Erythromycin derivative, preparation method therefor and use thereof

Abstract

Disclosed in the present invention is an erythromycin derivative as shown in formula I. It is proved that the erythromycin derivative has a good inhibitory effect on various pathogenic microorganisms such as streptococcus pneumoniae, streptococcus pyogenes, haemophilus influenzae, staphylococcus aureus, moraxella catarrhalis, mycoplasma or chlamydia; and the inhibitory effect is significantly better than that of clarithromycin, telithromycin, azithromycin and ciprofloxacin. In addition, the series of compounds have a simple preparation method, and therefore have certain prospects for industrial synthesis preparation.

Description

Erythromycin derivative, preparation method and application thereof

[0001] This application claims priority to the following prior application: Patent application number 202310628481X, filed with the State Intellectual Property Office of China on May 30, 2023, entitled “An erythromycin derivative, its preparation method, and use.” The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention relates to the fields of chemical synthesis and pharmaceutical manufacturing, and in particular to an erythromycin derivative and a preparation method and application thereof. Background Art

[0003] Macrolide-lincosamide-streptogramin B (MLS B ) share the same ribosomal binding site, conferring cross-resistance. Among them, erythromycin, a 14-membered macrolide antibiotic, is a very important antibacterial drug for upper and lower respiratory tract infections, clinically used to treat upper and lower respiratory tract infections caused by pathogenic microorganisms, as well as skin and soft tissue infections. It has mild side effects and has provided a highly effective and safe medication for humans, especially children, for half a century. Because its primary antibacterial mechanism involves hydrogen bonding between the hydroxyl group and the tertiary amino group of the 5-deoxyglucosamine at the 50S ribosomal peptide release channel, mutations in the A2058 / A2059 bases or methylation of A2058 at N6 by strains harboring the erm gene can dramatically reduce the affinity of erythromycins. Furthermore, strains harboring the mef gene are induced to express efflux pump proteins by erythromycins containing cladinose, reducing intracellular drug concentrations below the antibacterial level and conferring drug resistance. At present, more and more bacterial strains isolated clinically show drug resistance, such as Streptococcus pneumoniae (S.pneumoniae), Staphylococcus aureus (S.aureus) and Streptococcus pyogenes (S.pyogenes).

[0004] The second-generation erythromycins, clarithromycin and azithromycin, which appeared in the 1980s, are highly resistant to (gastric) acid and have good pharmacokinetic properties, but they lack antibacterial activity against erythromycin-resistant bacteria. The main reason is that the cladinose at the 3-position induces bacterial resistance, leading to modification of the key target site A2058 or its removal from the cell by efflux pumps.

[0005] As a third-generation erythromycin, telithromycin is the only erythromycin derivative approved for the treatment of community-acquired bacterial pneumonia infections. It has excellent antibacterial activity against inducible and efflux-resistant bacteria. It also acts on the base pairs A752 and U2609 of the microbial ribosome, thus having good antibacterial activity against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes, but is inactive against constitutively resistant Staphylococcus aureus and resistant Mycoplasma. Ketones such as solithromycin, which are under clinical phase III investigation, share the same antibacterial target as telithromycin. After telithromycin was launched, it was found to be hepatotoxic and its use was strictly restricted. Other clinical research compounds, as they all have similar ketolide structures, have been questioned for their safety, resulting in telithromycin being the only one to be launched in the past 20 years.

[0006] Therefore, what needs to be solved is to find a macrolide antibiotic with a new structure to treat infections caused by pathogenic microorganisms resistant to erythromycin.

[0007] Summary of the Invention

[0008] To solve the above technical problems, the present invention provides a compound represented by the following formula I, and its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs:

[0009] Where W is an oxygen atom O or NOC 1-12 Alkyl; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is an integer in the range of 1-10, n2 is an integer in the range of 0-6, m1 is 0, 1 or 2, m2 is 0, 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, Ra is a halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 alkoxy;

[0010] R 1 is a hydrogen atom, an amino group, a halogen, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; Rb is selected from halogen, amino, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 alkoxy;

[0011] R 2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 3-20Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; Rb is selected from halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 Alkoxy; Z is methine CH, CRc, nitrogen atom N, or when Z is C, it is the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R 2 Does not exist; Rc is halogen, nitrile, amino, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy or halogenated C 1-12 Alkoxy.

[0012] In some embodiments, W is an oxygen atom O or NOC 1-6 Alkyl; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is 1, 2, 3, 4, 5, 6 or 7, n2 is 0, 1, 2, 3, 4, 5 or 6, m1 is 0 or 1, m2 is 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, Ra is a halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy;

[0013] R 1 is a hydrogen atom, a halogen, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Rb is selected from halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0014] R 2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb: 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Rb is selected from halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0015] Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R2 Does not exist; Rc is a halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0016] In some preferred embodiments, W is an oxygen atom O or NOCH3; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is 2, 3, 4, 5, 6 or 7, n2 is 0, 1 or 2, m1 is 0 or 1, and m2 is 1 or 2; Q is a methine CH, a fluorine-substituted carbon atom CF or a nitrogen atom N;

[0017] R 1 is a hydrogen atom, a methyl group or an ethyl group;

[0018] R 2 is absent, a hydrogen atom, a methyl group, an ethyl group, a cyclopropyl group, a fluoroethyl group, a fluorocyclopropyl group; Z is a methine group CH, a fluorine-substituted carbon atom CF, a nitrogen atom N, a methoxy-substituted carbon atom C-OCH3, or when Z is C, the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R 2 Does not exist.

[0019] In some specific embodiments, the compound represented by Formula I is selected from the following:

[0020] The present invention also provides the use of the compound represented by the above formula I, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs in the preparation of antibacterial drugs.

[0021] According to an embodiment of the present invention, the pharmaceutically acceptable salt includes a salt formed by a tertiary amino group on 5'-desosamine or a nitrogen atom on a side chain heterocyclic ring with a pharmaceutically acceptable organic acid or inorganic acid. The prodrug is an ester formed by the carboxyl group of the quinolone moiety and RxOH, or an ester formed by the 2'-OH of desosamine and RxCOOH; wherein Rx is unsubstituted or optionally substituted by one, two or more Rb as follows: C 1-12 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; Rb is selected from halogen, C 1-12 Alkyl or C 1-12 Alkoxy.

[0022] According to an embodiment of the present invention, the antibacterial drug 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.

[0023] According to a specific embodiment of the present invention, the antibacterial drug is used to inhibit or kill at least one of the following bacterial species that are sensitive to erythromycin or have different drug resistance types: sensitive Streptococcus pneumoniae, constitutively resistant Streptococcus pneumoniae, efflux-resistant Streptococcus pneumoniae, sensitive Staphylococcus aureus, inducible-resistant Staphylococcus aureus, constitutively resistant Staphylococcus aureus, sensitive Streptococcus pyogenes, efflux-resistant Streptococcus pyogenes, inducible-resistant Streptococcus pyogenes, constitutively resistant Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis.

[0024] The present invention also provides a pharmaceutical composition comprising a compound of formula I, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, and optionally a pharmaceutically acceptable carrier.

[0025] According to an embodiment of the present invention, the pharmaceutical composition is used for preparing antibacterial drugs.

[0026] The present invention derivatizes the 3-position of clarithromycin with a carbamate. The present invention provides a novel macrolide-quinolone hybrid for combating drug-resistant bacteria, including tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs thereof. Its structural characteristics are that a side chain of suitable length is derived from the nitrogen atom of the 3-position carbamate functional group of clarithromycin, and the end of the side chain is connected to the quinolone via various heterocycles such as piperazine, pyrrolidine, and piperidine, replacing the 3-O-cladinose of the original clarithromycin. It is also combined with other modifications such as 11,12-OH ring carbonate esterification, 11,12-OH ring carbamate esterification, or 9-carbonyl oximation.

[0027] In the present application, a step-by-step introduction method can be used, that is, first constructing a side chain containing a hydroxyl group, introducing a good leaving group such as mesylate or p-toluenesulfonate on the terminal hydroxyl group of the side chain, and then coupling it with the nitrogen atom on the piperazine on the quinolone, or coupling it with the terminal nitrogen atom of the side chain with different atomic lengths on the piperazine, and finally removing the protecting group to obtain the target compound; or first introducing diamines of different lengths, and then reacting them with diols of different carbon chain lengths, and then introducing a good leaving group such as mesylate or p-toluenesulfonate on the terminal hydroxyl group, and then coupling it with the nitrogen atom on the piperazine on the quinolone, and finally removing the protecting group to obtain the target compound; furthermore, first introducing a side chain with a piperidine ring or a pyrrole ring on the 3-OH, and then coupling the NH at the terminal of the side chain with the boronate-protected quinolone mother ring, and removing the protecting group to obtain the target compound.

[0028] The present invention also provides a method for preparing the compound represented by the above formula I, comprising the following steps:

[0029] Among them, W, V, X, Y, n1, n2, m1, m2, R 1 , R2 , Z, Q have the definitions as described above;

[0030] R is Ac or Bz. Beneficial effects

[0031] The present invention discloses an erythromycin derivative, which has been shown to exhibit excellent inhibitory effects on a variety of pathogenic microorganisms, such as Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, mycoplasma or Chlamydia, and the inhibitory effects are significantly better than those of clarithromycin, telithromycin, azithromycin and ciprofloxacin.

[0032] In addition, the preparation method of this series of compounds is simple, so they have certain prospects for industrial synthesis and preparation.

[0033] Terms and Definitions

[0034] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and agents for delaying absorption of pharmaceutically active substances, which are well known in the art. Any conventional media or agents, except those incompatible with the compound, are contemplated for use in pharmaceutical compositions. Supplementary compounds may also be incorporated into the compositions.

[0035] The present invention also includes prodrugs of the compounds of the present invention, i.e., compounds that are administered in an undisclosed structure but are metabolized or converted into the compounds disclosed herein in the human body and act as active ingredients to exert their pharmacological effects. For the present invention, various pharmaceutically acceptable acids can form salts on the nitrogen of the dimethylamino group of 5-O-desaccharamine or on the nitrogen of the side chain piperazine in the general formula. The prodrug is esterified at the 3-carboxyl group of the quinolone, such as a methyl ester, ethyl ester, isopropyl ester, or other (cyclic) alkyl ester containing heteroatoms. The ester group is hydrolyzed in vivo to release the active 3-carboxyl group. Conventional methods for preparing prodrugs are described in Design of Prodrugs (H. Bundgaad, Elsevier, 1985). In one specific embodiment, the prodrug is an ethyl ester of the compound. For example, the prodrug of compound 69a is compound 69p.

[0036] In some compounds in this application, the marking (R) or (S) after the group definition CH indicates that the C at that location is a chiral carbon and can form an R or S configuration.

[0037] The NMR data of some compounds in this application are marked with ax or eq, where ax represents an axial bond and eq represents an equatorial bond.

[0038] Some substituents Indicates the connection site.

[0039] In this document, the term "halogen" means fluorine, chlorine, bromine and / or iodine. Correspondingly, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this document, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be monosubstituted, disubstituted or polysubstituted up to full substitution by halogen atoms, for example, "haloC 1-12 Alkyl" and "halogenated C 1-12 Alkoxy".

[0040] The term "C 1-12 "Alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C 1-6 Alkyl. "C 1-6 “Alkyl” is understood as meaning preferably a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-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, etc. or their isomers. In particular, the radical has 1, 2 or 3 carbon atoms (“C 1-3 "alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0041] The term "C 3-20 "Cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or polycyclic hydrocarbon ring (also called condensed hydrocarbon ring) having 3-20 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include paracyclic cycloalkyl, bridged cycloalkyl and spirocyclic cycloalkyl; the paracyclic refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spirocyclic refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. For example, the C 3-20 The cycloalkyl group may be C 3-8 Monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7-12 A cycloalkyl ring, such as a decalin ring.

[0042] The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably a "3-12 membered heterocyclyl". The term "3-12 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be attached to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.

[0043] The term "C 6-20 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0044] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-12 membered heteroaryl". The term "5-12 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0045] Unless otherwise indicated, a heterocyclyl, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene.

[0046] The term "C 1-12 Alkoxy" means "-OC 1-12 Alkyl", where C 1-12 Alkyl has the same definition as above.

[0047] The above term “C 1-12 The definition of "alkyl" also applies to 1-12 Other terms for "alkyl", such as the term "halo-C 1-12 Alkyl" or "C 1-12 Alkoxy" or "halogenated C 1-12 Alkoxy", "NOC 1-12 Alkyl" and so on.

[0048] As used herein, "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0049] Pharmaceutically acceptable salts include acid addition salts of compounds of the present invention having nitrogen atoms in the chain or ring and having sufficient basicity. In addition, basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long-chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromides, and the like. Physiologically / pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates, or meglumine salts, among others. DETAILED DESCRIPTION

[0050] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0051] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0052] 1. Raw Material Preparation

[0053] 1) 9-Methoxyoxime Series Starting Materials The compounds shown below are known compounds. Synthesis methods can be found in European Journal of Medicinal Chemistry 59 (2013) 54-63.

[0054] 2) Preparation of clarithromycin series raw materials

[0055] Reaction conditions and reagents: a. Benzoic anhydride, DMAP (4-dimethylaminopyridine), THF, N,N-dimethylethylenediamine, room temperature; b. CDI (carbonyldiimidazole), NaHMDS, THF / DMF = 1.5 / 1, room temperature; c. Aqueous ammonia, THF / DMF = 1.5 / 1, potassium tert-butoxide, room temperature; d. 4 M HCl solution, ethanol, 45°C.

[0056] Synthesis of compound 2

[0057] Clarithromycin (20.000 g, 26.740 mmol), DMAP (3.267 g, 26.740 mmol), and benzoic anhydride (18.148 g, 80.219 mmol) were dissolved in 150 mL of anhydrous tetrahydrofuran. Triethylamine (11.12 mL, 80.219 mmol) was added and stirred at room temperature. The reaction progress was monitored by TLC. After approximately 48 hours of complete reaction, N,N-dimethylethylenediamine (5.84 mL, 53.480 mmol) was added dropwise under an ice bath. After half an hour of reaction, the reaction solution was concentrated by rotary evaporation. 200 mL of dichloromethane was added to the system, and the organic phase was washed with saturated ammonium chloride solution, saturated sodium bicarbonate, water, and saturated brine, respectively. The organic phase was dried and recrystallized from anhydrous ethanol to obtain 22.440 g (23.469 mmol, 87.77%) of white crystals.

[0058] Synthesis of compound 3

[0059] Compound 2 (10.000 g, 10.458 mmol) and CDI (6.783 g, 41.832 mmol) were dispersed in a mixture of THF / DMF (42 mL / 15 mL). 2 mol / L NaHMDS solution (8.37 mL, 16.733 mmol) was slowly added dropwise with stirring. After the addition was complete, the mixture was stirred at room temperature for approximately 2 h. After the reaction was complete, 100 mL of ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate, water, and saturated brine, respectively. The organic phase was dried to yield 10.660 g (10.327 mmol, 98.75%) of a white solid.

[0060] Synthesis of compound 4

[0061] Under ice bath, compound 3 (10.660g, 10.327mmol) is dispersed in the mixed solution of THF / DMF (42mL / 15mL), and 20mL of concentrated ammonia is added. Stir under ice bath for 48h, transfer to room temperature reaction 48h. After reaction is complete, 100mL of ethyl acetate is added, and then saturated sodium bicarbonate, water, saturated common salt water washing are used respectively, and the organic phase is spin-dried and added 60mL THF, adds potassium tert-butoxide (1.158g, 10.327mmol), and room temperature reaction 30min. After reaction is complete, 100mL of ethyl acetate is added, and then saturated sodium bicarbonate, water, saturated common salt water washing are used respectively, and the organic phase is spin-dried. The product is recrystallized from ethanol to obtain a white solid.

[0062] The white solid was dispersed in 40 mL of ethanol and 40 mL of 4 M hydrochloric acid solution was slowly added dropwise at 45°C. The reaction progress was monitored by TLC. After the reaction was complete, 20 mL of water was added and the aqueous layer was washed with methyl tert-butyl ether and separated. The aqueous layer was adjusted to pH 9 with aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, respectively. The organic phase was dried to obtain 3.080 g (4.284 mmol, 41.48%) of a white solid. HRMS (ESI) (M+H) + m / z 719.4114, calculated value C 38 H 59 N2O 11 719.4223. 1 H NMR(CDCl3,400MHz)δ:8.11-8.03(m,2H,2H-Bz),7.60-7.52(m,1H,2H-Bz),7.48-7.42(m,2H,2H-Bz),5.7 7(s,1H,11-NH),5.16(dd,J=2.3Hz,10.9Hz,1H,H-13),5.04(dd,J=7.6Hz,10.5Hz,1H,H-2′),4.76(d,J=7 .6Hz,1H,H-1′),3.73(d,J=2.6Hz,1H,H-5),3.71(s,1H,H-11),3.61-3.51(m,1H,H-5′),3.46(dd,J=6.6H z,10.6Hz,1H,H-3),2.95-2.89(m,1H,H-3′),2.97(s,3H,6-O-CH3),2.79(q,J=6.5Hz,1H,H-10),2.64-2.5 4(m,1H,H-2),2.52-2.42(m,1H,H-8),2.28(s,6H,-N(CH3)2),2.18(d,J=6.5Hz,1H,3-OH),1.94-1.83(m, 2H,H-4,H-14eq),1.94-1.81(m,1H,H-4′a),1.66-1.55(m,1H,H-7a),1.52-1.37(m,3H,H-7b,H-14eq,H-4′ a),1.32(s,3H,12-CH3),1.31-1.24(m,6H,6-CH3,5′-CH3),1.22(d,J=6.8Hz,3H,2-CH3),1.09(d,J=6.6H z,3H,10-CH3),1.05(d,J=7.1Hz,3H,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.71(d,J=7.4Hz,3H,4-CH3). 13C NMR(CDCl3,100MHz)δ:217.87,175.24,165.40,158.54,132.73,130.65,129.79,128.26,99.79,83.95,80.83,77.96,77.65,75.53,72.11,68.99, 63.27,58.18,49.52,45.34,44.08,40.82,38.76,37.18,35.84,32.00,22.08,21.15,19.27,18.13,15.34,13.82,13.28,10.22,7.81.

[0063] Reaction conditions and reagents: a. phthalimide, triphenylphosphine, DIAD (diisopropyl azodicarboxylate), toluene, room temperature; b. 80% hydrazine hydrate, ethanol, 80°C.

[0064] Synthesis of compound 6

[0065] Compound 5 (1.000 g, 3.885 mmol), phthalimide (0.556 g, 3.885 mmol), and triphenylphosphine (1.121 g, 4.274 mmol) were dissolved in 30 mL of toluene. DIAD (0.84 mL, 4.274 mmol) was added dropwise to the reaction system under an ice bath. After the addition was complete, the reaction system was brought to room temperature. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was dried and purified by column chromatography (petroleum ether:ethyl acetate = 6:1). Compound 6 was obtained as a colorless oily liquid.

[0066] Synthesis of compound 7

[0067] Compound 6 was dissolved in ethanol, and 80% hydrazine hydrate (0.47 mL, 7.770 mmol) was added dropwise. The reaction was allowed to proceed at 80°C for approximately 1 h. After the reaction was completed, the filtrate was filtered and the pH of the filtrate was adjusted to 4-5 by adding concentrated hydrochloric acid. The filtrate was filtered again, and the filtrate was concentrated and recrystallized from ethyl acetate to obtain 0.631 g (2.460 mmol, 63.32%) of compound 7. HRMS (ESI) (M+H) + m / z 402.2198, calculated value C 22 H 29 FN3O3 402.2187. 1H NMR (CDCl3, 400MHz) δ: 8.94 (s, 1H), 7.96 (d, J = 13.1Hz, 1H), 7.32 (d, J = 7.1Hz, 1H), 3.79 (d, J = 12.4Hz, 2H), 3. 63(dt,J=3.3Hz,7.1Hz,1H),3.02-2.84(m,2H),2.66(t,J=6.8Hz,2H),1.86-1.77(m,2H),1.59-1.13(m,9H).

[0068] Reaction conditions and reagents: a. Boc anhydride (di-tert-butyl dicarbonate), triethylamine, THF, ice bath; b. 60% NaH, acrylonitrile, ice bath; c. platinum dioxide, glacial acetic acid, hydrogen (4 atm), room temperature.

[0069] Synthesis of compound 9

[0070] Compound 8 (2.000 g, 19.773 mmol) and triethylamine (4.11 mL, 29.659 mmol) were dissolved in 70 mL of tetrahydrofuran, and Boc anhydride (4.315 g, 19.773 mmol) was added under ice-cooling. After the reaction was completed, the reaction solution was concentrated, 100 mL of dichloromethane was added, and the mixture was washed with saturated sodium bicarbonate, water, and saturated sodium chloride, respectively. The organic phase was then dried to obtain compound 9.

[0071] General Synthesis Methods of Compounds 18-26

[0072] The BOC-protected raw material was dissolved in acrylonitrile, and 1.5 eq of NaH was added portionwise under an ice bath. TLC monitored the reaction progress, and the reaction was complete after approximately 10 min. 50 mL of dichloromethane was added, and water was added dropwise under an ice bath to quench the NaH. The reaction solution was filtered to remove insoluble solids, and the liquid was washed with saturated brine. The organic phase was then spin-dried and purified by column chromatography to obtain the product.

[0073] Synthesis of compound 18

[0074] Using compound 9 (3.980 g, 19.773 mmol) as starting material according to the general synthesis method, about 4.312 g (16.068 mmol, 81.26%) of compound 18 was obtained.

[0075] Synthesis of compound 19

[0076] Compound 10 (3.000 g, 13.935 mmol) was used as the starting material according to the general synthesis method to obtain about 3.600 g (13.415 mmol, 96.27%) of compound 19.

[0077] Synthesis of compound 20

[0078] Compound 11 (2.000 g, 8.721 mmol) was used as the starting material according to the general synthesis method to obtain about 2.400 g (8.853 mmol, 101.52%) of compound 20.

[0079] Synthesis of compound 21

[0080] Compound 12 (2.000 g, 10.681 mmol) was used as the starting material according to the general synthesis method to obtain about 2.100 g (8.739 mmol, 81.82%) of compound 21.

[0081] Synthesis of compound 22

[0082] Compound 13 (2.000 g, 10.681 mmol) was used as the starting material according to the general synthesis method to obtain about 2.200 g (9.155 mmol, 85.71%) of compound 22.

[0083] Synthesis of compound 23

[0084] Compound 14 (2.000 g, 9.937 mmol) was used as the starting material according to the general synthesis method to obtain about 2.640 g (10.380 mmol, 104.46%) of compound 23.

[0085] Synthesis of compound 24

[0086] Compound 15 (2.000 g, 9.937 mmol) was used as the starting material according to the general synthesis method to obtain about 2.400 g (9.436 mmol, 94.96%) of compound 24.

[0087] Synthesis of compound 25

[0088] Compound 16 (2.000 g, 9.937 mmol) was used as the starting material according to the general synthesis method to obtain about 2.400 g (9.436 mmol, 94.96%) of compound 25.

[0089] Synthesis of compound 26

[0090] Compound 17 (2.000 g, 9.937 mmol) was used as the starting material according to the general synthesis method to obtain about 2.500 g (9.830 mmol, 98.92%) of compound 26.

[0091] Compounds 18-26 were dissolved in glacial acetic acid and transferred to an autoclave. PtO₂ (0.1 times the mass of the raw material) was added, followed by ventilation. Hydrogen was introduced to a pressure of 4 atmospheres and the reaction was allowed to proceed at room temperature for 10-15 hours. After the reaction was complete, the filtrate was filtered and 50 mL of dichloromethane was added. The pH was adjusted to 10 with aqueous ammonia. The organic phase was then washed with saturated brine and dried by column chromatography to yield the product compounds 27-35.

[0092] Synthesis of compound 27

[0093] Compound 18 (4.312 g, 16.068 mmol) was used as the starting material. Following the general synthesis method, the reaction was completed and then column chromatography (dichloromethane:ethanol = 10:0.6) was performed to obtain approximately 1.028 g (3.982 mmol, 24.78%) of compound 27. HRMS (ESI) (M+H) + m / z 259.2015, calculated value C 13 H 27 N2O3 259.2016. 1 H NMR (CDCl3, 400MHz) δ: 3.84-3.71 (m, 2H), 3.55 (t, J = 6.2Hz, 2H), 3.44 (tt, J = 3.7Hz, 8.0Hz, 1H), 3.10 (ddd, J = 3.5Hz, 9.1Hz,13.1Hz,2H),2.82(t,J=6.8Hz,2H),1.90-1.79(m,2H),1.73(p,J=6.5Hz,2H),1.66-1.48(m,6H),1.47(s,9H).

[0094] Synthesis of compound 28

[0095] Compound 19 (3.600 g, 13.415 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then column chromatography (dichloromethane:ethanol:ammonia water = 10:0.6:0.1) was performed to obtain approximately 1.199 g (4.406 mmol, 32.84%) of compound 28. HRMS (ESI) (M+H) + m / z 273.2167, calculated value C 14 H 29 N2O3 273.2173. 1H NMR (CDCl3, 400MHz) δ: 4.10 (s, 2H), 3.48 (t, J = 6.2Hz, 2H), 3.25 (d, J = 6.1Hz, 2H), 2.79 (t, J = 6.8 Hz,2H),2.69(t,J=12.9Hz,2H),1.80-1.62(m,5H),1.45(s,9H),1.21(s,2H),1.20-1.06(m,2H).

[0096] Synthesis of compound 29

[0097] Compound 20 (2.400 g, 8.853 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.8:0.1) was performed to obtain approximately 0.981 g (3.428 mmol, 38.72%) of compound 29. HRMS (ESI) (M+H) + m / z 287.2327, calculated value C 15 H 31 N2O3 287.2329. 1 H NMR (CDCl3, 400MHz) δ: 4.06 (s, 2H), 3.55-3.37 (m, 4H), 2.80 (t, J = 6.8Hz, 2H), 2.68 (t, J = 1 2.9Hz,2H),1.77-1.61(m,4H),1.59-1.48(m,3H),1.48-1.33(s,11H),1.20-1.02(m,2H).

[0098] Synthesis of compound 30

[0099] Compound 21 (2.100 g, 8.739 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.7:0.1) was performed to obtain approximately 0.923 g (3.781 mmol, 41.30%) of compound 30. HRMS (ESI) (M+H) + m / z 245.1860, calculated value C 12 H 25 N2O3 245.1860. 1H NMR (CDCl3, 400MHz) δ: 4.00 (s, 1H), 3.50 (t, J = 5.9Hz, 2H), 3.47-3.27 (m, 4H), 2.79 ( t,J=6.8Hz,2H),2.03-1.86(m,2H),1.72(q,J=6.5Hz,2H),1.46(s,9H),1.32(s,2H).

[0100] Synthesis of compound 31

[0101] Compound 22 (2.200 g, 9.155 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.6:0.1) was performed to obtain approximately 0.876 g (3.588 mmol, 39.20%) of compound 31. HRMS (ESI) (M+H) + m / z 245.1857, calculated value C 12 H 25 N2O3 245.1860. 1 H NMR (CDCl3, 400MHz) δ: 4.07-3.93 (m, 1H), 3.50 (t, J = 6.0Hz, 2H), 3.47-3.28 (m, 4H), 2.7 9(t,J=6.8Hz,2H),2.08-1.85(m,2H),1.72(q,J=6.5Hz,2H),1.49(s,2H),1.46(s,9H).

[0102] Synthesis of compound 32

[0103] Compound 23 (2.640 g, 16.068 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then subjected to column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.8:0.1) to obtain approximately 0.620 g (2.402 mmol, 14.95%) of compound 32. HRMS (ESI) (M+H) + m / z 259.2017, calculated value C 13 H 27 N2O3 259.2016. 1 H NMR (CDCl3, 400MHz) δ: 3.50 (t, J = 6.2Hz, 2H), 3.47-3.23 (m, 4H), 3.14-2.98 (m, 1H), 2.79 (t,J=6.8Hz,2H),2.45(s,1H),1.95(s,1H),1.79-1.57(m,3H),1.46(s,9H),1.25(s,2H).

[0104] Synthesis of compound 33

[0105] Compound 24 (2.400 g, 9.436 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then subjected to column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.6:0.1) to obtain approximately 0.679 g (2.630 mmol, 27.87%) of compound 33. HRMS (ESI) (M+H) + m / z 259.2015, calculated value C 13 H 27 N2O3 259.2016. 1 H NMR (CDCl3, 400MHz) δ: 3.50 (t, J=6.2Hz, 2H), 3.48-3.23 (m, 4H), 3.16-2.98 (m, 1H), 2.79 (t, J= 6.8Hz,2H),2.52-2.38(m,1H),2.01-1.98(m,1H),1.78-1.59(m,3H),1.46(s,9H),1.20(s,2H).

[0106] Synthesis of compound 34

[0107] Compound 25 (2.400 g, 9.436 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then subjected to column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.6:0.1) to obtain approximately 0.993 g (3.847 mmol, 40.76%) of compound 34. HRMS (ESI) (M+H) + m / z 259.2009, calculated value C 13 H 27 N2O3 259.2016. 1 H NMR (CDCl3, 400MHz) δ: 3.91-3.66 (m, 1H), 3.66-3.47 (m, 3H), 3.28 (dt, J = 4.1 Hz, 8.0 Hz, 1H), 3.12-2.96 (m, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.00-1.85 (m, 1H), 1.80-1.64 (m, 3H), 1.54-1.36 (s, 11H), 1.29 (s, 2H). Synthesis of compound 35

[0108] Compound 26 (2.500 g, 9.830 mmol) was used as the starting material. Following the general synthetic method, the reaction was completed and then column chromatography (dichloromethane:ethanol:aqueous ammonia = 10:0.7:0.1) was performed to obtain approximately 1.031 g (3.994 mmol, 40.63%) of compound 35. HRMS (ESI) (M+H) + m / z 259.2012, calculated value C 13 H 27 N2O3 259.2016. 1 H NMR (CDCl3, 400MHz) δ: 3.90-3.60 (m, 1H), 3.68-3.47 (m, 3H), 3.28 (dt, J = 4.0Hz, 8.5Hz, 1H), 3.15-2.94 (m,2H),2.79(t,J=6.7Hz,2H),1.98-1.85(m,1H),1.97-1.63(m,3H),1.54-1.42(s,11H),1.39(s,2H).

[0109] Reaction conditions and reagents: a. N-Boc-bromoethylamine, Ar-a, potassium carbonate, water / DMF = 1:1, 50°C; b. 12 M hydrochloric acid, ethyl acetate.

[0110] Preparation of Compound 100

[0111] Dissolve N-Boc-bromoethylamine (2.000 g, 8.924 mmol) and compound Ar-a (2.957 g, 8.924 mmol) in 10 mL:10 mL water / DMF. Add potassium carbonate (4.934 g, 35.698 mmol) and react at 50°C for 12 hours. After completion of the reaction, add ethyl acetate, wash twice with water and once with saturated brine, and spin dry the organic layer to obtain a light yellow solid.

[0112] The solid obtained in the previous step was dissolved in 3 mL of ethyl acetate, and 2 mL of 12 M hydrochloric acid was added dropwise at room temperature. Stirring was continued at room temperature for approximately 30 min. After the reaction was complete, 20 mL of ethyl acetate was slowly added while stirring. The product 100 was filtered to obtain approximately 2.684 g (7.168 mmol, 80.32%). HRMS (ESI) (M+H) + m / z 375.1831, calculated value C 19 H 24 FN4O3 375.1827. 1H NMR (DMSO-d6, 400MHz) δ: 11.88 (s, 1H), 8.69 (s, 1H), 7.97 (d, J = 13.0Hz, 1H), 7.64 (d, J = 7.4Hz, 1H), 4.03- 3.63(m,5H),3.51(t,J=6.5Hz,4H),3.41(dq,J=7.0Hz,12.6Hz,4H),1.45-1.26(m,2H),1.26-1.15(m,2H).

[0113] Reaction conditions and reagents: a. 2N NaOH solution, 80°C; b. boric acid, acetic anhydride.

[0114] Synthesis of Compound Ar-n

[0115] Compound 101 (5.023 g, 13.109 mmol) was dissolved in 2N NaOH solution and stirred at 80°C for 2 hours. The pH was adjusted to 5-6 with 2M HCl. The mixture was cooled in an ice bath, filtered and dried to give a white solid (3.006 g, 64.58%). Boric acid (0.348 g, 5.632 mmol) and acetic anhydride (1.33 mL, 14.079 mmol) were added to a round-bottom flask and reacted at 90°C for half an hour. After the reaction was completed, the above-mentioned white solid (1.000 g, 2.816 mmol) was added to the reaction system and the temperature was raised to 105°C for half an hour. After the reaction was completed, the temperature was slowly lowered to room temperature and petroleum ether was added for crystallization to give compound Ar-n (0.876 g, 1.813 mmol, 41.95%).

[0116] 2. Preparation of intermediates

[0117] Reaction conditions and reagents: a. CDI, DMAP, dichloromethane, room temperature; b. ethylenediamine or propylenediamine, DMF, room temperature; c. Formic acid, NaNO2, ethylene glycol, -15°C; d. Aminoalkyl alcohols of different carbon atom lengths, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DMF, room temperature; e. Compounds 7, 27-35, DBU, DMF, room temperature.

[0118] General synthesis of compounds 36 and 37

[0119] Compound (1 eq), DMAP (2 eq), and CDI (3 eq) were added to a round-bottom flask, followed by anhydrous dichloromethane. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, monitored by TLC, additional dichloromethane was added. The mixture was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, water, and saturated brine. The organic phase was then dried to yield a white solid.

[0120] Synthesis of compound 36

[0121] Compound 1 (2.207 g, 3.213 mmol) was used as the starting material by general synthetic methods. The product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.05 / 0.05) to give about 1.384 g (1.775 mmol, 55.24%) of compound 36 as a light yellow fluffy solid.

[0122] Synthesis of compound 37

[0123] According to the general synthesis method, compound 4 (3.080 g, 4.284 mmol) was used to obtain about 3.415 g (4.201 mmol, 98.06%) of white solid compound 37.

[0124] Compound 37 (1 eq) was dissolved in DMF, and ethylenediamine (to prepare compound 38) or propylenediamine (to prepare compound 39) (5 eq) was added dropwise at room temperature. The reaction was allowed to react for 6 h. TLC was used to monitor the reaction progress. Upon completion, ethyl acetate was added. The organic layer was washed three times with water and once with saturated brine. The organic phase was purified by spin column chromatography to yield compounds 38 and 39.

[0125] Synthesis of compound 38

[0126] Compound 37 (1.000 g, 1.230 mmol) and ethylenediamine (0.41 mL, 6.150 mmol) were used according to the general synthetic method. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.1 to obtain approximately 0.670 g (0.956 mmol, 77.72%) of compound 38.

[0127] Synthesis of compound 39

[0128] Compound 37 (1.200 g, 1.476 mmol) and propylenediamine (0.61 mL, 7.381 mmol) were used according to the general synthesis method. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.1 to obtain approximately 0.721 g (1.008 mmol, 68.29%) of compound 39.

[0129] Compound 38 or 39 (1 eq) was dissolved in ethylene glycol (20-100 eq). The mixture was transferred to -20°C and formic acid (4.5 eq) was added dropwise. Then, sodium nitrite (6 eq) was added portionwise with stirring. The temperature was maintained overnight and then slowly raised to room temperature for 12 h. After TLC monitoring of the reaction completion, 20 mL of dichloromethane and 20 mL of distilled water were added to the mixture. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, respectively. The organic layer was then spin-dried and purified by column chromatography.

[0130] Synthesis of compound 40

[0131] Compound 38 (0.670 g, 0.956 mmol) was used according to the general synthesis method and column chromatography (100-200 mesh silica gel, mobile phase: petroleum ether / dichloromethane / ethanol / ammonia water = 3 / 7 / 0.2 / 0.1) to obtain approximately 0.412 g (0.488 mmol, 51.05%) of compound 40. HRMS (ESI) (M+H) + m / z 850.4665, calculated value C 43 H 68 N3O 14 850.4696. 1H NMR(CDCl3,400MHz)δ:8.10-8.04(m,2H,2H-Bz),7.62-7.56(m,1H,2H-Bz),7.51-7.44(m,2H,2H-Bz),5.78 (s,1H,11-NH),5.34(t,J=5.1Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),5.02-4.94(m, 1H,H-2′),4.88(d,J=11.0Hz,1H,H-3),4.31(d,J=7.5Hz,1H,H-1′),3.80(d,J=3.1Hz,1H,H-5),3.78-3.73( m,2H,-CH2-OH),3.69(m,1H,H-11),3.67-3.54(m,5H,-CH2-O-CH2-,3-O-CO-NH-CH2),3.49-3.40(m,2H,H-5 ′),3.39-3.30(m,1H,3-O-CO-NH-CH2),2.95(s,3H,6-O-CH3),2.94-2.84(m,1H,H-3′),2.83-2.70(m,2H,H -10,H-2),2.53-2.42(m,1H,H-8),2.28(s,6H,-N(CH3)2),1.99-1.82(m,2H,H-4,H-14eq),1.81-1.73(m,1H ,H-4′a),1.60-1.36(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.29-1.21(m,6H,6-CH3,5′-C H3),1.15-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.4Hz,3H,4-CH3).

[0132] Synthesis of compound 41

[0133] Compound 39 (0.721 g, 1.008 mmol) was used according to the general synthesis method and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.2 / 0.1) to obtain approximately 0.294 g (0.340 mmol, 33.73%) of compound 41. HRMS (ESI) (M+H) + m / z 872.4890, calculated value C 46 H 70 N3O 13 872.4903. 1H NMR(CDCl3,400MHz)δ:8.10-8.02(m,2H,2H-Bz),7.62-7.55(m,1H,2H-Bz),7.5 1-7.43(m,2H,2H-Bz),5.77(s,1H,11-NH),5.45(t,J=5.7Hz,1H,3-O-CO-NH-CH2 ),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),5.00(dd,J=7.3Hz,10.5Hz,1H,H-2′),4 .89(d,J=11.0Hz,1H,H-3),4.30(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.3Hz,1H,H- 5),3.70(m,1H,H-11),3.66-3.55(m,4H,-CH2-O-CH2-),),3.51-3.39(m,2H,H-5 ′,3-O-CO-NH-CH2),3.37-3.28(m,1H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2 .89-2.70(m,3H,H-3,H-10,H-2),2.55-2.41(m,3H,-CH2-C≡CH,H-8),2.27(s,6H ,-N(CH3)2),2.05(t,J=2.6Hz,1H,-CH2-C≡CH),1.98-1.81(m,2H,H-4,H-14eq), 1.79-1.70 (m, 1H, H-4′a), 1.60-1.36 (m, 4H, H-7a, H-7b, H-14eq, H-4′a), 1.31 (s, 3H, 12-CH3), 1.28-1.23 (m, 6H, 6-CH3, 5′-CH3), 1.16-1.03 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J = 7.4 Hz, 3H, 15-CH3), 0.74 (d, J = 7.5 Hz, 3H, 4-CH3). General synthesis of compounds 42-51

[0134] Compound 36 or 37 (1 eq) was dissolved in DMF, and 3 eq of aminoalkyl alcohols of varying carbon lengths and DBU (1 eq) were added dropwise at room temperature. The reaction was allowed to react for 12 h. TLC was used to monitor the reaction progress. Upon completion, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was then purified by spin column chromatography to yield the compound.

[0135] Synthesis of compound 42

[0136] According to the general synthetic method, compound 36 (0.5 g, 0.641 mmol), DBU (0.19 mL, 1.282 mmol), and 3-aminopropanol (0.098 mL, 1.282 mmol) were used as starting materials. The resulting product was purified by column chromatography using 100-200 mesh silica gel and a mixture of dichloromethane / ethanol / aqueous ammonia (10 / 0.3 / 0.1). Approximately 0.338 g (0.453 mmol, 70.76%) of compound 42 was obtained as a light yellow, fluffy solid.

[0137] Synthesis of compound 43

[0138] According to the general synthetic method, compound 36 (0.6 g, 0.769 mmol), DBU (0.34 mL, 2.307 mmol), and 4-aminobutanol (0.21 mL, 2.307 mmol) were used as starting materials. The resulting product was purified by column chromatography using 100-200 mesh silica gel and a mixture of dichloromethane / ethanol / aqueous ammonia (10 / 0.3 / 0.1). Approximately 0.290 g (0.382 mmol, 49.67%) of compound 43 was obtained as a light yellow, fluffy solid.

[0139] Synthesis of compound 44

[0140] According to the general synthetic method, compound 36 (0.6 g, 0.769 mmol), DBU (0.34 mL, 2.307 mmol), and 5-aminopentanol (0.24 mL, 2.307 mmol) were used as starting materials. The resulting product was purified by column chromatography using 100-200 mesh silica gel and a mixture of dichloromethane / ethanol / aqueous ammonia (10 / 0.2 / 0.1). Approximately 0.332 g (0.429 mmol, 55.79%) of compound 44 was obtained as a light yellow, fluffy solid.

[0141] Synthesis of compound 45

[0142] Compound 37 (1.000 g, 1.230 mmol) was used as starting material, 2-aminoethanol (0.15 mL, 2.460 mmol) was added to the reaction mixture, and the product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain approximately 0.408 g (0.547 mmol, 44.47%) of compound 45.

[0143] Synthesis of compound 46

[0144] Compound 37 (0.500 g, 0.615 mmol) was used as the starting material, and 3-aminopropanol (0.094 mL, 1.230 mmol) was added to the reaction mixture. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain approximately 0.282 g (0.371 mmol, 60.32%) of compound 46. HRMS (ESI) (M+H) + m / z 820.4589, calculated value C 42 H 66 N3O 13 820.4590. 1 H NMR(CDCl3,400MHz)δ:8.09-8.02(m,2H,2H-Bz),7.61-7.55(m,1H,2H-Bz),7.49-7.43(m,2H,2H-Bz),5 .80(s,1H,11-NH),5.35(t,J=6.0Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.3Hz,11.0Hz,1H,H-13),4.99( dd, J=7.5Hz, 10.5Hz, 1H, H-2′), 4.88 (d, J=11.0Hz, 1H, H-3), 4.30 (d, J=7.5Hz, 1H, H-1′), 3.80 (d, J=3. 1Hz,1H,H-5),3.78-3.72(m,2H,-CH2-OH),3.70(s,1H,H-11),3.60-3.50(m,1H,3-O-CO-NH-CH2),3.47- 3.38(m,1H,H-5′),3.33-3.24(m,1H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2.90-2.70(m,3H,H-3′,H -10,H-2),2.52-2.43(m,1H,H-8),2.28(s,6H,-N(CH3)2),1.99-1.69(m,5H,H-4,H-14eq,H-4′a,-CH2-) ,1.58-1.36(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.29-1.23(m,6H,6-CH3,5′-CH3) ,1.15-1.03(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.73(d,J=7.5Hz,3H,4-CH3).

[0145] Synthesis of compound 47

[0146] Compound 37 (0.768 g, 0.945 mmol) was used as the starting material, and 4-aminobutanol (0.17 mL, 1.890 mmol) was added to the reaction mixture. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain approximately 0.328 g (0.393 mmol, 41.59%) of compound 47. HRMS (ESI) (M+H) + m / z 834.4738, calculated value C 43 H 68 N3O 13 834.4747. 1 H NMR(CDCl3,400MHz)δ:8.09-8.02(m,2H,2H-Bz), 7.62-7.55(m,1H,2H-Bz),7.50-7.43(m,2H,2H-Bz),5.78(s,1H,11-NH),5.18(dd,J=2.2Hz,10.9H z,1H,H-13),5.10(t,J=6.0Hz,1H,3-O-CO-NH-CH2),4.98(dd,J=7.5Hz,10.5Hz,1H,H-2′),4.88(d ,J=11.0Hz,1H,H-3),4.29(d,J=7.5Hz,1H,H-1′),3.82(d,J=3.2Hz,1H,H-5),3.75-3.66(m,3H,H- 11,-CH2-OH),3.48-3.34(m,2H,H-5′,3-O-CO-NH-CH2),3.23-3.12(m,1H,3-O-CO-NH-CH2),2.96(s ,3H,6-O-CH3),2.89-2.70(m,3H,H-3′,H-10,H-2),2.53-2.42(m,1H,H-8),2.28(s,6H,-N(CH3)2) ,2.04-1.82(m,2H,H-4,H-14eq),1.81-1.74(m,1H,H-4′a),1.73-1.59(m,4H,2(-CH2-)),1.58-1. 35(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.29-1.21(m,6H,6-CH3,5′-CH3),1.1 5-1.02(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.3Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0147] Synthesis of compound 48

[0148] Compound 37 (1.317 g, 1.620 mmol) was used as the starting material, and 5-aminopentanol (0.34 mL, 3.240 mmol) was added to the reaction mixture. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain approximately 0.540 g (0.637 mmol, 39.32%) of compound 48. HRMS (ESI) (M+H) + m / z 848.4902, calculated value C 44 H 70 N3O 13 848.4903. 1 H NMR(CDCl3,400MHz)δ:8.09-8.00(m,2H,2H-Bz),7.62-7.54(m,1H,2H-Bz),7.50-7.43(m,2H,2H-Bz),5 .79(s,1H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),5.03-4.91(m,2H,3-O-CO-NH-CH2,H-2′),4.8 8(d,J=11.0Hz,1H,H-3),4.29(d,J=7.5Hz,1H,H-1′),3.82(d,J=3.2Hz,1H,H-5),3.70(s,1H,H-11),3. 65(t,J=6.3Hz,2H,-CH2-OH),3.48-3.32(m,2H,H-5′,3-O-CO-NH-CH2),3.19-3.06(m,1H,3-O-CO-NH-C H2),2.96(s,3H,6-O-CH3),2.88-2.68(m,3H,H-3′,H-10,H-2),2.53-2.43(m,1H,H-8),2.28(s,6H,-N( CH3)2),1.97-1.83(m,2H,H-4,H-14eq),1.80-1.72(m,1H,H-4′a),1.66-1.56(m,4H,2(-CH2-)),1.54- 1.37(m,6H,H-7a,H-7b,H-14eq,H-4′a,-CH2-),1.31(s,3H,12-CH3),1.29-1.22(m,6H,6-CH3,5′-CH3) ,1.15-1.02(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0149] Synthesis of compound 49

[0150] Compound 37 (0.600 g, 0.738 mmol) was used as the starting material, and 6-aminohexanol (0.173 g, 1.476 mmol) was added to the reaction mixture. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain approximately 0.332 g (0.385 mmol, 52.17%) of compound 49. HRMS (ESI) (M+H) + m / z 862.5057, calculated value C 45 H 72 N3O 13 862.5060. 1 H NMR(CDCl3,400MHz)δ:8.08-8.01(m,2H,2H-Bz),7.62-7.54(m,1H,2H-Bz),7.50-7.43(m,2H,2H-Bz) ,5.75(s,1H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),4.99(dd,J=7.6Hz,10.4Hz,1H,H-2′),4. 90-4.82(m,2H,3-O-CO-NH-CH2,H-3),4.28(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.2Hz,1H,H-5),3.70( s,1H,H-11),3.65(t,J=6.4Hz,2H,-CH2-OH),3.46-3.30(m,2H,H-5′,3-O-CO-NH-CH2),3.20-3.09(m, 1H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2.86-2.67(m,3H,H-3′,H-10,H-2),2.53-2.41(m,1H,H- 8),2.28(s,6H,-N(CH3)2),1.98-1.83(m,2H,H-4,H-14eq),1.80-1.72(m,1H,H-4′a),1.68-1.37(m,1 0H,3(-CH2-),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.28-1.24(m,6H,6-CH3,5′-CH3),1 .14-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0151] Synthesis of compound 50

[0152] Compound 37 (0.600 g, 0.738 mmol) was used as the starting material, and 7-aminoheptanol (0.194 g, 1.476 mmol) was added for reaction. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain 0.235 g (0.268 mmol, 36.31%) of compound 50. HRMS (ESI) (M+H) + m / z 876.5218, calculated value C 46 H 74 N3O 13 876.5216. 1 H NMR(CDCl3,400MHz)δ:8.08-8.00(m,2H,2H-Bz),7.61-7.55(m,1H,2H-Bz),7 .50-7.43(m,2H,2H-Bz),5.76(s,1H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H, H-13),4.99(dd,J=7.4Hz,10.4Hz,1H,H-2′),4.91-4.82(m,2H,3-O-CO-NH-C H2,H-3),4.28(d,J=7.4Hz,1H,H-1′),3.83(d,J=3.1Hz,1H,H-5),3.70(s,1H ,H-11),3.63(t,J=6.5Hz,2H,-CH2-OH),3.48-3.39(m,1H,H-5′),3.37-3.27 (1H,3-O-CO-NH-CH2),3.20-3.11(m,1H,3-O-CO-NH-CH2),2.95(s,3H,6-O-C H3),2.86-2.69(m,3H,H-3′,H-10,H-2),2.52-2.43(m,1H,H-8),2.28(s,6H, -N(CH3)2),1.98-1.83(m,2H,H-4,H-14eq),1.80-1.69(m,3H,H-4′a,-CH2-), 1.61-1.34(m,10H,4(-CH2-),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.28-1.23(m,6H,6-CH3,5′- CH3),1.14-1.03(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.73(d,J=7.5Hz,3H,4-CH3).

[0153] Synthesis of compound 51

[0154] Compound 37 (0.600 g, 0.738 mmol) was used as the starting material, and 8-aminooctanol (0.214 g, 1.476 mmol) was added for reaction. The product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.1 to obtain 0.167 g (0.188 mmol, 25.27%) of compound 51. HRMS (ESI) (M+H) + m / z 890.5374, calculated value C 47 H 76 N3O 13 890.5373. 1 H NMR(CDCl3,400MHz)δ:8.09-8.01(m,2H,2H-Bz),7.61-7.55(m,1H,2H-Bz),7.49-7.43(m,2H,2H-Bz),5 .76(s,1H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),4.99(dd,J=7.5Hz,10.5Hz,1H,H-2′),4.91-4 .81(m,2H,3-O-CO-NH-CH2,H-3),4.28(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.2Hz,1H,H-5),3.70(s,1H,H -11),3.62(t,J=6.5Hz,2H,-CH2-OH),3.47-3.38(m,1H,H-5′),3.38-3.27(1H,3-O-CO-NH-CH2),3.19- 3.09(m,1H,3-O-CO-NH-CH2),2.95(s,3H,6-O-CH3),2.86-2.69(m,3H,H-3′,H-10,H-2),2.53-2.42(m, 1H,H-8),2.28(s,6H,-N(CH3)2),1.98-1.83(m,2H,H-4,H-14eq),1.80-1.72(m,1H,H-4′a),1.68-1.33 (m,10H,6(-CH2-),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.28-1.24(m,6H,6-CH3,5′-CH3) ,1.15-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.3Hz,3H,15-CH3),0.73(d,J=7.5Hz,3H,4-CH3).

[0155] General Synthesis Methods of Compounds 52-62

[0156] Compound 36 or 37 and 1.5eq compound 7 or 27-35 are dissolved in anhydrous DMF, DBU is added and stirred at normal temperature for 12-18 hours, and TLC monitors the reaction process. After the reaction is completed, 50mL ethyl acetate is added, and saturated common salt water is washed once with water three times respectively, and the organic phase is spin-dried for column chromatography to obtain product. The upper step product is dissolved in 4mL ethanol, 12M HCl solution 3mL is slowly added dropwise, and normal temperature reaction is 5-20 minute. After the reaction is completed, 50mL dichloromethane is added in system, pH is adjusted to 10-11 with ammoniacal liquor, and then washed with saturated common salt water, and after separatory, organic layer is spin-dried for column chromatography to obtain product.

[0157] Synthesis of compound 52

[0158] Compound 36 (1.200 g, 1.538 mmol) and compound 27 (0.596 g, 2.308 mmol) were used according to the general synthetic method. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to give approximately 0.432 g (0.496 mmol, 32.24%) of compound 52. HRMS (ESI) (M+H) + m / z 871.5274, calculated value C 43 H 75 N4O 14 871.5274. 1H NMR (CDCl3, 400MHz) δ: 5.45 (t, J = 5.5Hz, 1H, 3-O-CO-NH-CH2), 5.17 (dd, J = 2.4Hz, 10.8Hz, 1H, H-13), 4.88-4.80 (m, 2H,H-11,H-3),4.72(dd,J=7.5Hz,10.5Hz,1H,H-2′),4.32(d,J=7.5Hz,1H,H-1′),3.81(s,3H,9-O-CH3),3.74(d,J =3.3Hz,1H,H-5),3.70-3.62(m,1H,H-8),3.62-3.53(m,2H,O-CH2),3.45-3.21(m,4H,H-5′,3-O-CO-NH-CH2,-N-(C H2-CH2)2-CH-),3.08(dt,J=4.5Hz,12.3Hz,2H,-N-(CH2-CH2)2),3.00(s,3H,6-O-CH3),2.87-2.76(m,1H,H-2),2. 70-2.57(m,2H,-N-(CH2-CH2)2),3.16-3.06(m,3H,-N-(CH2-CH2)2,H-3′),2.47(d,J=6.8Hz,1H,H-10),2.25(s,6H ,-N(CH3)2),2.11-1.99(m,4H,H-4,2′-OAc),1.99-1.73(m,6H,H-14eq,CH2,-N-(CH2-CH2)2,H-4′a),1.73-1.52(m ,6H,H-7a,H-4′a,H-7b,H-14eq,-N-(CH2-CH2)2),1.48(s,3H,12-CH3),1.29(s,3H,6-CH3),1.27-1.17(m,7H,5′-C H3,H-4′b,2-CH3),1.14(d,J=6.8Hz,3H,10-CH3),0.97-0.89(m,6H,4-CH3,8-CH3),0.86(t,J=7.4Hz,3H,15-CH3).

[0159] Synthesis of compound 53

[0160] According to the general synthetic method, compound 37 (1.000 g, 1.230 mmol) and compound 7 (0.631 g, 2.460 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to give approximately 0.231 g (0.256 mmol, 20.81%) of compound 53. HRMS (ESI) (M+H) +m / z 901.5535, calculated value C 48 H 77 N4O 12 901.5533. 1 H NMR(CDCl3,400MHz)δ:8.10-8.03(m,2H,2H-Bz),7.64-7.57(m,1H,2H-Bz),7.52-7.44(m,2H,2H-Bz),5.79(s,1H,11-NH), 5.20(dd,J=2.3Hz,10.9Hz,1H,H-13),5.00(dd,J=7.6Hz,10.4Hz,1H,H-2′),4.93-4.84(m,2H,H-3,3-O-CO-NH-CH2),4.30 (d,J=7.5Hz,1H,H-1′),3.84(d,J=3.2Hz,1H,H-5),3.71(s,1H,H-11),3.48-3.30(m,2H,H-5′,3-O-CO-NH-CH2),3.19-3.1 1(m,1H,3-O-CO-NH-CH2),3.07(dt,J=3.3Hz,12.0Hz,2H,-N-(CH2-CH2)2),2.99(s,3H,6-O-CH3),2.88-2.70(m,3H,H-3′, H-10,H-2),2.58(dt,J=2.5Hz,12.0Hz,2H,-N-(CH2-CH2)2),2.53-2.45(m,1H,H-8),2.29(s,6H,-N(C H3)2),2.02-1.85(m,2H,H-4,H-14eq),1.80-1.35(m,11H,H-4′a,2(-CH2-),H-7a,H-7b,H-14eq,-CH-( CH2-CH2)2),1.33(s,3H,12-CH3),1.32-1.22(m,9H,6-CH3,5′-CH3,H-4′b,-CH2-),1.15-1.02(m,11H, 2-CH3,10-CH3,8-CH3,-CH-(CH2-CH2)2),0.83(t,J=7.3Hz,3H,15-CH3),0.76(d,J=7.5Hz,3H,4-CH3).

[0161] Synthesis of compound 54

[0162] According to the general synthesis method

[0163] Compound 37 (1.000 g, 1.230 mmol) and compound 27 (0.476 g, 1.845 mmol) were used. After the reaction was completed, the BOC protecting group was removed and purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.520 g (0.576 mmol, 46.83%) of compound 54. HRMS (ESI) (M+H) + m / z 903.53256, calculated value C 47 H 75 N4O 13 903.53251. 1H NMR(CDCl3,400MHz)δ:8.10-8.02(m,2H,2H-Bz),7.64-7.57(m,1H,2H-Bz),7.51-7.44(m,2H,2H-Bz),5.79(s,1H,11 -NH),5.48(t,J=5.5Hz,1H,3-O-CO-NH-CH2),5.20(dd,J=2.3Hz,10.9Hz,1H,H-13),5.02(dd,J=7.5Hz,10.5Hz,1H,H- 2′),4.90(d,J=11.0Hz,1H,H-3),4.32(d,J=7.5Hz,1H,H-1′),3.85(d,J=3.2Hz,1H,H-5),3.72(s,1H,H-11),3.68-3. 58(m,2H,O-CH2),3.52-3.36(m,4H,H-5′,3-O-CO-NH-CH2,-N-(CH2-CH2)2-CH-),3.35-3.25(m,1H,3-O-CO-NH-CH2), 3.16-3.06(m,2H,-N-(CH2-CH2)2),2.98(s,3H,6-O-CH3),2.90-2.72(m,3H,H-3′,H-10,H-2),2.71-2.60(m,2H,-N-( CH2-CH2)2),2.55-2.44(m,1H,H-8),2.30(s,6H,-N(CH3)2),2.02-1.73(m,7H,H-4,H-14eq,CH2,-N-(CH2-CH2)2,H-4 ′a),1.58-1.37(m,6H,H-7a,H-4′a,H-7b,H-14eq,-N-(CH2-CH2)2),1.33(s,3H,12-CH3),1.31-1.22(m,7H,6-CH3,5′ -CH3,H-4′b),1.17-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.83(t,J=7.4Hz,3H,15-CH3),0.76(d,J=7.5Hz,3H,4-CH3).

[0164] Synthesis of compound 55

[0165] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 28 (0.602 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.6 / 0.1) to obtain approximately 0.300 g (0.327 mmol, 22.16%) of compound 55. HRMS (ESI) (M+H)+ m / z 917.5472, calculated value C 48 H 77 N4O 13 917.5482. 1 H NMR(CDCl3,400MHz)δ:8.09-8.00(m,2H,2H-Bz),7.61-7.54(m,1H,H-Bz),7.50-7.43(m,2H,2H-Bz),5.76(s,1H,11-NH),5.3 9(t,J=5.5Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),4.99(dd,J=7.5Hz,10.5Hz,1H,H-2′),4.88(d,J=1 1.0Hz,1H,H-3),4.32(d,J=7.5Hz,1H,H-1′),3.84(d,J=3.2Hz,1H,H-5),3.69(s,1H,H-11),3.55(t,J=5.6Hz,2H,O-CH2),3. 48-3.39(m,4H,H-5′,3-O-CO-NH-CH2),3.36-3.23(m,3H,3-O-CO-NH-CH2,O-CH2),3.15-3.04(m,2H,-N-(CH2-CH2)2),2.96( s,3H,6-O-CH3),2.87-2.76(m,3H,H-3′,H-10),2.75-2.68(m,1H,H-2),2.67-2.56(m,2H,-N-(CH2-CH2)2),2.54-2.42(m,1H ,H-8),2.28(s,6H,-N(CH3)2),1.99-1.78(m,4H,H-4,H-14eq,CH,H-4′a),1.78-1.68(m,4H,-N-(CH2-CH2)2,CH2),1.64(s,1 H,NH),1.56-1.35(m,4H,H-7a,H-4′a,H-7b,H-14eq),1.31(s,3H,12-CH3),1.29-1.23(m,6H,6-CH3,5′-CH3),1.23-1.14(m, 2H,-N-(CH2-CH2)2),1.14-1.03(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.3Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0166] Synthesis of compound 56

[0167] Compound 37 (1.200 g, 1.476 mmol) and compound 29 (0.629 g, 2.214 mmol) were used according to the general synthetic method. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to give approximately 0.334 g (0.358 mmol, 24.25%) of compound 56. HRMS (ESI) (M+H) + m / z 931.5648, calculated value C 49 H 79 N4O 13 931.5638. 1H NMR(CDCl3,400MHz)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),5.78(s,1H,11-NH), 5.34(t,J=5.6Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),4.99(dd,J=7.4Hz,10.4Hz,1H,H-2′),4.88( d,J=11.0Hz,1H,H-3),4.29(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.2Hz,1H,H-5),3.69(s,1H,H-11),3.57-3.37(m,6H,CH2OC H2,H-5′,3-O-CO-NH-CH2),3.33-3.21(m,1H,3-O-CO-NH-CH2),3.11-3.02(m,2H,-N-(CH2-CH2)2),2.97(s,3H,6-O-CH3), 2.87-2.70(m,3H,H-3′,H-10,H-2),2.66-2.53(m,2H,-N-(CH2-CH2)2),2.53-2.41(m,1H,H-8),2.28(s, 6H,-N(CH3)2),1.99-1.61(m,9H,H-4,H-14eq,CH,H-4′a,2(CH2),H-7a,),1.61-1.36(m,7H,-N-(CH2-CH2 )2CH,NH,H-4′a,H-7b,H-14eq),1.32(s,3H,12-CH3),1.30-1.22(m,6H,6-CH3,5′-CH3),1.23-1.03(m,1 1H,-N-(CH2-CH2)2,2-CH3,10-CH3,8-CH3),0.81(t,J=7.3Hz,3H,15-CH3),0.75(d,J=7.4Hz,3H,4-CH3).

[0168] Synthesis of compound 57

[0169] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 30 (0.540 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.382 g (0.430 mmol, 29.13%) of compound 57. HRMS (ESI) (M+H) + m / z 889.5169, calculated value C46 H 73 N4O 13 889.5169. 1 H NMR(CDCl3,400MHz)δ:8.09-8.02(m,2H,2H-Bz),7.62-7.55(m,1H,H-Bz),7.51-7.42(m,2H,2H-Bz),5.77(s,1 H,11-NH),5.36(t,J=5.6Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),4.99(dd,J=7.4Hz,10. 4 Hz, 1H, H-2′), 4.87 (d, J=11.0 Hz, 1H, H-3), 4.29 (d, J=7.5 Hz, 1H, H-1′), 4.06-3.98 (s, 1H, H-tetrahydropyrrole), 3.84 (d, J=3.2 Hz, 1H, H-5), 3.69 (s, 1H, H-11), 3.57-3.37 (m, 4H, O-CH2, 2H-tetrahydropyrrole), 3.29-3.18 (m, 1H, 3-O-CO-NH-CH2), 3.1 5-2.99 (m, 2H, H-5′, H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH3), 2.94-2.70 (m, 5H, 3-O-CO-NH-CH2, H-tetrahydropyrrole, H-10, H-2, H-3′), 2.52-2.41 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 2.08-1.98 (m, 2H, CH2), 1.97-1.70 (m, 6H, H-4, H-14eq, 2H-tetrahydropyrrole Hydropyrrole,H-4′a,H-7a),1.59-1.36(m,4H,NH,H-4′a,H-7b,H-14eq),1.31(s,3H,12-CH3),1.29-1.22(m,6H,6-CH3,5 ′-CH3), 1.17-1.03 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J=7.3Hz, 3H, 15-CH3), 0.75 (d, J=7.5Hz, 3H, 4-CH3).

[0170] Synthesis of compound 58

[0171] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 31 (0.540 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.400 g (0.450 mmol, 30.48%) of compound 58. HRMS (ESI) (M+H) + m / z 889.5166, calculated value C 46 H 73 N4O 13 889.5169. 1 H NMR(CDCl3,400MHz)δ:8.09-8.01(m,2H,2H-Bz),7.63-7.55(m,1H,H-Bz),7.51-7.42(m,2H,2H-Bz),5.77(s,1 H,11-NH),5.41(t,J=5.6Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),4.99(dd,J=7.4Hz,10. 5 Hz, 1H, H-2′), 4.88 (d, J=11.0 Hz, 1H, H-3), 4.30 (d, J=7.5 Hz, 1H, H-1′), 4.05-3.97 (m, 1H, H-tetrahydropyrrole), 3.84 (d, J=3.2 Hz, 1H, H-5), 3.69 (s, 1H, H-11), 3.55-3.37 (m, 4H, O-CH2, 2H-tetrahydropyrrole), 3.29-3.19 (m, 1H, 3-O-CO-NH-CH2), 3.1 8-2.99 (m, 2H, H-5′, H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH3), 2.94-2.70 (m, 5H, 3-O-CO-NH-CH2, H-tetrahydropyrrole, H-10, H-2, H-3′), 2.53-2.40 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 2.08-1.98 (m, 2H, CH2), 1.97-1.71 (m, 6H, H-4, H-14eq, 2H-tetrahydropyrrole Hydropyrrole,H-4′a,H-7a),1.61-1.35(m,4H,NH,H-4′a,H-7b,H-14eq),1.32(s,3H,12-CH3),1.29-1.21(m,6H,6-CH3,5 ′-CH3), 1.15-1.02 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J=7.3Hz, 3H, 15-CH3), 0.75 (d, J=7.5Hz, 3H, 4-CH3).

[0172] Synthesis of compound 59

[0173] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 32 (0.578 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.200 g (0.221 mmol, 14.97%) of compound 59. HRMS (ESI) (M+H) + m / z 903.5338, calculated value C 47 H 75 N4O 13 903.5325. 1H NMR(CDCl3,400MHz)δ:8.09-8.01(m,2H,2H-Bz),7.62-7.54(m,1H,H-Bz),7.50-7.43(m,2H,2H-Bz),5.75(s,1H,11-NH),5.53(t,J=5.3Hz,1H ,3-O-CO-NH-CH2),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),5.00(dd,J=7.5Hz,10.4Hz,1H,H-2′),4.88(d,J=11.0Hz,1H,H-3),4.31(d,J=7.5Hz, 3.83 (d, J = 3.2 Hz, 1H, H-5), 3.69 (s, 1H, H-11), 3.56 (t, J = 5.7 Hz, 2H, O-CH2), 3.50-3.38 (m, 3H, H-5', O-CH2), 3.39-3.32 (m, 1H, H-tetrahydropyrrole), 3.30-3.20 (m, 1H, 3-O-CO-NH-CH2), 3.14-2.99 (m, 2H, 3-O-CO-NH-CH2, H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH3), 2.94-2.84 (m, 2H, H-3', H-tetrahydropyrrole), 2.82-2.70 (m, 3H, H-tetrahydropyrrole, H-10, H-2), 2.53-2.36 (m, 2H, H-tetrahydropyrrole, H-8), 2.28 (s, 6H, -N(CH3)2), 1.99-1.72 (m, 6H, H-4, H-14eq, H-tetrahydropyrrole, H-4′a, CH2), 1.58-1.36 (m, 5H, NH, H-7a, H-4 ′a,H-7b,H-14eq),1.31(s,3H,12-CH3),1.29-1.22(m,6H,6-CH3,5′-CH3),1.16-1.01(m ,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.75(d,J=7.5Hz,3H,4-CH3).

[0174] Synthesis of compound 60

[0175] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 33 (0.578 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.328 g (0.363 mmol, 24.60%) of compound 60. HRMS (ESI) (M+H) +m / z 903.5327, calculated value C 47 H 75 N4O 13 903.5325. 1 H NMR(CDCl3,400MHz)δ:8.10-7.99(m,2H,2H-Bz),7.62-7.55(m,1H,H-Bz),7.51-7.42(m,2H,2H-Bz),5.77(s,1H ,11-NH),5.45(t,J=5.6Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),5.00(dd,J=7.4Hz,10.5H z,1H,H-2′), 4.88(d, J=11.0Hz,1H,H-3), 4.30(d, J=7.5Hz,1H,H-1′), 3.84(d, J=3.2Hz,1H,H-5), 3.69(s,1H,H-11), 3.56(t, J=5.8Hz,2H,O-CH2), 3.51-3.41(m,3H,H-5′,O-CH2), 3.39-3.32(m,2H,H-tetrahydropyrrole), 3.31-3.20(m,1H, 3-O-CO-NH-CH2), 3.12-2.99 (m, 2H, 3-O-CO-NH-CH2, H-tetrahydropyrrole), 2.97 (s, 3H, 6-O-CH3), 2.94-2.68 (m, 5H, H-3′, 2H-tetrahydropyrrole, H-10, H-2), 2.53-2.35 (m, 2H, H-tetrahydropyrrole, H-8), 2.28 (s, 6H, -N(CH3)2), 1.98-1.71 (m, 6H, H-4, H-14eq, H-tetrahydropyrrole pyro,H-4′a,CH2),1.61-1.34(m,5H,NH,H-7a,H-4′a,H-7b,H-14eq),1.31(s,3H,12-CH3),1.29-1.21(m,6H,6-CH3, 5′-CH3), 1.15-1.00 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J=7.3Hz, 3H, 15-CH3), 0.75 (d, J=7.5Hz, 3H, 4-CH3).

[0176] Synthesis of compound 61

[0177] According to the general synthetic method, compound 37 (1.200 g, 1.476 mmol) and compound 34 (0.571 g, 2.214 mmol) were used. After completion of the reaction, the BOC protecting group was removed and purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to obtain approximately 0.368 g (0.407 mmol, 27.57%) of compound 61. HRMS (ESI) (M+H) + m / z 903.5330, calculated value C 47 H 75 N4O 13 903.5325. 1 H NMR(CDCl3,400MHz)δ:8.09-8.00(m,2H,2H-Bz),7.63-7.53(m,1H,H-Bz),7.49-7.43(m,2H,2H-Bz),5.77(s,1 H,11-NH),5.69(t,J=5.6Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),4.99(dd,J=7.6Hz,10 .5Hz,1H,H-2′),4.88(d,J=11.0Hz,1H,H-3),4.30(d,J=7.5Hz,1H,H-1′),3.84(d,J=3.2Hz,1H,H-5),3.69(s, 1H,H-11),3.67-3.56(m,2H,O-CH2),3.54-3.38(m,2H,3-O-CO-NH-CH2,H-5′),3.37-3.31(m,1H,CH),3.30-3. 22 (m, 1H, 3-O-CO-NH-CH2), 3.12-3.05 (m, 1H, H-piperidinyl), 2.97 (s, 3H, 6-O-CH3), 2.89-2.65 (m, 6H, 3H-piperidinyl, H-10, H-2, H-3′), 2.53-2.41 (m, 1H, H-8), 2.28 (s, 6H, -N(CH3)2), 1.98-1.71 (m, 8H, CH2, H-4, H-14eq, 2H-tetrahydropyrrole, H-4′a ,H-7a),1.61-1.35(m,6H,NH,2H-tetrahydropyrrole,H-4′a,H-7b,H-14eq),1.32(s,3H,12-CH3),1.30-1.22(m,6H,6-CH3,5 ′-CH3), 1.16-1.01 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J=7.3Hz, 3H, 15-CH3), 0.74 (d, J=7.5Hz, 3H, 4-CH3).

[0178] Synthesis of compound 62

[0179] Compound 37 (1.200 g, 1.476 mmol) and compound 35 (0.571 g, 2.214 mmol) were used according to the general synthetic method. After completion of the reaction, the BOC protecting group was removed and the product was purified by column chromatography (dichloromethane / ethanol / ammonia water = 10 / 0.5 / 0.1) to give approximately 0.391 g (0.433 mmol, 29.33%) of compound 62. HRMS (ESI) (M+H) + m / z 903.5329, calculated value C 47 H 75 N4O 13 903.5325. 1H NMR(CDCl3,400MHz)δ:8.09-8.01(m,2H,2H-Bz),7.62-7.55(m,1H,H-Bz),7.50-7.42(m,2H,2H-Bz),5.84(t,J=5.7Hz,1H,3-O-CO-NH-CH2),5.77(s,1 H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),5.00(dd,J=7.4Hz,10.4Hz,1H,H-2′),4.88(d,J=11.0Hz,1H,H-3),4.31(d,J=7.5Hz,1H,H-1′),3.84 (d, J = 3.2 Hz, 1H, H-5), 3.69 (s, 1H, H-11), 3.60 (t, J = 3.6 Hz, 2H, O-CH2), 3.49-3.40 (m, 2H, 3-O-CO-NH-CH2, H-5′), 3.39-3.33 (m, 1H, CH), 3.33-3.26 (m, 1H, 3-O-CO-NH-CH2), 3.07-3.00 (m, 1H, H-piperidinyl), 2.97 (s, 3H, 6-O-CH3), 2.90-2.70 (m, 6H, 3H-piperidinyl, H-10, H-2, H-3′), 2.51-2.43 (m, 1H, H-8), 2.28 (s, 6 H,-N(CH3)2), 2.11-1.71 (m, 8H, CH2, H-4, H-14eq, 2H-tetrahydropyrrole, H-4′a, H-7a), 1.66-1.36 (m, 6H, NH, 2H-tetrahydropyrrole, H-4′a, H-7b, H-14eq), 1.31 (s, 3H, 12-CH3), 1.29-1.22 (m, 6H, 6-CH3, 5′-CH3), 1.16-1.02 (m, 9H, 2-CH3, 10-CH3, 8-CH3), 0.81 (t, J = 7.3 Hz, 3H, 15-CH3), 0.75 (d, J = 7.5 Hz, 3H, 4-CH3).

[0180] 3. Preparation of compounds of general formula

[0181] Reaction conditions and reagents: a. methanesulfonyl chloride, triethylamine, dichloromethane, room temperature; b. ciprofloxacin, acetonitrile, 70°C; c. methanol reflux.

[0182] General synthesis method of compound 63 and 64 series

[0183] Compound 40 or 41 (1 eq) was dissolved in 20 mL of dichloromethane, and triethylamine (2 eq) was added. Methanesulfonyl chloride (1.5 eq) was added dropwise at room temperature and stirred for approximately 10-20 min. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was washed twice with water and once with saturated brine. The organic phase was then spin-dried and purified by column chromatography.

[0184] Disperse the intermediate (1 eq) and the piperazine-containing quinolone (5 eq) in anhydrous acetonitrile and stir at 70°C for 72 h. After completion, the reaction mixture was spin-dried to dryness, added with 50 mL of dichloromethane, and washed three times with water and once with saturated brine. The organic phase was spin-dried to dryness, and 20 mL of methanol was added to reflux to remove the protecting group. After completion of the reaction, the reaction mixture was spin-dried and purified by column chromatography.

[0185] Synthesis of compound 63a

[0186] According to the synthesis method, compound 40 (0.412 g, 0.488 mmol) and methanesulfonyl chloride (0.044 mL, 0.533 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: petroleum ether / dichloromethane / ethanol / ammonia water = 7 / 3 / 0.05 / 0.05) to obtain approximately 0.253 g (0.253 mmol, 51.84%) of compound 87.

[0187] Compound 87 (0.235 g, 0.253 mmol) was reacted with compound Ar-a (0.251 g, 0.758 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 31.1 mg (0.0295 mmol, 11.68%) of compound 63a. Melting point: 162.3-165.8°C. HRMS (ESI) (M+H) + m / z 1059.5662, calculated value C 53 H 80 FN6O 15 1059.5660. 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H, 2″-quinolyl), 8.00 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.36 (s, 1H, 8″-quinolyl), 5.80 (s, 1H, 11-NH), 5.63 (s, 1H, 3-O-CO-NH-CH2), 5.22 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11 .0 Hz, 1H, H-3), 4.04 (d, J = 7.1 Hz, 1H, H-1′), 3.79 (d, J = 2.8 Hz, 1H, H-5), 3.77 (s, 1H, H-11), 3.66 (t, J = 5.5 Hz, 2H, -O-CH2-CH2-piperazinyl), 3.62-3.48 (m, 5H, 1H-cyclopropyl, 3-O-CO-NH-CH2-CH2), 3.47-3.31 (m, 5H, H -5′,4H-piperazinyl), 3.29-3.22 (m,1H,3-O-CO-NH-CH2), 3.18 (dd, J=7.3 Hz,10.0 Hz,1H,H-2′), 2.98 (s,3H,6-O-CH3), 2.93-2.79 (m,2H,H-10,H-2), 2.75 (s,4H,4H-piperazinyl), 3.69 (t, J=5.3 Hz,2H,-O-CH2-CH2-piperazine base),2.57-2.38(m,2H,H-8,H-3′),2.30(s,6H,-N(CH3)2),2.11-2.01(m,1H,H-4),1.98-1.85(m,1H,H -14eq),1.82-1.72(m,1H,H-7a),1.69-1.49(m,3H,H-7b,H-14eq,H-4′a),1.46-1.34(m,5H,12-CH3, 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.17-1.07 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.83 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.63,177.11,174.33,167.00,158.42,156.48,147.43,139.11,1 08.17,104.76,103.12,83.87,81.49,78.42,77.86,77.24,75.83,70.45,69.64,69.47,68 .19,66.08,58.12,57.57,53.16,49.82,49.62,45.30,43.36,41.01,40.35,39.11,37.29,35.82,35.32,28.64,22.03,21.20,19.30,18.27,15.07,13.87,13.29,10.25,9.12,8.26.

[0188] Synthesis of compound 64a

[0189] According to the synthesis method, compound 41 (0.294 g, 0.340 mmol) and methanesulfonyl chloride (0.029 mL, 0.357 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: petroleum ether / dichloromethane / ethanol / ammonia water = 3 / 7 / 0.1 / 0.05) to obtain approximately 0.233 g (0.247 mmol, 72.60%) of compound 88.

[0190] Compound 88 (0.233 g, 0.247 mmol) was reacted with compound Ar-a (0.410 g, 1.235 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 41.7 mg (0.0388 mmol, 15.73%) of compound 64a. Melting point: 163.6-164.7°C. HRMS (ESI) (M+H) + m / z 1073.5814, calculated value C 54 H 82 FN6O 15 1073.5817. 1H NMR (CDCl3, 400 MHz) δ: 8.74 (s, 1H, 2″-quinolyl), 7.97 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.81 (s, 1H, 11-NH), 5.56 (s, 1H, 3-O-CO-NH-CH2), 5.22 (dd, J = 2.4 Hz, 10.9 Hz, 1H, H-13), 4.92 (d, J = 10.9 Hz, 1H ,H-3), 4.05(d, J=7.2Hz,1H,H-1′),3.85-3.73(m,2H,H-5,H-11),3.68-3.51(m,4H,-CH2-O-CH2-CH2-piperazinyl)),3.48-3.27(m,7H,H-5′,1H-cyclopropyl,4H-piperazinyl,3-O-CO-NH-CH2-),3.25-3.13(m,2H,H-2′,3-O-CO-NH-CH2),2.98(s ,3H,6-O-CH3),2.93-2.79(m,2H,H-10,H-2),2.79-2.62(m,6H,4H-piperazinyl,-O-CH2-CH2-piperazinyl),2.58-2.39(m,2H,H-8,H-3′),2.28(s,6H,-N(CH3)2),2.12-2.01(m,1H,H-4),1.98-1.86(m,1H,H-14eq),1.85-1.71(m,3H,H-7 a, -CH2-), 1.69-1.49 (m, 3H, H-7b, H-14eq, H-4′a), 1.47-1.35 (m, 5H, 12-CH3, 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.18-1.06 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.83 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.62,177.05,174.37,166.96,158.40,156.43,152.37,147.37,139.11,1 19.72,112.43,112.20,108.10,104.77,103.15,83.88,81.46,78.09,77.88,77.25,75.76,70.48, 69.45,69.26,68.44,66.05,58.11,57.63,53.16,52.84,49.81,49.68,45.29,43.38,40.31,39.13,37.27,35.83,35.31,29.69,22.03,21.19,19.29,18.27,15.06,13.84,13.27,10.23,9.10,8.23.

[0191] Reaction conditions and reagents: a. methanesulfonyl chloride or p-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature; b. quinolone with piperazine, acetonitrile, 70°C; c. methanol reflux.

[0192] General Synthesis Method of Compounds 65-73 Series

[0193] Dissolve compounds 42-44, 46-51 (1 eq) in 20 mL of dichloromethane and add triethylamine (2 eq). Add methanesulfonyl chloride (1.5 eq) dropwise at room temperature, or add p-toluenesulfonyl chloride (2 eq) and stir for approximately 10-20 minutes. Monitor the reaction progress by TLC. After completion, wash the mixture twice with water and once with saturated brine. Purify the organic phase by spin drying and column chromatography.

[0194] Disperse the intermediate (1 eq) and the piperazine-containing quinolone (5 eq) in anhydrous acetonitrile and stir at 70°C for 72 h. After completion, the reaction mixture was spin-dried to dryness, added with 50 mL of dichloromethane, and washed three times with water and once with saturated brine. The organic phase was spin-dried to dryness, and 20 mL of methanol was added to reflux to remove the protecting group. After completion of the reaction, the reaction mixture was spin-dried and purified by column chromatography.

[0195] Synthesis of compound 65a

[0196] According to the synthesis method, compound 42 (0.338 g, 0.453 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 developing solvent) to obtain about 0.179 g (0.217 mmol, 47.90%) of compound 89 as a white fluffy solid.

[0197] Compound 89 (0.179 g, 0.217 mmol) was reacted with compound Ar-a (0.360 g, 1.085 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) to afford approximately 71.5 mg (0.0675 mmol, 31.11%) of compound 65a as a white, fluffy solid. Melting point: 182.9-184.0°C. HRMS (ESI) (M+H) + m / z 1059.5666, calculated value C 53 H 80 FN6O 15 1059.5660. 1H NMR (CDCl3, 700 MHz) δ: 8.75 (s, 1H, 2″-quinolyl), 7.99 (d, J = 12.7 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 6.7 Hz, 1H, 8″-quinolyl), 5.83 (br, 1H, 3-O-CO-NH-CH2), 5.16 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.91-4.81 (m, 2H, H-3, H-11), 4.04 (d, J = 6.9 Hz, 1H, H-1′), 3.82 ( s, 3H, 9-O-CH3), 3.80-3.75 (m, 1H, H-5), 3.73-3.66 (m, 1H, H-8), 3.60-3.52 (m, 1H, H-5′), 3.50-3.25 (m, 6H, 1H-cyclopropyl, 3-O-CO-NH-CH2, 4H-piperazinyl), 3.25-3.15 (m, 1H, H-2′, 3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 2.88-2.80 (m, 1H, H-2), 2.75-2.62 (m, 4H, 4H-piperazinyl), 2.60-2.51 (m, 2H, -CH2-piperazinyl), 2.50-2.37 (m, 2H, H-3′, H-10) 2.30 (s, 6H, -N(CH3)2), 2.11-2.02 (m, 1H, H-4), 1.94-1.85 (m, 1H, H-14eq), 1.84-1.70 (m, 2H, CH2), 1.70-1.62 (m, 1H, H-4′a), 1.60-1.50 (m, 1H, H-14ax), 1.47 (s, 3H, 1 2-CH3), 1.45-1.34 (m, 3H, 2H-cyclopropyl, H-4′b), 1.33 (s, 3H, 6-CH3), 1.30-1.17 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH3, 10-CH3), 1.15 (d, J = 6.8 Hz, 3H, 2-CH3), 1.06 (d, J = 7.5 Hz, 3H, 4-CH3), 0.94 (d, J = 7.0 Hz, 3H, 8-CH3), 0.85 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:177.06,174.05,167.00,164.54,156.35,154.66,147.41, 139.10,104.88,84.99,83.19,78.36,77.27,75.49,70.46,69.49,66.25,61.42, 56.44,52.84,49.82,43.42,40.39,37.32,35.99,35.36,32.72,29.69,28.66,26.44,25.60,22.22,21.21,19.34,18.86,15.59,14.97,13.02,10.18,8.96,8.25.

[0198] Synthesis of compound 66a

[0199] According to the synthesis method, compound 43 (0.452 g, 0.595 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 developing solvent) to obtain about 0.355 g (0.424 mmol, 71.26%) of compound 90 as a white fluffy solid.

[0200] Compound 90 (0.249 g, 0.208 mmol) was reacted with compound Ar-a (0.346 g, 1.043 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) to obtain approximately 72.6 mg (0.0676 mmol, 32.52%) of compound 66a as a white, fluffy solid. Melting point: 185.4-186.2°C. HRMS (ESI) (M+H) + m / z 1073.5828, calculated value C 54 H 82 FN6O 15 1073.5817. 1H NMR (CDCl3, 700 MHz) δ: 8.79 (s, 1H, 2"-quinolyl), 8.05 (d, J = 12.8 Hz, 1H, 5"-quinolyl), 7.73 (d, J = 6.9 Hz, 1H, 8"-quinolyl), 5.58 (br, 1H, 3-O-CO-NH-CH2), 5.18 (dd, J = 2.6 Hz, 10.5 Hz, 1H, H-13), 4.90 (d, J = 11.1 Hz, 1H, H-3), 4.87 (s, 1H, H-11), 4.04 (d, J = 7. 2Hz,1H,H-1′), 3.83(s,3H,9-O-CH3),3.79-3.73(m,1H,H-5),3.72-3.66(m,1H,H-8),3.61-3.53(m,1H,1H-cyclopropyl),3.48-3.24(m,6H,H-5′,3-O-CO-NH-CH2,4H-piperazinyl),3.24-3.16(m,1H,H-2′),3.15-3.06(m,1H,3-O-CO-NH-CH2),3.03(s,3H,6- O-CH3), 2.89-2.80 (m, 1H, H-2), 2.75-2.60 (m, 4H, 4H-piperazinyl), 2.54-2.36 (m, 4H, H-3′, H-10, -CH2-piperazinyl), 2.30 (s, 6H, -N(CH3)2), 2.13-2.04 (m, 1H, H-4), 1.95-1.83 (m, 1H, H-14eq), 1.73-1.53 ​​(m, 6H, 2(-CH2-), H-4′a, H-14ax), 1.49 (s, 3H, 12- CH3), 1.46-1.36 (m, 3H, 2H-cyclopropyl, H-4′b), 1.34 (s, 3H, 6-CH3), 1.31-1.19 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH3, 10-CH3), 1.16 (d, J = 6.8 Hz, 3H, 2-CH3), 1.07 (d, J = 7.6 Hz, 3H, 4-CH3), 0.94 (d, J = 7.0 Hz, 3H, 8-CH3), 0.84 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:174.04,167.02,164.49,154.66,147.42,139.12,112.56, 108.19,104.78,84.98,83.20,78.34,77.25,75.46,70.44,69.45,66.23,61.43, 57.86,52.80,49.83,43.37,41.07,40.40,37.34,35.98,35.32,32.72,28.10,25.60,24.22,22.24,21.21,19.33,18.87,15.61,14.96,13.03,10.21,9.05,8.25.

[0201] Synthesis of compound 66g

[0202] According to the synthesis method, compound 43 (0.452 g, 0.595 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 mobile phase) to obtain about 0.355 g (0.424 mmol, 71.26%) of white fluffy solid compound 90.

[0203] Compound 90 (0.201 g, 0.250 mmol) was reacted with compound Ar-g (0.415 g, 1.250 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 0.9 / 0.5) to obtain compound 66 g (approximately 13.9 mg, 0.0129 mmol, 5.18%) as a white, fluffy solid. Melting point: 165.6-165.9°C. HRMS (ESI) (M+2H) 2+ m / z (z = 2) 537.7910, calculated value C 53 H 82 FN7O 15 537.7921. 1H NMR (CDCl3, 700 MHz) δ: 8.75 (s, 1H, 2″-quinolyl), 8.09 (d, J = 13.3 Hz, 1H, 5″-quinolyl), 5.61 (br, 1H, 3-O-CO-NH-CH2), 5.18 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.89 (d, J = 11.2 Hz, 1H, H-3), 4.87 (s, 1H, H-11), 4.03 (d, J = 7.3 Hz, 1H, H-1′), 3.99-3.91 (m, 4H, 4H-piperazinyl), 3.83 (s, 3H, 9-O-CH3), 3.77 (s, 1H, H-5), 3.73-3.63 (m, 1H, H-8), 3.63 (tt, J = 4.2 Hz, 7.5 Hz, 1H, 1H-cyclopropyl), 3.45-3.33 (m, 2H, H-5′, -O-CO-NH-CH2), 3.21 (dd, J = 7.3 Hz ,10.1Hz,1H,H-2′),3.15-3.08(m,1H,3-O-CO-NH-CH2),3.03(s,3H,6-O-CH3),2.89-2.81(m,1H,H-2),2.65-2.55(m,4H,4H-piperazinyl),2.52-2.38(m,4H,H-3′,H-10,-CH2-piperazinyl),2.30(s,6H,-N(CH 3)2),2.13-2.05(m,1H,H-4),1.96-1.87(m,1H,H-14eq),1.71-1.53(m,6H,2(-CH2-),H-4′a,H -14ax),1.49(s,3H,12-CH3),1.44-1.36(m,1H,H-4′b),1.34(s,3H,6-CH3),1.30-1.19(m,10H, H-7a, H-7b, 5′-CH3, 2H-cyclopropyl, 10-CH3), 1.16 (d, J = 6.8 Hz, 3H, 2-CH3), 1.09 (d, J = 4.2 Hz, 2H, 2H-cyclopropyl), 1.08 (d, J = 7.4 Hz, 3H, 4-CH3), 0.94 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:177.15,174.00,166.81,164.48,154.65,146.55,120.2 4,108.97,84.98,83.21,78.34,78.34,77.24,75.55,70.44,61.44,57.84,53. 00,49.81,46.87,43.41,41.04,40.40,37.36,35.98,34.65,32.73,28.07,25.59,24.21,22.25,21.22,19.34,18.86,15.61,14.96,13.03,10.20,8.98,7.47.

[0204] Synthesis of compound 66h

[0205] According to the synthesis method, compound 43 (0.452 g, 0.595 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 mobile phase) to obtain about 0.355 g (0.424 mmol, 71.26%) of white fluffy solid compound 90.

[0206] Compound 90 (0.150 g, 0.179 mmol) was reacted with compound Ar-h (0.321 g, 0.890 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) to obtain approximately 17.8 mg (0.0161 mmol, 9.01%) of compound 66h as a white, fluffy solid. Melting point: 153.0-154.1°C. HRMS (ESI) (M+H) + m / z 1103.5912, calculated value C 55 H 84 FN6O 16 1103.5922. 1H NMR (CDCl3, 700 MHz) δ: 8.82 (s, 1H, 2″-quinolyl), 7.88 (d, J = 12.1 Hz, 1H, 5″-quinolyl), 5.70 (br, 1H, 3-O-CO-NH-CH2), 5.18 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.90 (d, J = 11.0 Hz, 1H, H-3), 4.87 (s, 1H, H-11), 4.08-4.00 (m, 2H, H-1′, 1H-cyclopropyl), 3.83 (s, 3H, 9- O-CH3),3.79(s,3H,O-CH3),3.78(d,J=3.0Hz,1H,H-5),3.74-3.67(m,1H,H-8),3.47(br,4H,4H-piperazinyl),3.43-3.32(m,2H, H-5′,-O-CO-NH-CH2),3.21(dd,J=7.3Hz,10.1Hz,1H,H-2′),3.16-3.09(m,1H,3-O-CO-NH-CH2),3.03(s,3H,6-O-CH3),2. 89-2.81(m,1H,H-2),2.62(br,4H,4H-piperazinyl),2.53-2.40(m,4H,H-3′,H-10,-CH2-piperazinyl),2.31(s,6H,-N(CH3)2),2.12-2.04(m,1H,H-4),1.96-1.87(m,1H,H-14eq),1.72-1.53(m,6H,2(-CH2-),H-4′a,H-14ax),1.50(s,3H,12-CH3),1.43-1.35(m ,1H,H-4′b),1.34(s,3H,6-CH3),1.31-1.19(m,10H,H-7a,H-7b,5′-CH3,2H-cyclopropyl,10-CH3),1.17(d,J=6.8Hz,3H,2-CH3),1.08(d,J=7.5Hz,3H,4-CH3),1.01(d,J=4.0Hz,2H,2H-cyclopropyl),0.94(d,J=7.0Hz,3H,8-CH3),0.87(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:177.05,174.05,166.73,164.51,156.40,154.67,149.94,145.38,139.44,133. 92,121.90,108.41,108.17,107.82,103.30,85.00,83.21,81.32,78.34,78.15,77.24,75.53,70.46, 69.46,66.19,62.33,61.44,58.12,53.79,50.66,49.81,43.40,41.07,40.54,40.37,37.35,36.00,32.73,28.70,28.04,25.60,24.24,22.25,21.23,19.34,18.86,15.61,14.97,13.04,10.20,9.56,8.98.

[0207] Synthesis of compound 66i

[0208] According to the synthesis method, compound 43 (0.452 g, 0.595 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 mobile phase) to obtain about 0.355 g (0.424 mmol, 71.26%) of white fluffy solid compound 90.

[0209] Compound 90 (0.150 g, 0.179 mmol) was reacted with compound Ar-i (0.310 g, 0.890 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) to obtain approximately 19.0 mg (0.0174 mmol, 9.74%) of compound 66i as a white, fluffy solid. Melting point: 163.7-163.9°C. HRMS (ESI) (M+H) + m / z 1089.5768, calculated value C 54 H 82 FN6O 16 1089.5766. 1H NMR (CDCl3, 700 MHz) δ: 8.65 (s, 1H, 2″-quinolyl), 7.73 (d, J = 12.1 Hz, 1H, 5″-quinolyl), 5.92 (t, J = 5.7 Hz, 1H, 3-O-CO-NH-CH2), 5.18 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.90 (d, J = 11.0 Hz, 1H, H-3), 4.87 (s, 1H, H-11), 4.55 (s, 1H, N-CH2), 4.47 (d, J = 12.3 Hz, O-CH2-), 4. 37 (d, J = 11.3 Hz, O-CH2-), 4.05 (d, J = 7.3 Hz, 1H, H-1'), 3.83 (s, 3H, 9-O-CH3), 3.79 (d, J = 3.1 Hz, 1H, H-5), 3.74-3.66 (m, 1H, H-8), 3.49-3.37 (m, 5H, H-5', 4H-piperazinyl), 3.37-3.30 (m, 1H, 3-O-CO-NH-CH2), 3.21 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2'), 3.17-3.10 (m, 1 H,3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 2.90-2.82 (m, 1H, H-2), 2.66-2.54 (m, 4H, 4H-piperazinyl), 2.53-2.40 (m, 4H, H-3′, H-10, -CH2-piperazinyl), 2.31 (s, 6H, -N(CH3)2), 2.12-2.05 (m, 1H, H-4), 1.96-1.87 (m, 1H, H-14eq), 1.72-1.53 ​​(m, 9H, 2(-CH2-), H-4′a, H-14 ax,N-CH-CH3),1.50(s,3H,12-CH3),1.45-1.36(m,1H,H-4′b),1.34(s,3H,6-CH3),1.30-1.20(m,8H,H-7a,H-7b,5′-CH3,10- CH3),1.17(d,J=6.8Hz,3H,2-CH3),1.08(d,J=7.5Hz,3H,4-CH3),0.94(d,J=7.0Hz,3H,8-CH3),0.87(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:177.14,174.08,167.14,164.52,156.38,154.67,144.68,139.34,133.06,12 4.72,107.90,105.46,105.22,103.22,85.01,83.22,81.17,78.34,78.06,78.06,77.24,75.51,70.4 4,69.45,68.18,66.25,61.43,58.10,55.52,53.76,50.59,49.81,43.39,41.10,40.40,37.35,36.00,32.73,28.05,25.60,24.28,22.25,21.22,19.34,18.86,18.36,15.61,14.97,13.04,10.21,8.98.

[0210] Synthesis of compound 67a

[0211] According to the synthesis method, compound 44 (0.332 g, 0.429 mmol) was used and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 mobile phase) to obtain about 0.197 g (0.132 mmol, 30.77%) of white fluffy solid compound 91.

[0212] Compound 91 (0.197 g, 0.231 mmol) was reacted with compound Ar-a (0.383 g, 1.155 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) to obtain approximately 68.5 mg (0.0630 mmol, 27.27%) of compound 67a as a white, fluffy solid. Melting point: 153.9-154.5°C. HRMS (ESI) (M+H) + m / z 1087.5970, calculated value C 55 H 84 FN6O 15 1087.5973. 1H NMR (CDCl3, 700 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 8.01 (d, J = 12.8 Hz, 1H, 5″-quinolyl), 7.37 (d, J = 6.9 Hz, 1H, 8″-quinolyl), 5.17 (dd, J = 2.8 Hz, 10.4 Hz, 1H, H-13), 5.02 (br, 1H, 3-O-CO-NH-CH2), 4.91-4.81 (m, 2H, H-3, H-11), 4.02 (br, 1H, H-1′), 3.82 (s, 3H,9-O-CH3), 3.76-3.65 (m, 2H, H-5, H-8), 3.61-3.52 (m, 1H, H-5′), 3.49-3.30 (m, 5H, 1H-cyclopropyl, 4H-piperazinyl), 3.30-3.23 (m, 1H, 3-O-CO-NH-CH2), 3.23-3.17 (m, 1H, H-2′), 3.12-3. 05(m,1H,3-O-CO-NH-CH2),3.03(s,3H,6-O-CH3),2.90-2.80(m,1H,H-2),2.75-2.58(m,4H,4H-piperazinyl),2.53-2.38(m,4H,-CH2-piperazinyl,H-3′,H-10),2.30(s,6H,-N(CH3)2),2.13-2 .04(m,1H,H-4),1.95-1.86(m,1H,H-14eq),1.71-1.52(m,6H,H-4′a,2(-CH2-),H-14ax),1.49(s,3H,12-CH3),1.46-1.36(m,5H,2H-cyclopropyl,H-4′b,CH2),1.33(s,3H,6-CH3),1.3 0-1.18(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3),1.16(d,J=6.8Hz,3H,2-CH3),1.0 8(d,J=7.5Hz,3H,4-CH3),0.94(d,J=7.0Hz,3H,8-CH3),0.86(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:177.10,174.08,167.04,164.56,154.67,152.43,147.41, 139.11,108.15,104.76,85.03,83.21,78.34,77.25,75.50,70.47,61.42,58.30 ,52.87,49.83,43.35,41.06,40.37,37.33,35.97,35.30,32.72,30.10,26.47,25.61,24.63,22.23,21.21,19.33,18.87,15.61,14.91,13.02,10.20,8.94,8.25.

[0213] Synthesis of compound 68a

[0214] According to the synthesis method, compound 46 (0.282 g, 0.371 mmol) and methanesulfonyl chloride (0.033 mL, 0.408 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.241 g (0.268 mmol, 72.24%) of compound 92.

[0215] Compound 92 (0.120 g, 0.134 mmol) was reacted with compound Ar-a (0.133 g, 0.401 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 21.8 mg (0.212 mmol, 15.81%) of compound 68a. Melting point: 162.2-164.4°C. HRMS (ESI) (M+H) + m / z 1029.5548, calculated value C 52 H 78 FN6O 14 1029.5555. 1H NMR (CDCl3, 400 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 8.01 (d, J = 12.9 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 5.2 Hz, 1H, 8″-quinolyl), 5.80 (s, 1H, 3-O-CO-NH-CH2), 5.73 (s, 1H, 11-NH), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.92 (d, J = 11.0 Hz, 1H, H-3), 4.0 6 (d, J = 7.0 Hz, 1H, H-1′), 3.81 (d, J = 2.8 Hz, 1H, H-5), 3.78 (s, 1H, H-11), 3.61-3.51 (m, 1H, 1H-cyclopropyl), 3.50-3.25 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.24-3.12 (m, 2H, H-2′, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.93-2.80 (m, 2 H,H-10,H-2), 2.69(s,4H,4H-piperazinyl), 2.60-2.46(m,3H,H-8,-CH2-piperazinyl), 2.46-2.37(m,1H,H-3′), 2.30(s,6H,-N(CH3)2), 2.11-2.01(m,1H,H-4), 1.97-1.85(m,1H,H-14eq), 1.84-1.72(m,3H,-CH2-CH2-piperazinyl,H-7a), 1.70-1.62(m,1H ,H-7b), 1.62-1.48 (m,2H,H-14eq,H-4′a), 1.46-1.37 (m,5H,12-CH3,2H-cyclopropyl), 1.32-1.21 (m,7H,6-CH3,H-4′b,5′-CH3), 1.21-1.18 (m,2H,2H-cyclopropyl), 1.17-1.07 (m,12H,2-CH3,10-CH3,4-CH3,8-CH3), 0.84 (t, J = 7.3 Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.64,174.36,167.05,158.43,156.34,147.47,108.19,83.87,77.87,77.24,75.82,70.49,66.24,58.13,56.38,52.8 5,49.83,45.29,43.44,40.36,40.17,39.13,37.30,35.82,35.34,29.7 0,22.04,21.22,19.32,18.27,15.09,13.88,13.31,10.25,9.10,8.27.

[0216] Synthesis of compound 69a

[0217] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0218] Compound 93 (0.210 g, 0.231 mmol) was reacted with compound Ar-a (0.230 g, 0.693 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 49.0 mg (0.0470 mmol, 20.33%) of compound 69a. Melting point: 186.7-187.5°C. HRMS (ESI) (M+H) + m / z 1043.5717, calculated value C 53 H 80 FN6O 14 1043.5711. 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H, 2″-quinolyl), 8.00 (d, J = 13.1 Hz, 1H, 5″-quinolyl), 7.36 (s, 1H, 8″-quinolyl), 5.80 (s, 1H, 11-NH), 5.63 (s, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11.0 Hz, 1H, H-3), 4.04 (d, J = 7.2 Hz, 1H, H-1′), 3.80 (d, J = 2.8 Hz, 1H, H-5), 3.77 (s, 1H, H-11), 3.61-3.52 (m, 1H, 1H-cyclopropyl), 3.46-3.29 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.23-3.15 (m, 1H, H-2′), 3.14-3.04 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H ,6-O-CH3),2.94-2.79(m,2H,H-10,H-2),2.68(s,4H,4H-piperazinyl),2.56-2.37(m,4H,H-8,-CH2-piperazinyl,H-3′),2.29(s,6H,-N(CH3)2),2.12-2.02(m,1H,H-4),1.97-1.87(m,1H,H-14eq),1.83-1.72(m,1H,H-7a),1.70-1.48(m,7 H,-CH2-CH2-CH2-piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH3), 1.40 (br, 2H, 2H-cyclopropyl), 1.32-1.18 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.18-1.04 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.62,177.13,174.35,167.00,158.41,156.37,147.43,139.11,112 .56,112.32,108.18,104.78,103.19,83.87,81.67,78.19,77.85,77.24,75.82,70.46,69.5 1,66.24,58.13,57.85,52.79,49.82,45.30,43.40,41.08,40.38,39.13,37.29,35.80,35.32,28.65,28.07,24.20,22.04,21.23,19.31,18.28,15.08,13.88,13.31,10.26,9.16,8.26.

[0219] Synthesis of compound 69b

[0220] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0221] Compound 93 (0.300 g, 0.329 mmol) was reacted with compound Ar-b (0.229 g, 0.717 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 144.2 mg (0.140 mmol, 42.50%) of compound 69b. Melting point: 162.3-163.6°C. HRMS (ESI) (M+H) + m / z 1031.5722, calculated value C 52 H 80 FN6O 14 1031.5711. 1H NMR (CDCl3, 400 MHz) δ: 8.68 (s, 1H, 2″-quinolyl), 8.03 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 6.86 (d, J = 6.7 Hz, 1H, 8″-quinolyl), 5.81 (s, 1H, 11-NH), 5.79 (s, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11.0 Hz, 1H, H-3), 4.35 (br, 2H, N-CH2CH3), 4.05(d,J=7.2Hz,1H,H-1′),3.80(d,J=2.9Hz,1H,H-5),3.77(s,1H,H-11),3.44 -3.29(m,6H,H-5′,4H-piperazinyl,3-O-CO-NH-CH2),3.19(dd,J=7.2Hz,10.1Hz,1H,H-2′ ),3.13-3.03(m,1H,3-O-CO-NH-CH2),2.98(s,3H,6-O-CH3),2.94-2.79(m,2H,H-10,H-2),2.68(s,4H,4H-piperazinyl),2.56-2.38(m,4H,H-8,-CH2-piperazinyl,H-3′),2.30(s,6 H,-N(CH3)2),2.11-2.01(m,1H,H-4),1.96-1.86(m,1H,H-14eq),1.82-1.72(m,1 H,H-7a),1.71-1.48(m,10H,-CH2-CH2-CH2-piperazinyl,H-7b,H-14eq,H-4′a,N-CH2CH3) ,1.42(s,3H,12-CH3),1.28(s,3H,6-CH3),1.23(d,J=6.1Hz,3H,5′-CH3),1.19-1 .04(m,13H,H-4′b,2-CH3,10-CH3,4-CH3,8-CH3),0.84(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.63,176.99,174.37,167.22,158.43,156.37,154.78,152.28,147.15,146.0 5,145.95,137.14,120.60,112.84,112.61,108.36,103.90,103.10,83.88,81.54,78.12,77.85,77.25 ,75.80,70.47,69.49,66.26,58.13,57.82,52.76,49.81,49.75,45.29,43.39,41.08,40.37,39.11,37.29,35.79,28.68,28.05,24.23,22.04,21.22,19.31,18.27,15.06,14.49,13.87,13.31,10.26,9.20.

[0222] Synthesis of compound 69c

[0223] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the product was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0224] Compound 93 (0.149 g, 0.150 mmol) was reacted with compound Ar-c (0.149 g, 0.450 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 58.8 mg (0.0578 mmol, 38.54%) of compound 69c. HRMS (ESI) (M+2H) 2+ m / z (z = 2) 509.2821, calculated value C 51 H 79 FN6O 14 509.2813. 1H NMR (CD3OD, 400 MHz) δ: 8.73 (s, 1H, 2″-quinolyl), 7.87 (d, J = 13.1 Hz, 1H, 5″-quinolyl), 7.05 (s, 1H, 8″-quinolyl), 5.18 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.90 (d, J = 11.1 Hz, 1H, H-3), 4.14 (d, J = 7.1 Hz, 1H, H-1′) ,4.02(s,3H,N-CH3),3.87(d,J=3.1Hz,1H,H-5),3.80(s,1H,H-11),3.50-3.34(m,5H,H-5′,4H-piperazinyl),3.29-3.22(m,2H,H-2′,3-O-CO-NH-CH2),3.12-3.02(m,2H,H-10,3-O-CO-NH-CH2),2.99(s ,3H,6-O-CH3),2.94-2.88(m,1H,H-2),2.78-2.64(m,5H,H-3′,4H-piperazinyl),2.55-2.43(m,3H,H-8,-CH2-piperazinyl),2.40(s,6H,-N(CH3)2),2.17-2.08(m,1H,H-4),1.92-1.73(m,3H,H-14eq,H-7a,H-4′ a),1.68-1.54(m,6H,2(-CH2-),H-7b,H-14eq),1.47(s,3H,12-CH3),1.34-1.18(m,7H,H-4′b,6 -CH3,5′-CH3),1.17-1.08(m,12H,2-CH3,10-CH3,4-CH3,8-CH3),0.85(t,J=7.4Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.98,174.82,159.44,157.38,101.75,84.49,7 8.66,77.89,77.47,75.50,70.73,68.76,64.55,58.05,57.79,52.61,49 .22,48.94,45.35,43.20,40.40,39.53,38.66,37.42,35.71,30.89,27. 60,23.40,21.80,20.03,18.43,17.17,14.04,12.93,12.22,9.43,8.14.

[0225] Synthesis of compound 69d

[0226] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to give 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0227] Compound 93 (0.150 g, 0.164 mmol) was reacted with compound Ar-d (0.0852 g, 0.426 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 32.8 mg (0.0310 mmol, 18.91%) of compound 69d. Melting point: 158.5-160.8°C. HRMS (ESI) (M+H) + m / z 1057.5861, calculated value C 54 H 82 FN6O 14 1057.5868. 1H NMR (CDCl3, 400 MHz) δ: 8.74 (s, 1H, 2″-quinolyl), 7.98 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.34 (d, J = 7.2 Hz, 1H, 8″-quinolyl), 5.80 (s, 1H, 11-NH), 5.67 (br, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.94 (d, J = 11.0 Hz, 1H, H-3), 4.04 (d, J = 7.4 H z,1H,H-1′), 3.80 (d, J=2.8 Hz,1H,H-5), 3.77 (s,1H,H-11), 3.63-3.55 (m,1H,1H-cyclopropyl), 3.54-3.44 (m,2H,2H-piperazinyl), 3.44-3.33 (m,2H,H-5′,3-O-CO-NH-CH2), 3.30-3.14 (m,2H,H-2′,1H-piperazinyl), 3.11-3.03 (m,1H,3-O-CO-NH-CH2), 3.02-2.94 (m,4H ,6-O-CH3,1H-piperazinyl), 2.94-2.67(m,5H,H-10,H-2,3H-piperazinyl), 2.59-2.47(m,2H,H-8,H-3′), 2.46-2.33(m,2H,-CH2-piperazinyl), 2.29(s,6H,-N(CH3)2), 2.13-2.01(m,1H,H-4), 1.97-1.87(m,1H,H-14eq), 1.83-1.72(m,1H,H-7a), 1.69-1.49(m,7H,-CH2 -CH2-CH2-piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH3), 1.42-1.36 (m, 2H, 2H-cyclopropyl), 1.28 (s, 3H, 6-CH3), 1.26-1.18 (m, 9H, H-4′b, 5′-CH3, 2H-cyclopropyl, -piperazinyl-CH3), 1.18-1.06 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.64,177.08,174.37,167.02,158.42,156.38,147.36,139.14,112.46, 112.22,108.10,104.71,103.17,83.88,81.65,78.20,77.85,77.25,75.80,70.45,69.48,66.18,5 8.13,56.59,54.64,52.98,50.01,49.81,45.30,43.40,41.13,40.32,39.12,37.28,35.79,35.33,28.65,28.23,23.68,22.03,21.22,19.31,18.27,15.28,15.08,13.87,13.30,10.26,9.20,8.24.

[0228] Synthesis of compound 69e

[0229] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0230] Compound 93 (0.150 g, 0.164 mmol) was reacted with compound Ar-e (0.0852 g, 0.426 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 13.5 mg (0.0128 mmol, 7.79%) of compound 69e. Melting point: 162.5-163.6°C. HRMS (ESI) (M+H) + m / z 1057.5859, calculated value C 54 H 82 FN6O 14 1057.5868. 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H, 2″-quinolyl), 8.01 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.33 (d, J = 7.1 Hz, 1H, 8″-quinolyl), 5.79 (s, 1H, 11-NH), 5.41 (br, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.4 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11.0 Hz, 1H, H-3), 4.03 (d, J = 7.4 Hz, 1H, H-1′), 3.83-3.74 (m, 2H, H-5, H-11), 3.61-3.43 (m, 3H, 1H-cyclopropyl, 2H-piperazinyl), 3.43-3. 30 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.25-3.14 (m, 2H, H-2′, 1H-piperazinyl), 3.13-3.04 (m, 1H, 3-O-CO-NH-CH2), 3.02-2.67 (m, 9H, 6-O-CH3, H-10, H-2, 4H-piperazinyl), 2.59-2.46 (m ,2H,H-8,H-3′),2.44-2.34(m,2H,-CH2-piperazinyl),2.28(s,6H,-N(CH3)2),2.12-2.01(m,1H,H-4),1.97-1.86(m,1H,H-14eq),1.82-1.73(m,1H,H-7a),1.69-1.49(m,7H, -CH2-CH2-CH2-piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH3), 1.41-1.35 (m, 2H, 2H-cyclopropyl), 1.28 (s, 3H, 6-CH3), 1.27-1.18 (m, 9H, H-4′b, 5′-CH3, 2H-cyclopropyl, -piperazinyl-CH3), 1.18-1.07 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.65,177.13,174.36,167.06,158.43,156.39,154.36,152.93,147.41,145.83,145 .78,139.14,119.73,112.53,112.40,108.19,104.63,103.23,83.87,81.65,78.27,77.86,75.82,70.48,69.5 5,66.17,58.13,56.58,54.52,52.99,49.93,49.83,45.30,43.38,41.08,40.37,39.13,37.29,35.80,35.28,29.71,28.57,28.22,23.50,22.03,21.23,19.31,18.28,15.26,15.08,13.88,13.30,10.26,9.14,8.26,8.24.

[0231] Synthesis of compound 69f

[0232] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0233] Compound 93 (0.156 g, 0.171 mmol) was reacted with compound Ar-f (0.161 g, 0.513 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 35.9 mg (0.0350 mmol, 20.47%) of compound 69f. Melting point: 161.8-164.2°C. HRMS (ESI) (M+H) + m / z 1052.5785, calculated value C 53 H 81 N6O 14 1025.5805. 1H NMR (CDCl3, 400 MHz) δ: 8.70 (s, 1H, 2"-quinolyl), 8.26 (d, J = 9.1 Hz, 1H, 5"-quinolyl), 7.18 (s, 1H, 8"-quinolyl), 7.13 (d, J = 9.4 Hz, 1H, 6"-quinolyl), 5.81 (s, 1H, 11-NH), 5.76 (t, J = 6.2 Hz, 1H, 3-O-CO-NH-CH2), 5.22 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11. 0 Hz, 1H, H-3), 4.04 (d, J = 7.3 Hz, 1H, H-1′), 3.79 (d, J = 3.1 Hz, 1H, H-5), 3.77 (s, 1H, H-11), 3.57-3.44 (m, 5H, 1H-cyclopropyl, 4H-piperazinyl), 3.43-3.30 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.14-3.06 (m, 1H, 3-O-CO-NH-CH2) ,2.98(s,3H,6-O-CH3),2.89(q,J=6.4Hz,1H,H-10),2.85-2.77(m,1H,H-2),2.65(s,4H,4H-piperazinyl),2.57-2.38(m,4H,H-8,-CH2-piperazinyl,H-3′),2.30(s,6H,-N(CH3)2),2.10-2.01(m,1H,H-4),1.97-1.86(m,1H,H-14eq),1.83-1.72(m,1H,H-7a),1 .70-1.48 (m, 7H, -CH2-CH2-CH2-piperazinyl, H-7b, H-14eq, H-4′a), 1.41 (s, 3H, 12-CH3), 1.40-1.33 (m, 2H, 2H-cyclopropyl), 1.30-1.20 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.20-1.06 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.83 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.69,177.43,174.37,167.49,158.45,156.39,154.55,147.63,143.24, 127.96,117.18,114.54,108.05,103.16,98.56,83.89,81.69,78.17,77.84,77.26,75.78,70.45, 69.48,66.16,58.12,57.88,52.66,49.82,47.21,45.31,43.38,41.07,40.35,39.11,37.28,35.78,34.92,28.66,28.09,24.27,22.03,21.24,19.32,18.28,15.10,13.89,13.29,10.27,9.18,8.18.

[0234] Synthesis of compound 69g

[0235] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to give 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0236] Compound 93 (0.208 g, 0.249 mmol) was reacted with compound Ar-g (0.413 g, 1.243 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 104.5 mg (0.100 mmol, 40.21%) of compound 69g of the general formula. Melting point: 187.0-188.1°C. HRMS (ESI) (M+H) + m / z 1044.5668, calculated value C 52 H 79 FN7O 14 1044.5664. 1H NMR (CD3OD, 400 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 8.02 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.20 (dd, J = 2.4 Hz, 10.7 Hz, 1H, H-13), 4.91 (d, J = 11.2 Hz, 1H, H-3), 4.17 (d, J = 7.2 Hz, 1H, H-1′), 3.95 (s, 4H, 4H-piperazinyl), 3.88 (d, J = 3.0 Hz, 1H, H-5), 3.81 (s, 1H, H-11), 3.74-3.63 (m, 1H, 1H-cyclopropyl), 3.41-3.41 (m, 1H, H-5′), 3.31-3.25 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.16-3.03 (m, 2H, H-10, 3-O-CO-NH-CH2), 3.01 (m, 3H, 6-O-CH3), 2.97 -2.88 (m, 1H, H-2), 2.84-2.74 (m, 1H, H-3′), 2.66 (s, 4H, 4H-piperazinyl), 2.56-2.40 (m, 9H, H-8, -CH2-piperazinyl, -N(CH3)2), 2.21-2.09 (m, 1H, H-4), 1.96-1.77 (m, 3H, H-7a, H-14eq, H-4′a), 1.68-1.53 ​​(m, 6H, 2(-CH2- ), H-7b, H-14eq), 1.49 (s, 3H, 12-CH3), 1.37-1.25 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH3), 1.22 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.20-1.02 (m, 14H, 2H-cyclopropyl, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.88 (t, J = 7.3 Hz, 3H, 15-CH3). 13 C NMR(CDCl3,100MHz)δ:217.70,180.59,174.33,166.84,161.69,158.46,1 56.34,146.27,103.17,83.88,77.84,75.80,70.51,69.58,66.25,58.13, 53.47,53.00,49.83,46.87,45.32,43.38,40.40,39.12,37.27,35.80,34 .66,22.03,21.25,19.32,18.30,15.10,13.90,13.30,10.28,9.12,7.48.

[0237] Synthesis of compound 69j

[0238] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to give 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0239] Compound 93 (0.180 g, 0.197 mmol) was reacted with compound Ar-j (0.189 g, 0.591 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 79.2 mg (0.0767 mmol, 38.95%) of compound 69j. Melting point: 152.2-153.7°C HRMS (ESI) (M+H) + m / z 1032.5683, calculated value C 51 H 79 FN7O 14 1032.5664. 1H NMR (CDCl3, 400 MHz) δ: 8.70 (s, 1H, 2″-quinolyl), 8.10 (d, J = 13.3 Hz, 1H, 5″-quinolyl), 5.81 (s, 1H, 11-NH), 5.64 (t, J = 5.7 Hz, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11.0 Hz, 1H, H-3), 4.41 (q, J = 7.2 Hz, 2H, N-CH2CH3), 4.0 3 (d, J = 7.3 Hz, 1H, H-1′), 3.95-3.84 (m, 4H, 4H-piperazinyl), 3.82-3.75 (m, 2H, H-5, H-11), 3.43-3.30 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.13-3.04 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.90 (q, J = 6.6 Hz, 1 H,H-10), 2.87-2.79 (m,1H,H-2), 2.60 (t, J = 4.9 Hz,4H,4H-piperazinyl), 2.56-2.47 (m,1H,H-8), 2.48-2.35 (m,3H,-CH2-piperazinyl,H-3′), 2.30 (s,6H,-N(CH3)2), 2.11-2.03 (m,1H,H-4), 1.98-1.88 (m,1H,H-14eq), 1.83-1.74 (m,1H,H-7a), 1.69-1.53 ​​(m,7 H,-CH2-CH2-CH2-piperazinyl,H-7b,H-14eq,H-4′a),1.51(t,J=7.2Hz,3H,N-CH2CH3),1.43(s,3H,12-CH3),1.28(m,3H,6-CH3) ,1.23(d,J=6.2Hz,3H,5′-CH3),1.18-1.06(m,13H,H-4′b,2-CH3,10-CH3,4-CH3,8-CH3),0.85(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.65,177.06,174.34,166.97,158.43,156.36,146.41, 145.07,120.32,120.20,113.80,109.32,103.21,83.88,81.77,78.25,77.85,77.82,75.81,75.78,7 0.45,69.50,66.18,58.14,57.80,52.95,52.92,49.81,49.78,47.76,46.97,46.92,45.29,43.41,41 .04,40.34,40.32,39.12,37.29,37.26,35.78,28.62,28.02,24.17,22.04,22.01,21.23,21.20,19.31,19.28,18.26,18.23,15.07,15.05,14.98,14.95,13.88,13.85,13.30,13.27,10.26,10.23,9.11.

[0240] Synthesis of compound 69k

[0241] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to give 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0242] Compound 93 (0.150 g, 0.164 mmol) was reacted with compound Ar-k (0.149 g, 0.492 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 36.9 mg (0.0363 mmol, 22.26%) of compound 69k. HRMS (ESI) (M+H) + m / z 1015.5708, calculated value C 50 H 79 N8O 14 1015.5710. 1H NMR (CD3OD, 400 MHz) δ: 9.18 (s, 1H, 5″-quinolyl), 8.74 (s, 1H, 2″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.89 (d, J = 11.1 Hz, 1H, H-3), 4.75 (q, J = 7.3 Hz, 2H, N-CH2CH3), 4.15 (d, J = 7.2 Hz, 1H, H-1′), 4.0 0 (s, 4H, 4H-piperazinyl), 3.86 (d, J = 3.1 Hz, 1H, H-5), 3.79 (s, 1H, H-11), 3.50-3.40 (m, 1H, H-5′), 3.30-3.23 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.11-3.02 (m, 2H, H-10, 3-O-CO-NH-CH2), 2.99 (s, 3H, 6-O-CH3), 2. 94-2.86 (m, 1H, H-2), 2.85-2.74 (m, 1H, H-3′), 2.57 (s, 4H, 4H-piperazinyl), 2.52-2.39 (m, 9H, H-8, -CH2-piperazinyl, -N(CH3)2), 2.17-2.08 (m, 1H, H-4), 1.92-1.78 (m, 3H, H-14eq, H-7a, H-4′a), 1.68-1.52 (m, 6H, 2( -CH2-),H-7b,H-14eq),1.47(s,3H,12-CH3),1.43(t,J=7.1Hz,N-CH2CH3),1.35-1.23(m,7H,H-4′b ,6-CH3,5′-CH3),1.23-1.08(m,12H,2-CH3,10-CH3,4-CH3,8-CH3),0.86(t,J=7.3Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.89,174.80,159.42,157.37,101.65,84.49,7 8.75,77.88,77.47,75.52,70.58,68.69,64.66,58.06,57.67,52.48,48 .94,45.34,43.56,43.21,40.36,39.45,38.68,37.42,35.70,27.55,23. 41,21.82,19.99,18.42,17.17,14.03,13.55,12.92,12.23,9.44,8.09.

[0243] Synthesis of compound 69p

[0244] According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.210 g (0.231 mmol, 58.78%) of compound 93.

[0245] Compound 93 (0.150 g, 0.164 mmol) was reacted with compound Ar-p (0.177 g, 0.492 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.2 / 0.1) was performed to obtain 16.8 mg (0.0156 mmol, 9.51%) of compound 69p. Melting point: 154.9-155.9°C. HRMS (ESI) (M+H) + m / z 1071.6019, calculated value C 55 H 84 FN6O 14 1071.6024. 1H NMR (CDCl3, 400 MHz) δ: 8.52 (s, 1H, 2″-quinolyl), 8.04 (d, J = 13.3 Hz, 1H, 5″-quinolyl), 7.26 (d, J = 7.6 Hz, 1H, 8″-quinolyl), 5.80 (s, 1H, 11-NH), 5.76 (t, J = 6.6 Hz, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.93 (d, J = 11.0 Hz, 1H, H-3), 4.39 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.04 (d, J = 7.3 Hz, 2H, OCH2CH3 z, 1H, H-1′), 3.80 (d, J = 2.9 Hz, 1H, H-5), 3.77 (s, 1H, H-11), 3.49-3.40 (m, 1H, 1H-cyclopropyl), 3.40-3.25 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.17 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.13-3.05 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.89 (q, J = 6. 8Hz,1H,H-10),2.87-2.77(m,1H,H-2),2.67(s,4H,4H-piperazinyl),2.56-2.49(m,1H,H-8),2.48-2.42(m,2H,-CH2-piperazinyl),2.42-2.32(m,1H,H-3′),2.27(s,6H,-N(CH3)2),2.12-2.01(m,1H,H-4),1.97-1.86(m,1H,H-14eq),1.81-1.71(m,1H,H-7a),1.69-1 0.48 (m, 7H, -CH2-CH2-CH2-piperazinyl, H-7b, H-14eq, H-4'a), 1.45-1.36 (m, 6H, 12-CH3, OCH2CH3), 1.35-1.29 (m, 2H, 2H-cyclopropyl), 1.29-1.18 (m, 7H, 6-CH3, H-4'b, 5'-CH3), 1.19-1.05 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.65,174.34,173.15,165.88,158.43,156.35,148.12,138.05,113.48, 113.25,110.54,104.68,103.18,83.88,81.61,78.15,77.85,77.25,75.81,70.44,69.54,66.27,6 0.92,58.13,57.89,52.92,49.82,45.30,43.41,41.12,40.38,39.12,37.29,35.80,34.48,29.70,28.57,28.08,24.29,22.04,21.24,19.31,18.27,15.09,14.45,13.88,13.31,10.26,9.17,8.17.

[0246] Synthesis of compound 70a

[0247] According to the synthesis method, compound 48 (0.540 g, 0.637 mmol) and methanesulfonyl chloride (0.057 mL, 0.701 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.512 g (0.552 mmol, 86.66%) of compound 94.

[0248] Compound 94 (0.256 g, 0.276 mmol) was reacted with compound Ar-a (0.274 g, 0.828 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain 34.8 mg (0.0329 mmol, 11.92%) of compound 70a. Melting point: 160.1-163.5°C. HRMS (ESI) (M+H) + m / z 1057.5875, calculated value C 54 H 82 FN6O 14 1057.5868. 1H NMR (CDCl3, 400 MHz) δ: 8.74 (s, 1H, 2″-quinolyl), 7.98 (d, J = 13.1 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 6.8 Hz, 1H, 8″-quinolyl), 5.82 (s, 1H, 11-NH), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 5.04 (s, 1H, 3-O-CO-NH-CH2), 4.92 (d, J = 11.0 Hz, 1H, H-3), 4.0 3 (d, J = 7.2 Hz, 1H, H-1'), 3.94-3.74 (m, 2H, H-5, H-11), 3.61-3.50 (m, 1H, 1H-cyclopropyl), 3.46-3.27 (m, 6H, H-5', 4H-piperazinyl, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.2 Hz, 10.0 Hz, 1H, H-2'), 3.12-3.02 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.94-2.81 (m, 2H, H-10, H-2), 2.66 (s, 4H, 4H-piperazinyl), 2.56-2.47 (m, 1H, H-8), 2.48-2.36 (m, 3H, -CH2-piperazinyl, H-3′), 2.29 (s, 6H, -N(CH3)2), 2.12-2.03 (m, 1H, H-4), 1.97-1.86 (m, 1H, H-14eq), 1.84-1.74 (m, 1H, H-7a), 1.69-1.49 (m, 7H, 2(-CH2-), H-7b, H-14eq, H-4'a), 1.43 (s, 3H, 12-CH3), 1.40 (br, 4H, -CH2-, 2H-cyclopropyl), 1.28 (s, 3H, 6-CH3), 1.25-1.18 (m, 6H, H-4'b, 5'-CH3, 2H-cyclopropyl), 1.18-1.05 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.67,177.08,174.40,167.01,158.43,156.40,154.93,152.43,147.39,145.95,1 45.86,139.11,119.77,119.69,112.47,112.23,108.11,104.76,103.23,83.91,81.63,78.26,77.86,77.2 6,75.76,70.48,69.52,66.13,58.29,58.13,52.87,49.83,45.32,43.37,41.09,40.37,39.13,37.28,35.79,35.30,30.09,28.62,26.49,24.65,22.03,21.23,19.31,18.29,15.03,13.88,13.29,10.26,9.06,8.24.

[0249] Synthesis of compound 70b

[0250] According to the synthesis method, compound 48 (0.540 g, 0.637 mmol) and methanesulfonyl chloride (0.057 mL, 0.701 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to give 0.512 g (0.552 mmol, 86.66%) of compound 94.

[0251] Compound 94 (0.256 g, 0.276 mmol) was reacted with compound Ar-b (0.264 g, 0.828 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / aqueous ammonia = 10 / 1 / 0.5) was performed to obtain approximately 134.6 mg (0.128 mmol, 46.66%) of compound 70b. Melting point: 159.8-160.7°C. HRMS (ESI) (M+H) + m / z 1045.5874, calculated value C 53 H 82 FN6O 14 1045.5868. 1H NMR (CDCl3, 400 MHz) δ: 8.67 (s, 1H, 2″-quinolyl), 8.01 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 6.84 (s, 1H, 8″-quinolyl), 5.83 (s, 1H, 11-NH), 5.23 (dd, J = 2.3 Hz, 11.0 Hz, 1H, H-13), 5.12 (t, J = 5.9 Hz, 1H, 3-O-CO-NH-CH2), 4.92 (d, J = 11.0 Hz, 1H, H-3), 4.34 (s, 1H, 2-O-CO-NH-CH2). (br, 2H, N-CH2CH3), 4.04 (d, J = 7.2 Hz, 1H, H-1′), 3.83-3.74 (m, 2H, H-5, H-11), 3.44-3.27 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.12-3.03 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.9 4-2.81(m,2H,H-10,H-2),2.66(s,4H,4H-piperazinyl),2.57-2.47(m,1H,H-8),2.47-2.35(m,3H,-CH2-piperazinyl,H-3′),2.29(s,6H,-N(CH3)2),2.11-2.03(m,1H,H-4),1.96-1.86(m,1H,H-14eq),1.84-1.74(m,1H,H-7a),1.69-1.49(m,10H,2( -CH2-),H-7b,H-14eq,H-4′a,N-CH2CH3),1.43(s,3H,12-CH3),1.41-1.36(m,2H,-CH2-),1.28(s,3H,6-CH3),1.23 (d,J=6.1Hz,3H,5′-CH3),1.19-1.06(m,13H,H-4′b,2-CH3,10-CH3,4-CH3,8-CH3),0.84(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.69,176.96,174.43,167.24,158.45,156.41,147.12,137.15,112 .76,112.53,108.29,103.17,83.92,81.53,78.20,77.86,77.27,75.74,70.49,69.50,66.09 ,58.25,58.12,52.84,49.86,49.82,45.31,43.36,41.07,40.36,39.11,37.27,35.78,30.05,28.63,26.44,24.61,22.02,21.21,19.30,18.28,15.02,14.44,13.87,13.29,10.25,9.06.

[0252] Synthesis of compound 71a

[0253] According to the synthesis method, compound 49 (0.332 g, 0.385 mmol) and methanesulfonyl chloride (0.038 mL, 0.462 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.163 g (0.174 mmol, 54.19%) of compound 95.

[0254] Compound 95 (0.163 g, 0.174 mmol) was reacted with compound Ar-a (0.173 g, 0.521 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 63.0 mg (0.0588 mmol, 33.80%) of compound 71a. Melting point: 165.5-166.7°C. HRMS (ESI) (M+H) + m / z 1071.6022, calculated value C 55 H 84 FN6O 14 1071.6024. 1H NMR (CDCl3, 400 MHz) δ: 8.74 (s, 1H, 2″-quinolyl), 7.98 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.82 (s, 1H, 11-NH), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 5.03 (s, 1H, 3-O-CO-NH-CH2), 4.92 (d, J = 11.1 Hz, 1H, H-3), 4.04 (d, J = 7.3 Hz, 1H, H-1′), 3.84-3.73 (m, 2H, H-5, H-11), 3.61-3.50 (m, 1H, 1H-cyclopropyl), 3.45-3.24 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2′), 3.11-3.01 (m, 1H, 3-O -CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.94-2.79 (m, 2H, H-10, H-2), 2.66 (s, 4H, 4H-piperazinyl), 2.56-2.46 (m, 1H, H-8), 2.47-2.35 (m, 3H, -CH2-piperazinyl, H-3′), 2.29 (s, 6H, -N(CH3) 2),2.12-2.02(m,1H,H-4),1.97-1.86(m,1H,H-14eq),1.84-1.73(m,1H,H-7a),1.6 8-1.48(m,7H,2(-CH2-),H-7b,H-14eq,H-4′a),1.43(s,3H,12-CH3),1.42-1.32(m, 6H, 2(-CH2-), 2H-cyclopropyl), 1.28 (s, 3H, 6-CH3), 1.26-1.18 (m, 6H, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.18-1.06 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.68,177.10,174.43,167.04,158.44,156.41,154.93,152.43,147.39,145.98,14 5.87,139.11,119.75,119.67,112.45,112.22,108.10,104.75,103.18,83.92,81.59,78.20,77.86,77.26,7 5.75,70.50,69.48,66.06,58.40,58.13,52.87,49.82,45.32,43.37,41.07,40.35,39.13,37.28,35.79,35.30,30.17,28.64,27.16,26.78,26.70,22.03,21.21,19.30,18.29,15.02,13.87,13.29,10.25,9.05,8.23.

[0255] Synthesis of compound 71j

[0256] According to the synthesis method, compound 49 (0.300 g, 0.348 mmol) and p-toluenesulfonyl chloride (0.0995 g, 0.522 mmol) were reacted. After completion of the reaction, the product was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.265 g (0.261 mmol, 75.00%) of compound 96.

[0257] Compound 96 (0.265 g, 0.261 mmol) was reacted with compound Ar-j (0.251 g, 0.782 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 16.5 mg (0.0156 mmol, 5.96%) of compound 71j. HRMS (ESI) (M+H) + m / z 1060.5978, calculated value C 53 H 83 FN7O 14 1060.5977. 1H NMR (CD3OD, 400 MHz) δ: 8.79 (s, 1H, 2″-quinolyl), 8.03 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.4 Hz, 1H, H-13), 4.88 (d, J = 11.1 Hz, 1H, H-3), 4.47 (q, J = 7.2 Hz, 2H, N-CH2CH3), 4.14 (d, J = 7.2 Hz, 1H, H-1′), 3.89 (s, 4H, 4H-piperazinyl), 3.85 (d, J = 3.1 Hz, 1H, H-5), 3.80 (s, 1H, H-11), 3.48-3.38 (m, 1H, H-5′), 3.29-3.17 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.14-3.00 (m, 2H, H-10, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.94-2 .87(m,1H,H-2),2.76-2.57(m,5H,H-3′,4H-piperazinyl),2.52-2.35(m,9H,H-8,-CH2-piperazinyl,-N(CH3)2),2.16-2.08(m,1H,H-4),1.93-1.72(m,3H,H-14eq,H-7a,H-4′a),1.66-1.51(m,6H,2(-CH2-),H-7b,H-14eq),1 .50-1.43(m,6H,12-CH3,N-CH2CH3),1.42-1.28(m,5H,2(-CH2-),H-4′b),1.26(s,3H,6-CH3),1.20(d, J=6.1Hz,3H,5′-CH3),1.17-1.09(m,12H,2-CH3,10-CH3,4-CH3,8-CH3),0.86(t,J=7.4Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.96,174.83,159.43,157.39,101.74,84.50,78 .76,77.90,77.44,75.50,70.76,68.72,64.52,58.07,52.71,48.92,45.35 ,43.25,40.41,39.53,38.69,37.42,35.71,30.91,29.51,26.83,26.32,2 6.02,21.82,20.01,18.43,17.17,14.01,13.89,12.92,12.23,9.42,8.07.

[0258] Synthesis of compound 71k

[0259] According to the synthesis method, compound 49 (0.300 g, 0.348 mmol) and p-toluenesulfonyl chloride (0.0995 g, 0.522 mmol) were reacted. After completion of the reaction, the product was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.265 g (0.261 mmol, 75.00%) of compound 96.

[0260] Compound 96 (0.150 g, 0.148 mmol) was reacted with compound Ar-k (0.134 g, 0.443 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 24.9 mg (0.0239 mmol, 16.13%) of compound 71k. HRMS (ESI) (M+H) + m / z 1043.6017, calculated value C 52 H 83 FN8O 14 1043.6023. 1H NMR (CD3OD, 400 MHz) δ: 9.21 (s, 1H, 5″-quinolyl), 8.78 (s, 1H, 2″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.89 (d, J = 11.1 Hz, 1H, H-3), 4.38 (q, J = 7.4 Hz, 2H, N-CH2CH3), 4.15 (d, J = 7.2 Hz, 1H, H-1′), 4.02 (s ,4H,4H-piperazinyl), 3.86 (d, J=3.2 Hz,1H,H-5), 3.80 (s,1H,H-11), 3.50-3.39 (m,1H,H-5′), 3.29-3.21 (m,2H,H-2′,3-O-CO-NH-CH2), 3.14-3.01 (m,2H,H-10,3-O-CO-NH-CH2), 2.99 (s,3H,6-O-CH3), 2.96-2.8 7 (m, 1H, H-2), 2.86-2.74 (m, 1H, H-3′), 2.58 (s, 4H, 4H-piperazinyl), 2.54-2.39 (m, 9H, H-8, -CH2-piperazinyl, -N(CH3)2), 2.16-2.08 (m, 1H, H-4), 1.93-1.76 (m, 3H, H-14eq, H-7a, H-4′a), 1.66-1.51 (m, 6H, 2 (-CH2-), H- 7b,H-14eq),1.48(s,3H,12-CH3),1.47(t,J=7.1Hz,3H,N-CH2CH3),1.41-1.17(m,11H,2(-CH2-),H-4 ′b,6-CH3,5′-CH3),1.17-1.09(m,12H,2-CH3,10-CH3,4-CH3,8-CH3),0.86(t,J=7.3Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.89,174.83,157.40,101.59,84.50,78.75,77.88,77.43,75.52,70.44,68.63,58.07,48.93,45.34,43.55,43 .22,40.40,39.34,38.68,37.43,35.70,29.51,26.81,26.30,26.07, 21.81,19.94,18.41,17.17,13.99,13.49,12.91,12.22,9.41,8.04.

[0261] Synthesis of compound 72a

[0262] According to the synthesis method, compound 50 (0.235 g, 0.268 mmol) and p-toluenesulfonyl chloride (0.0492 g, 0.403 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.182 g (0.177 mmol, 65.91%) of compound 97.

[0263] Compound 97 (0.182 g, 0.177 mmol) was reacted with compound Ar-a (0.176 g, 0.531 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 89.7 mg (0.0826 mmol, 46.69%) of compound 72a. HRMS (ESI) (M+H) + m / z 1085.6187, calculated value C 56 H 86 FN6O 14 1085.6181. 1H NMR (CD3OD, 400 MHz) δ: 8.75 (s, 1H, 2″-quinolyl), 7.80 (d, J = 13.4 Hz, 1H, 5″-quinolyl), 7.46 (s, 1H, 8″-quinolyl), 5.17 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.87 (d, J = 11.0 Hz, 1H, H-3), 4.15 (d, J = 7.2 Hz, 1H, H-1 ′), 3.84 (d, J=3.0 Hz, 1H, H-5), 3.79 (s, 1H, H-11), 3.72-3.62 (m, 1H, 1H-cyclopropyl), 3.49-3.41 (m, 1H, H-5′), 3.36 (m, 4H, 4H-piperazinyl), 3.29-3.17 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.12-3.01 (m, 2H, H-10, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.94-2.86 (m, 1H, H-2), 2.81-2.65 (m, 5H, H-3′, 4H-piperazinyl), 2.53-2.36 (m, 9H, H-8, -CH2-piperazinyl, -N(CH3)2), 2.16-2.07 (m, 1H, H-4), 1.92-1.74 (m, 3H, H-14eq, H-7a, H-4′a), 1.66-1.49 (m, 6H, 2 (- CH2-), H-7b, H-14eq), 1.47 (s, 3H, 12-CH3), 1.43-1.27 (m, 9H, 3(-CH2-), 2H-cyclopropyl, H-4'b), 1.25 (s, 3H, 6-CH3), 1.19 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.17-1.07 (m, 14H, 2H-cyclopropyl, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.97,174.83,159.39,157.38,101.69,84.49,78.78, 77.90,77.41,75.49,70.75,68.68,64.52,58.19,58.07,52.61,49.16,48.95,4 5.35,43.24,40.48,39.55,38.69,37.41,35.69,30.97,29.53,28.88,27.17,26.45,25.94,21.82,20.03,18.44,17.19,14.03,12.95,12.25,9.45,8.10,7.17.

[0264] Synthesis of compound 73a

[0265] According to the synthesis method, compound 51 (0.167 g, 0.188 mmol) and p-toluenesulfonyl chloride (0.0460 g, 0.376 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.120 g (0.115 mmol, 61.12%) of compound 98.

[0266] Compound 98 (0.120 g, 0.115 mmol) was reacted with compound Ar-a (0.114 g, 0.345 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain approximately 17.9 mg (0.0163 mmol, 14.16%) of compound 73a. HRMS (ESI) (M+H) + m / z 1099.6334, calculated value C 57 H 88 FN6O 14 1099.6337. 1H NMR (CD3OD, 400 MHz) δ: 8.75 (s, 1H, 2″-quinolyl), 7.84 (s, 1H, 5″-quinolyl), 7.51 (s, 1H, 8″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.88 (d, J = 11.1 Hz, 1H, H-3), 4.14 (d, J = 7.2 Hz, 1H, H-1′), 3.85 (d, J = 3.0 Hz, 1H ,H-5),3.80(s,1H,H-11),3.76-3.66(m,1H,1H-cyclopropyl),3.50-3.33(m,5H,H-5′,4H-piperazinyl),3.29-3.17(m,2H,H-2′,3-O-CO-NH-CH2),3.13-3.00(m,2H,H-10,3-O-CO-NH-CH2),2.98(s,3H,6-O-CH3),2.94-2.86 (m,1H,H-2),2.78-2.65(m,5H,H-3′,4H-piperazinyl),2.54-2.36(m,9H,H-8,-CH2-piperazinyl,-N(CH3)2),2.16-2.07(m,1H,H-4),1.91-1.73(m,3H,H-14eq,H-7a,H-4′a),1.66-1.49(m,6H,2(-CH2-),H-7b,H-14eq),1.4 7 (s, 3H, 12-CH3), 1.43-1.28 (m, 9H, 3(-CH2-), 2H-cyclopropyl, H-4'b), 1.25 (s, 3H, 6-CH3), 1.20 (d, J = 6.0 Hz, 3H, 5'-CH3), 1.17-1.08 (m, 14H, 2H-cyclopropyl, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.96,174.83,159.41,157.39,101.72,84.49,78.80,77 .90,77.43,75.50,70.73,68.70,64.54,58.26,58.07,52.63,49.16,48.93,45.3 5,43.25,40.51,39.51,38.69,37.42,35.70,30.88,29.55,29.16,28.95,27.15,26.43,26.03,21.82,20.02,18.43,17.17,14.01,12.93,12.24,9.44,8.08,7.16.

[0267] Reaction conditions and reagents: a. methanesulfonyl chloride, triethylamine, dichloromethane, room temperature; b. compound 100, acetonitrile, 70°C; c. methanol reflux.

[0268] General Synthesis Method of Compound 74-75 Series

[0269] Compounds 45 and 46 (1 eq) were dissolved in 20 mL of dichloromethane and triethylamine (2 eq) was added. Methanesulfonyl chloride (1.5 eq) or p-toluenesulfonyl chloride (2 eq) was added dropwise at room temperature and stirred for approximately 10-20 minutes. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was washed twice with water and once with saturated brine. The organic phase was then spin-dried and purified by column chromatography.

[0270] Disperse the intermediate (1 eq) and compound 100 (5 eq) in anhydrous acetonitrile and stir at 80°C for 72 h. After completion, the reaction mixture was spin-dried to dryness, added with 50 mL of dichloromethane, and washed three times with water and once with saturated brine. The organic phase was spin-dried to dryness, and 20 mL of methanol was added to reflux to remove the protecting group. After completion of the reaction, the reaction mixture was spin-dried and purified by column chromatography.

[0271] Synthesis of compound 74a

[0272] According to the synthesis method, compound 45 (0.408 g, 0.547 mmol) and methanesulfonyl chloride (0.049 mL, 0.602 mmol) were reacted. After completion of the reaction, the product was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.200 g (0.226 mmol, 41.32%) of compound 99.

[0273] Compound 99 (0.200 g, 0.226 mmol) was reacted with compound 100 (0.102 g, 0.271 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 15.3 mg (0.0144 mmol, 6.40%) of compound 74a. Melting point: 163.4-164.9°C. HRMS (ESI) (M+H) + m / z 1058.5786, calculated value C 53 H 81 FN7O 14 1058.5802. 1H NMR (CDCl3, 400 MHz) δ: 8.76 (s, 1H, 2″-quinolyl), 8.00 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.35 (s, 1H, 8″-quinolyl), 5.80 (s, 1H, 11-NH), 5.49 (s, 1H, 3-O-CO-NH-CH2), 5.23 (dd, J = 2.3 Hz, 10.9 Hz, 1H, H-13), 4.92 (d, J = 11.0 Hz, 1H, H-3), 4 .05 (d, J = 7.2 Hz, 1H, H-1′), 3.83-3.74 (m, 2H, H-5, H-11), 3.60-3.40 (m, 2H, 1H-cyclopropyl, 3-O-CO-NH-CH2-), 3.40-3.28 (m, 5H, H-5′, 4H-piperazinyl), 3.24-3.13 (m, 2H, 3-O-CO-NH-CH2, H-2′), 2.98 (s, 3H, 6-O-CH3), 2.93-2.79 (m, 6 H,H-10,H-2,-CH2-N-CH2-CH2-piperazinyl), 2.69(s,4H,4H-piperazinyl), 3.64-2.57(m,2H,-N-CH2-CH2-piperazinyl), 2.56-2.44(m,2H,H-8,H-3′), 2.30(s,6H,-N(CH3)2), 2.12-2.03(m,1H,H-4), 1.98-1.88(m,1H,H-14eq), 1.83-1.74(m,1 H, H-7a), 1.68-1.50 (m, 3H, H-7b, H-14eq, H-4′a), 1.46-1.35 (m, 5H, 12-CH3, 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.17-1.07 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13 C NMR(CDCl3,100MHz)δ:217.67,177.02,158.44,147.47,139.05,103.06,83.89,78.36,77.87,77.25,75.80,70.53,58.14,52.8 8,49.81,45.31,43.41,40.38,39.12,37.29,35.83,35.23,22.03,21.21,19.31,18.28,15.12,13.88,13.30,10.26,9.08,8.25.

[0274] Synthesis of compound 75a

[0275] According to the synthesis method, compound 46 (0.282 g, 0.371 mmol) and methanesulfonyl chloride (0.033 mL, 0.408 mmol) were reacted. After completion of the reaction, the residue was purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain approximately 0.241 g (0.268 mmol, 72.24%) of compound 92.

[0276] Compound 92 (0.241 g, 0.268 mmol) was reacted with compound 100 (0.0979 g, 0.282 mmol) and column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / methanol / ammonia water = 10 / 1 / 0.5) was performed to obtain 12.5 mg (0.0116 mmol, 4.35%) of compound 75a. Melting point: 163.6-164.2°C. HRMS (ESI) (M+H) + m / z 1072.5975, calculated value C 54 H 83 FN7O 14 1072.5977. 1H NMR (CDCl3, 400 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 8.01 (d, J = 13.0 Hz, 1H, 5″-quinolyl), 7.35 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.81 (s, 1H, 11-NH), 5.72 (s, 1H, 3-O-CO-NH-CH2), 5.22 (dd, J = 2.3 Hz, 10.8 Hz, 1H, H-13), 4.90 (d, J = 11.0 Hz, 1H, H-3 ), 4.05(d, J=7.2Hz,1H,H-1′),3.83-3.72(m,2H,H-5,H-11),3.58-3.49(m,1H,1H-cyclopropyl),3.49-3.26(m,6H,H-5′,4H-piperazinyl,3-O-CO-NH-CH2-),3.23-3.12(m,2H,H-2′,3-O-CO-NH-CH2),2.97(s,3H,6-O-CH3),2.93-2.83(m,2H, H-10,H-2), 2.82-2.73 (m,4H,-CH2-N-CH2-CH2-piperazinyl), 2.72-2.57 (m,6H,4H-piperazinyl,-N-CH2-CH2-piperazinyl), 2.55-2.41 (m,2H,H-8,H-3′), 2.30 (s,6H,-N(CH3)2), 2.11-2.02 (m,1H,H-4), 1.97-1.88 (m,1H,H-14eq), 1.83-1.70 (m,3H, , H-7a, -CH2-), 1.68-1.51 (m, 3H, H-7b, H-14eq, H-4′a), 1.45-1.35 (m, 5H, 12-CH3, 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH3, H-4′b, 5′-CH3, 2H-cyclopropyl), 1.18-1.07 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.84 (t, J = 7.2 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.79,177.23,174.56,167.29,158.57,147.59,145.94,139. 21,120.01,112.67,112.53,108.47,104.82,103.25,84.01,81.65,78.30,77.98,75. 91,70.63,58.24,52.99,49.92,49.88,45.41,43.50,40.48,39.24,37.40,35.93,35.37,29.82,22.14,21.32,19.42,18.40,18.35,15.20,14.00,13.41,10.38,9.17,8.37.

[0277] General synthesis method of compound 76-86 series

[0278] Compounds 52-62 (1 eq) and compound (1.5 eq) were dissolved in acetonitrile, and triethylamine (2 eq) was added to the system. The reaction was carried out at 70°C for 2-4 hours. After completion of the reaction, the reaction solution was spin-dried and purified by column chromatography. The product was then dissolved in 2 mL of ethanol and 2 mL of 2N NaOH aqueous solution was added. After completion of the reaction, dichloromethane was added for extraction. The organic phase was spin-dried and methanol was added to reflux for 12-14 hours. After completion of the reaction, column chromatography was performed to obtain compounds 76-86.

[0279] Synthesis of compound 76o

[0280] According to the general synthesis method, compound 52 (0.216 g, 0.248 mmol) was reacted with compound Ar-o (0.153 g, 0.372 mmol) to obtain approximately 179.3 mg (0.167 mmol, 67.24%) of compound 76o. Melting point: 155.7-156.4°C. HRMS (ESI) (M+H) + m / z 1075.5617, calculated value C 53 H 80 FN6O 16 1075.5609. 1H NMR (CD3OD, 400 MHz) δ: 8.70 (s, 1H, 2″-quinolyl), 7.97 (d, J = 13.7 Hz, 1H, 5″-quinolyl), 5.13 (dd, J = 2.4 Hz, 11.2 Hz, 1H, H-13), 4.89-4.81 (m, 2H, H-3, H-11), 4.26-4.16 (m, 2H, N-(CH2-CH2)2), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 3.88-3.80 (m 4H,H-5,9-O-CH3), 3.79-3.65 (m,5H,1H-cyclopropyl,-N-(CH2-CH2)2-CH,H-8), 3.62 (d, J=6.0 Hz,2H,O-CH2)3.51-3.36 (m,2H,3-O-CO-NH-CH2,H-5′), 3.28 (dd, J=7.3 Hz,10.2 Hz ,1H,H-2′),3.21-3.12(m,1H,3-O-CO-NH-CH2),3.05(s,3H,6-O-CH3),2.97-2.86(m ,1H,H-2),2.82-2.70(m,1H,H-3′),2.66(q,J=6.8Hz,1H,H-10),2.43(s,6H,-N(CH3) 2),2.16-1.99(m,1H,H-4,CH2),1.91-1.62(m,1H,H-14eq,-N-(CH2-CH2)2,H-4′a,H -14eq),1.56(s,3H,12-CH3),1.52-1.36(m,3H,H-7b,H-7b,H-4′b),1.32(s,3H,6-CH 3), 1.31-1.25 (m, 2H, 2H-cyclopropyl), 1.25-1.18 (m, 6H, 5′-CH 3 , 2-CH 3 ), 1.18-1.06 (m, 8H, 2-CH 3 , 4-CH 3 , 2H-cyclopropyl), 0.98 (d, J = 7.1 Hz, 3H, 8-CH 3 ), 0.89 (t, J = 7.4 Hz, 3H, 15-CH 3 ). 13C NMR(CDCl3,176MHz)δ:177.08,174.01,166.87,165.97,164.53,156.34,154.67,150.22,150.17,148.17,146.93,146.69,14 6.47,134.24,129.49,119.99,119.87,113.22,108.87,103.34,85.00,83.20,81.25,78.34,78.22,75.54,74.05,70.45,69. 52,66.36,66.16,61.43,49.82,44.41,44.36,43.37,40.39,39.31,38.91,37.33,35.98,34.65,32.72,31.11,31.08,30.57,30.19,28.99,28.56,25.60,23.99,22.97,22.23,21.21,19.33,18.86,15.61,14.94,14.05,13.01,11.10,10.20,8.86,7.46.

[0281] Synthesis of compound 771

[0282] According to the general synthesis method, compound 53 (0.231 g, 0.256 mmol) was reacted with compound Ar-1 (0.210 g, 0.512 mmol) to obtain approximately 139.3 mg (0.134 mmol, 52.21%) of compound 771. Melting point: 186.7-187.0°C. HRMS (ESI) (M+H) + m / z 1042.5772, calculated value C 54 H 81 FN5O 14 1042.5759. 1H NMR (CD3OD, 400 MHz) δ: 8.72 (s, 1H, 2″-quinolyl), 7.79 (s, 1H, 5″-quinolyl), 7.48 (s, 1H, 8″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.1 Hz, 1H, H-3), 4.15 (d, J = 7.2 Hz, 1H, H-1′), 3.85 (d, J = 3.0 Hz, 1H, H- 5),3.80(s,1H,H-11),3.77-3.59(m,3H,-N-(CH2-CH2)2,1H-cyclopropyl),3.50-3.39(m,1H,H-5′),3.29-3.21(m,2H,H-2′,3-O-CO-NH-CH2),3.14-3.01(m,2H,H-10,3-O-CO-NH-CH2),2.99(s,3H,6-O-CH3),2.95-2. 70(m,4H,H-2,H-3′,-N-(CH2-CH2)2),2.54-2.47(m,1H,H-8),2.43(s,6H,-N(CH3)2),2.17-2.06(m,1H ,H-4),1.92-1.75(m,5H,-CH-(CH2-CH2)2,H-14eq,H-7a),1.60-1.45(m,8H,H-7b,H-4′a,H-14eq,-CH-( 1.44-1.28 (m, 9H, 3(-CH2-), 2H-cyclopropyl, H-4'b), 1.25 (m, 3H, 6-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.18-1.06 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13 C NMR(CDCl3,100MHz)δ:217.69,177.09, 167.17,158.45,147.28,146.42,139.19,108.04,104.73,83.93,77.87,77.25,75.78,70.54,58.14,50.53,49.85,45.33,43.36,41.05,40.38,39.15,37.28,36.08,35.80,35.49,35.28,32.09,30.53,23.84,22.05,21.22,19.30,18.30,15.01,13.88,13.29,10.26,9.07,8.22.

[0283] Synthesis of compound 77o

[0284] According to the general synthesis method, compound 53 (0.155 g, 0.172 mmol) and compound Ar-o (0.212 g, 0.516 mmol) were used to obtain approximately 53.1 mg (0.0509 mmol, 29.59%) of compound 77o. Melting point: 152.0-152.4°C. HRMS (ESI) (M+H) + m / z 1043.5710, calculated value C 53 H 80 FN6O 14 1043.5711. 1H NMR (CD3OD, 400 MHz) δ: 8.64 (s, 1H, 2″-quinolyl), 7.90 (s, 1H, 5″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.1 Hz, 1H, H-3), 4.68 (d, J = 13.2 Hz, 2H, -N-(CH2-CH2)2), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.85 (d, J = 3.1 Hz, 1H, H- 5), 3.79 (s, 1H, H-11), 3.73-3.63 (m, 1H, 1H-cyclopropyl), 3.47-3.35 (m, 1H, H-5′), 3.29-3.21 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.15 (td, J=2.7 Hz, 13.2 Hz, 2H, -N-(CH2-CH2)2), 3.11-3.01 (m, 2H, H-10, 3-O-CO-NH-CH2), 2.99 (s, 3H, 6-O-CH 3),2.95-2.70(m,4H,H-2),2.94-2.86(m,1H,H-3′,),2.52-2.45(m,1H,H-8),2.40(s,6H,-N(CH3)2),2.16-2.08( m,1H,H-4),1.93-1.80(m,4H,H-14eq,H-7a,CH2),1.80-1.71(m,1H,H-4′a),1.71-1.50(m,5H,H-7b,H-14eq,-CH- (CH2-CH2)2, CH2), 1.47 (s, 3H, 12-CH3), 1.45-1.27 (m, 9H, 3(-CH2-), 2H-cyclopropyl, H-4'b), 1.25 (m, 3H, 6-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.17-1.06 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.66,177.04,174.40,167.00,158.45,156.43,150.24,150.16,148.71,147. 02,146.33,146.12,119.81,119.59,112.85,108.75,103.21,83.91,81.69,78.29,77.87,70.52,69.50 ,66.07,58.15,49.82,47.71,47.62,45.31,43.38,41.05,40.35,39.15,37.30,36.11,36.06,35.78,34.63,32.40,30.48,28.67,23.81,22.04,21.21,19.30,18.28,14.99,13.88,13.30,10.25,9.06,7.44.

[0285] Synthesis of compound 78l

[0286] According to the general synthesis method, compound 54 (0.200 g, 0.221 mmol) and compound Ar-1 (0.272 g, 0.664 mmol) were used to obtain approximately 73.3 mg (0.0702 mmol, 31.76%) of compound 781. Melting point: 181.1-181.6°C. HRMS (ESI) (M+H) + m / z 1044.55559, calculated value C 53 H 79 FN5O 15 1044.55512. 1H NMR (CD3OD, 400 MHz) δ: 8.72 (s, 1H, 2″-quinolyl), 7.79 (d, J = 13.2 Hz, 1H, 5″-quinolyl), 7.50 (s, 1H, 8″-quinolyl), 5.17 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.88 (d, J = 11.5 Hz, 1H, H-3), 4.15 (d, J = 7.2 Hz, 1H, H-1′), 3.85 (d ,J=3.0Hz,1H,H-5),3.79(s,1H,H-11),3.75-3.65(m,1H,1H-cyclopropyl),3.64-3.50(m,5H,-N-(CH2-CH2)2-CH-O-CH2),3.49-3.41(m,1H,H-5′),3.41-3.33(m,1H,3-O-CO-NH-CH2),3.27(dd,J=7.4Hz,10.1Hz, 1H,H-2′),3.22-3.11(m,3H,3-O-CO-NH-CH2,-N-(CH2-CH2)2),3.08(q,J=6.7Hz,H-10),2.98(s,3H,6-O-CH3),2.94-2.84(m,1H,H -2),2.81-2.71(m,1H,H-3′),2.53-2.45(m,1H,H-8),2.42(s,6H,-N(CH3)2),2.16-2.00(m,3H,H-4,CH2),1.92-1.70(m,7H,-N-(CH 1.66-1.54 (m, 2H, H-7b, H-14eq), 1.47 (s, 3H, 12-CH3), 1.42-1.27 (m, 3H, 2H-cyclopropyl, H-4'b), 1.25 (m, 3H, 6-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5'-CH3), 1.17-1.07 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:220.00,178.75,163.36,161.27,105.62,88.42,82.65,8 1.82,81.39,79.44,79.42,77.72,74.61,72.64,69.01,68.44,61.98,52.89,49. 28,47.14,43.44,42.58,41.94,41.35,39.63,34.88,34.73,34.65,33.93,25.74,23.99,22.39,22.37,21.11,18.02,16.88,16.18,16.16,13.39,12.03,11.11.

[0287] Synthesis of compound 78m

[0288] According to the general synthesis method, compound 54 (0.150 g, 0.166 mmol) was reacted with compound Ar-m (0.097 g, 0.249 mmol) to obtain approximately 34.9 mg (0.0338 mmol, 20.37%) of compound 78m. Melting point: 172.8-173.0°C. HRMS (ESI) (M+H) + m / z 1032.5559, calculated value C 52 H 79 FN5O 15 1032.5551. 11H NMR (CD3OD, 400 MHz) δ: 8.82 (s, 1H, 2″-quinolyl), 7.93 (d, J = 13.3 Hz, 1H, 5″-quinolyl), 7.13 (s, 1H, 8″-quinolyl), 5.20 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.91 (d, J = 11.5 Hz, 1H, H-3), 4.50 (s, 2H, NCH2CH3), 4.16 (d, J = 7.3 Hz, 1H, H-1′), 3.87 (d, J = 3.1 Hz, 1H, H-5), 3.81 (s, 1H, H-11), 3.85 - 3.76 (m, 3H, -N-(CH2-CH2)2-CH), 3.69 - 3.52 (m, 5H, O-CH2, N-(CH2-CH2)2CH), 3.49 - 3.36 (m, 5H, H-5′, 3-O-CO-NH-CH2), N-(CH2-CH2)2), 3.27 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2′), 3.25 - 3.04 (m, 4H, 3-O-CO-NH-CH2, H-10, N-(CH2-CH2)2), 3.00 (s, 3H, 6-O-CH3), 2.96 - 2.87 (m, 1H, H-2), 2.79 - 2.69 (m, 1H, H-3′), 2.56 - 2.47 (m, 1H, H-8), 2.43 (s, 6H, -N(CH3)2), 2.19 - 2.00 (m, 3H, H-4, CH2), 1.94 - 1.63 (m, 7H, -N-(CH2-CH2)2, H-14eq, H-7a, H-4′a), 1.69 - 1.58 (m, 2H, H-7b, H-14eq), 1.58 - 1.51 (m, 3H, NCH2CH3), 1.49 (s, 3H, 12-CH3), 1.39 - 1.30 (m, 1H, H-4′b), 1.28 (s, 3H, 6-CH3), 1.22 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.19 - 1.09 (m, 12H, 2-CH3, 10-CH3, 4-CHx3, 8-CH3), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.66,176.96,174.40,167.27,158.44,154.23,152.80,147.05,146. 36,146.30,137.18,108.32,103.90,103.17,83.89,77.86,75.78,73.74,70.46,69.51,66.27, 66.10,58.12,49.83,49.73,47.38,45.31,43.37,40.36,39.12,37.28,35.80,30.89,30.15,29.70,22.03,21.21,19.31,18.29,15.06,14.53,14.47,13.88,13.84,13.29,10.26,9.24,9.06.

[0289] Synthesis of compound 78n

[0290] According to the general synthesis method, compound 54 (0.150 g, 0.166 mmol) was reacted with compound Ar-n (0.126 g, 0.332 mmol) to obtain approximately 28.2 mg (0.0275 mmol, 16.55%) of compound 78n. Melting point: 164.5-165.0°C. HRMS (ESI) (M+H) + m / z 1026.5648, calculated value C 53 H 80 N5O 15 1026.5645. 1H NMR (CD3OD, 400 MHz) δ: 8.73 (s, 1H, 2″-quinolyl), 8.17 (d, J = 9.16 Hz, 1H, 5″-quinolyl), 7.37 (s, 1H, 8″-quinolyl), 7.30 (d, J = 9.3 Hz, 1H, 6″-quinolyl), 5.19 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.88 (d, J = 11.5 Hz,1H,H-3),4.14(d,J=7.2Hz,1H,H-1′),3.87(d,J=3.2Hz,1H,H-5),3.85-3.76(m,3H,H-11,1 H-cyclopropyl,-N-(CH2-CH2)2-CH),3.74-3.56(m,4H,O-CH2,N-(CH2-CH2)2),3.48-3.36(m,4H,H-5′, 3-O-CO-NH-CH2,N-(CH2-CH2)2),3.27(dd,J=7.2Hz,10.1Hz,1H,H-2′),3.21-3.04(m,2H,3-O- CO-NH-CH2,H-10),3.00(s,3H,6-O-CH3),2.93-2.82(m,2H,H-2),2.76-2.63(m,1H,H-3′),2.56 -2.45(m,1H,H-8),2.41(s,6H,-N(CH3)2),2.18-2.09(m,1H,H-4),2.09-2.00(m,2H,CH2),1.9 5-1.69(m,7H,-N-(CH2-CH2)2,H-14eq,H-7a,H-4′a),1.68-1.56(m,2H,H-7b,H-14eq),1.49(s ,3H,12-CH3),1.45-1.29(m,3H,2H-cyclopropyl,H-4′b),1.27(s,3H,6-CH3),1.21(d,J=6.1Hz,3H,5′-CH3),1.19-1.09(m,14H,2-CH3,10-CH3,4-CH3,8-CH3,2H-cyclopropyl),0.86(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.66,177.28,174.37,167.52,158.44,156.33,154.31,147.50,143.35,127.92 ,116.65,114.67,107.92,103.10,98.42,83.89,81.56,78.17,77.84,75.78,73.91,70.44,69.45,66.33, 66.12,58.12,49.82,45.30,44.82,44.79,43.35,40.33,39.35,39.10,37.28,35.77,34.87,30.41,30.23,30.12,29.70,28.68,22.02,21.20,19.30,18.28,18.25,15.06,13.88,13.27,10.26,10.24,9.04,8.15.

[0291] Synthesis of compound 78o

[0292] According to the general synthesis method, compound 54 (0.200 g, 0.221 mmol) was reacted with compound Ar-o (0.454 g, 1.105 mmol) to obtain approximately 105.6 mg (0.101 mmol, 45.71%) of compound 78o. Melting point: 140.5-141.2°C. HRMS (ESI) (M+H) + m / z 1045.55057, calculated value C 52 H 78 FN6O 15 1045.55037. 1H NMR (CD3OD, 400 MHz) δ: 8.67 (s, 1H, 2″-quinolyl), 7.90 (d, J = 13.9 Hz, 1H, 5″-quinolyl), 5.17 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.87 (d, J = 11.5 Hz, 1H, H-3), 4.23-4.09 (m, 3H, H-1′, -N-(CH2-CH2)2), 3.84 (d, J = 3.0 Hz, 1H, H-5), 3. 79 (s, 1H, H-11), 3.37-3.61 (m, 4H, 1H-cyclopropyl, -N-(CH2-CH2)2-CH), 6.01 (t, J = 3.6 Hz, 1H, O-CH2), 3.51-3.41 (m, 1H, H-5′), 3.40-3.32 (m, 1H, 3-O-CO-NH-CH2), 3.30-3.24 (m, 1H, H-2′), 3.20-3.04 (m, 2H, 3-O-CO-NH-CH2, H -10),2.98(s,3H,6-O-CH3),2.92-2.78(m,2H,H-2,H-3′),2.54-2.40(m,7H,H-8,-N(CH3)2),2.16-2.06(m, 1H,H-4),2.05-1.94(m,2H,CH2),1.90-1.74(m,5H,-N-(CH2-CH2)2,H-14eq,H-7a,H-4′a),1.74-1.54(m,4H, H-7b, H-14eq, -N-(CH2-CH2)2), 1.46 (s, 3H, 12-CH3), 1.35-1.22 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH3), 1.19 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.16-0.98 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:220.00,180.44,178.73,163.32,161.25,105.53,88.41,82.63, 81.81,81.33,79.42,79.40,77.94,74.54,72.57,69.10,68.48,61.98,52.92,51.93,49 .29,48.23,48.18,47.12,43.59,43.45,42.57,41.91,41.34,39.61,34.92,34.84,33.97,25.75,23.98,22.40,22.39,21.14,18.04,16.92,16.21,16.19,13.43,12.04,10.45.

[0293] Synthesis of compound 79l

[0294] According to the general synthesis method, compound 55 (0.150 g, 0.164 mmol) was reacted with compound Ar-1 (0.100 g, 0.246 mmol) to obtain 100.7 mg (0.0952 mmol, 43.06%) of compound 791. Melting point: 173.5-174.8°C. HRMS (ESI) (M+H) + m / z 1058.5710, calculated value C 54 H 81 FN5O 15 1058.5708. 1H NMR (CD3OD, 400 MHz) δ: 8.78 (s, 1H, 2″-quinolyl), 7.85 (d, J = 13.2 Hz, 1H, 5″-quinolyl), 7.52 (s, 1H, 8″-quinolyl), 5.18 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.86 (d, J = 11.5 Hz, 1H, H-3), 4.16 (d, J = 7.2 Hz, 1H, H-1′), 3.87 (d, J = 3.0 Hz, 1H, H-5), 3.80 (s, 1H, H-11) ,3.77-3.67(m,3H,1H-cyclopropyl,-N-(CH2-CH2)2-),3.55(t,J=6.0Hz,2H,O-CH2),3.51-3.43(m,1H,H-5′),3.44-3.35(m,1H,3-O-CO-NH-CH2,O-CH2),3.29(dd,J=7.3Hz,10.3Hz,1H,H-2′),3.22-3.03(m,1H,3-O-CO-NH-CH2),3.09(q,J=6.5Hz,1H ,H-10),2.99(s,3H,6-O-CH3),2.97-2.86(m,3H,H-2,N-(CH2-CH2)2),2.83-2.69(m,1H,H-3′),2.56-2.38(m,7H,H-8,- N(CH3)2),2.18-2.07(m,1H,H-4),1.98-1.74(m,7H,-N-(CH2-CH2)2-CH-CH2-O-CH2CH2,H-14eq,H-4′a),1.69-1.50(m, 4H, H-7a, H-14eq, -N-(CH2-CH2)2), 1.45 (s, 3H, 12-CH3), 1.43-1.29 (m, 4H, 2H-cyclopropyl, H-4′b, H-7b), 1.27 (s, 3H, 6-CH3), 1.22 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.19-1.06 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.65,177.08,174.38,173.69,167.08,158.43,147.32, 146.37,139.16,104.85,104.82,103.12,83.89,81.42,77.86,75.79,70.46,69.5 5,58.12,50.20,49.83,45.31,43.40,40.37,39.14,37.28,36.14,35.79,35.28,29.12,29.05,22.04,21.21,19.30,18.29,15.06,13.88,13.26,10.26,8.97,8.23.

[0295] Synthesis of compound 79o

[0296] According to the general synthesis method, compound 55 (0.150 g, 0.164 mmol) was reacted with compound Ar-o (0.101 g, 0.246 mmol) to obtain approximately 132.3 mg (0.125 mmol, 76.16%) of compound 79o. Melting point: 174.8-175.3°C. HRMS (ESI) (M+H) + m / z 1059.5653, calculated value C 53 H 80 FN6O 15 1059.5660. 1H NMR (CD3OD, 400 MHz) δ: 8.74 (s, 1H, 2″-quinolyl), 7.98 (d, J = 13.8 Hz, 1H, 5″-quinolyl), 5.19 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.89 (d, J = 11.5 Hz, 1H, H-3), 4.70 (d, J = 13.1 Hz, 2H, -N-(CH2-CH2)2-), 4.15 (d, J = 7.2 Hz, 1H, H-1′), 3.86 (d, J = 3.0 Hz, 1 H,H-5),3.81(s,1H,H-11),3.73-3.63(m,1H,1H-cyclopropyl),3.52(td,J=2.0Hz,5.9Hz,2H,O-CH2),3.48-3.40(m,2H,H-5′, 3-O-CO-NH-CH2),3.39-3.34(m,1H,O-CH2),3.28(dd,J=7.3Hz,10.3Hz,1H,H-2′),3.24-3.06(m,4H,3-O-CO-NH-CH2, N-(CH2-CH2)2,H-10),3.00(s,3H,6-O-CH3),2.94-2.86(m,3H,H-2),2.81-2.69(m,1H,H-3′),2.56-2.38(m,7H,H-8, -N(CH3)2),2.17-2.08(m,1H,H-4),2.06-1.74(m,8H,-N-(CH2-CH2)2-CH-CH2-O-CH2CH2,H-14eq,H-4′a,H-7a),1.69 -1.54 (m, 4H, H-14eq, H-7b), 1.53-1.38 (m, 5H, 12-CH3, N-(CH2-CH2)2), 1.36-1.24 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH3), 1.19 (d, J = 6.2 Hz, 3H, 5′-CH3), 1.17-1.04 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,100MHz)δ:217.67,177.06,176.59,174.39,166.92,158.43,150. 30,146.99,146.36,108.80,83.90,81.48,77.85,75.58,70.49,69.54,58.11 ,49.83,47.26,45.31,43.37,40.36,39.13,37.26,36.66,35.81,34.64,29.33,29.26,22.02,21.19,19.29,18.29,15.05,13.87,13.26,10.26,8.99,7.44.

[0297] Synthesis of compound 801

[0298] According to the general synthesis method, compound 56 (0.167 g, 0.179 mmol) was reacted with compound Ar-1 (0.110 g, 0.268 mmol) to obtain approximately 77.7 mg (0.0725 mmol, 40.48%) of compound 801. Melting point: 168.2-168.8°C. HRMS (ESI) (M+H) + m / z 1072.5868, calculated value C 55 H 83 FN5O 15 1072.5864. 1H NMR (CD3OD, 400 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 7.85 (d, J = 11.8 Hz, 1H, 5″-quinolyl), 7.52 (s, 1H, 8″-quinolyl), 5.19 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.89 (d, J = 11.5 Hz, 1H, H-3), 4.17 (d, J = 7.2 Hz, 1H, H-1′), 3.87 (d, J = 3.1 Hz, 1H, H-5), 3.80 (s, 1 H,H-11), 3.79-3.63 (m,3H,1H-cyclopropyl,-N-(CH2-CH2)2-), 3.61-3.48 (m,4H,CH2-O-CH2), 3.48-3.43 (m,1H,H-5′), 3.41-3.35 (m,1H,3-O-CO-NH-CH2), 3.29 (dd, J=7.3Hz,10.3Hz,1H,H-2′), 3.20-3.05 (m,2H,3-O-CO-NH-CH2,H-10), 2.99 (s,3H,6-O-CH3),2.97-2.86(m,3H,H-2,N-(CH2-CH2)2),2.84-2.69(m,1H,H-3′),2.55-2.40(m,7H,H-8,-N(CH3)2 ),2.18-2.09(m,1H,H-4),1.99-1.69(m,9H,-N-(CH2-CH2)2-CH,H-14eq,2(CH2),H-4′a),1.68-1.56(m,5H,H-7a,H- 7b, H-14eq, -N-(CH2-CH2)2), 1.48 (s, 3H, 12-CH3), 1.46-1.29 (m, 5H, 2H-cyclopropyl, H-4′b, CH2), 1.27 (s, 3H, 6-CH3), 1.23 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.19-1.10 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.77,217.69,177.07,174.43,167.13,158.44,154.43,153.00,147.27,146.47,146.41,139 .18,119.32,112.31,112.17,108.02,104.75,103.18,83.90,77.85,75.74,70.47,69.53,69.15,68.65,58.11,58.07, 53.45,50.47,50.44,49.84,45.31,43.35,40.37,39.12,37.27,36.17,35.82,35.28,32.68,32.12,32.08,29.92,22.02,21.96,21.21,19.30,19.28,18.29,18.23,15.06,13.88,13.86,13.27,13.23,10.25,10.22,9.07,8.24,8.23,8.10.

[0299] Synthesis of compound 80o

[0300] According to the general synthesis method, compound 56 (0.167 g, 0.179 mmol) was reacted with compound Ar-o (0.110 g, 0.268 mmol) to obtain approximately 133.8 mg (0.125 mmol, 69.64%) of compound 80o. Melting point: 141.2-142.4°C. HRMS (ESI) (M+H) + m / z 1073.5824, calculated value C 54 H 82 FN6O 15 1073.5817. 1H NMR (CD3OD, 400 MHz) δ: 8.71 (s, 1H, 2″-quinolyl), 7.97 (d, J = 13.8 Hz, 1H, 5″-quinolyl), 5.20 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.90 (d, J = 11.5 Hz, 1H, H-3), 4.71 (d, J = 13.2 Hz, 2H, -N-(CH2-CH2)2-), 4.16 (d, J = 7.2 Hz, 1H, H-1′), 3.88 (d, J = 3.2 Hz ,1H,H-5),3.81(s,1H,H-11),3.75-3.66(m,1H,1H-cyclopropyl),3.57-3.48(m,4H,CH2OCH2),3.48-3.36(m,2H,H-5′,3-O- CO-NH-CH2),3.29(dd,J=7.3Hz,10.2Hz,1H,H-2′),3.24-3.06(m,4H,3-O-CO-NH-CH2,N-(CH2-CH2)2,H-10),3.00(s ,3H,6-O-CH3),2.97-2.87(m,3H,H-2),2.80-2.68(m,1H,H-3′),2.56-2.47(m,1H,H-8),2.44(s,6H,-N(CH3)2),2. 18-2.09(m,1H,H-4),1.97-1.74(m,8H,-N-(CH2-CH2)2-CH-CH2O-CH2CH2,H-14eq,H-4′a,H-7a),1.69-1.54(m,4H,C H2, H-14eq, H-7b), 1.49 (s, 3H, 12-CH3), 1.45-1.29 (m, 5H, N-(CH2-CH2)2, 2H-cyclopropyl, H-4′b), 1.27 (s, 3H, 6-CH3), 1.23 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.20-1.07 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.88 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.66,177.05,177.03,174.38,166.95,158.43,156.32,1 50.20,150.15,148.15,147.02,146.67,146.34,119.82,119.69,112.92,112.90, 108.79,103.23,83.88,81.59,78.21,77.86,75.79,70.45,69.54,69.19,68.49,66.12,58.12,49.83,47.64,47.59,45.31,43.39,40.36,39.32,39.13,37.28,36.18,35.82,34.63,33.17,32.42,32.39,29.94,28.52,22.03,21.22,19.31,18.28,15.05,13.88,13.29,10.26,9.05,7.45.

[0301] Synthesis of compound 811

[0302] According to the general synthesis method, compound 57 (0.191 g, 0.215 mmol) was reacted with compound Ar-1 (0.132 g, 0.323 mmol) to obtain approximately 77.3 mg (0.0750 mmol, 34.90%) of compound 811. Melting point: 167.7-168.4°C. HRMS (ESI) (M+H) + m / z 1030.5395, calculated value C 52 H 77 FN5O 15 1030.5395. 1H NMR (CD3OD, 400 MHz) δ: 8.67 (s, 1H, 2″-quinolyl), 7.75 (d, J = 14.3 Hz, 1H, 5″-quinolyl), 7.07 (d, J = 7.3 Hz, 1H, 8″-quinolyl), 5.16 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.83 (d, J = 11.1 Hz, 1H, H-3), 4.29 (s, 1H, H-tetrahydropyrrole), 4.11 (d, J = 7.3 Hz, 1H, H-1′), 3.90- 3.80 (m, 2H, H-5, H-tetrahydropyrrole), 3.77 (s, 1H, H-11), 3.76-3.64 (m, 5H, 1H-cyclopropyl, O-CH2, 2H-tetrahydropyrrole), 3.62-3.53 (m, 1H, H-tetrahydropyrrole), 3.46-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.25 (dd, J=7.3 Hz, 10.2 Hz, 1H, H-2′), 3.18-3.04 (m, 2H, 3-O-CO-NH-CH2, H-10), 2.97 (s, 3H, 6-O-CH3), 2.80-2.59 (m, 2H, H-2, H-3′), 2.54-2.45 (m, 1H, H-8), 2.38 (s, 6H, -N(CH3)2), 2.33-2.22 (m, 1H, H-tetrahydropyrrole), 2.21-2.11 (m, 1H, H-tetrahydropyrrole), 2.11-2.03 (m, 1H, H-4), 1.94-1.68 (m, 5H, CH2, H-14eq, H-7a, H-4′a) ,1.67-1.55 (m, 2H, H-7b, H-14eq),1.45 (s, 3H, 12-CH3),1.43-1.27 (m, 3H, 2H-cyclopropyl, H-4′b),1.25 (s, 3H, 6-CH3),1.17 (d, J = 6.2 Hz, 3H, 5′-CH3),1.16-1.02 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.84 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,176.40,174.35,167.33,158.45,156.36,151.19,149.78,146.81,142.02,141.95,13 9.73,115.47,115.43,111.75,111.61,107.39,103.21,99.47,99.44,83.91,81.62,78.20,78.06,77.84,75.78,70.4 4,69.49,67.17,66.08,58.11,55.59,55.55,53.45,49.80,47.98,47.95,45.31,43.34,40.31,39.20,39.09,37.28,35.74,35.14,30.47,29.99,28.54,22.01,21.19,19.29,18.27,15.03,13.88,13.30,13.26,10.26,8.91,8.11,8.08.

[0303] Synthesis of compound 81o

[0304] According to the general synthesis method, compound 57 (0.191 g, 0.215 mmol) was reacted with compound Ar-o (0.132 g, 0.323 mmol) to obtain approximately 162.6 mg (0.158 mmol, 73.34%) of compound 81o. Melting point: 159.6-160.6°C. HRMS (ESI) (M+H) + m / z 1031.5345, calculated value C 51 H 76 FN6O 15 1031.5347. 1H NMR (CD3OD, 400 MHz) δ: 8.67 (s, 1H, 2″-quinolyl), 7.91 (d, J = 12.6 Hz, 1H, 5″-quinolyl), 5.17 (dd, J = 2.3 Hz, 10.8 Hz, 1H, H-13), 4.85 (d, J = 11.2 Hz, 1H, H-3), 4.27 (s, 1H, H-tetrahydropyrrole), 4.11 (d, J = 7.3 Hz, 1H, H-1′), 4.09-3.99 (m, 2H, O-CH2), 3. 98-3.86 (m, 2H, H-tetrahydropyrrole), 3.83 (d, J = 3.1 Hz, 1H, H-5), 3.78 (s, 1H, H-11), 3.76-3.65 (m, 2H, 1H-cyclopropyl, H-tetrahydropyrrole), 3.62-3.54 (m, 1H, H-tetrahydropyrrole), 3.45-3.36 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.26 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2′), 3.18-3. 05(m,2H,3-O-CO-NH-CH2,H-10),2.97(s,3H,6-O-CH3),2.82-2.64(m,2H,H-2,H-3′),2.55-2.44(m,1H,H-8),2.40(s,6H,-N(CH3)2),2.32-2.21(m,1H,H-tetrahydropyrrole),2.18-2.05(m,2H,H-tetrahydropyrrole,H-4),1.93-1.70(m,5H,CH2,H-14eq ,H-7a,H-4′a),1.68-1.55(m,2H,H-7b,H-14eq),1.47(s,3H,12-CH3),1.35-1.27(m,3H,2H-cyclopropyl,H-4′b),1.26(s,3H,6-CH3),1.21-1.04(m,17H,2-CH3,5′-CH3,10-CH3,4-CH3,8-CH3,2H-cyclopropyl),0.84(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,176.93,174.31,167.00,158.44,156.35,149.23,149.16,147. 49,147.25,145.99,145.78,118.10,117.98,111.74,108.67,103.27,83.90,81.70,78.28,77 .84,75.81,70.42,69.52,67.18,66.11,58.11,49.80,45.31,43.34,40.32,39.09,37.28,35.74,34.66,30.03,28.50,22.01,21.19,19.29,18.27,15.02,13.88,13.27,10.26,8.91,7.42.

[0305] Synthesis of compound 821

[0306] According to the general synthesis method, compound 58 (0.200 g, 0.225 mmol) was reacted with compound Ar-1 (0.138 g, 0.338 mmol) to obtain approximately 91.6 mg (0.0889 mmol, 39.52%) of compound 821. Melting point: 164.5-165.0°C. HRMS (ESI) (M+H) + m / z 1030.5389, calculated value C 52 H 77 FN5O 15 1030.5395. 1H NMR (CD3OD, 400 MHz) δ: 8.65 (s, 1H, 2″-quinolyl), 7.74 (d, J = 14.3 Hz, 1H, 5″-quinolyl), 7.06 (d, J = 7.4 Hz, 1H, 8″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.5 Hz, 1H, H-3), 4.27 (s, 1H, H-tetrahydropyrrole), 4.11 (d, J = 7.3 Hz, 1H, H-1′) ,3.91-3.82 (m, 2H, H-5, H-tetrahydropyrrole),3.79 (s, 1H, H-11),3.77-3.58 (m, 6H, 1H-cyclopropyl, O-CH2, 3H-tetrahydropyrrole),3.46-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2),3.24 (dd, J=7.3Hz, 10.2Hz, 1H, H-2′),3.17-3.05 (m, 2H, 3-O-CO-NH-CH2, H-10),2.99 (s,3H,6-O-CH3),2.85-2.74(m,2H,H-2),2.71-2.59(m,1H,H-3′),2.56-2.44(m,1H,H-8),2.37(s,6H,-N(CH3)2),2.33-2.23(m,1H,H-tetrahydropyrrole),2.21-2.13(m,1H,H-tetrahydropyrrole),2.13-2.04(m,1H,H-4),1.93-1.68(m,5H,CH2,H-14eq ,H-7a,H-4′a),1.67-1.56(m,2H,H-7b,H-14eq),1.47(s,3H,12-CH3),1.43-1.29(m,3H,2H-cyclopropyl,H-4′b),1.26(s,3H,6-CH3),1.24-1.06(m,17H,2-CH3,10-CH3,5′-CH3,4-CH3,8-CH3,2H-cyclopropyl),0.85(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,176.35,176.33,174.38,167.30,158.44,156.40,151.20,149.79,146.75,142.07,1 42.00,139.72,115.38,115.34,111.64,111.50,107.33,103.15,99.48,99.45,83.90,81.47,78.24,78.16,77.84, 75.78,70.45,69.51,66.89,66.07,58.11,55.39,55.35,49.81,48.03,48.01,45.31,43.32,40.33,39.10,38.82,37.27,35.75,35.12,30.69,29.98,28.50,22.02,21.19,19.29,18.28,15.02,13.88,13.27,10.26,8.94,8.09,8.06.

[0307] Synthesis of compound 82o

[0308] According to the general synthesis method, compound 58 (0.200 g, 0.225 mmol) was reacted with compound Ar-o (0.138 g, 0.338 mmol) to obtain approximately 154.5 mg (0.150 mmol, 66.59%) of compound 82o. Melting point: 164.9-165.9°C. HRMS (ESI) (M+H) + m / z 1031.5349, calculated value C 51 H 76 FN6O 15 1031.5347. 1H NMR (CD3OD, 400 MHz) δ: 8.67 (s, 1H, 2″-quinolyl), 7.91 (d, J = 12.8 Hz, 1H, 5″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.2 Hz, 1H, H-3), 4.27 (s, 1H, H-tetrahydropyrrole), 4.12 (d, J = 7.3 Hz, 1H, H-1′), 4.08-3.96 (m, 2H, 2H-tetrahydropyrrole), 3.96-3.87 (m, 2H, H-tetrahydropyrrole), 3.83 (d, J = 3.1 Hz, 1H, H-5), 3.80 (s, 1H, H-11), 3.77-3.56 (m, 3H, 1H-cyclopropyl, O-CH2), 3.45-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.26 (dd, J=7.2 Hz, 10.2 Hz, 1H, H-2′), 3.18-3.05 (m, 2H, 3-O-CO-NH-CH2, H-10), 2.99 (s, 3H, 6-O-CH3), 2.89-2.79 (m, 1H, H-2), 2.76-2.64 (m, 1H, H-3′), 2.56-2.44 (m, 1H, H-8), 2.39 (s, 6H, -N(CH3)2), 2.31-2.21 (m, 1H, H-tetrahydropyrrole), 2.18-2.05 (m, 2H, H-tetrahydropyrrole, H-4), 1.92-1.71 (m, 5H, CH2, H-14eq, H-7a, H-4'a), 1.68-1.54 (m, 2H, H-7b, H-14eq), 1.48 (s, 3H, 12-CH3), 1.35-1.27 (m, 3H, 2H-cyclopropyl, H-4'b), 1.26 (s, 3H, 6-CH3), 1.20-1.07 (m, 17H, 2-CH3, 5'-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.67,176.93,174.32,167.00,158.44,156.37,149.25,149.18,147.49,14 7.25,145.99,145.78,118.11,118.00,111.75,108.69,103.29,83.89,81.70,78.31,77.85,77.22,7 5.83,70.44,69.54,67.00,66.12,58.13,49.80,45.31,43.35,40.34,40.31,39.11,38.94,37.28,35.76,34.65,30.06,28.48,22.02,21.19,19.30,18.27,15.03,13.88,13.29,10.27,8.97,7.43,7.41.

[0309] Synthesis of compound 831

[0310] According to the general synthesis method, compound 59 (0.100 g, 0.110 mmol) was reacted with compound Ar-1 (0.0679 g, 0.166 mmol) to obtain approximately 43.3 mg (0.0415 mmol, 37.70%) of compound 831. Melting point: 157.9-158.6°C. HRMS (ESI) (M+H) + m / z 1044.5557, calculated value C 53 H 79 FN5O 15 1044.5551. 1H NMR (CD3OD, 400 MHz) δ: 8.64 (s, 1H, 2″-quinolyl), 7.72 (d, J = 14.4 Hz, 1H, 5″-quinolyl), 7.04 (d, J = 7.4 Hz, 1H, 8″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.5 Hz, 1H, H-3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.86 (d, J = 3.1 Hz, 1H, H-5), 3.80 (s ,1H,H-11),3.77-3.64(m,3H,1H-cyclopropyl,2H-tetrahydropyrrole),3.63-3.52(m,3H,O-CH2,H-tetrahydropyrrole),3.55-3.47(m,2H,O-CH2,),3.46-3.36(m,2H,H-5′,3-O-CO-NH-CH2),3.26(dd,J=7.3Hz,10.2Hz,1H,H-2′),3.20-3.12(m,1H,3-O-CO-NH-CH2),3.09(q,J=6 .5Hz,1H,H-10),2.99(s,3H,6-O-CH3),2.91-2.82(m,1H,H-2),2.74-2.63(m,2H,H-tetrahydropyrrole,H-3′),2.56-2.45(m,1H,H-8),2.40(s,6H,-N(CH3)2),2.25-2.16(m,1H,H-tetrahydropyrrole),2.15-2.06(m,1H,H-4),1.98-1.71(m,6H,H-tetrahydropyrrole,CH2,H-14eq,H-4 'a, H-7a,), 1.68-1.55 (m, 2H, H-14eq, H-7a), 1.47 (s, 3H, 12-CH3), 1.44-1.29 (m, 3H, 2H-cyclopropyl, H-4'b), 1.27 (s, 3H, 6-CH3), 1.24-1.18 (m, 5H, 5'-CH3, 2H-cyclopropyl), 1.17-1.07 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.67,176.41,174.39,167.36,158.44,156.34,151.18,149.77,146.75,142.09,142 .03,139.74,115.33,111.70,111.57,107.40,103.18,99.38,83.90,81.60,78.24,77.85,75.79,72.56,70.4 6,69.51,69.45,66.11,58.12,52.94,49.82,49.53,49.50,45.31,43.39,40.34,39.17,39.12,38.82,37.28,35.78,35.12,29.85,28.59,28.03,22.02,21.20,19.31,18.28,15.05,13.88,13.27,10.27,9.00,8.10,8.07.

[0311] Synthesis of compound 83o

[0312] According to the general synthesis method, compound 59 (0.100 g, 0.110 mmol) was reacted with compound Ar-o (0.0679 g, 0.166 mmol) to obtain approximately 88.9 mg (0.0850 mmol, 77.32%) of compound 83o. Melting point: 151.0-152.2°C. HRMS (ESI) (M+H) + m / z 1045.5509, calculated value C 52 H 78 FN6O 15 1045.5504. 1H NMR (CD3OD, 400 MHz) δ: 8.65 (s, 1H, 2″-quinolyl), 7.86 (d, J = 12.8 Hz, 1H, 5″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.89 (d, J = 11.5 Hz, 1H, H-3), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 4.09-3.93 (m, 2H, 2H-tetrahydropyrrole), 3.89-3.83 (m, 2H, H -5,1H-cyclopropyl), 3.81(s,1H,H-11),3.78-3.62(m,2H,2H-tetrahydropyrrole),3.61-3.48(m,4H,CH2-O-CH2),3.46-3.35(m,2H,H-5′,3-O-CO-NH-CH2),3.27(dd,J=7.3Hz,10.1Hz,1H,H-2′),3.20-3.05(m,2H,3-O-CO-NH-CH2,H-10),3.00( s,3H,6-O-CH3),2.93-2.82(m,1H,H-2),2.76-2.61(m,2H,H-tetrahydropyrrole,H-3′),2.55-2.45(m,1H,H-8),2.42(s,6H,-N(CH3)2),2.24-2.08(m,1H,H-tetrahydropyrrole,H-4),1.96-1.73(m,6H,H-tetrahydropyrrole,CH2,H-14eq,H-4′a,H-7a,),1.69-1.53 (m, 2H, H-14eq, H-7a), 1.48 (s, 3H, 12-CH3), 1.38-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.28 (s, 3H, 6-CH3), 1.21 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.17-1.07 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.69,176.84,174.38,167.04,158.44,156.34,149.15,149.08,147 .50,147.24,145.85,145.76,117.86,117.74,111.52,108.55,103.19,83.91,81.57,78.22,7 7.85,75.77,72.37,70.46,69.49,66.10,58.12,49.82,45.31,43.38,40.35,39.11,37.27,35.79,34.65,29.90,22.02,21.20,19.30,18.28,15.04,13.88,13.28,10.26,9.00,7.44,7.34.

[0313] Synthesis of compound 841

[0314] According to the general synthesis method, compound 60 (0.164 g, 0.181 mmol) was reacted with compound Ar-1 (0.112 g, 0.272 mmol) to obtain approximately 88.7 mg (0.0849 mmol, 46.93%) of compound 841. Melting point: 165.2-166.3°C. HRMS (ESI) (M+H) + m / z 1044.5553, calculated value C 53 H 79 FN5O 15 1044.5551. 1H NMR (CD3OD, 400 MHz) δ: 8.62 (s, 1H, 2″-quinolyl), 7.69 (d, J = 14.4 Hz, 1H, 5″-quinolyl), 7.03 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.5 Hz, 1H, H-3), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 3.85 (d, J = 3.1 Hz, 1H, H-5), 3.79 (s ,1H,H-11),3.77-3.64(m,3H,1H-cyclopropyl,2H-tetrahydropyrrole),3.63-3.55(m,3H,O-CH2,H-tetrahydropyrrole),3.56-3.48(m,2H,O-CH2,),3.48-3.35(m,2H,H-5′,3-O-CO-NH-CH2),3.27(dd,J=7.3Hz,10.2Hz,1H,H-2′),3.22-3.12(m,1H,3-O-CO-NH-CH2),3.09(q,J=6 .4Hz,1H,H-10),2.99(s,3H,6-O-CH3),2.89-2.79(m,1H,H-2),2.75-2.63(m,2H,H-tetrahydropyrrole,H-3′),2.54-2.45(m,1H,H-8),2.40(s,6H,-N(CH3)2),2.25-2.14(m,1H,H-tetrahydropyrrole),2.14-2.06(m,1H,H-4),1.98-1.73(m,6H,H-tetrahydropyrrole,CH2,H-14eq,H- 4′a, H-7a), 1.67-1.53 ​​(m, 2H, H-14eq, H-7a), 1.46 (s, 3H, 12-CH3), 1.42-1.30 (m, 3H, 2H-cyclopropyl, H-4′b), 1.28 (s, 3H, 6-CH3), 1.24-1.17 (m, 5H, 5′-CH3, 2H-cyclopropyl), 1.18-1.08 (m, 12H, 2-CH3, 10-CH3, 4-CH3, 8-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,176.35,176.33,174.38,167.32,158.44,156.33,151.16,149.75,146.68,142.08,1 42.01,139.72,115.24,115.20,111.59,111.46,107.33,103.15,99.38,99.34,83.90,81.52,78.19,77.85,72.37, 70.45,69.52,69.45,66.09,58.11,52.84,52.81,49.82,49.57,49.54,45.31,43.37,40.34,39.20,39.11,38.74,37.27,35.77,35.12,29.84,28.58,28.08,22.01,21.21,19.30,18.28,15.05,13.88,13.25,10.26,8.99,8.08,8.05.

[0315] Synthesis of compound 84o

[0316] According to the general synthesis method, compound 60 (0.164 g, 0.181 mmol) was reacted with compound Ar-o (0.112 g, 0.272 mmol) to obtain approximately 137.8 mg (0.132 mmol, 72.84%) of compound 84o. Melting point: 144.2-145.3°C. HRMS (ESI) (M+H) + m / z 1045.5501, calculated value C 52 H 78 FN6O 15 1045.5504. 1H NMR (CD3OD, 400 MHz) δ: 8.63 (s, 1H, 2″-quinolyl), 7.83 (d, J = 12.8 Hz, 1H, 5″-quinolyl), 5.17 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.86 (d, J = 11.5 Hz, 1H, H-3), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 4.09-3.95 (m, 2H, 2H-tetrahydropyrrole), 3.89-3.83 (m, 2H, H-5,1H-cyclopropyl), 3.80 (s, 1H, H-11), 3.78-3.63 (m, 2H, 2H-tetrahydropyrrole), 3.63-3.48 (m, 4H, CH2-O-CH2), 3.49-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.27 (dd, J=7.3 Hz, 10.1 Hz, 1H, H-2′), 3.21-3.06 (m, 2H, 3-O-CO-NH-CH2, H-10), 2.99 (s, 3H, 6-O-CH3), 2.91-2.81 (m, 1H, H-2), 2.75-2.63 (m, 2H, H-tetrahydropyrrole, H-3′), 2.56-2.46 (m, 1H, H-8), 2.41 (s, 6H, -N(CH3)2), 2.27-2.06 (m, 1H, H-tetrahydropyrrole, H-4), 1.98-1.72 (m, 6H, H-tetrahydropyrrole, CH2, H-14eq, H-4′a, H-7a), 1.69-1.53 (m, 2H, H-14eq, H-7a), 1.47 (s, 3H, 12-CH3), 1.35-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.27 (s, 3H, 6-CH3), 1.21 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.18-1.07 (m, 14H, 2-CH3, 10-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.85 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.66,176.90,174.34,167.04,158.43,156.31,149.15,149.08,147.51,14 7.24,145.89,145.76,117.97,117.85,111.60,111.59,108.63,103.20,83.88,81.61,78.25,77.85, 72.21,70.45,69.53,69.49,66.13,58.12,49.82,45.31,43.38,40.35,39.18,39.12,37.28,35.77,34.65,29.88,28.57,22.02,21.21,19.30,18.28,15.05,13.88,13.27,10.26,8.99,7.46,7.44,7.34.

[0317] Synthesis of compound 85l

[0318] According to the general synthesis method, compound 61 (0.184 g, 0.204 mmol) was reacted with compound Ar-1 (0.125 g, 0.305 mmol) to obtain approximately 151.3 mg (0.145 mmol, 71.08%) of compound 851. Melting point: 168.2-169.2°C. HRMS (ESI) (M+H) + m / z 1044.5560, calculated value C 53 H 79 FN5O 15 1044.5551. 1H NMR (CD3OD, 400 MHz) δ: 8.76 (s, 1H, 2″-quinolyl), 7.88 (d, J = 13.2 Hz, 1H, 5″-quinolyl), 7.58 (s, 1H, 8″-quinolyl), 5.16 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.84 (d, J = 11.1 Hz, 1H, H-3), 4.12 (d, J = 7.3 Hz, 1H, H-1′), 3.84 ( d, J = 3.2 Hz, 1H, H-5), 3.79 (s, 1H, H-11), 3.78-3.72 (m, 1H, H-cyclopropyl), 3.71-3.54 (m, 4H, 1, O-CH2, H-piperidinyl, CH), 3.52-3.37 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.31-3.18 (m, 3H, H-2′, 3-O-CO-NH-CH2, H-piperidinyl), 3.1 6-3.04 (m, 2H, H-10, H-piperidinyl), 2.99 (s, 3H, 6-O-CH3), 2.88-2.78 (m, 1H, H-2), 2.77-2.67 (m, 1H, H-3′), 2.57-2.36 (m, 7H, H-8, -N(CH3)2), 2.15-1.96 (m, 3H, H-4, CH2), 1.95-1.54 (m, 9H, 4H-piperidinyl, H-14eq, H- 7a, H-4′a, H-7b, H-14eq), 1.48 (s, 3H, 12-CH3), 1.45-1.28 (m, 3H, 2H-cyclopropyl, H-4′b), 1.26 (s, 3H, 6-CH3), 1.25-0.99 (m, 17H, 2-CH3, 10-CH3, 5′-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.69,177.07,174.36,167.02,158.44,156.34,15 4.33,152.91,147.42,146.27,146.22,139.18,119.63,119.58,112.48,112 .35,108.11,105.06,103.21,83.90,81.59,78.22,77.85,75.78,73.87,70.45,69.52,66.77,66.10,58.11,54.38,54.35,50.31,49.81,45.31,43.38, 40.34,39.34,39.11,37.28,35.77,35.30,30.12,29.52,28.48,22.37,22.02,21.21,19.31,18.28,15.03,13.88,13.28,10.26,8.94,8.28,8.24.

[0319] Synthesis of compound 85o

[0320] According to the general synthesis method, compound 61 (0.184 g, 0.204 mmol) was reacted with compound Ar-o (0.125 g, 0.305 mmol) to obtain approximately 110.8 mg (0.106 mmol, 51.96%) of compound 85o. Melting point: 165.4-166.2°C. HRMS (ESI) (M+H) + m / z 1045.5510, calculated value C 52 H 78 FN6O 15 1045.5504. 1H NMR (CD3OD, 400 MHz) δ: 8.72 (s, 1H, 2″-quinolyl), 7.96 (d, J = 13.7 Hz, 1H, 5″-quinolyl), 5.18 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.85 (d, J = 11.2 Hz, 1H, H-3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 4.10-3.87 (m, 3H, 2H-piperidinyl, CH), 3.84 (d, J = 3.4 Hz, 1H, H-5), 3.80 (s, 1H, H-11), 3.78-3.63 (m, 3H, H-cyclopropyl, 2H-piperidinyl), 3.64-3.54 (m, 3H, O-CH2, H-piperidinyl), 3.45-3.36 (m, 1H, H-5′), 3.31-3.14 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.10 (q, J = 6.5 Hz, 1H, H-10), 3.0 5-2.94(s,4H,6-O-CH3,H-piperidinyl),2.92-2.82(m,1H,H-2),2.81-2.68(m,1H,H-3′),2.56-2.36(m,7H,H-8,-N(CH3)2),2.15-2.07(m,1H,H-4),2.07-1.94(m,2H,CH2),1.92-1.74(m,4H,2H-piperidinyl,H-14eq,H-4′a,), 1.74-1.56 (m, 5H, 2H-piperidinyl, H-7a, H-7b, H-14eq), 1.48 (s, 3H, 12-CH3), 1.37-1.23 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH3), 1.23-1.02 (m, 17H, 2-CH3, 10-CH3, 5′-CH3, 4-CH3, 8-CH3, 2H-cyclopropyl), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,177.06,174.34,166.82,158.44,156.34,150.57,148.08,146.93,146.60,146.51 ,146.35,119.93,119.80,113.12,108.88,103.24,83.90,81.63,78.33,77.86,75.81,73.86,70.45,69.54,66.60 ,66.13,58.13,53.45,51.34,51.27,49.80,47.69,47.65,45.31,43.37,40.34,40.30,39.12,39.03,37.28,35.79,34.69,30.23,29.92,28.50,28.43,22.15,22.02,21.20,19.31,18.28,15.02,13.88,13.29,10.27,9.00,7.49.

[0321] Synthesis of compound 861

[0322] According to the general synthesis method, compound 62 (0.195 g, 0.216 mmol) was reacted with compound Ar-1 (0.133 g, 0.325 mmol) to obtain approximately 62.8 mg (0.0601 mmol, 27.84%) of compound 861. Melting point: 172.3-173.0°C. HRMS (ESI) (M+H) + m / z 1044.5550, calculated value C 53 H 79 FN5O 15 1044.5551. 1H NMR (CD3OD, 400 MHz) δ: 8.77 (s, 1H, 2″-quinolyl), 7.87 (d, J = 13.2 Hz, 1H, 5″-quinolyl), 7.59 (s, 1H, 8″-quinolyl), 5.16 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.82 (d, J = 11.1 Hz, 1H, H-3), 4.11 (d, J = 7.2 Hz, 1 H,H-1′), 3.83 (d, J=3.2 Hz,1H,H-5), 3.77 (s,1H,H-11), 3.76-3.71 (m,1H,H-cyclopropyl), 3.70-3.59 (m,3H,O-CH2,CH), 3.59-3.50 (m,1H,H-piperidinyl), 3.49-3.36 (m,3H,H-5′,3-O-CO-NH-CH2,H-piperidinyl ),3.30-3.21(m,3H,H-2′,3-O-CO-NH-CH2),3.17-3.03(m,2H,H-10,H-piperidinyl),2.98(s,3H,6-O-CH3),2.78-2.66(m,2H,H-2,H-3′),2.54-2.37(m,7H,H-8,-N(CH3)2),2.13-1.95(m,3H,H-4 , CH2), 1.93-1.68 (m, 7H, 4H-piperidinyl, H-14eq, H-7a, H-4′a), 1.67-1.53 ​​(m, 2H, H-7b, H-14eq), 1.45 (s, 3H, 12-CH3), 1.43-1.27 (m, 3H, 2H-cyclopropyl, H-4′b), 1.26 (s, 3H, 6-CH3), 1.24-1.09 (m, 12H, 2-CH3, 10-CH3, 5′-CH3, 8-CH3), 1.08-0.95 (m, 5H, 4-CH3, 2H-cyclopropyl), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,177.05,174.31,167.00,158.45,156.27,154.34,152.92,147.39,146.35,139.16,119.65,1 19.60,112.49,112.36,108.12,105.10,103.01,83.90,81.26,78.09,77.82,77.79,75.76,73.61,70.46,69.52,66.77,66. 11,58.08,54.35,54.31,50.08,49.82,45.36,45.31,43.38,40.34,40.31,39.42,39.09,37.27,35.68,35.30,29.89,29.38,28.46,22.33,22.00,21.20,19.30,19.27,18.35,18.28,14.98,13.88,13.84,13.20,10.25,10.19,8.91,8.84,8.28,8.23.

[0323] Synthesis of compound 86o

[0324] According to the general synthesis method, compound 62 (0.195 g, 0.216 mmol) was reacted with compound Ar-o (0.133 g, 0.325 mmol) to obtain approximately 92.3 mg (0.0883 mmol, 40.88%) of compound 86o. Melting point: 163.0-164.2°C. HRMS (ESI) (M+H) + m / z 1045.5504, calculated value C 52 H 78 FN6O 15 1045.5504. 1H NMR (CD3OD, 400 MHz) δ: 8.71 (s, 1H, 2″-quinolyl), 7.96 (d, J = 13.4 Hz, 1H, 5″-quinolyl), 5.19 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.85 (d, J = 11.2 Hz, 1H, H-3), 4.20-3.98 (m, 4H, H-1′, 3H-piperidinyl), 3.83 (d, J = 3.2 Hz, 1H, H -5), 3.79 (s, 1H, H-11), 3.77-3.65 (m, 2H, H-cyclopropyl, CH), 3.63-3.51 (m, 3H, O-CH2, H-piperidinyl), 3.39-3.34 (m, 1H, H-5′), 3.31-3.14 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.10 (q, J=6.5 Hz, 1H, H-10), 3.05-2.94 (s, 4H, 6-O-CH3,H-piperidinyl), 2.89-2.82 (m,1H,H-2), 2.79-2.67 (m,1H,H-3′), 2.58-2.39 (m,7H,H-8,-N(CH3)2), 2.17-2.08 (m,1H,H-4), 2.08-1.93 (m,2H,CH2), 1.92-1.74 (m,3H,2H-piperidinyl,H-14eq), 1.77-1.56 (m,6 H,H-4′a,2H-piperidinyl,H-7a,H-7b,H-14eq), 1.48 (s,3H,12-CH3), 1.37-1.22 (m,6H,2H-cyclopropyl,H-4′b,6-CH3), 1.22-1.04 (m,17H,2-CH3,10-CH3,5′-CH3,4-CH3,8-CH3,2H-cyclopropyl), 0.86 (t, J = 7.3 Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.69,177.05,174.33,166.82,158.45,156.29,150.58,148.08,146.92,146.50,119. 93,119.80,113.13,108.88,103.21,83.91,81.57,78.26,77.85,75.82,73.84,70.45,69.54,66.69,66.15,58 .12,53.44,51.24,51.18,49.81,47.65,45.31,43.37,40.34,39.11,39.03,37.28,35.75,34.68,33.86,30.12,29.92,29.70,28.47,22.13,22.02,21.18,19.30,18.28,15.00,13.88,13.27,10.27,8.96,7.52,7.49,7.46.

[0325] Test Example 1 In vitro antibacterial activity experiment

[0326] According to the standards recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010), the in vitro antibacterial activities of some target compounds against sensitive Streptococcus pneumoniae ATCC49619, MEF-efflux-resistant Streptococcus pneumoniae PU-09, constitutively erm-resistant (c-erm) Streptococcus pneumoniae 07P390, inducible ermB (i-ermB)-resistant Streptococcus pyogenes, constitutively ermA (c-ermA)-resistant Streptococcus pyogenes 12-206, Staphylococcus aureus ATCC29213, inducible ermA (i-ermA)-resistant Staphylococcus aureus PU32, constitutively resistant Staphylococcus aureus 19D052, 19B133, 19B130, 19E131, 15B196, Haemophilus influenzae ATCC49247, and catarrhalis 13L332 were determined by the broth dilution method. Each bacterial strain was purified by plate transfection before testing, and fresh bacteria were used in the tests. A standard strain served as a quality control for sensitivity testing in each experiment; a bacterial solution without antimicrobial agents served as a growth control for the test strains. The minimum inhibitory concentration (MIC) was determined using the two-fold broth dilution method. The antimicrobial agent concentration range was 256–0.008 μg / mL, and the final concentration of the test solution was approximately 5 × 10 5 CFU / ml.

[0327] The measurement results are shown in the table below:

[0328] Table 1. Antibacterial activity MIC data of compounds (μg / mL)

[0329] Note: “—” in the above table means not tested.

[0330] Table 2. Antibacterial activity MIC data of compounds and control drugs (μg / mL)

[0331] (MCX-198 is compound 14n in the literature Eur J Med Chem, 125 (2017) 210-224.)

[0332] Table 3. Antibacterial activity MIC data of compounds (μg / mL)

[0333] Table 4. MIC data of anti-Staphylococcus aureus activity of compounds and control drugs (μg / mL)

[0334] cMLS B : Constitutive resistance to macrolide-lincosamide-streptogramin B.

[0335] Table 5. Antibacterial activity MIC data of compounds and control drugs (μg / mL)

[0336] Table 6. Antibacterial activity MIC data of compounds and control drugs (μg / mL)

[0337] Table 7. MICs of 78o, 84o, and control drugs against different species of drug-resistant bacteria 50 and MIC 90 Statistics (μg / mL)

[0338] Note: In the above table, "all (59)" refers to all Staphylococcus aureus; "MSSA (24)" refers to methicillin-sensitive Staphylococcus aureus; "MRSA (34)" refers to methicillin-resistant Staphylococcus aureus; sensitive, inducible, and constitutive all refer to the phenotypes of the strains resistant to erythromycin; Ery<8 and Ery>8 refer to the MIC (μg / mL) range of erythromycin for the test strains, and so on.

[0339] MICs of compounds 78o and 84o against different species of drug-resistant bacteria 50 and MIC 90Statistical results showed that compounds 78o and 84o had better antibacterial activity than the second-generation macrolide clarithromycin, and were equivalent to or better than the third-generation macrolide telithromycin.

[0340] Table 8. Antibacterial activity of compounds against constitutive Staphylococcus aureus MIC (μg / mL)

[0341] In constitutively isolated Staphylococcus aureus, compounds 78o and 84o showed better antibacterial activity than the control drugs clarithromycin, telithromycin, MCX-219, and MCX-190.

[0342] Table 9. MICs (μg / mL) of 78o, 84o, and control drugs against different species of drug-resistant bacteria

[0343] Compounds 78o and 84o showed better antibacterial activity against different species of drug-resistant bacteria than first-, second-, and third-generation macrolides.

[0344] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. The compound represented by Formula I, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs: in, W is an oxygen atom O or NOC 1-12 Alkyl; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is an integer in the range of 1-10, n2 is an integer in the range of 0-6, m1 is 0, 1 or 2, m2 is 0, 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, Ra is a halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 alkoxy; R 1 is a hydrogen atom, an amino group, a halogen, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; Rb is selected from halogen, amino, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 alkoxy; R 2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl; Rb is selected from halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 Alkoxy; Z is methine CH, CRc, nitrogen atom N, or when Z is C, it is the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R 2 Does not exist; Rc is halogen, nitrile, amino, C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy or halogenated C 1-12 Alkoxy.

2. The compound according to claim 1, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, characterized in that W is an oxygen atom O or NOC 1-6 Alkyl; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is 1, 2, 3, 4, 5, 6 or 7, n2 is 0, 1, 2, 3, 4, 5 or 6, m1 is 0 or 1, m2 is 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, Ra is a halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy; R 1 is a hydrogen atom, a halogen, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Rb is selected from halogen, C 1-6 Alkyl or C 1-6 alkoxy; R 2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb: 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Rb is selected from halogen, C 1-6 Alkyl or C 1-6 alkoxy; Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R 2 Does not exist; Rc is a halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

3. The compound according to claim 2, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, characterized in that W is an oxygen atom O or NOCH3; V is an oxygen atom O or a secondary amine NH, X is a methylene CH2, a secondary amine NH or an oxygen atom O; Y is a nitrogen atom N or a methine CH; n1 is 2, 3, 4, 5, 6 or 7, n2 is 0, 1 or 2, m1 is 0 or 1, and m2 is 1 or 2; Q is a methine CH, a fluorine-substituted carbon atom CF or a nitrogen atom N; R 1 is a hydrogen atom, a methyl group or an ethyl group; R 2 is absent, a hydrogen atom, a methyl group, an ethyl group, a cyclopropyl group, a fluoroethyl group, a fluorocyclopropyl group; Z is a methine group CH, a fluorine-substituted carbon atom CF, a nitrogen atom N, a methoxy-substituted carbon atom C-OCH3, or when Z is C, the same as R 2 The connected N is connected to form a ring, wherein the connecting part between Z and N is -OCH2-CH(CH3)-, then R 2 Does not exist.

4. The compound according to any one of claims 1 to 3, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, characterized in that The compound represented by formula I is selected from the following:

5. Use of the compound according to any one of claims 1 to 4, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs in the preparation of antibacterial drugs.

6. The use according to claim 5, characterized in that The antibacterial drug 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.

7. The use according to claim 5 or 6, characterized in that The antibacterial drug is used to inhibit or kill at least one of the following bacterial species that are sensitive to erythromycin or have different types of resistance: sensitive Streptococcus pneumoniae, constitutively resistant Streptococcus pneumoniae, efflux-resistant Streptococcus pneumoniae, sensitive Staphylococcus aureus, inducibly resistant Staphylococcus aureus, constitutively resistant Staphylococcus aureus, sensitive Streptococcus pyogenes, efflux-resistant Streptococcus pyogenes, inducibly resistant Streptococcus pyogenes, constitutively resistant Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis.

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 4, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, and optionally a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition is used for preparing antibacterial drugs.

10. The method for preparing the compound according to any one of claims 1 to 4, characterized in that: The steps include: Among them, W, V, X, Y, n1, n2, m1, m2, R 1 , R 2 , Z, Q have the definitions described in any one of claims 1-4; R is Ac or Bz.

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