m, 2H, 2H-Bz), 7.60-7.53 (m, 1H, H-Bz), 7.49-7.41 (m, 2H, 2H-Bz), 5.09-4.99 (m, 2H, H-13, H-2'), 4.72 (d, J = 7.5 Hz, 1H, H-1'), 3.97 (dt, J = 2.8 Hz, 14.3 Hz, 1H, CH2), 3.85-3.69 (m, 3H, H-5, CH2), 3.66 (s, 1H, H-11), 3.61-3.52 (m, 1H, H-5'), 3.46 (dd, J = 6.6 Hz, 10.6 Hz, 1H, H-3), 3.01-2.94 (s, 4H, 6-O-CH3, CH2), 2.94-2.84 (m, 1H, H-3'), 2.71-2.55 (m, 3H, H-10, H-2, H-8), 2.28 (s, 6H, -N(CH3)2), 1.97-1.84 (m, 2H, H-4, H-14eq), 1.84 (d, J = 6.7 Hz, 1H, 3-OH), 1.84-1.73 (m, 1H, H-4'a), 1.52-1.29 (m, 10H, H-7a, H-7b, H-14ax, H-4'b, 12-CH3, 6-CH3), 1.27 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.23 (d, J = 6.7 Hz, 3H, 2-CH3), 1.16 (d, J = 6.8 Hz, 3H, 10-CH3), 0.98 (d, J = 7.1 Hz, 3H, 8-CH3), 0.80 (t, J = 7.4 Hz, 3H, 15-CH3), 0.70 (d, J = 7.5 Hz, 3H, 4-CH3). 13 C NMR (CDC13, 100 MHz) δ: 181.27, 175.35, 165.33, 156.39, 132.68, 130.74, 129.77, 128.25, 99.98, 81.90, 80.37, 78.76, 77.67, 75.47, 72.12, 69.03, 63.36, 60.23, 49.44, 49.24, 44.20, 43.41, 42.62, 40.85, 37.88, 36.55, 36.21, 32.02, 21.99, 21.19, 19.68, 19.37, 15.34, 12.65, 11.05, 10.21, 7.74.

[0135] Preparation Example 6: General synthetic procedure for compounds 8-11

[0136] Compound 4-6 was dissolved in ethanol (40 mL), 2M hydrochloric acid solution (40 mL) was added, and stirred for 2 h at 40°C in an oil bath. After the reaction was completed, water and methyl tert-butyl ether were added, the water layer was added with ethyl acetate and adjusted to pH 10, the ethyl acetate layer was washed with water and saturated brine, respectively, and the organic layer was spin dried to obtain the target compound 8-11 by column chromatography.

[0137] Synthesis of compound 8

[0138] Compound 8 (12.89 g, 17.59 mmol, 90.3%) was obtained by using compound 4 (19.36 g, 19.47 mmol) as a raw material, following the general synthetic method of the present preparation example, and purifying the product by column chromatography (100-200 mesh silica gel, developing agent: dichloromethane: ethanol: ammonia water = 10 / 0.2 / 0.1). HRMS (ESI) (M+H) + m / z 733.4238, calcd for C 39 H 61 N2O 11 733.4270. 1H NMR (CDC13, 400 MHz) δ: 8.10-8.03 (m, 2H, 2H-Bz), 7.61-7.53 (m, 1H, H-Bz), 7.49-7.41 (m, 2H, 2H-Bz), 5.04 (dd, J = 7.6 Hz, 10.5 Hz, 1H, H-2'), 4.99 (dd, J = 2.4 Hz, 11.0 Hz, 1H, H-13), 4.75 (d, J = 7.6 Hz, 1H, H-1'), 3.75 (d, J = 2.7 Hz, 1H, H-5), 3.63-3.51 (m, 2H, H-11, H-5'), 3.42 (dd, J = 6.5 Hz, 10.6 Hz, 1H, H-3), 3.06 (s, 3H, CH3), 2.93 (s, 3H, 6-O-CH3), 2.92-2.84 (m, 2H, H-3', H-10), 2.66-2.57 (m, 1H, H-2), 2.56-2.47 (m, 1H, H-8), 2.27 (s, 6H, -N(CH3)2), 2.03-1.83 (m, 3H, 3-OH, H-4, H-14eq), 1.83-1.74 (m, 1H, H-4'a), 1.58-1.49 (m, 1H, H-7a), 1.49-1.35 (m, 3H, H-7b, H-14ax, H-4'a), 1.34-1.28 (m, 6H, 12-CH3, 6-CH3), 1.27 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.22 (d, J = 6.8 Hz, 3H, 2-CH3), 1.07 (d, J = 7.11 Hz, 3H, 8-CH3), 1.01 (d, J = 6.7 Hz, 3H, 10-CH3), 0.79 (t, J = 7.3 Hz, 3H, 15-CH3), 0.71 (d, J = 7.5 Hz, 3H, 4-CH3).

[0139] Synthesis of compound 9

[0140] Using compound 5 (5.25 g, 5.21 mmol) as starting material, the product was prepared according to the general procedure of the preparation example and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.2 / 0.1) to give compound 9 (3.62 g, 4.84 mmol, 92.9%). HRMS (ESI) (M+H) + m / z 747.4393, calcd for C 40 H 63 N2O 11 747.4426. 1H NMR (CDC13, 400 MHz) δ: 8.14-8.01 (m, 2H, 2H-Bz), 7.61-7.51 (m, 1H, H-Bz), 7.50-7.40 (m, 2H, 2H-Bz), 5.09-4.95 (m, 2H, H-13, H-2'), 4.75 (d, J = 7.6 Hz, 1H, H-1'), 3.77 (d, J = 2.7 Hz, 1H, H-5), 3.71-3.46 (m, 4H, H-11, H-5', CH2), 3.41 (dd, J = 6.1 Hz, 10.6 Hz, 1H, H-3), 3.01-2.83 (m, 5H, H-3', 6-0-CH3, H-10), 2.68-2.56 (m, 1H, H-2), 2.57-2.47 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 2.01 (s, 1H, 3-OH), 1.97-1.82 (m, 2H, H-4, H-14eq), 1.83-1.72 (m, 1H, H-4'a), 1.62-1.50 (m, 1H, H-7a), 1.50-1.36 (m, 3H, H-7b, H-14ax, H-4'a), 1.32 (s, 9H, 12-CH3, 6-CH3, 5'-CH3), 1.24-1.15 (m, 6H, CH3, 2-CH3), 1.07 (d, J = 7.1 Hz, 3H, 8-CH3), 1.00 (d, J = 6.7 Hz, 3H, 10-CH3), 0.79 (t, J = 7.2 Hz, 3H, 15-CH3), 0.72 (d, J = 7.4 Hz, 3H, 4-CH3).

[0141] Synthesis of compound 10

[0142] Compound 3 (8.42 g, 8.22 mmol) was dissolved in dichloromethane, CbzCl (1.2 mL, 9.04 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the organic phase was washed with water, saturated sodium bicarbonate, and saturated brine, respectively, and then dried to obtain an intermediate. The intermediate was subjected to the general synthetic method of this preparation example to remove the sugar at the 3-position, and column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane: ethanol: ammonia water = 10 / 0.2 / 0.1) was performed to obtain compound 10 (3.73 g, 4.16 mmol, 50.6 %). HRMS (ESI) (M+H) + m / z 896.4915, calcd for C 48 H70N3O 13 896.4903. 1H NMR (CDC13, 400 MHz) δ: 8.10-8.02 (m, 2H, 2H-Bz), 7.60-7.52 (m, 1H, H-Bz), 7.48-7.42 (m, 2H, 2H-Bz), 7.37-7.27 (m, 5H, Bn), 5.79 (t, J = 5.4 Hz, 1H, NH), 5.16-4.96 (m, 4H, CH2, H-13, H-2'), 4.71 (d, J = 7.6 Hz, 1H, H-1'), 3.96-3.83 (m, 1H, CH2), 3.74 (d, J = 3.0 Hz, 1H, H-5), 3.71-3.61 (m, 1H, CH2), 3.61-3.50 (m, 3H, H-11, CH2), 3.48 (dd, J = 6.5 Hz, 10.6 Hz, 1H, H-3), 3.33-3.22 (m, 1H, H-5'), 2.93 (s, 3H, 6-O-CH3), 2.91-2.83 (m, 1H, H-3'), 2.65-2.57 (m, 1H, H-2), 2.56-2.46 (m, 1H, H-8), 2.29 (s, 6H, -N(CH3)2), 1.95-1.82 (m, 4H, H-4, H-14eq, 3-OH, H-4'a), 1.59-1.35 (m, 4H, H-7a, H-7b, H-14ax, H-4'b), 1.34-1.29 (m, 6H, 12-CH3, 6-CH3), 1.28 (d, J = 6.2 Hz, 3H, 5'-CH3), 1.22 (d, J = 6.7 Hz, 3H, 2-CH3), 1.07 (d, J = 7.2 Hz, 3H, 8-CH3), 0.99 (d, J = 6.8 Hz, 3H, 10-CH3), 0.75-0.64 (m, 6H, 15-CH3, 4-CH3).

[0143] Synthesis of compound 11

[0144] Synthesis of compound 11 was carried out using compound 6 (3.60 g, 3.05 mmol) as a starting material according to the general synthetic method of the preparation example, and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane: ethanol: ammonia water = 10 / 0.2 / 0.1) to obtain compound 11 (2.05 g, 2.23 mmol, 73.1%).

[0145] Preparation Example 7: General synthetic method of compounds 12-16

[0146] In a round bottom flask was added compound 7-11 (1 eq), DMAP (2 eq), CDI (3 eq), anhydrous dichloromethane was added, and the reaction was allowed to proceed at room temperature for 12 h. After monitoring the reaction completion by TLC, dichloromethane was added, and the organic phase was washed successively with saturated ammonium chloride, saturated sodium bicarbonate, water, and saturated brine, and was then dried over sodium sulfate to give the target compound 12-16 as a white solid.

[0147] Synthesis of compound 12

[0148] Using compound 7 (3.14 g, 4.72 mmol) as the starting material, compound 12 (3.06 g, 3.65 mmol, 77.3%) was obtained according to the general synthetic method of the present preparation example.

[0149] Synthesis of compound 13

[0150] Using compound 8 (12.89 g, 17.59 mmol) as the starting material, compound 13 (13.80 g, 15.05 mmol, 85.6%) was obtained according to the general synthetic method of the present preparation example.

[0151] Synthesis of compound 14

[0152] Using compound 9 (3.62 g, 4.84 mmol) as the starting material, compound 14 (3.85 g, 4.13 mmol, 85.3%) was obtained according to the general synthetic method of the present preparation example.

[0153] Synthesis of compound 15

[0154] Using compound 10 (3.73 g, 4.16 mmol) as the starting material, compound 15 (3.20 g, 3.23 mmol, 77.6%) was obtained according to the general synthetic method of the present preparation example.

[0155] Synthesis of compound 16

[0156] Using compound 11 (2.05 g, 2.23 mmol) as the starting material, compound 16 (2.10 g, 1.90 mmol, 85.2%) was obtained according to the general synthetic method of the present preparation example.

[0157] Preparation Example 8: General synthetic method of compounds 17-21, 27-31

[0158] Compounds 12-16 (1 eq) were dissolved in DMF, and side chains (W1 or W2) (1.3-1.5 eq) and DBU (1 eq) were added dropwise at room temperature. The reaction was carried out at room temperature for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was evaporated to dryness to obtain the intermediate. The intermediate was dissolved in 4 mL of ethanol, and then 2 mL of 12 M HCl was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, dichloromethane was added, and the pH was adjusted to 10 with ammonia. The organic phase was washed with water, saturated sodium bicarbonate, and saturated brine, respectively. The organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography or recrystallization to obtain the compound.

[0159] Synthesis of Compound 17

[0160] Compound 12 (1.50 g, 1.79 mmol) and side chain W1 (0.77 g, 2.68 mmol) were used. o Using l) as the starting material, compound 17 was prepared according to the general synthetic method of this preparation example. The product was recrystallized from ethyl acetate to obtain compound 17 (1.03 g, 1.11 mm). o l, 62.0%). HRMS(ESI)(M+H) + m / z 928.5629, calcd for C 49 H 78 N5O 12 928.5641. 1H NMR (CDC13, 400 MHz) δ: 8.09-7.96 (m, 2H, 2H-Bz), 7.63-7.53 (m, 1H, H-Bz), 7.49-7.40 (m, 2H, 2H-Bz), 5.45 (t, J = 5.5 Hz, 1H, CONH), 5.05 (dd, J = 2.2 Hz, 10.9 Hz, 1H, H-13), 5.00 (dd, J = 7.6 Hz, 10.5 Hz, 1H, H-2'), 4.88 (d, J = 11.1 Hz, 1H, H-3), 4.30 (d, J = 7.5 Hz, 1H, H-1'), 4.01-3.91 (m, 1H, CH2), 3.86 (d, J = 3.4 Hz, 1H, H-5), 3.82-3.69 (m, 2H, CH2, O-CH), 3.66 (s, 1H, H-11), 3.66-3.56 (m, 2H, O-CH2), 3.51-3.34 (m, 3H, 3-O-CO-NH-CH2, CH2, H-5'), 3.33-3.22 (m, 1H, 3-O-CO-NH-CH2), 3.15-3.09 (m, 2H, -N-(CH2-CH2)2), 3.07 (s, 3H, 6-O-CH3), 3.03-2.93 (m, 1H, CH2), 2.90-2.79 (m, 1H, H-3'), 2.79-2.70 (m, 1H, H-2), 2.70-2.55 (m, 4H, H-10, H-8, -N-(CH2-CH2)2), 2.28 (s, 6H, -N(CH3)2), 2.01-1.90 (m, 3H, H-4, CH2), 1.91-1.79 (m, 3H, -N-(CH2-CH2)2, H-14ax), 1.79-1.69 (m, 1H, H-4'a), 1.54-1.38 (m, 4H, H-7b, H-7a, H-14eq, H-4'b), 1.36-1.29 (m, 8H, 12-CH3, -N-(CH2-CH2)2, 6-CH3), 1.27 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.15 (d, J = 6.8 Hz, 3H, 2-CH3,), 1.11 (d, J = 6.8 Hz, 3H, 10-CH3), 0.99 (d, J = 7.1 Hz, 3H, 8-CH3), 0.80 (t, J = 7.3 Hz, 3H, 15-CH3), 0.74 (d, J = 7.5 Hz, 3H, 4-CH3).

[0161] Synthesis of compound 27

[0162] Prepared according to the general procedure of the previous example using compound 12 (1.56 g, 1.86 mmol) and side chain W2 (0.69 g, 2.43 mmol) as starting materials. The product was recrystallized from ethyl acetate to give compound 27 (1.05 g, 1.13 mmol, 60.7 %). HRMS (ESI) (M+H) o m / z 928.5610, calcd for C + H 49 H 78 N5O 12 928.5641. 1H NMR (CDC13, 400 MHz) δ: 8.09-8.00 (m, 2H, 2H-Bz), 7.62-7.54 (m, 1H, H-Bz), 7.50-7.41 (m, 2H, 2H-Bz), 5.45 (t, J = 5.6 Hz, 1H, CONH), 5.05 (dd, J = 2.2 Hz, 11.0 Hz, 1H, H-13), 5.00 (dd, J = 8.3 Hz, 11.2 Hz, 1H, H-2'), 4.88 (d, J = 11.0 Hz, 1H, H-3), 4.30 (d, J = 7.5 Hz, 1H, H-1'), 4.01-3.91 (m, 1H, CH2), 3.86 (d, J = 3.4 Hz, 1H, H-5), 3.83-3.69 (m, 2H, CH2), 3.66 (s, 1H, H-11), 3.60-3.52 (m, 2H, O-CH2), 3.50-3.33 (m, 4H, 3-O-CO-NH-CH2, O-CH2, H-5'), 3.31-3.21 (m, 1H, 3-O-CO-NH-CH2), 3.08 (s, 3H, 6-O-CH3), 3.06-2.69 (m, 7H, 3H-pyrrolyl, CH2, H-3', H-2, H-10), 2.68-2.57 (m, 2H, H-8, H-pyrrolyl, 2.46-2.33 (m, 1H, H-pyrrolyl), 2.28 (s, 6H, -N(CH3)2), 2.03-1.78 (m, 7H, H-4, CH2, 2H-pyrrolyl, H-14ax, H-7a), 1.79-1.70 (m, 1H, H-4'a), 1.54-1.37 (m, 3H, H-7b, H-14eq, H-4'b), 1.37-1.29 (m, 6H, 12-CH3, 6-CH3), 1.27 (d, J = 6.0 Hz, 3H, 5'-CH3), 1.15 (d, J = 6.9 Hz, 3H, 2-CH3), 1.11 (d, J = 6.8 Hz, 3H, 10-CH3), 0.99 (d, J = 7.1 Hz, 3H, 8-CH3), 0.79 (t, J = 7.3 Hz, 3H, 15-CH3), 0.74 (d, J = 7.5 Hz, 3H, 4-CH3).

[0163] Synthesis of compound 18

[0164] Compound 18 was prepared using compound 13 (1.50 g, 1.81 mmol) and side chain W1 (0.78 g, 2.72 mmol) as starting materials, following the general synthetic method of this preparation example. The product was recrystallized from ethyl acetate to give compound 18 (0.65 g, 0.71 mmol, 39.2%). HRMS(ESI)(M+H) + m / z 917.5503, calcd for C 48 H 77 N4O13917.5482. 1 H NMR (CDCl3, 400MHz) δ: 8.09-8.00 (m, 2H, 2H-Bz), 7.61-7.54 (m, 1H, H-Bz), 7.50-7.41 (m, 2H, 2H-Bz), 5.47 (t, J=5.6Hz, 1H, CONH), 5.04-4.9 6 (m, 2H, H-13, H-2′), 4.83 (d, J=11.1Hz, 1H, H-3), 4.30 (d, J=7.5Hz, 1H, H-1′), 3.86 (d, J=3.4Hz, 1H, H-5), 3.67-3.57 (m, 2H, O-CH2), 3.55( s1H, H-11), 3.50-3.34 (m, 3H, O-CH, 3-O-CO-NH-CH2, H-5'), 3.34-3.23 (m, 1H, 3-O-CO-NH-CH2), 3.15-3.08 (m, 2H, -N-(CH2-CH2)2), 3.06 (s, 3H, 6-O-CH3), 3.02 (s, 3H, NCH3), 2.92 (q, J = 6.8 Hz, 1H, H-10), 2.87-2.73 (m, 1H, H-3', H-2), 2.70-2.59 (m, 2H, -N-(CH2-CH2)2), 2.58-2.47 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 2.03-1.91 (m, 3H, H-4, CH2), 1.91-1.80 (m, 3H, -N-(CH2-CH2)2, H-14ax), 1.79-1.71 (m, 1H, H-4'a), 1.53-1.36 (m, 6H, H-7b, H-7a, H-14eq, H-4'b, -N-(CH2-CH2)2), 1.33-1.28 (m, 6H, 12-CH3, 6-CH3), 1.26 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.11 (d, J = 6.7 Hz, 3H, 2-CH3), 1.07 (d, J = 7.1 Hz, 3H, 8-CH3), 1.00 (d, J = 6.7 Hz, 3H, 10-CH3), 0.79 (t, J = 7.4 Hz, 3H, 15-CH3), 0.75 (d, J = 7.5 Hz, 3H, 4-CH3).

[0165] Synthesis of compound 28

[0166] Using compound 13 (1.54 g, 1.87 mmol) and side chain W2 (0.69 g, 2.43 mmol) as starting materials, the product was prepared according to the general synthetic procedure of the preparation example, and recrystallized using ethyl acetate to give compound 28 (0.98 g, 1.07 mmol, 57.2 %). HRMS (ESI) (M+H) + m / z 917.5499, calcd for C 48 H 77 N4O 13 917.5482. 1H NMR (CDC13, 400 MHz) δ: 8.10-8.01 (m, 2H, 2H-Bz), 7.62-7.54 (m, 1H, H-Bz), 7.51-7.41 (m, 2H, 2H-Bz), 5.47 (t, J = 5.6 Hz, 1H, CONH), 5.04-4.96 (m, 2H, H-13, H-2'), 4.83 (d, J = 11.1 Hz, 1H, H-3), 4.30 (d, J = 7.5 Hz, 1H, H-1'), 3.86 (d, J = 3.5 Hz, 1H, H-5), 3.63-3.51 (m, 3H, H-11, O-CH2), 3.51-3.35 (m, 4H, 3-O-CO-NH-CH2, O-CH2, H-5'), 3.31-3.20 (m, 1H, 3-O-CO-NH-CH2), 3.08 (s, 3H, 6-O-CH3), 3.03 (s, 3H, NCH3), 3.00-2.69 (m, 8H, 4H-pyrrolyl, CH2, H-3', H-2, H-10), 2.58-2.48 (m, 1H, H-8), 2.46-2.33 (m, 1H, H-pyrrolyl), 2.28 (s, 6H, -N(CH3)2), 2.07-1.79 (m, 7H, H-4, CH2, 2H-pyrrolyl, H-14ax, H-7a), 1.79-1.70 (m, 1H, H-4'a), 1.54-1.37 (m, 4H, H-7b, H-14eq, NH, H-4'b), 1.34-1.28 (m, 6H, 12-CH3, 6-CH3), 1.26 (d, J = 6.0 Hz, 3H, 5'-CH3), 1.10 (d, J = 6.8 Hz, 3H, 2-CH3,), 1.07 (d, J = 7.1 Hz, 3H, 8-CH3), 1.00 (d, J = 6.7 Hz, 3H, 10-CH3), 0.79 (t, J = 7.3 Hz, 3H, 15-CH3), 0.75 (d, J = 7.7 Hz, 3H, 4-CH3).

[0167] Synthesis of compound 19

[0168] Using compound 14 (1.50 g, 1.78 mmol) and side chain W1 (0.76 g, 2.68 mmol) as starting material, prepared according to the general procedure of the preparation example, purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give compound 19 (0.71 g, 0.76 mmol, 42.7%). HRMS (ESI) (M+H) +m / z 931.5660, calcd for C 49 H 79 N4O 13 931.5638. 1 H NMR (CDC13, 400 MHz) δ: 8.10-7.99 (m, 2H, 2H-Bz), 7.61-7.53 (m, 1H, H-Bz), 7.50-7.41 (m, 2H, 2H-Bz), 5.51 (t, J = 5.5 Hz, 1H, CONH), 5.06-4.96 (m, 2H, H-13, H-2'), 4.83 (d, J = 11.1 Hz, 1H, H-3), 4.32 (d, J = 7.5 Hz, 1H, H-1'), 3.87 (d, J = 3.4 Hz, 1H, H-5), 3.75-3.52 (m, 5H, O-CH2, H-11, NCH2CH3), 3.50-3.34 (m, 3H, O-CH, 3-O-CO-NH-CH2, H-5'), 3.33-3.22 (m, 1H, 3-O-CO-NH-CH2), 3.15-3.06 (m, 2H, -N-(CH2-CH2)2), 3.04 (s, 3H, 6-O-CH3), 2.96 (q, J = 6.7 Hz, 1H, H-10), 2.89-2.73 (m, 1H, H-3', H-2), 2.70-2.57 (m, 2H, -N-(CH2-CH2)2), 2.57-2.47 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 2.06-1.80 (m, 5H, H-4, CH2, -N-(CH2-CH2)2, H-14ax), 1.80-1.71 (m, 1H, H-4'a), 1.62-1.35 (m, 7H, H-7b, H-7a, NH, H-14eq, H-4'b, -N-(CH2-CH2)2), 1.33-1.28 (m, 6H, 12-CH3, 6-CH3), 1.26 (d, J = 6.4 Hz, 3H, 5'-CH3), 1.21 (t, J = 7.1 Hz, 3H, NCH2CH3), 1.11 (d, J = 6.7 Hz, 3H, 2-CH3), 1.08 (d, J = 7.1 Hz, 3H, 8-CH3), 1.00 (d, J = 6.7 Hz, 3H, 10-CH3), 0.85-0.70 (m, 6H, 15-CH3, 4-CH3).

[0169] Synthesis of compound 29

[0170] Preparation of Compound 29 was performed using Compound 14 (1.57 g, 1.87 mmol) and side chain W2 (0.69 g, 2.43 mmol) as starting materials according to the general synthetic method of the preparation, and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give Compound 29 (0.58 g, 0.62 mmol, 33.2%). HRMS (ESI) (M+H) + m / z 931.5660, calcd for C 49 H 79 N4O 13 931.5638. 1H NMR (CDC13, 400 MHz) δ: 8.09-8.00 (m, 2H, 2H-Bz), 7.62-7.55 (m, 1H, H-Bz), 7.50-7.42 (m, 2H, 2H-Bz), 5.47 (t, J = 5.6 Hz, 1H, CONH), 5.07-4.96 (m, 2H, H-13, H-2'), 4.83 (d, J = 11.4 Hz, 1H, H-3), 4.31 (d, J = 7.5 Hz, 1H, H-1'), 3.87 (d, J = 3.5 Hz, 1H, H-5), 3.33-3.64 (m, 1H, NCH2CH3), 3.63 (s, 1H, H-11), 3.61-3.51 (m, 3H, O-CH2, NCH2CH3), 3.51-3.36 (m, 4H, 3-O-CO-NH-CH2, O-CH2, H-5'), 3.30-3.20 (m, 1H, 3-O-CO-NH-CH2), 3.11-3.05 (m, 1H, H-pyrrolyl), 3.04 (s, 3H, 6-O-CH3), 3.02-2.69 (m, 6H, 3H-pyrrolyl, H-3', H-2, H-10), 2.58-2.46 (m, 1H, H-8), 2.45-2.34 (m, 1H, H-pyrrolyl), 2.28 (s, 6H, -N(CH3)2), 2.08-1.79 (m, 6H, H-4, CH2, 2H-pyrrolyl, H-14ax), 1.79-1.71 (m, 1H, H-4'a), 1.55-1.36 (m, 5H, H-7b, H-14eq, H-7a, NH, H-4'b), 1.33-1.27 (m, 6H, 12-CH3, 6-CH3), 1.26 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.20 (t, J = 7.2 Hz, 3H, NCH2CH3), 1.11 (d, J = 6.8 Hz, 3H, 2-CH3,), 1.08 (d, J = 7.2 Hz, 3H, 8-CH3), 1.00 (d, J = 6.7 Hz, 3H, 10-CH3), 0.85-0.72 (m, 6H, 15-CH3, 4-CH3).

[0171] Synthesis of compound 20

[0172] Preparation of Compound 20 was performed using Compound 15 (1.50 g, 1.52 mmol) and side chain Wl (0.65 g, 2.27 mmol) as starting materials according to the general synthetic method of the preparation, and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give Compound 20 (0.66 g, 0.61 mmol, 40.1%). HRMS (ESI) (M+H) + m / z 1080.6102, calcd for C 57 H 86 N5O 15 1080.6115. 1H NMR (CDC13, 400 MHz) δ: 8.011-7.99 (m, 2H, 2H-Bz), 7.63-7.54 (m, 1H, H-Bz), 7.50-7.41 (m, 2H, 2H-Bz), 7.38-7.28 (m, 5H, Bn), 5.89 (t, J = 5.9 Hz, 1H, NH), 5.47 (t, J = 5.5 Hz, 1H, CONH), 5.18-4.93 (m, 4H, CH2, H-13, H-2'), 4.82 (d, J = 11.1 Hz, 1H, H-3), 4.31 (d, J = 7.5 Hz, 1H, H-1'), 4.01-3.88 (m, 1H, CH2), 3.86 (d, J = 3.7 Hz, 1H, H-5), 3.75-3.58 (m, 4H, CH2, O-CH2), 3.56 (s, 1H, H-11), 3.51-3.34 (m, 3H, 3-O-CO-NH-CH2, O-CH, H-5'), 3.33-3.15 (m, 2H, CH2, 3-O-CO-NH-CH2), 3.16-3.06 (m, 2H, -N-(CH2-CH2)2), 3.05 (s, 3H, 6-O-CH3), 3.03-2.94 (m, 1H, H-10), 2.89-2.73 (m, 2H, H-8, H-2), 2.70-2.58 (m, 2H, -N-(CH2-CH2)2), 2.57-2.46 (m, 1H, H-3'), 2.28 (s, 6H, -N(CH3)2), 2.02-1.68 (m, 7H, H-4, CH2, -N-(CH2-CH2)2, H-14ax, H-4'a), 1.54-1.38 (m, 6H, H-7b, H-7a, H-14eq, H-4, b, -N-(CH2-CH2)2), 1.33-1.21 (m, 9H, 12-CH3, 6-CH3, 5'-CH3), 1.16-1.04 (m, 6H, 2-CH3, 8-CH3), 0.89 (d, J = 6.7 Hz, 3H, 10-CH3), 0.76 (d, J = 7.6 Hz, 3H, 4-CH3), 0.74 (d, J = 7.2 Hz, 3H, 15-CH3).

[0173] Synthesis of compound 30

[0174] Preparation of compound 30 was carried out using compound 15 (1.50 g, 1.52 mmol) and side chain W2 (0.65 g, 2.27 mmol) as starting materials following the general synthetic method of this preparation example and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give compound 30 (0.33 g, 0.30 mmol, 19.7%). HRMS (ESI) (M+H) + m / z 1080.6117, calcd for C 57 H 86 N5O 15 1080.6115. 1H NMR (CDC13, 400 MHz) δ: 8.09-7.99 (m, 2H, 2H-Bz), 7.63-7.54 (m, 1H, H-Bz), 7.50-7.42 (m, 2H, 2H-Bz), 7.37-7.29 (m, 5H, Bn), 5.89 (t, J = 6.2 Hz, 1H, CONH), 5.47 (t, J = 5.6 Hz, 1H, CONH), 5.17-4.95 (dd, 4H, CH2, H-13, H-2'), 4.82 (d, J = 11.1 Hz, 1H, H-3), 4.31 (d, J = 7.5 Hz, 1H, H-1'), 3.99-3.89 (m, 1H, CH2), 3.87 (d, J = 3.7 Hz, 1H, H-5), 3.75-3.64 (m, 2H, CH2), 3.62-3.50 (m, 3H, H-11, O-CH2), 3.49-3.35 (m, 4H, 3-O-CO-NH-CH2, O-CH2, H-5'), 3.31-3.16 (m, 1H, 3-O-CO-NH-CH2), 3.04 (s, 3H, 6-O-CH3), 3.02-2.71 (m, 8H, 4H-pyrrolyl, CH2, H-3', H-2, H-10), 2.59-2.47 (m, 1H, H-8, 2.47-2.36 (m, 1H, H-pyrrolyl), 2.28 (s, 6H, -N(CH3)2), 2.01-1.70 (m, 8H, H-4, CH2, 2H-pyrrolyl, H-14ax, H-7a, H-4'a), 1.55-1.37 (m, 3H, H-7b, H-14eq, H-4'b), 1.34-1.21 (m, 9H, 12-CH3, 6-CH3, 5'-CH3), 1.16-1.05 (m, 6H, 2-CH3, 8-CH3), 0.98 (d, J = 6.8 Hz, 3H, 10-CH3), 0.76 (t, J = 7.4 Hz, 3H, 4-CH3), 0.67 (d, J = 7.3 Hz, 3H, 15-CH3).

[0175] Synthesis of compound 21

[0176] Using compound 16 (1.06 g, 1.04 mmol) and side chain Wl (0.39 g, 1.36 mmol) as starting material, compound 21 was prepared according to the general procedure of the preparation example and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give compound 21 (0.45 g, 0.41 mmol, 39.4%). HRMS (ESI) (M+H) +m / z 1102.6421, calcd for C 59 H 88 N7O 13 1102.6435. 1 H NMR (CDC13, 400 MHz) δ: 8.94 (d, J = 2.2 Hz, 1H, H-pyridyl), 8.44 (dd, J = 1.7 Hz, 4.8 Hz, 1H, H-pyridyl), 8.14-8.00 (m, 3H, H-pyridyl, 2H-Bz), 7.65-7.54 (m, 2H, H-pyridyl, H-Bz), 7.50-7.43 (m, 2H, 2H-Bz), 7.34 (s, 1H, H-imidazolyl), 7.31-7.24 (m, 1H, H-pyridyl), 5.49 (t, J = 5.5 Hz, 1H, 3-O-CO-NH), 5.07-4.94 (m, 2H, H-13, H-2'), 4.82 (d, J = 11.1 Hz, 1H, H-3), 4.32 (d, J = 7.5 Hz, 1H, H-1'), 4.11-3.98 (m, 2H, CH2), 3.85 (d, J = 3.7 Hz, 1H, H-5), 3.80-3.63 (m, 2H, CONCH2), 3.63-3.54 (m, 3H, H-11, CH20), 3.53-3.35 (m, 3H, H-5', OCH, 3-O-CO-NH-CH2), 3.18-3.07 (m, 1H, 3-O-CO-NH-CH2), 3.16-3.06 (m, 2H, -N-(CH2-CH2)2), 3.06-2.93 (m, 4H, H-10, 6-O-CH3), 2.89-2.75 (m, 2H, H-3', H-2), 2.75-2.62 (m, 2H, -N-(CH2-CH2)2), 2.60-2.46 (m, 1H, H-8), 2.29 (s, 6H, -N(CH3)2), 2.06-1.62 (m, 11H, H-4, CH2, H-14eq, H-4'a, H-7a, H-7b, -N-(CH2-CH2)2), 1.55-1.35 (m, 6H, 2(CH2), H-14ax, H-4'b), 1.33-1.20 (m, 9H, 12-CH3, 5'-CH3, 6-CH3), 1.13 (d, J = 6.7 Hz, 3H, 10-CH3), 1.09 (d, J = 7.1 Hz, 3H, 8-CH3), 0.98 (d, J = 6.7 Hz, 3H, 2-CH3), 0.82-0.69 (m, 6H, 15-CH3, 4-CH3).

[0177] Synthesis of compound 31

[0178] Using compound 16 (1.06 g, 1.04 mmol) and side chain W2 (0.39 g, 1.36 mmol) as the starting material, it was prepared according to the general synthetic procedure of the preparation example, and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.6 / 0.1) to give compound 31 (0.49 g, 0.44 mmol, 42.3%). HRMS (ESI) (M+H) + m / z 1102.6423, calcd for C 59 H 88 N7O 13 1102.6435. 1H NMR (CDC13, 400 MHz) δ: 8.94 (d, J = 2.2 Hz, IH, H-pyridyl), 8.44 (dd, J = 1.7 Hz, 4.8 Hz, IH, H-pyridyl), 8.11-8.01 (m, 3H, H-pyridyl, 2H-Bz), 7.63-7.52 (m, 2H, H-pyridyl, H-Bz), 7.50-7.42 (m, 2H, 2H-Bz), 7.35 (s, IH, H-imidazolyl), 7.31-7.24 (m, IH, H-pyridyl), 5.54 (t, J = 5.6 Hz, IH, 3-O-CO-NH), 5.07-4.93 (m, 2H, H-13, H-2'), 4.83 (d, J = 11.1 Hz, IH, H-3), 4.32 (d, J = 7.6 Hz, IH, H-I'), 4.08-3.97 (m, 2H, CH2), 3.85 (d, J = 3.7 Hz, IH, H-5), 3.80-3.63 (m, 2H, CONCH2), 3.60 (s, IH, H-11), 3.59-3.50 (m, 2H, CH20), 3.50-3.34 (m, 3H, H-5', OCH, 3-O-CO-NH-CH2), 3.30-3.17 (m, IH, 3-O-CO-NH-CH2), 3.14-3.05 (m, IH, H-pyrrolyl), 3.05-2.92 (m, 6H, H-10, 6-O-CH3, 2H-pyrrolyl), 2.89-2.73 (m, 3H, H-3', H-2, H-pyrrolyl), 2.59-2.48 (m, IH, H-8), 2.49-2.36 (m, 3H, 3H-pyrrolyl), 2.28 (s, 6H, -N(CH3)2), 2.04-1.65 (m, 9H, H-4, CH2, H-14eq, H-4'a, H-7a, H-7b, CH2), 1.56-1.36 (m, 4H, CH2, H-14ax, H-4'b), 1.34-1.21 (m, 9H, 12-CH3, 5'-CH3, 6-CH3), 1.13 (d, J = 6.7 Hz, 3H, 10-CH3), 1.09 (d, J = 7.1 Hz, 3H, 8-CH3), 0.98 (d, J = 6.7 Hz, 3H, 2-CH3), 0.82-0.68 (m, 6H, 15-CH3, 4-CH3).

[0179] Preparation 9: General synthesis of compounds 22-26, 32-36

[0180] Compound 17-21, 27-31 and compound Vl (1.5-2 eq) were dissolved in acetonitrile, triethylamine (3 eq) was added to the system, and then stirred in an oil bath at 75 °C for 8 h. After the reaction was completed, the acetonitrile was spun dry, the product was added to dichloromethane, washed with water and saturated brine respectively to obtain the intermediate. The intermediate was dissolved in ethanol, and then an equal volume of 2M sodium hydroxide solution was added, stirred at room temperature for 1 h to remove the borate protecting group, the product was added to dichloromethane, washed with water and saturated brine respectively, and then the organic phase was spun dry, the residue was dissolved in methanol to remove the benzoyl protecting group of 2' to obtain the target compound 22-26, 32-36.

[0181] Synthesis of compound 22

[0182] Using compound 17 (0.25 g, 0.27 mm o l) as raw material, prepared according to the general synthetic method of this preparation example, purified by column chromatography (100-200 mesh silica gel, developing agent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to obtain compound 22 (150.0 mg, 0.14 mmol, 51.8%). HRMS (ESI) (M+H) + m / z 1070.5825, calcd for C 54 H 81 FN7O 14 1070.5820. 1H NMR (CDCI3, 400 MHz) δ: 8.73 (s, 1 H, 2"-quinolyl), 8.06 (d, J = 13.3 Hz, 1 H, 5"-quinolyl), 5.29 (br, 1 H, CONH), 5.09 (dd, J = 2.2 Hz, 10.9 Hz, 1 H, H-13), 4.91 (d, J = 11.0 Hz, 1 H, H-3), 4.21-4.09 (m, 2H, -N-(CH2-CH2)2), 4.07-3.95 (m, 2H, H-1 ', CH2), 3.87-3.66 (m, 6H, -N-(CH2-CH2)2, H-5, H-11, CH2, O-CH), 3.67-3.54 (m, 4H, 1 H-cyclopropyl, CH2, O-CH2), 3.50-3.41 (m, 1 H, 3-O-CO-NH-CH2), 3.40-3.30 (m, 1 H, H-5'), 3.29-3.14 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.08 (s, 3H, 6-O-CH3), 3.06-2.95 (m, 1 H, CH2), 2.89-2.80 (m, 1 H, H-2), 2.77 (q, J = 6.8 Hz, 1 H, H-10), 2.71-2.67 (m, 1 H, H-8), 2.45-2.33 (m, 1 H, H-3'), 2.27 (s, 6H, -N(CH3)2), 2.14-2.07 (m, 1 H, H-4), 2.06-1.96 (m, 2H, CH2), 1.95-1.69 (m, 6H, -N-(CH2-CH2)2, H-14ax, H-7a, ), 1.66-1.46 (m, 4H, H-4'a, H-7b, H-14eq, H-4'b), 1.43 (s, 3H, 12-CH3), 1.32 (s, 3H, 6-CH3), 1.26 (d, J = 6.9 Hz, 2H, 2H-cyclopropyl), 1.24-1.17 (m, 6H, 2-CH3, 5'-CH3), 1.14 (d, J = 6.8 Hz, 3H, 10-CH3), 1.11-1.05 (m, 5H, 2H-cyclopropyl, 8-CH3), 1.03 (d, J = 7.1 Hz, 3H, 4-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 181.08, 174.59, 166.87, 156.37, 146.93, 146.48, 108.89, 103.27, 81.91, 78.64, 75.63, 74.07, 70.51, 69.54, 60.15, 49.46, 44.43, 44.34, 43.40, 42.63, 40.39, 39.33, 38.12, 36.62, 36.16, 34.65, 31.11, 30.19, 28.62, 21.94, 21.24, 19.79, 19.39, 15.05, 12.60, 11.06, 10.25, 8.95, 7.46.

[0183] Synthesis of compound 23

[0184] Compound 23 was prepared by the general method of the preparation using compound 18 (0.25 g, 0.27 mmol) as the starting material. Purification by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) gave compound 23 (184.4 mg, 0.17 mmol, 63.0 %). HRMS (ESI) (M+H) + m / z 1059.5660, calcd for C 53 H 80 FN6O 15 1059.5660. 1H NMR (CDCI3, 400 MHz) δ: 8.72 (s, 1 H, 2"-quinolyl), 8.06 (d, J = 13.3 Hz, 1 H, 5"-quinolyl), 5.28 (br, 1 H, CONH), 5.05 (dd, J = 2.4 Hz, 11.0 Hz, 1 H, H-13), 4.87 (d, J = 11.0 Hz, 1 H, H-3), 4.21-4.10 (m, 2H, -N-(CH2-CH2)2), 4.04 (d, J = 7.3 Hz, 1 H, H-1'), 3.81 (d, J = 3.1 Hz, 1 H, H-5), 3.76-3.52 (m, 7H, -N-(CH2-CH2)2, H-11, 1 H-cyclopropyl, CH-O-CH2), 3.50-3.40 (m, 1 H, 3-O-CO-NH-CH2), 3.40-3.31 (m, 1 H, H-5'), 3.30-3.13 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.08 (s, 3H, 6-O-CH3), 3.04 (s, 3H, NCH3), 3.03-2.97 (m, 1 H, H-10), 2.91-2.78 (m, 1 H, H-2), 2.61-2.51 (m, 1 H, H-8), 2.45-2.33 (m, 1 H, H-3'), 2.27 (s, 6H, -N(CH3)2), 2.18-2.06 (m, 1 H, H-4), 2.06-1.98 (m, 2H, CH2), 1.97-1.47 (m, 10H, -N-(CH2-CH2)2, H-14ax, H-7a, H-4'a, H-7b, H-14eq, H-4'b), 1.41 (s, 3H, 12-CH3), 1.30 (s, 3H, 6-CH3), 1.26 (d, J = 6.8 Hz, 2H, 2H-cyclopropyl), 1.26 (d, J = 6.8 Hz, 3H, 5'-CH3), 1.24-1.17 (m, 11 H, 2-CH3, 10-CH3, 2H-cyclopropyl, 8-CH3), 1.05 (d, J = 6.7 Hz, 3H, 10-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 215.21, 157.67, 146.49, 82.88, 80.76, 78.20, 74.09, 70.47, 69.59, 66.35, 62.44, 49.74, 45.72, 44.36, 43.34, 40.37, 39.33, 38.80, 38.50, 35.73, 34.65, 32.57, 31.11, 22.06, 21.22, 19.43, 18.70, 14.92, 14.07, 13.70, 10.22, 8.87, 7.47.

[0185] Synthesis of compound 24

[0186] Using compound 19 (0.25 g, 0.27 mmol) as the starting material, compound 24 (194.8 mg, 0.18 mmol, 66.7%) was prepared by following the general synthetic procedure of the preparation example and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4). HRMS (ESI) (M+H) + m / z 1073.5829, calcd for C 54 H 82 FN6O 15 1073.5817. 1H NMR (CDCI3, 400 MHz) δ: 8.72 (s, 1 H, 2"-quinolyl), 8.06 (d, J = 13.3 Hz, 1 H, 5"-quinolyl), 5.28 (t, J = 5.8 Hz, 1 H, CONH), 5.07 (dd, J = 2.6 Hz, 11.0 Hz, 1 H, H-13), 4.87 (d, J = 11.0 Hz, 1 H, H-3), 4.21-4.08 (m, 2H, -N-(CH2-CH2)2), 4.05 (d, J = 7.3 Hz, 1 H, H-1'), 3.83 (d, J = 3.1 Hz, 1 H, H-5), 3.78-3.51 (m, 8H, -N-(CH2-CH2)2, H-11, 1 H-cyclopropyl, CH-O-CH2, NCH2CH3), 3.49-3.40 (m, 1 H, 3-O-CO-NH-CH2), 3.41-3.32 (m, 1 H, H-5'), 3.29-3.13 (m, 3H, 3-O-CO-NH-CH2, H-2', NCH2CH3), 3.11-3.07 (m, 1 H, H-10), 3.06 (s, 3H, 6-O-CH3), 2.91-2.79 (m, 1 H, H-2), 2.62-2.49 (m, 1 H, H-8), 2.45-2.34 (m, 1 H, H-3'), 2.27 (s, 6H, -N(CH3)2), 2.18-2.07 (m, 1 H, H-4), 2.07-1.97 (m, 2H, CH2), 1.97-1.47 (m, 10H, -N-(CH2-CH2)2, H-14ax, H-7a, H-4'a, H-7b, H-14eq, H-4'b), 1.41 (s, 3H, 12-CH3), 1.30 (s, 3H, 6-CH3), 1.28-1.16 (m, 8H, 2H-cyclopropyl, 5'-CH3, 2-CH3), 1.18-1.07 (m, 11 H, 4-CH3, 10-CH3, 2H-cyclopropyl, NCH2CH3), 1.04 (d, J = 7.2 Hz, 3H, 8-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 215.59, 174.44, 166.87, 157.08, 146.49, 103.17, 82.68, 80.52, 78.27, 70.49, 60.12, 50.05, 45.77, 44.44, 40.38, 38.78, 38.69, 38.49, 34.65, 31.12, 30.20, 22.12, 21.23, 19.50, 18.98, 14.88, 14.37, 14.06, 12.48, 10.27, 8.93, 7.46.

[0187] Synthesis of compound 25

[0188] Using compound 20 (0.30 g, 0.23 mmol) as starting material, the intermediate was obtained following the general procedure of the preparation example. The intermediate was dissolved in methanol and Pd / C (0.080 g) was added. The reaction was carried out at room temperature under hydrogen atmosphere. After the reaction was completed, the Pd / C was removed by suction filtration. The filtrate was rotary evaporated and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to give compound 25 (50.2 mg, 0.046 mmol, 20.0 %). HRMS (ESI) (M+H) + m / z 1088.5940, calcd for C 54 H 83 FN7O 15 1088.5926. 1H NMR (CDCI3, 400 MHz) δ: 8.69 (s, 1 H, 2"-quinolyl), 7.96 (d, J = 13.8 Hz, 1 H, 5"-quinolyl), 5.08 (dd, J = 2.7 Hz, 10.8 Hz, 1 H, H-13), 4.81 (d, J = 11.0 Hz, 1 H, H-3), 4.26-4.09 (m, 3H, H-1 ', -N-(CH2-CH2)2), 3.88 (d, J = 3.4 Hz, 1 H, H-5), 3.82-3.54 (m, 9H, CH2, -N-(CH2-CH2)2, H-11, CH2-O-CH, 1 H-cyclopropyl), 3.50-3.35 (m, 2H, 3-O-CO-NH-CH2, H-5'), 3.29-3.18 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.17-3.07 (m, 1 H, CH2), 3.04 (s, 3H, 6-O-CH3), 3.01-2.84 (m, 3H, CH2, H-2, H-10), 2.73-2.60 (m, 1 H, H-3'), 2.58-2.47 (m, 1 H, H-8), 2.37 (s, 6H, -N(CH3)2), 2.17-2.07 (m, 1 H, H-4), 2.07-1.92 (m, 2H, CH2), 1.92-1.55 (m, 10H, -N-(CH2-CH2)2, H-14ax, H-7a, H-4'a, H-7b, H-14eq, H-4'b), 1.48 (s, 3H, 12-CH3), 1.26 (s, 3H, 6-CH3), 1.23 (d, J = 6.4 Hz, 2H, 2H-cyclopropyl), 1.19 (d, J = 6.7 Hz, 3H, 2-CH3), 1.17-1.09 (m, 9H, 5'-CH3, 10-CH3, 8-CH3), 1.08-1.04 (m, 2H, 2H-cyclopropyl,), 1.02 (d, J = 6.8 Hz, 3H, 4-CH3), 0.85 (t, J = 7.2 Hz, 3H, 15-CH3). 13C NMR (CD3OD, 100 MHz) δ: 216.76, 176.46, 175.16, 158.46, 157.32, 101.87, 83.83, 78.39, 78.09, 77.65, 76.98, 75.94, 74.03, 70.80, 68.79, 64.92, 64.40, 60.82, 49.35, 45.73, 45.31, 44.21, 43.08, 39.55, 38.71, 38.23, 37.96, 35.79, 34.08, 30.94, 29.98, 21.78, 20.07, 18.64, 17.64, 13.95, 13.34, 12.90, 9.30, 7.97, 6.48.

[0189] Synthesis of compound 26

[0190] Using compound 21 (0.25, 0.23 mmol) as the starting material, compound 26 (111.3 mg, 0.089 mmol, 38.7%) was prepared by following the general synthetic procedure under the preparation examples and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4). HRMS (ESI) (M+H) + m / z 1244.6611, calcd for C 64 H 91 FN9O 15 1244.6613. 1H NMR(CDCl3,400MHz)δ:8.94(d,J=2.2Hz,1H,H-pyridyl),8.72(s,1H,2″-quinolyl),8.44(dd,J=1.7Hz,4.8Hz,1H,H-pyridyl),8.12-7.99(m,2H,5″-quinolyl,H-pyridyl),7.55(s,1H,H-imidazolyl),7.37(s,1H,H-imidazolyl),7.32-7.24(m,1H,H-pyridyl),5.34(br,1H,CONH),5.04(dd,J=2.4Hz,10.9Hz,1H,H-13),4.86(d,J=11.0Hz,1H,H-3),4.23-4.09(m,2H,-N-(CH2-CH2)2),4.10-3.97(m,3H,H-1′,CH2),3.87-3.73(m,2H,H-5,CONCH2),3.73-3.50(m,8H,H-11,H-cyclopropyl,CHOCH2,CONCH2,-N-(CH2-CH2)2),3.48-3.30(m,3H,H-5′,OCH2,3-O-CO-NH-CH2),3.28-3.14(m,2H,H-2′,3-O-CO-NH-CH2),3.10(q,J=6.9Hz,1H,H-10),3.04(s,3H,6-O-CH3),2.93-2.81(m,1H,H-2),2.63-2.50(m,1H,H-8),2.46-2.32(m,1H,H-3′),2.27(s,6H,-N(CH3)2),2.18-2.07(m,1H,H-4),2.07-1.80(m,8H,-N-(CH2-CH2)2,CH2,H-4′a,H-14ax),1.80-1.50(m,8H,H-7a,H-4′b,H-14eq,2(CH2),H-7b),1.42(m,3H,12-CH3),1.28(s,3H,6-CH3),1.27-1.19(m,5H,5′-CH3,2H-cyclopropyl),1.19-1.06(m,11H,2-CH3,8-CH3,10-CH3,2H-cyclopropyl),1.03(d,J=6.7Hz,4-CH3),0.77(t,J=7.3Hz,3H,15-CH3). 13C NMR (CDC13, 100 MHz) δ: 215.81, 177.09, 166.87, 157.43, 147.57, 146.91, 146.47, 139.05, 137.80, 131.98, 130.34, 123.51, 115.60, 108.88, 87.74, 82.80, 78.39, 70.46, 69.62, 66.11, 56.32, 56.22, 50.17, 46.93, 45.81, 44.46, 43.15, 42.70, 40.36, 38.84, 38.53, 34.64, 31.13, 28.84, 24.34, 22.11, 21.22, 19.50, 19.00, 14.89, 14.36, 14.19, 10.36, 8.88, 7.46.

[0191] Synthesis of compound 32

[0192] Compound 32 was prepared by the general method of the preparation using compound 27 (0.25 g, 0.27 mmol) as the starting material. Purification by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) gave compound 32 (182.8 mg, 0.17 mmol, 63.0 %). HRMS (ESI) (M+H) + m / z 1070.5862, calcd for C 54 H81FN7O 14 1070.5820. 1H NMR (CDCI3, 400 MHz) δ: 8.66 (s, 1 H, 2"-quinolyl), 7.95 (d, J = 12.5 Hz, 1 H, 5"-quinolyl), 5.26 (d, J = 5.8 Hz, 1 H, CONH), 5.09 (dd, J = 2.2 Hz, 11.0 Hz, 1 H, H-13), 4.91 (d, J = 11.0 Hz, 1 H, H-3), 4.07-3.92 (m, 3H, 1 H-pyrrolyl, H-1 ', CH2), 3.88-3.74 (m, 4H, 1 H-pyrrolyl, H-5, CH2), 3.72 (s, 1 H, H-11), 3.66-3.60 (m, 1 H, 1 H-cyclopropyl), 3.57 (t, J = 11.0 Hz, OCH2), 3.52 (d, J = 6.5 Hz, OCH2), 3.47-3.31 (m, 2H, 3-O-CO-NH-CH2, H-5'), 3.30-3.14 (m, 3H, 1 H-pyrrolyl, 3-O-CO-NH-CH2, H-2'), 3.08 (s, 3H, 6-O-CH3), 3.05-2.94 (m, 1 H, CH2), 2.87-2.72 (m, 2H, H-2, 1 H-pyrrolyl), 2.72-2.59 (m, 2H, H-10, H-8), 2.46-2.35 (m, 1 H, H-3'), 2.28 (s, 6H, -N(CH3)2), 2.23-2.13 (m, 1 H, 1 H-pyrrolyl), 2.14-2.05 (m, 1 H, H-4), 1.96-1.74 (m, 5H, 2H-pyrrolyl, H-14ax, H-7a, CH2), 1.69-1.44 (m, 4H, H-4'a, H-7b, H-14eq, H-4'b), 1.42 (s, 3H, 12-CH3), 1.32 (s, 3H, 6-CH3), 1.29-1.17 (m, 8H, 2H-cyclopropyl, 2-CH3, 5'-CH3), 1.13 (d, J = 6.8 Hz, 3H, 10-CH3), 1.10-0.98 (m, 8H, 2H-cyclopropyl, 8-CH3, 4-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 181.08, 176.90, 174.57, 167.04, 156.37, 149.06, 147.52, 145.90, 118.05, 117.85, 108.65, 103.26, 81.91, 80.89, 78.64, 78.15, 75.62, 72.21, 70.51, 69.53, 66.11, 60.15, 49.46, 43.40, 42.63, 40.37, 39.20, 38.13, 36.62, 36.13, 34.65, 29.88, 28.62, 21.93, 21.24, 19.79, 19.39, 15.04, 12.57, 11.06, 10.25, 8.94, 7.46, 7.35.

[0193] Synthesis of compound 33

[0194] Synthesis was performed using compound 28 (0.25 g, 0.27 mmol) as a starting material according to the general synthetic method of the preparation example, and column chromatography purification (100-200 mesh silica gel, developing solvent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to obtain compound 33 (221.3 mg, 0.21 mmol, 77.8 %). HRMS (ESI) (M+H) + m / z 1059.5678, calcd for C 53 H 80 FN6O 15 1059.5660. 1H NMR (CDCI3, 400 MHz) δ: 8.65 (s, 1 H, 2"-quinolyl), 7.95 (d, J = 12.4 Hz, 1 H, 5"-quinolyl), 5.26 (d, J = 5.8 Hz, 1 H, CONH), 5.09 (dd, J = 2.2 Hz, 11.0 Hz, 1 H, H-13), 4.91 (d, J = 11.0 Hz, 1 H, H-3), 4.01-3.91 (m, 2H, 1 H-pyrrolyl, H-1 '), 3.87-3.73 (m, 2H, 1 H-pyrrolyl, H-5), 3.67-3.47 (m, 6H, H-11, 1 H-cyclopropyl, CH20CH2), 3.47-3.33 (m, 2H, 3-0-CO-NH-CH2, H-5'), 3.31-3.15 (m, 3H, 1 H-pyrrolyl, 3-0-CO-NH-CH2, H-2'), 3.08 (s, 3H, 6-0-CH3), 3.03 (s, 3H, NCH3), 3.02-2.94 (m, 1 H, H-10), 2.88-2.75 (m, 1 H, H-2), 2.73-2.61 (m, 1 H, 1 H-pyrrolyl), 2.61-2.50 (m, 1 H, H-8), 2.47-2.34 (m, 1 H, H-3'), 2.28 (s, 6H, -N(CH3)2), 2.23-2.15 (m, 1 H, 1 H-pyrrolyl), 2.15-2.06 (m, 1 H, H-4), 1.99-1.76 (m, 6H, 2H-pyrrolyl, H-14ax, H-7a, CH2), 1.77-1.47 (m, 4H, H-4'a, H-7b, H-14eq, H-4'b), 1.41 (s, 3H, 12-CH3), 1.30 (s, 3H, 6-CH3), 1.28-1.17 (m, 5H, 2H-cyclopropyl, 5'-CH3), 1.18-0.97 (m, 14H, 10-CH3, 2-CH3, 2H-cyclopropyl, 8-CH3, 4-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 215.22, 174.59, 167.05, 157.67, 156.36, 147.51, 145.91, 103.18, 82.89, 80.71, 78.20, 76.15, 72.24, 70.48, 69.59, 66.11, 62.44, 49.74, 45.72, 43.33, 40.36, 38.79, 38.50, 35.71, 34.64, 32.57, 29.87, 28.53, 22.04, 21.21, 19.43, 18.70, 14.91, 14.07, 13.67, 10.23, 8.87, 7.45, 7.34.

[0195] Synthesis of compound 34

[0196] Using compound 29 (0.25 g, 0.27 mmol) as the starting material, compound 34 (146.2 mg, 0.14 mmol, 51.8%) was prepared by following the general procedure of the preparation and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4). HRMS (ESI) (M+H) + m / z 1073.5835, calcd for C 54 H 82 FN6O 15 1073.5817. 1H NMR (CDCI3, 400 MHz) δ: 8.66 (s, 1 H, 2"-quinolyl), 7.96 (d, J = 12.4 Hz, 1 H, 5"-quinolyl), 5.25 (d, J = 6.0 Hz, 1 H, CONH), 5.07 (dd, J = 2.2 Hz, 11.0 Hz, 1 H, H-13), 4.86 (d, J = 11.0 Hz, 1 H, H-3), 4.09-3.91 (m, 2H, 1 H-pyrrolyl, H-1 '), 3.88-3.76 (m, 2H, 1 H-pyrrolyl, H-5), 3.75-3.47 (m, 7H, H-11, 1 H-cyclopropyl, CH20CH2, NCH2CH3), 3.47-3.32 (m, 3H, 3-0-CO-NH-CH2, H-5', NCH2CH3), 3.33-3.13 (m, 3H, 1 H-pyrrolyl, 3-0-CO-NH-CH2, H-2'), 3.05 (s, 3H, 6-0-CH3), 3.04-2.69 (m, 1 H, H-10), 2.91-2.78 (m, 1 H, H-2), 2.73-2.61 (m, 1 H, 1 H-pyrrolyl), 2.61-2.49 (m, 1 H, H-8), 2.48-2.35 (m, 1 H, H-3'), 2.28 (s, 6H, -N(CH3)2), 2.23-2.05 (m, 2H, 1 H-pyrrolyl, H-4), 2.01-1.45 (m, 10H, 2H-pyrrolyl, H-14ax, H-7a, CH2, H-4'a, H-7b, H-14eq, H-4'b), 1.40 (s, 3H, 12-CH3), 1.30 (s, 3H, 6-CH3), 1.28-1.18 (m, 8H, 2H-cyclopropyl, 5'-CH3, 10-CH3), 1.18-1.08 (m, 14H, 2-CH3, 2H-cyclopropyl, 4-CH3), 1.04 (d, J = 7.3 Hz, 3H, 8-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (101 MHz, CDC13) δ 215.59, 174.43, 167.05, 157.09, 145.94, 117.92, 82.68, 80.50, 78.27, 76.30, 70.48, 69.59, 60.12, 50.04, 45.78, 43.23, 40.36, 38.70, 38.49, 35.68, 34.63, 29.88, 28.53, 22.11, 21.22, 19.49, 18.99, 14.87, 14.37, 14.02, 12.48, 10.27, 8.92, 7.35.

[0197] Synthesis of compound 35

[0198] Using compound 30 (0.33 g, 0.23 mmol) as starting material, the intermediate was obtained following the general procedure of the preparation example. The intermediate was dissolved in methanol and Pd / C (0.080 g) was added. The reaction was stirred at room temperature under hydrogen atmosphere. After the reaction was completed, the Pd / C was removed by filtration. The filtrate was concentrated and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to give compound 35 (51.0 mg, 0.047 mmol, 20.4%). HRMS (ESI) (M+H) + m / z 1088.5905, calcd for C 54 H 83 FN7O 15 1088.5926. 1H NMR (CDCI3, 400 MHz) δ: 8.61 (s, 1 H, 2"-quinolyl), 7.83 (d, J = 13.3 Hz, 1 H, 5"-quinolyl), 5.02 (dd, J = 2.4 Hz, 10.9 Hz, 1 H, H-13), 4.75 (d, J = 11.1 Hz, 1 H, H-3), 4.12 (d, J = 7.3 Hz, 1 H, H-1'), 4.02-3.86 (m, 2H, 2H-pyrrolyl), 3.86-3.76 (m, 2H, H-5, CH2), 3.76-3.60 (m, 5H, H-11, H-pyrrolyl, 1 H-cyclopropyl, OCH2), 3.58-3.48 (m, 4H, OCH2, H-pyrrolyl, CH2), 3.48-3.36 (m, 3H, 3-O-CO-NH-CH2, H-pyrrolyl, H-5'), 3.28-3.14 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.13-3.00 (m, 3H, H-10, CH2), 2.97 (s, 3H, 6-O-CH3), 2.90-2.80 (m, 1 H, H-2), 2.70-2.58 (m, 2H, H-3', 1 H-pyrrolyl), 2.57-2.46 (m, 1 H, H-8), 2.35 (s, 6H, -N(CH3)2), 2.22-2.09 (m, 1 H, 1 H-pyrrolyl), 2.09-1.99 (m, 1 H, H-4), 1.91-1.69 (m, 6H, H-14ax, H-7a, CH2, H-4'a, H-4, b), 1.69-1.44 (m, 2H, H-7b, H-14eq), 1.45 (s, 3H, 12-CH3), 1.30-1.20 (m, 5H, 6-CH3, 2H-cyclopropyl), 1.18 (d, J = 6.0 Hz, 3H, 5'-CH3), 1.14 (d, J = 7.1 Hz, 3H, 2-CH3), 1.10 (d, J = 7.5 Hz, 3H, 4-CH3), 1.07-0.69 (m, 8H, 2H-cyclopropyl, 8-CH3, 10-CH3), 0.81 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR (CD3OD, 100 MHz) δ: 216.64, 174.95, 158.47, 157.10, 147.14, 101.85, 83.84, 78.34, 77.75, 76.89, 75.82, 72.08, 70.83, 68.81, 64.38, 60.95, 49.30, 45.69, 45.26, 43.09, 39.58, 38.65, 38.24, 38.11, 37.68, 35.66, 34.00, 30.93, 29.47, 21.75, 20.07, 18.63, 17.63, 13.88, 13.35, 12.85, 9.30, 7.98, 6.54, 6.34.

[0199] Synthesis of compound 36

[0200] Using compound 31 (0.25, 0.23 mmol) as the starting material, it was prepared by the general method of the preparation example, and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4). Compound 36 (113.0 mg, 0.091 mmol, 39.5%) was obtained after column chromatography purification. HRMS (ESI) (M+H) o m / z 1244.6597, calcd for C + m / z 1244.6597, calcd for C 64 H 91 FN9O 15 1244.6613. 1H NMR(CDCl3,400MHz)δ:8.94(d,J=2.2Hz,1H,H-pyridyl),8.63(s,1H,2″-quinolyl),8.43(dd,J=1.7Hz,4.8Hz,1H,H-pyridyl),8.07(dt,J=2.0Hz,7.9Hz,1H,H-pyridyl),7.93(d,J=12.5Hz,1H,5″-quinolyl),7.55(s,1H,H-imidazolyl),7.36(s,1H,H-imidazolyl),7.32-7.22(m,1H,H-pyridyl),5.33(br,1H,CONH),5.03(dd,J=2.4Hz,11.0Hz,1H,H-13),4.86(d,J=10.9Hz,1H,H-3),4.15-3.88(m,5H,2H-pyrrolyl,CH2,H-1′),3.88-3.73(m,3H,H-5,H-pyrrolyl,CONCH2),3.73-3.48(m,9H,H-11,H-cyclopropyl,CH2OCH2,CONCH2,2H-pyrrolyl),3.48-3.13(m,2H,H-5′,3-O-CO-NH-CH2),3.29-3.13(m,2H,H-2′,3-O-CO-NH-CH2),3.10(q,J=6.9Hz,1H,H-10),3.04(s,3H,6-O-CH3),2.92-2.79(m,1H,H-2),2.72-2.50(m,2H,H-8,H-pyrrolyl),2.47-2.34(m,1H,H-3′),2.28(s,6H,-N(CH3)2),2.24-2.05(m,2H,H-4,H-pyrrolyl),1.99-1.77(m,6H,2(CH2),H-4′a,H-14ax),1.76-1.49(m,6H,H-7a,H-4′b,H-14eq,CH2,H-7b),1.41(m,3H,12-CH3),1.29(s,3H,6-CH3),1.27-1.18(m,5H,5′-CH3,2H-cyclopropyl),1.19-1.05(m,11H,2-CH3,8-CH3,10-CH3,2H-cyclopropyl),1.03(d,J=6.8Hz,4-CH3),0.77(t,J=7.2Hz,3H,15-CH3). 13C NMR (CDC13, 100 MHz) δ: 215.86, 176.95, 174.83, 167.10, 157.48, 147.60, 146.46, 145.92, 139.08, 137.85, 132.01, 130.39, 123.55, 115.67, 87.78, 82.86, 78.45, 70.52, 60.20, 56.40, 56.36, 56.35, 56.33, 56.31, 56.29, 50.22, 46.98, 45.86, 43.22, 42.76, 40.42, 38.89, 38.57, 34.70, 29.91, 28.89, 24.40, 22.15, 21.27, 19.55, 19.05, 14.94, 14.41, 14.22, 10.41, 8.93, 7.51, 7.39.

[0201] The following examples illustrate the preparation of compounds 37-47 of the present application, the reaction scheme being:

[0202] Reaction conditions and reagents: a. 1) Pd / C, methanol, rt; 2) Boc anhydride, triethylamine, dichloromethane; 3) CDI, DMAP, dichloromethane, rt.

[0203] Reaction conditions and reagents: a. Octyne amine hydrochloride, DMF, rt; b. Compound V2, CuI, Pd(PPh3)2Cl2, triethylamine, acetonitrile, 70 °C, c. 1) Lithium hydroxide monohydrate, water / THF (1:1), rt; 2) methanol reflux. d. 1,3-Propylenediamine, DMF, rt; e. Formic acid, NaNO2, 3-butyn-1-ol, -15 °C. f. Compound V2, CuI, Pd(PPh3)2Cl2, triethylamine, acetonitrile, 70 °C, g. 1) Lithium hydroxide monohydrate, water / THF (1:1), rt; 2) methanol reflux.

[0204] Preparation example 10: synthesis of compound 37

[0205] Compound 10 (3.90 g, 3.37 mmol) was dissolved in methanol, Pd / C (0.15 g) was added and stirred at room temperature under hydrogen atmosphere for 8 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was evaporated to dryness. The dried product (2.67 g, 3.12 mmol) was dissolved in dichloromethane, Boc anhydride (1.02 g, 4.68 mmol) and triethylamine (1.30 mL, 9.365 mmol) were added and stirred at room temperature for 1 h. After completion of the reaction, the organic layer was washed with water, saturated sodium bicarbonate and saturated brine. The organic layer was evaporated to dryness to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: methanol: ammonia water = 10 / 0.2 / 0.1) to obtain the intermediate (2.54 g, 2.95 mmol, 87.5%).

[0206] The intermediate (2.54 g, 2.95 mmol) obtained above was reacted with CDI, DMAP, dichloromethane at room temperature to obtain compound 37 (2.11 g, 2.21 mmol, 74.9%).

[0207] Preparation Example 11: General method for synthesis of compounds 38-41

[0208] Compound 12-14, 37 (1 eq) was dissolved in DMF, octyne amine hydrochloride (1.5 eq) and DBU (3 eq) were added dropwise and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added and the organic layer was washed with water three times and saturated brine once. The organic layer was evaporated to dryness to obtain compounds 38-41.

[0209] Synthesis of compound 38

[0210] Compound 12 (0.61 g, 0.73 mmol) was used as a starting material and the general method of synthesis described in this preparation example was used to prepare the product which was recrystallized with ethyl acetate to obtain compound 38 (0.26 g, 0.29 mmol, 39.7%).

[0211] Synthesis of compound 39

[0212] Compound 13 (0.80 g, 0.97 mmol) was used as a starting material and the general method of synthesis described in this preparation example was used to prepare the product which was recrystallized with ethyl acetate to obtain compound 39 (0.25 g, 0.28 mmol, 28.9%).

[0213] Synthesis of compound 40

[0214] Using compound 14 (0.85 g, 1.01 mmol) as starting material, the general synthetic method of this preparation example was used to prepare, the product was recrystallized with ethyl acetate to obtain compound 40 (0.26 g, 0.29 mmol, 28.7%).

[0215] Synthesis of compound 41

[0216] Using compound 37 (0.90 g, 0.94 mmol) as starting material, the general synthetic method of this preparation example was used to prepare, the product was purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: ethanol: ammonia water = 10 / 0.1 / 0.1) to obtain compound 41 (0.30 g, 0.29 mmol, 30.8%).

[0217] Preparation example 12: general synthetic method of compounds 42-45, 47

[0218] In a pressure bottle, compound 3 (1 eq), dichlorobis(triphenylphosphine)palladium (0.05 eq), compound V2 (1.2 eq), cuprous iodide (0.1 eq) and triethylamine (1.5 eq) were added, after aeration, it was sealed and transferred to a 75°C bath kettle, and reacted for 4h. After the reaction was monitored to be completed, 30 mL of dichloromethane was added to the reaction system, which was washed with water, saturated sodium bicarbonate, saturated sodium chloride solution in turn, and the organic phase was rotary evaporated. The product was dissolved in methanol and refluxed overnight, and after the reaction was completed, the reaction liquid was rotary evaporated to obtain the intermediate. Then the product was dissolved in water / THF (1:1), and lithium hydroxide monohydrate (2 eq) was added. The reaction was carried out at room temperature for 2h, and the product was purified by column chromatography to obtain compounds 42-45, 47.

[0219] Synthesis of compound 42

[0220] Using compound 38 (0.20 g, 0.22 mmol) as starting material, the general synthetic method of this preparation example was used to prepare, the product was purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane: methanol: ammonia water = 10 / 0.9 / 0.4) to obtain compound 42 (94.9 mg, 0.096 mmol, 43.6%). + m / z 992.55539, calcd for C 53 H 78 N5O 13 992.55539, calcd for C 1H NMR (CDCI3, 400 MHz) δ: 8.81 (s, 1 H, 2"-quinolyl), 8.30 (d, J = 8.3 Hz, 1 H, 5"-quinolyl), 7.70 (br, 1 H, 8"-quinolyl), 7.40 (br, 1 H, 6"-quinolyl), 5.02 (dd, J = 2.2 Hz, 10.7 Hz, 1 H, H-13), 4.85 (d, J = 11.0 Hz, 1 H, H-3), 4.13 (d, J = 7.3 Hz, 1 H, H-1'), 4.07-3.91 (m, 4H, CH2, NCH3), 3.90-3.77 (m, 2H, H-5, CH2), 3.76-3.62 (m, 2H, H-11, CH2), 3.53-3.39 (m, 1 H, H-5'), 3.29-3.21 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.07 (s, 3H, 6-O-CH3), 3.05-2.97 (m, 2H, 3-O-CO-NH-CH2, CH2), 2.99-2.90 (m, 1 H, H-10), 2.90-2.82 (m, 1 H, H-2), 2.82-2.73 (m, 1 H, H-3'), 2.73-2.63 (m, 1 H, H-8), 2.56-2.46 (m, 2H, CH2-C≡C-), 2.43 (s, 6H, -N(CH3)2), 2.13-1.98 (m, 1 H, H-4), 1.89-1.72 (m, 2H, CH2), 1.73-1.36 (m, 14H, 3(CH2), H-14ax, H-7a, H-4'a, H-7b, H-14eq, 12-CH3), 1.32 (s, 3H, 6-CH3), 1.28-1.23 (m, 1 H, H-4'b), 1.24-1.16 (m, 6H, 2-CH3, 5'-CH3), 1.15-1.02 (m, 9H, 10-CH3, 8-CH3, 4-CH3), 0.82 (t, J = 7.5 Hz, 3H, 15-CH3). 13C NMR (CDC13, 100 MHz) δ: 174.95, 157.39, 156.81, 101.73, 82.49, 79.50, 78.62, 78.11, 77.20, 75.17, 70.60, 68.65, 64.55, 60.19, 48.66, 43.21, 42.35, 42.16, 40.95, 40.44, 39.50, 37.83, 36.71, 36.00, 30.91, 29.39, 28.27, 28.13, 25.99, 21.64, 20.03, 18.69, 18.52, 18.41, 14.00, 11.46, 9.88, 9.42, 8.02.

[0221] Synthesis of compound 43

[0222] Using compound 39 (0.20 g, 0.23 mmol) as the starting material, it was prepared by the general synthesis method of this preparation example, and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to give compound 43 (123.9 mg, 0.13 mmol, 56.5%). HRMS (ESI) (M+H) + m / z 981.54130, calcd for C 52 H 77 N4O 14 981.54308. 1H NMR (CDCI3, 400 MHz) δ: 8.80 (s, 1 H, 2"-quinolyl), 8.30 (d, J = 8.3 Hz, 1 H, 5"-quinolyl), 7.73 (br, 1 H, 8"-quinolyl), 7.43 (br, 1 H, 6"-quinolyl), 4.98 (dd, J = 2.2 Hz, 10.7 Hz, 1 H, H-13), 4.83 (d, J = 11.0 Hz, 1 H, H-3), 4.14 (d, J = 7.3 Hz, 1 H, H-1'), 3.99 (s, 3 H, NCH3), 3.87 (d, J = 3.1 Hz, 1 H, H-5), 3.65 (s, 1 H, H-11), 3.51-3.38 (m, 1 H, H-5'), 3.29-3.21 (m, 2 H, 3-O-CO-NH-CH2, H-2'), 3.21-3.11 (m, 1 H, H-10), 3.10-2.95 (m, 7 H, NCH3, 6-O-CH3, 3-O-CO-NH-CH2), 2.94-2.81 (m, 1 H, H-2), 2.82-2.64 (m, 1 H, H-3'), 2.57-2.46 (m, 3 H, H-8, CH2-C≡C-), 2.42 (s, 6 H, -N(CH3)2), 2.18-2.03 (m, 1 H, H-4), 1.90-1.71 (m, 3 H, CH2, H-14ax), 1.71-1.35 (m, 13 H, 3(CH2), H-7a, H-4'a, H-7b, H-14eq, 12-CH3), 1.36-1.29 (m, 1 H, H-4, b), 1.26 (s, 3 H, 6-CH3), 1.21-1.06 (m, 12 H, 2-CH3, 5'-CH3, 10-CH3, 4-CH3), 1.02 (d, J = 6.5 Hz, 3 H, 8-CH3), 0.82 (t, J = 7.4 Hz, 3 H, 15-CH3). 13 C NMR (CDCI3, 100 MHz) δ: 216.49, 174.95, 158.46, 157.39, 101.69, 83.69, 79.46, 78.22, 78.05, 77.18, 75.66, 70.64, 68.68, 64.50, 62.57, 48.90, 45.69, 43.18, 40.99, 40.48, 39.50, 38.63, 38.13, 35.64, 31.72, 30.88, 29.40, 28.30, 28.12, 26.02, 21.74, 20.02, 18.69, 18.57, 17.45, 13.87, 13.06, 12.49, 9.38, 7.97.

[0223] Synthesis of compound 44

[0224] Using compound 40 (0.20 g, 0.22 mmol) as the starting material, it was prepared by the general synthesis method of this preparation example and purified by column chromatography (100-200 mesh silica gel, eluent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to give compound 44 (103.8 mg, 0.10 mmol, 45.5%). HRMS (ESI) (M+H) + m / z 995.55606, calcd for C 53 H 79 N4O14995.55873. 1 H NMR (CD3OD, 400 MHz) δ: 8.81 (s, 1H, 2"-quinolyl), 8.30 (d, J = 8.3 Hz, 1H, 5"-quinolyl), 7.69 (br, 1H, 8"-quinolyl), 7.39 (br, 1H, 6"-quinolyl), 5.04 (dd, J = 2.2 Hz, 10.6 Hz, 1H, H-13), 4.83 (d, J = 11.0 Hz, 1H, H-3), 4.16 (d, J = 7.2 Hz, 1H, H-1'), 3.98 (s, 3H, NCH3), 3.87 (d, J = 3.1 Hz, 1H, H-5), 3.73 (s, 1H, H-11), 3.66-3.50 (m, 2H, NCH2CH3), 3.50-3.37 (m, 1H, H-5'), 3.28-3.21 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.20-3.14 (m, 1H, H-10), 3.11-2.97 (m, 4H, 6-O-CH3, 3-O-CO-NH-CH2), 2.95-2.84 (m, 1H, H-2), 2.82-2.73 (m, 1H, H-3'), 2.58-2.46 (m, 3H, H-8, CH2-C≡C-), 2.44 (s, 6H, -N(CH3)2), 2.19-2.07 (m, 1H, H-4), 1.90-1.71 (m, 3H, CH2, H-14ax), 1.72-1.34 (m, 13H, 3(CH2), H-7a, H-4'a, H-7b, H-14eq, 12-CH3), 1.26 (s, 3H, 6-CH3), 1.23-1.06 (m, 13H, H-4'b, 2-CH3, 5'-CH3, 10-CH3, 4-CH3), 1.01 (d, J = 6.5 Hz, 3H, 8-CH3), 0.82 (t, J = 7.5 Hz, 3H, 15-CH3). 13C NMR (CD3OD, 100 MHz) δ: 216.80, 174.84, 157.86, 157.40, 101.63, 83.49, 79.48, 78.30, 77.85, 77.09, 75.79, 70.62, 68.65, 64.50, 60.38, 49.16, 45.73, 43.08, 40.94, 40.50, 39.51, 38.61, 38.53, 38.13, 35.61, 29.41, 28.32, 28.14, 26.04, 21.79, 20.03, 18.70, 18.63, 17.70, 13.87, 13.37, 12.85, 11.48, 9.41, 8.02.

[0225] Synthesis of compound 45

[0226] Using compound 41 (0.25 g, 0.25 mmol) as starting material, it was prepared by the general synthetic procedure of this preparation example. After the reaction was completed, the intermediate was dissolved in ethanol (4 mL), 2 mL of 12M HCl was added dropwise, and the Boc protecting group was removed by reaction at room temperature. After the reaction was completed, dichloromethane was added, and the pH was adjusted to 10 with ammonia water. Then, it was washed with water and saturated brine, the organic phase was spin-dried, and purified by column chromatography (100-200 mesh silica gel, developing agent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4) to obtain compound 45 (56.4 mg, 0.056 mmol, 22.4%). HRMS (ESI) (M+H) + m / z 1010.56576, calcd for C 53 H 80 N5O 14 1010.56963. 1H NMR (CDCI3, 400 MHz) δ: 8.73 (s, 1 H, 2"-quinolyl), 8.28 (d, J = 8.3 Hz, 1 H, 5"-quinolyl), 7.68 (br, 1 H, 8"-quinolyl), 7.44 (d, J = 8.3 Hz, 1 H, 6"-quinolyl), 5.04 (dd, J = 2.2 Hz, 10.7 Hz, 1 H, H-13), 4.79 (d, J = 11.2 Hz, 1 H, H-3), 4.12 (d, J = 7.3 Hz, 1 H, H-1'), 3.97 (s, 3H, NCH3), 3.85 (d, J = 3.2 Hz, 1 H, H-5), 3.82-3.59 (m, 3H, H-11, CH2), 3.50-3.37 (m, 1 H, H-5'), 3.37-3.32 (m, 1 H, 3-O-CO-NH-CH2), 3.26-3.15 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.16-3.01 (m, 1 H, H-2, CH2), 2.99 (s, 3H, 6-O-CH3), 2.93-2.84 (m, 1 H, H-8), 2.72-2.59 (m, 1 H, H-3'), 2.60-2.44 (m, 3H, H-10, CH2-C≡C-), 2.36 (s, 6H, -N(CH3)2), 2.16-1.99 (m, 1 H, H-4), 1.89-1.70 (m, 3H, CH2, H-14ax), 1.70-1.36 (m, 13H, 3(CH2), H-7a, H-4'a, H-7b, H-14eq, 12-CH3), 1.35-1.26 (m, 1 H, H-4, b), 1.23 (s, 3H, 6-CH3), 1.21-1.05 (m, 12H, 2-CH3, 5'-CH3, 10-CH3, 4-CH3), 1.02 (d, J = 6.6 Hz, 3H, 8-CH3), 0.82 (t, J = 7.3 Hz, 3H, 15-CH3).. 13C NMR (CD3OD, 100 MHz) δ: 216.73, 177.03, 175.11, 158.44, 157.35, 126.45, 119.25, 101.86, 94.32, 83.92, 79.76, 78.35, 77.62, 76.83, 75.78, 70.79, 68.78, 64.38, 60.89, 49.35, 45.71, 43.08, 40.75, 40.18, 39.53, 38.68, 38.09, 35.76, 30.85, 29.21, 28.00, 25.69, 21.74, 20.08, 18.63, 17.60, 13.89, 13.33, 12.84. 9.25. 7.94.

[0227] Synthesis of compound 46

[0228] Compound 12 (2.50 g, 2.98 mmol) was dissolved in DMF, propylenediamine (0.77 mL, 8.95 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, ethyl acetate was added, and the organic phase was washed with saturated sodium bicarbonate solution, water, and saturated brine solution, respectively. The organic layer was dried and purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane: ethanol: ammonia water = 10 / 0.8 / 0.1) to obtain an intermediate (1.60 g, 2.16 mmol, 72.5%).

[0229] To the intermediate obtained in the foregoing step (1.60 g, 2.16 mmol), 3-butyn-1-ol (4.55 mL, 64.87 mmol) was added as a solvent, and the system was transferred to -20°C. Formic acid (0.37 mL, 9.73 mmol) was added dropwise, and then sodium nitrite (0.90 g, 12.97 mmol) was added portionwise while stirring. The temperature was maintained overnight, and then the reaction was allowed to proceed at room temperature for 12 h. After the completion of the reaction was confirmed by TLC, dichloromethane (20 mL) and distilled water (20 mL) were added to the system, and the organic phase was washed with saturated sodium bicarbonate solution, water, and saturated brine solution, respectively. The organic layer was dried, and the product was recrystallized with ethyl acetate to obtain compound 46 (0.83 g, 0.92 mmol, 42.6%).

[0230] Synthesis of compound 47

[0231] Compound 46 (0.20 g, 0.23 mmol) was used as a starting material, and compound 47 (45.3 mg, 0.046 mmol, 20.0%) was prepared by the general synthetic method of the present preparation example and purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane:methanol:ammonia water = 10 / 0.9 / 0.4). HRMS (ESI) (M+H)+ m / z 994.53505, calcd for C 52 H 76 N5O 14 994.53833. 1 H NMR (CD3OD, 400 MHz) δ: 8.83 (s, 1 H, 2"-quinolyl), 8.31 (d, J = 8.0 Hz, 1 H, 5"-quinolyl), 7.77 (br, 1 H, 8"-quinolyl), 7.47 (br, 1 H, 6"-quinolyl), 5.01 (dd, J = 2.2 Hz, 10.7 Hz, 1 H, H-13), 4.83 (d, J = 11.0 Hz, 1 H, H-3), 4.12 (d, J = 7.3 Hz, 1 H, H-1'), 4.07-3.91 (m, 4H, CH2, NCH3), 3.90-3.76 (m, 2H, H-5, CH2), 3.77-3.52 (m, 6H, H-11, CH2, CH2OCH2), 3.49-3.34 (m, 2H, H-5', 3-O-CO-NH-CH2), 3.28-3.15 (m, 2H, 3-O-CO-NH-CH2, H-2'), 3.07 (s, 3H, 6-O-CH3), 3.03-2.87 (m, 2H, CH2, H-2), 2.86-2.58 (m, 5H, H-3', H-10, H-8, CH2-C≡C-), 2.44 (s, 6H, -N(CH3)2), 2.12-1.98 (m, 1 H, H-4), 1.90-1.73 (m, 4H, CH2, H-14ax, H-7a), 1.72-1.49 (m, 3H, H-4'a, H-7b, H-14eq), 1.46 (s, 3H, 12-CH3), 1.38-1.30 (m, 1 H, H-4, b), 1.29 (s, 3H, 6-CH3), 1.24-1.13 (m, 6H, 2-CH3, 5'-CH3), 1.13-0.99 (m, 9H, 10-CH3, 8-CH3, 4-CH3), 0.81 (t, J = 7.5 Hz, 3H, 15-CH3). 13C NMR (CD3OD, 100 MHz) δ: 174.94, 157.28, 156.77, 101.73, 82.47, 79.92, 78.61, 78.09, 77.22, 75.17, 70.53, 68.67, 68.51, 68.16, 64.61, 60.16, 46.97, 43.17, 42.13, 41.01, 39.46, 38.11, 37.84, 36.70, 35.98, 30.79, 29.53, 21.61, 20.27, 20.01, 18.52, 18.36, 14.01, 11.44, 9.85, 9.40, 8.02.

[0232] Preparation Example 13: Synthesis of Control TE-802

[0233] TE-802 was obtained as a control according to the synthesis method of the literature Journal of Antibiotics, 2001, 54(8): 664. and the spectrum was consistent with the literature, and the spectrum was as follows: HRMS (ESI) (M+H) + m / z 638.39845, calcd for C 33 H 56 N3O9638.40111. 1H NMR (CDC13, 400 MHz) δ: 4.95 (dd, J = 2.5 Hz, 10.5 Hz, 1H, H-13), 4.30 (d, J = 7.3 Hz, 1H, H-1'), 4.21 (d, J = 8.6 Hz, 1H, H-5), 3.99 (dt, J = 2.8 Hz, 14.4 Hz, 1H, CH2), 3.88-3.74 (m, 3H, CH2, H-2), 3.73 (d, J = 1.5 Hz, 1H, H-11), 3.59-3.50 (m, 1H, H-5'), 3.47 (s, 1H, 2'-OH), 3.19 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2'), 3.14-3.03 (m, 1H, H-4), 3.01-2.89 (m, 1H, CH2), 2.80-2.64 (m, 5H, 6-O-CH3, H-10, H-8), 2.51-2.39 (m, 1H, H-3'), 2.26 (s, 6H, -N(CH3)2), 1.97-1.85 (m, 1H, H-14ax), 1.74-1.63 (m, 2H, H-4'a, H-7a), 1.62-1.45 (m, 5H, H-7b, H-14eq, 12-CH3), 1.39 (d, J = 6.8 Hz, 3H, 2-CH3), 1.36 (s, 3H, 6-CH3), 1.29 (d, J = 7.5 Hz, 3H, 4-CH3), 1.26-1.18 (m, 7H, 10-CH3, 5'-CH3, H-4'b), 1.05 (d, J = 7.0 Hz, 3H, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13 C NMR (CDC13, 100 MHz) δ: 204.24, 181.09, 169.55, 156.08, 103.91, 81.52, 79.19, 78.52, 76.51, 70.35, 69.58, 65.90, 59.94, 51.21, 49.60, 49.10, 48.14, 42.86, 42.36, 40.26, 38.60, 36.36, 28.16, 22.10, 21.19, 19.64, 19.14, 16.46, 14.40, 12.86, 10.90, 10.45.

[0234] Determination of the in vitro antibacterial activity

[0235] The in vitro antibacterial activities of some target compounds were determined against sensitive S. pneumoniae ATCC49619, mef efflux-type resistant S. pneumoniae PU-09, constitutive erm-type resistant S. pneumoniae 07P390, constitutive erm-type plus mef resistant S. pneumoniae 05O173, induced ermB-type resistant S. pyogenes 01-968, constitutive ermA-type resistant S. pyogenes 12-206, induced ermA-type resistant S. aureus PU32, constitutive resistant S. aureus 15B196, PU20, H. influenzae ATCC49247, azithromycin-resistant H. influenzae 21B402 and M. catarrhalis 13L332 by broth dilution method according to the standard recommended by Clinical and Laboratory Standards Institute (CLSI, 2010). Each strain was subcultured on agar plates before the test, and fresh bacteria were used in the test. Standard strain was used as sensitive control in each test, and bacteria solution without antibacterial agent was used as growth control of the test strain. The minimum inhibitory concentration (MIC) was determined by broth double dilution method. The concentration range of the antibacterial agent was 256-0.008 μg / mL, and the final concentration of the test bacteria solution was about 5×10 5 CFU / m1.

[0236] The determination results are shown in Tables 1-3:

[0237] The structural formula of the compound MCX-162 is as follows:

[0238] Table 1: Antibacterial activities (MIC, μg / mL) of the compounds of the present application against S. pneumoniae and S. pyogenes

[0239] Table 2: Antibacterial activities (MIC, μg / mL) of the compounds of the present application against H. influenzae, S. aureus and M. catarrhalis

[0240] As shown by the test results in Tables 1 and 2, the antibacterial activities of the compounds of the present application are better than those of clarithromycin, MCX-162, TE-802 and telithromycin.

[0241] Table 3. MIC (MIC, μg / mL) of the compounds of the present application against SQ110 series of E. coli engineering bacteria

[0242] SQ110 DTC E. coli is an engineering bacteria for studying the mechanism of macrolide antibiotics, macrolide antibiotics can easily penetrate the outer membrane of bacteria, and there is only one set of ribosome RNA operator. When the action site of SQ110 DTC ribosome or topoisomerase is mutated, the MIC of the antibiotic acting on the site will be higher than that of the unmutated SQ110 DTC bacteria, such as the positive drugs clarithromycin, telithromycin and ciprofloxacin; this shows that clarithromycin and telithromycin only act on ribosomes, and ciprofloxacin only acts on topoisomerase. As can be seen in Table 3, the MIC change multiples of the compounds in the application are not large when the ribosome A2058 site or the topoisomerase Ser83Leu site is mutated; but when both sites are mutated, the MIC increases, thus proving that the compounds not only act on ribosomes but also can act on topoisomerase, are double-target compounds, and such compounds are not easy to induce bacteria to produce mutations in use, thus having high practical value.

[0243] Cytotoxicity test of compounds

[0244] Cell lines HEK293T (3101HUMGNHu17) and HepG2 (1101HUM-PUMC000035) were purchased from the Cell Resource Center of Beijing Union Medical College (PCRC). All cell lines were obtained in 2023, and the continuous passage in culture was not more than 30 times. Cells were cultured in DMEM (11995065, Gibco) supplemented with 10% FBS (164210-50, Procell), 100 units of penicillin and 100 mg / mL of streptomycin (PB180120, Procell). HepG2 cells (6x10 3 ) and HEK293T cells (4x10 3 ) were seeded into 96-well plates, each containing 10% fetal bovine serum DMEM medium (90 μL) per well. All test compounds were prepared into 10 mM DMSO stock solution (final concentration ≤0.5%). After overnight incubation of the cells, the test compound stock solution was diluted to the target concentration with DMEM medium containing 10% fetal bovine serum, and 10 μL was added to each well. Three parallel experiments were set up for each compound. After 48 hours of incubation, 10 μL of CCK-8 reagent was added to each well according to the manufacturer's instructions. After incubation in a 37°C incubator for 1-2 hours, the absorbance was measured at a wavelength of 450 nm by Thermo Scientific Multiskan FC detection. The experiment was repeated independently for 3 times. The data was processed by GraphPad Prism. The cytotoxicity of the compounds to HepG2 and 293T cell lines is shown in Figure 1, and the cytotoxicity of the compounds of the application is small, proving that the compounds of the application have high safety.

[0245] CYP3A4 enzyme inhibition test of compounds

[0246] A mixture of midazolam substrate (metabolic substrate for CYP3A4 enzyme) and human liver microsomes (HLM) in phosphate buffer and 1 μL of test compound (final concentrations of 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM and 0.01 μM) were added to each well of a plate (two replicates for each compound). The plate was pre-warmed at 37 °C for 10 minutes, after which the reaction was initiated by adding 20 μL of NADPH solution in phosphate buffer (10 mM). After the addition of NADPH, the plate was incubated for an additional 3.5 minutes at 37 °C. The reaction was quenched by adding 200 μL of stop solution. The plate was centrifuged at 3220 g for 10 minutes. 100 μL of supernatant was diluted 1 : 1 with water and analyzed by LC-MS / MS. Inhibition of each P450 enzyme in human liver microsomes was measured by the percent decrease in the formation of the labeled metabolite compared to the DMSO control (100% activity). When the percent inhibition at the highest concentration (30 μM) was less than 50%, the IC50value was reported as ">30 μM". The test compounds were Compound 22, Compound 23 and Telithromycin (TEL), with ketoconazole used as a positive control. 50 50

[0247] Table 4. CYP3A4 enzyme inhibition IC50values of compounds 50

[0248] The macrolides are metabolic substrates for CYP3A4 enzyme and the compounds of the present invention have less CYP3A4 enzyme inhibition than Telithromycin, demonstrating less drug-drug interactions for the compounds of the present invention.

[0249] The above embodiments of the technical solutions of the present disclosure are exemplarily described. It should be understood that the protection scope of the present disclosure is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of the present application.

Claims

A compound of Formula (I), a stereoisomer, a tautomer, an isotopically-labeled version, a nitroxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof: wherein X represents O or NH; A represents O or NR; R represents the following groups, either unsubstituted or substituted by one, two, or more R3 groups: C 1-6 Alkyl, -3-10 membered heterocyclic group -C 1-6 Alkyl group, -CH=NO-C 1-6 Alkyl; where X represents NH, A represents NR, and R is selected from C 1-6 In the case of alkyl groups, C 1-6 The alkyl terminus can be attached to X to form a ring; each R3 is the same or different, independently selected from H, halogen, OH, CN, NO2, NH2, COOH, -R4, -R4-R5; R4, R5represent C 6-10 aryl or 5-10 membered heteroaryl, which C 6-10 The aryl or 5-10 membered heteroaryl can be unsubstituted or substituted by one, two or more halogen, OH, CN, NO2, NH2, COOH; Z represents CH2, NH or O; Y represents C 2-6 alkynyl or 3-10 membered heterocyclyl containing one heteroatom selected from N, O, or S; D represents CH or N; R1represents C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; said C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl can be unsubstituted or substituted by one, two or more halogen, OH, CN, NO2, NH2, COOH; R2represents H, halogen, C 1-6 alkyl or C 1-6 alkoxy; m is selected from an integer from 0 to 10; for example, an integer from 0 to 8, such as 1, 2, 3, 4 or 5; n is selected from an integer from 0 to 10, for example, an integer from 0 to 6, such as 0, 1, 2 or 3; and with the proviso that A is not O when Y represents C 2-6 alkynyl; Preferably, A is selected from O or NR, R is selected from C 1-6 alkyl, -C 1-6 alkyl-NH2, -C 1-6 alkyl-R4-R5; R4, R5are selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein at least one heteroatom is selected from N, for example 1, 2 or 3 heteroatoms are selected from N; for example R4, R5are phenyl, naphthyl, pyridyl, imidazolyl, triazolyl, benzoquinolyl, diazanaphthyl, thiazolyl; Preferably, A is selected from NR, and R is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, -methyl-NH2, -ethyl-NH2, -propyl-NH2, -butyl-NH2, -propyl-imidazole-pyridine, -butyl-imidazole-pyridine, -butyl-triazole-pyridine, -butyl-triazole-aminobenzene, -pentyl-imidazole-pyridine; when X represents NH, A represents NR, and R is selected from ethyl, propyl or butyl, the end of the ethyl, propyl or butyl group can be connected with X to form a ring; Preferably, A is selected from NR, R is selected from methyl, ethyl, ethyl-NH2, when X represents NH, A represents NR, and R is selected from ethyl, the end of the ethyl group can be connected with X to form a ring; Preferably, Z represents CH2or O; Preferably, Y represents ethynyl, propynyl, pyrrolidinyl or piperidinyl; Preferably, Y represents ethynyl, (As )、 Preferably, R1represents methyl, ethyl, cyclopropyl, fluorocyclopropyl; Preferably, R2represents H, halogen, for example, selected from fluorine, preferably substituted at the 6-position; Preferably, m is selected from 2, 3, 4 or 5; Preferably, n is selected from 0 or 1 or 2. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compound of formula (I) has a structure represented by formula (I-1): wherein R' represents -C 1-6 alkyl-, Z, Y, D, R1, R2, m, n have the definitions given in claim 1; Preferably, R' is selected from -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH(CH3)-, -C(CH3)(CH3)CH(CH3)-, -C(CH3)(CH3)CH2-, -C(CH3)(CH3)C(CH3)(CH3)-; Alternatively, the compound of formula (I) has a structure represented by formula (I-2): wherein R, Z, Y, D, R1, R2, m, n have the definitions as described in claim 1. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compound of formula (I) has the structure of formula (II): wherein X, A, Z, R1, R2, m, n have the definitions as described in claim 1. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compound of formula (I) has the structure of formula (II-1): wherein R' represents -C 1-6 alkyl-, Z, R1, R2, m, n have the definitions as in claim 1; Alternatively, the compound of formula (I) has a structure according to formula (II-2): wherein R, Z, R1, R2, m, n have the definitions as described in claim 1. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compound of formula (I) has the structure of formula (III): wherein X, A, Z, R1, R2, m, n have the definitions as described in claim 1. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compound of formula (I) has the structure of formula (III-1): wherein R' represents -C 1-6 alkyl-, Z, R1, R2, m, n have the definitions as in claim 1; Alternatively, the compound of formula (I) has a structure according to formula (III-2) wherein R, Z, R1, R2, m, n have the definitions as described in claim 1. The compound, stereoisomer, tautomer, isotopically-labeled, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, The compounds of formula (I) are selected from the following specific compounds: A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-7, a stereoisomer, a tautomer, an isotopically-labeled, a nitroxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof. Use of a compound of formula (I) as described in any one of claims 1-7, a stereoisomer, a tautomer, an isotopically-labeled, a nitroxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutical composition as described in claim 8, in the preparation of an anti-pathogenic microorganism medicament. Use according to claim 9, characterized in that, The anti-pathogenic microorganism medicine is used for inhibiting or killing at least one of the following pathogenic microorganisms: Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, Staphylococcus epidermidis, Moraxella catarrhalis, mycoplasma or chlamydia; Preferably, the anti-pathogenic microorganism medicine is used for inhibiting or killing at least one of the following bacteria of different sensitivity or resistance types to erythromycin: sensitive Streptococcus pneumoniae, constitutive resistant Streptococcus pneumoniae, efflux resistant Streptococcus pneumoniae, sensitive Staphylococcus aureus, induced resistant Staphylococcus aureus, constitutive resistant Staphylococcus aureus, sensitive Streptococcus pyogenes, efflux resistant Streptococcus pyogenes, induced resistant Streptococcus pyogenes, constitutive resistant Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis.

Images