WO2024245303A1 - Erythromycin derivative, preparation method therefor and use thereof - Google Patents

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

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, preparation method and application thereof”. The entire text of the prior application is incorporated into this application by reference.

Technical Field

The invention relates to the field of chemical synthesis and pharmacy, and in particular to an erythromycin derivative and a preparation method and application thereof.

Background Art

Macrolide-lincosamide-streptogramin B (MLS _B ) has the same ribosomal binding site and has cross-resistance. Among them, erythromycin, a 14-membered macrolide antibiotic, is a very important drug for treating upper and lower respiratory tract infections. It is clinically used in the treatment of 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 very efficient and safe way of medication for humans, especially children, for half a century. Since the main antibacterial mechanism is that the hydroxyl group and tertiary amino group of the 5-position desaccharide amine act in the form of hydrogen bonds with the bases A2058/A2059 of the nascent peptide release channel of the 50S subunit of the ribosome, the mutation of the bacterial ribosome A2058/A2059 bases, or the expression of methylase by strains containing the erm gene leading to the methylation of N6 of A2058 will lead to a sharp decrease in the affinity of erythromycin drugs; in addition, strains containing the mef gene will be induced by erythromycin containing cladinose to express efflux pump proteins, resulting in the reduction of the intracellular drug molecule concentration to below the antibacterial level and 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).

The second generation of erythromycins, clarithromycin and azithromycin, which appeared in the 1980s, have high resistance to (gastric) acid and good pharmacokinetic properties, but have no antibacterial activity against erythromycin-resistant bacteria. The main reason is that the 3-position clarithromycin sugar induces bacterial resistance, causing the key target A2058 to be modified or pumped out of the cell by an efflux pump.

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. At the same time, it acts on the base pairs A752 and U2609 of the microbial ribosome, so it has good antibacterial activity against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes, but has no activity against constitutively resistant Staphylococcus aureus and resistant mycoplasma. Ketolides such as solithromycin in Phase III clinical trials have 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 were questioned for their safety because they all had similar ketolide structures, resulting in telithromycin being the only one to be launched in the past 20 years.

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.

Summary of the invention

In order to solve the above technical problems, the present invention provides a compound as shown in the following formula I, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs:

Wherein, W is an oxygen atom O or a NOC _1-12 alkyl group; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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, and m2 is 0, 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, and Ra is a halogen, a C _1-12 alkyl group, a halogenated C _1-12 alkyl group or a C _1-12 alkoxy group;

^R1 is a hydrogen atom, an amino group, a halogen, unsubstituted or optionally substituted by one, two or more Rb: a _C1-12 alkyl group, a _C3-20 cycloalkyl group, a 3-20 membered heterocyclyl group, a _C6-20 aryl group or a 5-20 membered heteroaryl group; Rb is selected from halogen, an amino group, a _C1-12 alkyl group, a halogenated _C1-12 alkyl group or a _C1-12 alkoxy group;

^R2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb as follows: _C1-12 alkyl, _C3-20 cycloalkyl, 3-20 membered heterocyclyl, _C6-20 aryl or 5-20 membered heteroaryl; Rb is selected from halogen, _C1-12 alkyl, halogenated _C1-12 alkyl or _C1-12 alkoxy; Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, it is connected to N connected to ^R2 to form a ring, wherein the connecting part between Z and N is _-OCH2- CH( _CH3 )-, in which case ^R2 is absent; Rc is halogen, nitrile, amino, _C1-12 alkyl, halogenated _C1-12 alkyl, _C1-12 alkoxy or halogenated _C1-12 alkoxy.

In some embodiments, W is an oxygen atom O or a NOC _1-6 alkyl group; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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, and m2 is 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, and Ra is a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group;

^R1 is a hydrogen atom, a halogen, unsubstituted or optionally substituted by one, two or more Rb: a _C1-6 alkyl group, a _C3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a _C6-12 aryl group or a 5-12 membered heteroaryl group; Rb is selected from halogen, a _C1-6 alkyl group or a _C1-6 alkoxy group;

^R2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb as follows: _C1-6 alkyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-12 aryl or 5-12 membered heteroaryl; Rb is selected from halogen, _C1-6 alkyl or _C1-6 alkoxy;

Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, it is connected to N connected to R ² to form a ring, wherein the connecting part between Z and N is -OCH ₂ -CH(CH ₃ )-, and R ² does not exist at this time; Rc is a halogen, a C _1-6 alkyl or a C _1-6 alkoxy.

In some preferred embodiments, W is an oxygen atom O or NOCH ₃ ; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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;

^R1 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, or a fluorocyclopropyl group; Z is a methine group CH, a carbon atom CF substituted with fluorine, a nitrogen atom N, a carbon atom C-OCH ₃ substituted with methoxy, or when Z is C, it is connected to N connected to R ² to form a ring, wherein the connecting part between Z and N is -OCH ₂ -CH(CH ₃ )-, and R ² is absent at this time.

In some specific embodiments, the compound represented by formula I is selected from the following:

The present invention also provides the use of the compound shown in the above formula I, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug in the preparation of antibacterial drugs.

According to an embodiment of the present invention, the pharmaceutically acceptable salt comprises a tertiary amino group on 5'-decanamine or a nitrogen atom on a side chain heterocyclic ring and a pharmaceutically acceptable salt. The prodrug is an ester formed by the carboxyl group of the quinolone part and RxOH, or the 2'-OH of the desaccharide amine 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 heterocyclic group, C _6-20 aryl or 5-20 heteroaryl; Rb is selected from halogen, C _1-12 alkyl or C _1-12 alkoxy.

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.

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 types of resistance: sensitive Streptococcus pneumoniae, constitutively resistant Streptococcus pneumoniae, exudative resistant Streptococcus pneumoniae, sensitive Staphylococcus aureus, inducible resistant Staphylococcus aureus, constitutively resistant Staphylococcus aureus, sensitive Streptococcus pyogenes, exudative resistant Streptococcus pyogenes, inducible resistant Streptococcus pyogenes, constitutively resistant Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis.

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.

According to an embodiment of the present invention, the pharmaceutical composition is used for preparing an antibacterial drug.

The present invention uses carbamate to derive the 3-position of clarithromycin. The present invention provides a novel macrolide-quinolone heterocompound for resisting drug-resistant bacteria, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, and its structural characteristics are that a side chain of suitable length is introduced from the nitrogen atom in the 3-position carbamate functional group of clarithromycin, and its end is connected to quinolone through various piperazine, pyrrolidine, piperidine and other heterocycles, replacing the 3-O-cladinose of the original clarithromycin; at the same time, it is combined with other modifications such as 11,12-OH ring carbonation, or 11,12-OH ring carbamate, or 9-carbonyl oximation.

In the present application, a step-by-step introduction method can be used, that is, first construct a side chain containing a hydroxyl group, introduce a good leaving group such as mesylate or p-toluenesulfonate on the terminal hydroxyl group of the side chain, and then couple it with the nitrogen atom on the piperazine of the quinolone, or couple it with the terminal nitrogen atom of the side chain linked to different atomic lengths on piperazine, and finally remove the protecting group to obtain the target compound; or first introduce diamines of different lengths, and then react with diols of different carbon chain lengths, and then introduce a good leaving group such as mesylate or p-toluenesulfonate on the terminal hydroxyl group, and then couple it with the nitrogen atom on the piperazine of the quinolone, and finally remove the protecting group to obtain the target compound; furthermore, first introduce a side chain with a piperidine ring or a pyrrole ring at the end on 3-OH, and then couple the NH at the end of the side chain with the quinolone mother ring protected by borate, and remove the protecting group to obtain the target compound.

The present invention also provides a method for preparing the compound shown in the above formula I, comprising the following steps:

Wherein, W, V, X, Y, n1, n2, m1, m2, R ¹ , R ² , Z, Q have the same definitions as above;

R is Ac or Bz.

Beneficial Effects

The invention discloses an erythromycin derivative, which is proved to have excellent 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 preparation method of this series of compounds is simple, so it has certain prospects for industrial synthetic preparation.

Terms and Definitions

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 that are incompatible with the compound, are contemplated for use in the pharmaceutical composition. Supplementary compounds may also be added to the composition.

The present invention also includes prodrugs of the compounds of the present invention, that is, a compound that is administered in a certain structure that is not disclosed but is metabolized or converted into the compounds disclosed in the present invention in the human body, and exerts a pharmacological effect as a pharmacological component. For the present invention, various pharmaceutically acceptable acids can form salts on the nitrogen of the dimethylamino group of 5-O-desaccharamine or the nitrogen of the side chain piperazine in the general formula; the prodrug is esterified on the 3-carboxyl group of the quinolone, such as methyl ester, ethyl ester, isopropyl ester, or other (cyclic) alkyl esters containing heteroatoms, and the ester group is hydrolyzed in vivo to release the active group 3-carboxyl group. Conventional methods for preparing prodrugs are shown in "Design of Prodrugs" (H.Bundgaad, Elsevier, 1985). In a specific embodiment, the prodrug is the ethyl ester of the compound, for example, the prodrug of compound 69a is compound 69p.

In some compounds of the present application, the group definition CH is followed by (R) or (S), which means that the C at that location is a chiral carbon and can form an R or S configuration.

The NMR data of some compounds in the present application are marked with ax or eq, where ax represents an upright bond and eq represents an equatorial bond.

Partial Substituents The ligation sites are indicated.

In this article, 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 article, when an atom, residue, group or part is halogenated, the atom at the halogenated position can be monosubstituted, disubstituted or polysubstituted by a halogen atom up to full substitution, for example "halogenated C _1-12 alkyl" and "halogenated C _1-12 alkoxy".

The term "C _1-12 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably a C _1-6 alkyl group. "C _1-6 alkyl" is understood to mean preferably a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group 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 isomers thereof. In particular, the group has 1, 2 or 3 carbon atoms ("C _1-3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

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 includes 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 cycloalkyl can be a C _3-8 monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a C _7-12 paracyclic cycloalkyl, such as a decalin ring.

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 connected 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]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The ring containing the nitrogen atom 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.

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 a "C _6-14 aryl". The term " _C6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12 carbon atoms (" _C6-14 aryl"), in particular a ring having 6 carbon atoms (" _C6 aryl"), for example phenyl; or biphenyl, or a ring having 9 carbon atoms (" _C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms (" _C10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (" _C13 aryl"), for example fluorenyl, or a ring having 14 carbon atoms (" _C14 aryl"), for example anthracenyl.

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 heteroatoms independently selected from N, O and S. 1 to 3, preferably 1 to 3, heteroatoms which are each independently selected from N, O and S and, in addition, may in each case be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, 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 azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

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

The term "C _1-12 alkoxy" means "-OC _1-12 alkyl", wherein C _1-12 alkyl has the above definition.

The above definition of the term "C _1-12 alkyl" also applies to other terms containing "C _1-12 alkyl", such as the term "halogenated C _1-12 alkyl" or "C _1-12 alkoxy" or "halogenated C _1-12 alkoxy", "NOC _1-12 alkyl", etc.

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.

Pharmaceutically acceptable salts include acid addition salts of compounds of the invention having nitrogen atoms in the chain or ring with sufficient basicity. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: 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, etc. As examples, physiologically/pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

DETAILED DESCRIPTION

The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions 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 included in the scope that the present invention is intended to protect.

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

1. Raw Materials Preparation

1) 9-Methoxyoxime series starting materials The compounds shown below are known compounds. The synthesis method can be found in European Journal of Medicinal Chemistry 59 (2013) 54-63.

2) Preparation of clarithromycin series raw materials

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. 4M HCl solution, ethanol, 45°C.

Synthesis of compound 2

Clarithromycin (20.000g, 26.740mmol), DMAP (3.267g, 26.740mmol), benzoic anhydride (18.148g, 80.219mmol) were dissolved in 150mL of anhydrous tetrahydrofuran, triethylamine (11.12mL, 80.219mmol) was added, stirred at room temperature, and the reaction progress was monitored by TLC. After about 48h of complete reaction, N,N-dimethylethylenediamine (5.84mL, 53.480mmol) was added dropwise under ice bath, and after half an hour of reaction, the reaction solution was concentrated by rotary evaporation, 200mL 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 by rotary evaporation and recrystallized with anhydrous ethanol to obtain 22.440g (23.469mmol, 87.77%) of white crystals.

Synthesis of compound 3

Disperse compound 2 (10.000 g, 10.458 mmol) and CDI (6.783 g, 41.832 mmol) in a mixed solution of THF/DMF (42 mL/15 mL), slowly add 2 mol/L NaHMDS solution (8.37 mL, 16.733 mmol) while stirring, and stir at room temperature for about 2 h after the addition is complete. After the reaction is completed, add 100 mL of ethyl acetate, and then wash with saturated sodium bicarbonate, water, and saturated brine respectively, and spin-dry the organic phase to obtain 10.660 g (10.327 mmol, 98.75%) of white solid.

Synthesis of compound 4

Under ice bath, compound 3 (10.660 g, 10.327 mmol) was dispersed in a mixed solution of THF/DMF (42 mL/15 mL), and 20 mL of concentrated aqueous ammonia was added. Stir under ice bath for 48 h, and transfer to room temperature for reaction for 48 h. After the reaction was complete, 100 mL of ethyl acetate was added, and then washed with saturated sodium bicarbonate, water, and saturated brine respectively. The organic phase was spin-dried and 60 mL of THF was added. Potassium tert-butoxide (1.158 g, 10.327 mmol) was added and reacted at room temperature for 30 min. After the reaction was completed, 100 mL of ethyl acetate was added, and then washed with saturated sodium bicarbonate, water, and saturated brine respectively, and the organic phase was spin-dried. The product was recrystallized from ethanol to obtain a white solid.

The white solid was dispersed in 40 mL of ethanol, and 40 mL of 4M 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 ammonia water, extracted with ethyl acetate, and 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 N ₂ O ₁₁ 719.4223. ¹ H NMR (CDCl ₃ ,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 .77(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＝6.6Hz,10.6Hz,1H,H-3),2.95-2.89(m,1H,H-3′),2.97(s,3H,6-O-CH ₃ ),2.79(q,J＝6.5Hz,1H,H-10),2.64-2.54(m,1H,H-2),2.52-2.42(m,1H,H-8),2.28(s,6H,-N(CH ₃ ) 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-CH ₃ ),1.31-1.24(m,6H,6-CH ₃ ,5′-CH ₃ ),1.22(d,J＝6.8Hz,3H,2-CH ₃ ),1.09(d,J＝6.6Hz,3H,10-CH ₃ ),1.05(d,J＝7.1Hz,3H,8-CH ₃ ),0.81(t,J＝7.4Hz,3H,15-CH ₃ ), 0.71 (d, J=7.4Hz, 3H, 4-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

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

Synthesis of compound 6

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, and 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 moved to room temperature. TLC monitored the reaction progress, and after the reaction was completed, the reaction solution was dried and purified by column chromatography (petroleum ether: ethyl acetate = 6:1). A colorless oily liquid compound 6 was obtained.

Synthesis of compound 7

Compound 6 was dissolved in ethanol, 80% hydrazine hydrate (0.47 mL, 7.770 mmol) was added dropwise, and the mixture was reacted at 80°C for about 1 h. After the reaction was completed, the mixture was filtered, and concentrated hydrochloric acid was added to the filtrate to adjust the pH to 4-5, and the mixture was filtered again. The filtrate was concentrated and ethyl acetate was added for recrystallization to obtain 0.631 g (2.460 mmol, 63.32%) of compound 7. HRMS (ESI) (M+H) ⁺ m/z 402.2198, calculated for C ₂₂ H ₂₉ FN ₃ O ₃ 402.2187. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 8.94 (s, 1H), 7.96 (d, J=13.1 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 3.79 (d, J=12.4 Hz, 2H), 3.63 (dt, J=3.3 Hz, 7.1 Hz, 1H), 3.02-2.84 (m, 2H), 2.66 (t, J=6.8 Hz, 2H), 1.86-1.77 (m, 2H), 1.59-1.13 (m, 9H).

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.

Synthesis of compound 9

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 bath. 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, and the organic phase was spin-dried to obtain compound 9.

General Synthesis Methods of Compounds 18-26

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

Synthesis of compound 18

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

Synthesis of compound 19

Using compound 10 (3.000 g, 13.935 mmol) as raw material according to the general synthesis method, about 3.600 g (13.415 mmol, 96.27%) of compound 19 was obtained.

Synthesis of compound 20

Using compound 11 (2.000 g, 8.721 mmol) as raw material according to the general synthesis method, about 2.400 g (8.853 mmol, 101.52%) of compound 20 was obtained.

Synthesis of compound 21

Using compound 12 (2.000 g, 10.681 mmol) as raw material according to the general synthesis method, about 2.100 g (8.739 mmol, 81.82%) of compound 21 was obtained.

Synthesis of compound 22

Using compound 13 (2.000 g, 10.681 mmol) as raw material according to the general synthesis method, about 2.200 g (9.155 mmol, 85.71%) of compound 22 was obtained.

Synthesis of compound 23

Using compound 14 (2.000 g, 9.937 mmol) as raw material according to the general synthesis method, about 2.640 g (10.380 mmol, 104.46%) of compound 23 was obtained.

Synthesis of compound 24

Using compound 15 (2.000 g, 9.937 mmol) as raw material according to the general synthesis method, about 2.400 g (9.436 mmol, 94.96%) of compound 24 was obtained.

Synthesis of compound 25

Using compound 16 (2.000 g, 9.937 mmol) as raw material according to the general synthesis method, about 2.400 g (9.436 mmol, 94.96%) of compound 25 was obtained.

Synthesis of compound 26

Using compound 17 (2.000 g, 9.937 mmol) as raw material according to the general synthesis method, about 2.500 g (9.830 mmol, 98.92%) of compound 26 was obtained. General synthesis method of compounds 27-35

Compound 18-26 was used as raw material, dissolved in glacial acetic acid and transferred to an autoclave, 0.1 times the mass of PtO ₂ of the raw material was added, and then the air was ventilated, and hydrogen was charged to make the pressure of the reaction system reach 4 atmospheres and reacted at room temperature for 10-15 hours. After the reaction was completed, the filtrate was filtered and 50 mL of dichloromethane was added to the system, and the pH was adjusted to 10 with ammonia water, and then saturated brine was added to wash the organic phase, and the organic phase was spin-dried and column chromatography was performed to obtain the product compound 27-35.

Synthesis of compound 27

Compound 18 (4.312 g, 16.068 mmol) was used as the starting material. After the reaction was completed according to the general synthesis method, column chromatography (dichloromethane: ethanol = 10:0.6) was performed to obtain about 1.028 g (3.982 mmol, 24.78%) of compound 27. HRMS (ESI) (M+H) ⁺ m/z 259.2015, calculated for C ₁₃ H ₂₇ N ₂ O ₃ 259.2016. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.84-3.71 (m, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.44 (tt, J=3.7 Hz, 8.0 Hz, 1H), 3.10 (ddd, J=3.5 Hz, 9.1 Hz, 13.1 Hz, 2H), 2.82 (t, J=6.8 Hz, 2H), 1.90-1.79 (m, 2H), 1.73 (p, J=6.5 Hz, 2H), 1.66-1.48 (m, 6H), 1.47 (s, 9H).

Synthesis of compound 28

Compound 19 (3.600 g, 13.415 mmol) was used as the starting material. After the reaction was completed according to the general synthesis method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.6: 0.1) was performed to obtain about 1.199 g (4.406 mmol, 32.84%) of compound 28. HRMS (ESI) (M+H) ⁺ m/z 273.2167, calculated for C ₁₄ H ₂₉ N ₂ O ₃ 273.2173. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.10 (s, 2H), 3.48 (t, J = 6.2 Hz, 2H), 3.25 (d, J = 6.1 Hz, 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).

Synthesis of compound 29

Compound 20 (2.400 g, 8.853 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.8: 0.1) was performed to obtain about 0.981 g (3.428 mmol, 38.72%) of compound 29. HRMS (ESI) (M+H) ⁺ m/z 287.2327, calculated for C ₁₅ H ₃₁ N ₂ O ₃ 287.2329. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.06 (s, 2H), 3.55-3.37 (m, 4H), 2.80 (t, J=6.8 Hz, 2H), 2.68 (t, J=12.9 Hz, 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).

Synthesis of compound 30

Compound 21 (2.100 g, 8.739 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.7: 0.1) was performed to obtain about 0.923 g (3.781 mmol, 41.30%) of compound 30. HRMS (ESI) (M+H) ⁺ m/z 245.1860, calculated for C ₁₂ H ₂₅ N ₂ O ₃ 245.1860. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.00 (s, 1H), 3.50 (t, J=5.9 Hz, 2H), 3.47-3.27 (m, 4H), 2.79 (t, J=6.8 Hz, 2H), 2.03-1.86 (m, 2H), 1.72 (q, J=6.5 Hz, 2H), 1.46 (s, 9H), 1.32 (s, 2H).

Synthesis of compound 31

Compound 22 (2.200 g, 9.155 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.6: 0.1) was performed to obtain about 0.876 g (3.588 mmol, 39.20%) of compound 31. HRMS (ESI) (M+H) ⁺ m/z 245.1857, calculated for C ₁₂ H ₂₅ N ₂ O ₃ 245.1860. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.07-3.93 (m, 1H), 3.50 (t, J=6.0 Hz, 2H), 3.47-3.28 (m, 4H), 2.79 (t, J=6.8 Hz, 2H), 2.08-1.85 (m, 2H), 1.72 (q, J=6.5 Hz, 2H), 1.49 (s, 2H), 1.46 (s, 9H).

Synthesis of compound 32

Compound 23 (2.640 g, 16.068 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.8: 0.1) was performed to obtain about 0.620 g (2.402 mmol, 14.95%) of compound 32. HRMS (ESI) (M+H) ⁺ m/z 259.2017, calculated for C ₁₃ H ₂₇ N ₂ O ₃ 259.2016. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.50 (t, J=6.2 Hz, 2H), 3.47-3.23 (m, 4H), 3.14-2.98 (m, 1H), 2.79 (t, J=6.8 Hz, 2H), 2.45 (s, 1H), 1.95 (s, 1H), 1.79-1.57 (m, 3H), 1.46 (s, 9H), 1.25 (s, 2H).

Synthesis of compound 33

Compound 24 (2.400 g, 9.436 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.6: 0.1) was performed to obtain about 0.679 g (2.630 mmol, 27.87%) of compound 33. HRMS (ESI) (M+H) ⁺ m/z 259.2015, calculated for C ₁₃ H ₂₇ N ₂ O ₃ 259.2016. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.50 (t, J=6.2 Hz, 2H), 3.48-3.23 (m, 4H), 3.16-2.98 (m, 1H), 2.79 (t, J=6.8 Hz, 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).

Synthesis of compound 34

Compound 25 (2.400 g, 9.436 mmol) was used as the starting material. After the reaction was completed according to the general synthetic method, column chromatography (dichloromethane: ethanol: ammonia water = 10: 0.6: 0.1) was performed to obtain about 0.993 g (3.847 mmol, 40.76%) of compound 34. HRMS (ESI) (M+H) ⁺ m/z 259.2009, calculated for C ₁₃ H ₂₇ N ₂ O ₃ 259.2016. ¹ H NMR (CDCl ₃ , 400 MHz) 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

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

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

Preparation of Compound 100

N-Boc-bromoethylamine (2.000 g, 8.924 mmol) and compound Ar-a (2.957 g, 8.924 mmol) were dissolved in water/DMF = 10 mL: 10 mL, potassium carbonate (4.934 g, 35.698 mmol) was added, and the mixture was reacted at 50°C for 12 hours. After the reaction was completed, ethyl acetate was added, and the mixture was washed with water twice and saturated brine once, and the organic layer was dried to obtain a light yellow solid.

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. The mixture was stirred for about 30 min at room temperature, and 20 mL of ethyl acetate was slowly added while stirring after the reaction was completed. The product 100 was filtered to obtain about 2.684 g (7.168 mmol, 80.32%). HRMS (ESI) (M+H) ⁺ m/z 375.1831, calculated for C ₁₉ H ₂₄ FN ₄ O ₃ 375.1827. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 11.88 (s, 1H), 8.69 (s, 1H), 7.97 (d, J=13.0 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 4.03-3.63 (m, 5H), 3.51 (t, J=6.5 Hz, 4H), 3.41 (dq, J=7.0 Hz, 12.6 Hz, 4H), 1.45-1.26 (m, 2H), 1.26-1.15 (m, 2H).

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

Synthesis of Compound Ar-n

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. Cool in an ice bath, filter and dry to obtain 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 white solid (1.000 g, 2.816 mmol) was added to the reaction system and heated to 105 °C for half an hour. After the reaction was completed, the temperature was slowly cooled to room temperature, and petroleum ether was added to crystallize to obtain compound Ar-n (0.876 g, 1.813 mmol, 41.95%).

2. Preparation of intermediates

Reaction conditions and reagents: a. CDI, DMAP, dichloromethane, room temperature; b. Ethylenediamine or propylenediamine, DMF, room temperature; c. Formic acid, NaNO ₂ , 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.

General Synthesis of Compounds 36 and 37

Compound (1 eq), DMAP (2 eq), CDI (3 eq) were added to a round-bottom flask, and anhydrous dichloromethane was added, and the mixture was reacted at room temperature for 12 h. After the reaction was completed under TLC monitoring, dichloromethane was added, and the mixture was washed with saturated ammonium chloride, saturated sodium bicarbonate, water, and saturated brine in sequence, and the organic phase was dried to obtain a white solid.

Synthesis of compound 36

Compound 1 (2.207 g, 3.213 mmol) was used as the starting material by a general synthetic method and 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 light yellow fluffy solid compound 36.

Synthesis of compound 37

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. General synthesis method of compound 38 and 39

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, and the reaction was carried out for 6 h at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was purified by spin column chromatography to obtain compounds 38 and 39.

Synthesis of compound 38

Compound 37 (1.000 g, 1.230 mmol) and ethylenediamine (0.41 mL, 6.150 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 about 0.670 g (0.956 mmol, 77.72%) of compound 38.

Synthesis of compound 39

Compound 37 (1.200 g, 1.476 mmol) and propylenediamine (0.61 mL, 7.381 mmol) were used according to the general synthesis method, and the product was purified by column chromatography using 100-200 mesh silica gel and a mobile phase of dichloromethane/ethanol/ammonia water = 10/0.8/0.1 to obtain about 0.721 g (1.008 mmol, 68.29%) of compound 39. General synthesis method of compounds 40 and 41

Compound 38 or 39 (1 eq) was dissolved in ethylene glycol (20-100 eq) as a solvent, the system was transferred to -20°C, formic acid (4.5 eq) was added dropwise, and then sodium nitrite (6 eq) was added in batches while stirring, the temperature was maintained overnight for reaction, and then the temperature was slowly raised to room temperature for reaction for 12 hours. After TLC monitoring of the reaction was complete, 20 mL of dichloromethane and 20 mL of distilled water were added to the system, and the organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, respectively, the organic layer was spin-dried, and purified by column chromatography.

Synthesis of compound 40

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) was used to obtain about 0.412 g (0.488 mmol, 51.05%) of compound 40. HRMS (ESI) (M+H) ⁺ m/z 850.4665, calculated for C ₄₃ H ₆₈ N ₃ O ₁₄ 850.4696. ¹ H NMR (CDCl ₃ , 400 MHz) 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=5.1 Hz, 1H, 3-O-CO-NH-CH ₂ ),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,1 H,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,-CH ₂ -OH),3.69(m,1H,H-11),3.67-3.54(m,5H,-CH ₂ -O-CH ₂ -,3-O-CO-NH-CH ₂ ),3.49-3.40(m,2H,H-5′),3.39-3.30(m,1H,3-O-CO-NH-CH ₂ ),2.95(s,3H,6-O-CH ₃ ),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(CH ₃ ) 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-CH ₃ ),1.29-1.21(m,6H,6-CH ₃ ,5′-CH ₃ ), 1.15-1.04 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.4Hz, 3H, 15-CH ₃ ), 0.74 (d, J＝7.4Hz, 3H, 4-CH ₃ ).

Synthesis of compound 41

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) was used to obtain about 0.294 g (0.340 mmol, 33.73%) of compound 41. HRMS (ESI) (M+H) ⁺ m/z 872.4890, calculated for C ₄₆ H ₇₀ N ₃ O ₁₃ 872.4903. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 8.10-8.02 (m, 2H, 2H-Bz), 7.62-7.55 (m, 1H, 2H-Bz), 7.51-7.43 (m, 2H, 2H-Bz), 5.77 (s, 1H, 11-NH), 5.45 (t, J=5.7 Hz, 1H, 3-O-CO-NH-CH ₂ ),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,-CH ₂ -O-CH ₂ -),),3.51-3.39(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.37-3.28(m,1H,3-O-CO-NH-CH ₂ ),2.96(s,3H,6-O-CH ₃ ),2.89-2.70(m,3H,H-3,H-10,H-2),2.55-2.41(m,3H,-CH ₂ -C≡CH,H-8),2.27(s,6H,-N(CH ₃ ) ₂ ),2.05(t,J＝2.6Hz,1H,-CH ₂ -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-CH ₃ ), 1.28-1.23 (m, 6H, 6-CH ₃ , 5′-CH ₃ ), 1.16-1.03 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.4 Hz, 3H, 15-CH ₃ ), 0.74 (d, J＝7.5 Hz, 3H, 4-CH ₃ ). General synthesis method of compounds 42-51

Compound 36 or 37 (1 eq) was dissolved in DMF, and aminoalkyl alcohols (3 eq) of different carbon atom lengths and DBU (1 eq) were added dropwise at room temperature, and the reaction was carried out for 12 h at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was purified by spin column chromatography to obtain the compound.

Synthesis of compound 42

According to the general synthesis 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 raw materials, and the obtained product was purified by column chromatography using 100-200 mesh silica gel and dichloromethane/ethanol/ammonia water = 10/0.3/0.1 to obtain about 0.338 g (0.453 mmol, 70.76%) of light yellow fluffy solid compound 42.

Synthesis of compound 43

According to the general synthesis 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 raw materials, and the obtained product was purified by column chromatography using 100-200 mesh silica gel and dichloromethane/ethanol/ammonia water = 10/0.3/0.1 to obtain about 0.290 g (0.382 mmol, 49.67%) of light yellow fluffy solid compound 43.

Synthesis of compound 44

According to the general synthesis 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 raw materials, and the obtained product was purified by column chromatography using 100-200 mesh silica gel and dichloromethane/ethanol/ammonia water = 10/0.2/0.1 to obtain about 0.332 g (0.429 mmol, 55.79%) of light yellow fluffy solid compound 44.

Synthesis of compound 45

Compound 37 (1.000 g, 1.230 mmol) was used as the starting material, 2-aminoethanol (0.15 mL, 2.460 mmol) was added for reaction, 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 about 0.408 g (0.547 mmol, 44.47%) of compound 45.

Synthesis of compound 46

Compound 37 (0.500 g, 0.615 mmol) was used as the starting material, 3-aminopropanol (0.094 mL, 1.230 mmol) was added for reaction, 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 about 0.282 g (0.371 mmol, 60.32%) of compound 46. HRMS (ESI) (M+H) ⁺ m/z 820.4589, calculated for C ₄₂ H ₆₆ N ₃ O ₁₃ 820.4590. ¹ H NMR (CDCl ₃ , 400 MHz) 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=6.0 Hz, 1H, 3-O-CO-NH-CH ₂ ),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,-CH ₂ -OH),3.70(s,1H,H-11),3.60-3.50(m,1H,3-O-CO-NH-CH ₂ ),3.47-3.38(m,1H,H-5′),3.33-3.24(m,1H,3-O-CO-NH-CH ₂ ),2.96(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),1.99-1.69(m,5H,H-4,H-14eq,H-4′a,-CH ₂ -),1.58-1.36(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH ₃ ),1.29-1.23(m,6H,6-CH ₃ ,5′-CH ₃ ),1.15-1.03(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ), 0.81 (t, J＝7.4Hz, 3H, 15-CH ₃ ), 0.73 (d, J＝7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 47

Compound 37 (0.768 g, 0.945 mmol) was used as the raw material, 4-aminobutanol (0.17 mL, 1.890 mmol) was added for reaction, 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 about 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 N ₃ O ₁₃ 834.4747. ¹ H NMR (CDCl ₃ , 400 MHz) 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,10.9Hz,1H,H-13),5.10(t,J＝6.0Hz,1H,3-O-CO-NH-CH ₂ ),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,-CH ₂ -OH),3.48-3.34(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.23-3.12(m,1H,3-O-CO-NH-CH ₂ ),2.96(s,3H,6-O-CH ₃ ),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(CH ₃ ) 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(-CH ₂ -)),1.58-1.35(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH ₃ ),1.29-1.21(m,6H,6-CH ₃ ,5′-CH ₃ ),1.15-1.02(m,9H,2-CH ₃ ,10-CH _3,8 -CH ₃ ), 0.81 (t, J＝7.3Hz, 3H, 15-CH ₃ ), 0.74 (d, J＝7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 48

Compound 37 (1.317 g, 1.620 mmol) was used as the starting material, 5-aminopentanol (0.34 mL, 3.240 mmol) was added for reaction, 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 about 0.540 g (0.637 mmol, 39.32%) of compound 48. HRMS (ESI) (M+H) ⁺ m/z 848.4902, calculated for C ₄₄ H ₇₀ N ₃ O ₁₃ 848.4903. ¹ H NMR (CDCl ₃ , 400 MHz) 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=2.3 Hz, 10.9 Hz, 1H, H-13), 5.03-4.91 (m, 2H, 3-O-CO-NH-CH ₂ ,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),3.70(s,1H,H-11),3.65(t,J＝6.3Hz,2H,-CH ₂ -OH),3.48-3.32(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.19-3.06(m,1H,3-O-CO-NH-CH ₂ ),2.96(s,3H,6-O-CH ₃ ),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(CH ₃ ) 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(-CH ₂ -)),1.54-1.37(m,6H,H-7a,H-7b,H-14eq,H-4′a,-CH ₂ -),1.31(s,3H,12-CH ₃ ),1.29-1.22(m,6H,6-CH ₃ ,5′-CH ₃ ), 1.15-1.02 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.4Hz, 3H, 15-CH ₃ ), 0.74 (d, J＝7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 49

Compound 37 (0.600 g, 0.738 mmol) was used as the starting material, 6-aminohexanol (0.173 g, 1.476 mmol) was added for reaction, 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 about 0.332 g (0.385 mmol, 52.17%) of compound 49. HRMS (ESI) (M+H) ⁺ m/z 862.5057, calculated for C ₄₅ H ₇₂ N ₃ O ₁₃ 862.5060. ¹ H NMR (CDCl ₃ , 400 MHz) 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=2.3 Hz, 10.9 Hz, 1H, H-13), 4.99 (dd, J=7.6 Hz, 10.4 Hz, 1H, H-2′), 4.90-4.82 (m, 2H, 3-O-CO-NH-CH ₂ ,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,-CH ₂ -OH),3.46-3.30(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.20-3.09(m,1H,3-O-CO-NH-CH ₂ ),2.96(s,3H,6-O-CH ₃ ),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(CH ₃ ) 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,10H,3(-CH ₂ -),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH ₃ ),1.28-1.24(m,6H,6-CH ₃ ,5′-CH ₃ ),1.14-1.04(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.4Hz,3H,15-CH ₃ ),0.74(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 50

Compound 37 (0.600 g, 0.738 mmol) was used as the starting material, 7-aminoheptanol (0.194 g, 1.476 mmol) was added for reaction, 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 compound 50 0.235 g (0.268 mmol, 36.31%). HRMS (ESI) (M+H) ⁺ m/z 876.5218, calculated for C ₄₆ H ₇₄ N ₃ O ₁₃ 876.5216. ¹ H NMR (CDCl ₃ , 400 MHz) 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=2.3 Hz, 10.9 Hz, 1H, H-13), 4.99 (dd, J=7.4 Hz, 10.4 Hz, 1H, H-2′), 4.91-4.82 (m, 2H, 3-O-CO-NH-CH ₂ ,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,-CH ₂ -OH),3.48-3.39(m,1H,H-5′),3.37-3.27(1H,3-O-CO-NH-CH ₂ ),3.20-3.11(m,1H,3-O-CO-NH-CH ₂ ),2.95(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),1.98-1.83(m,2H,H-4,H-14eq),1.80-1.69(m,3H,H-4′a,-CH ₂ -), 1.61-1.34(m,10H,4(-CH ₂ -),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH ₃ ),1.28-1.23(m,6H,6-CH ₃ ,5′-CH ₃ ),1.14-1.03(m,9H,2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J = 7.4Hz, 3H, 15-CH ₃ ), 0.73 (d, J = 7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 51

Compound 37 (0.600 g, 0.738 mmol) was used as raw material, 8-aminooctanol (0.214 g, 1.476 mmol) was added for reaction, 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 0.167 g (0.188 mmol, 25.27%) of compound 51. HRMS (ESI) (M+H) ⁺ m/z 890.5374, calculated for C ₄₇ H ₇₆ N ₃ O ₁₃ 890.5373. ¹ H NMR (CDCl ₃ , 400 MHz) 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=2.3 Hz, 10.9 Hz, 1H, H-13), 4.99 (dd, J=7.5 Hz, 10.5 Hz, 1H, H-2′), 4.91-4.81 (m, 2H, 3-O-CO-NH-CH ₂ ,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,-CH ₂ -OH),3.47-3.38(m,1H,H-5′),3.38-3.27(1H,3-O-CO-NH-CH ₂ ),3.19-3.09(m,1H,3-O-CO-NH-CH ₂ ),2.95(s,3H,6-O-CH ₃ ),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(CH ₃ ) 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(-CH ₂ -),H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH ₃ ),1.28-1.24(m,6H,6-CH ₃ ,5′-CH ₃ ),1.15-1.04(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.73(d,J＝7.5Hz,3H,4-CH ₃ ).

General Synthesis Methods of Compounds 52-62

Dissolve compound 36 or 37 and 1.5eq compound 7 or 27-35 in anhydrous DMF, add DBU and stir at room temperature for 12-18 hours, and monitor the reaction progress by TLC. After the reaction is completed, add 50mL of ethyl acetate, wash three times with water and once with saturated brine, and spin dry the organic phase by column chromatography to obtain the product. Dissolve the product from the previous step in 4mL of ethanol, slowly add 3mL of 12M HCl solution, and react at room temperature for 5-20 minutes. After the reaction is completed, add 50mL of dichloromethane to the system, adjust the pH to 10-11 with ammonia water, and then wash with saturated brine. After separation, spin dry the organic layer by column chromatography to obtain the product.

Synthesis of compound 52

According to the general synthesis method, compound 36 (1.200 g, 1.538 mmol) and compound 27 (0.596 g, 2.308 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 about 0.432 g (0.496 mmol, 32.24%) of compound 52. HRMS (ESI) (M+H) ⁺ m/z 871.5274, calculated for C ₄₃ H ₇₅ N ₄ O ₁₄ 871.5274. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 5.45 (t, J = 5.5 Hz, 1H, 3-O-CO-NH-CH ₂ ), 5.17 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.88-4.80 (m, 2H, H-11, H-3), 4.72 (dd, J = 7.5 Hz, 10.5 Hz, 1H, H-2′), 4.32 (d, J = 7.5 Hz, 1H, H-1′), 3.81 (s, 3H, 9-O-CH ₃ ),3.74(d,J＝3.3Hz,1H,H-5),3.70-3.62(m,1H,H-8),3.62-3.53(m,2H,O-CH ₂ ),3.45-3.21(m,4H,H-5′,3-O-CO-NH-CH ₂ ,-N-(CH ₂ -CH ₂ ) ₂ -CH-),3.08(dt,J＝4.5Hz,12.3Hz,2H,-N-(CH ₂ -CH ₂ ) ₂ ),3.00(s,3H,6-O-CH ₃ ),2.87-2.76(m,1H,H-2),2.70-2.57(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),3.16-3.06(m,3H,-N-(CH ₂ -CH ₂ ) ₂ ,H-3′),2.47(d,J＝6.8Hz,1H,H-10),2.25(s,6H,-N(CH ₃ ) ₂ ),2.11-1.99(m,4H,H-4,2′-OAc),1.99-1.73(m,6H,H-14eq,CH ₂ ,-N-(CH ₂ -CH ₂ ) ₂ ,H-4′a),1.73-1.52(m,6H,H-7a,H-4′a,H-7b,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ),1.48(s,3H,12-CH ₃ ),1.29(s,3H,6-CH ₃ ),1.27-1.17(m,7H,5′-CH ₃ ,H-4′b,2-CH ₃ ),1.14(d,J＝6.8Hz,3H,10-CH ₃ ),0.97-0.89(m,6H,4-CH ₃ ,8-CH ₃ ),0.86(t,J＝7.4Hz,3H,15-CH ₃ ).

Synthesis of compound 53

According to the general synthesis method, compound 37 (1.000 g, 1.230 mmol) and compound 7 (0.631 g, 2.460 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 about 0.231 g (0.256 mmol, 20.81%) of compound 53. HRMS (ESI) (M+H) ⁺ m/z 901.5535, calculated for C ₄₈ H ₇₇ N ₄ O ₁₂ 901.5533. ¹ H NMR (CDCl ₃ , 400 MHz) 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=2.3 Hz, 10.9 Hz, 1H, H-13), 5.00 (dd, J=7.6 Hz, 10.4 Hz, 1H, H-2′), 4.93-4.84 (m, 2H, H-3, 3-O-CO-NH-CH ₂ ),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-CH ₂ ),3.19-3.11(m,1H,3-O-CO-NH-CH ₂ ),3.07(dt,J＝3.3Hz,12.0Hz,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.99(s,3H,6-O-CH ₃ ),2.88-2.70(m,3H,H-3′, H-10,H-2),2.58(dt,J＝2.5Hz,12.0Hz,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.53-2.45(m,1H,H-8),2.29(s,6H,-N(CH ₃ ) ₂ ),2.02-1.85(m,2H,H-4,H-14eq),1.80-1.35(m,11H,H-4′a,2(-CH ₂ -),H-7a,H-7b,H-14eq,-CH-(CH ₂ -CH ₂ ) ₂ ),1.33(s,3H,12-CH ₃ ),1.32-1.22(m,9H,6-CH ₃ ,5′-CH ₃ ,H-4′b,-CH ₂ -),1.15-1.02(m,11H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ,-CH-(CH ₂ -CH ₂ ) ₂ ),0.83(t,J＝7.3Hz,3H,15-CH ₃ ),0.76(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 54

According to the general synthesis method

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 about 0.520 g (0.576 mmol, 46.83%) of compound 54. HRMS (ESI) (M+H) ⁺ m/z 903.53256, calculated for C ₄₇ H ₇₅ N ₄ O ₁₃ 903.53251. ¹ H NMR (CDCl ₃ , 400 MHz) 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=5.5 Hz, 1H, 3-O-CO-NH-CH ₂ ),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-CH ₂ ),3.52-3.36(m,4H,H-5′,3-O-CO-NH-CH ₂ ,-N-(CH ₂ -CH ₂ ) ₂ -CH-),3.35-3.25(m,1H,3-O-CO-NH-CH ₂ ),3.16-3.06(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.98(s,3H,6-O-CH ₃ ),2.90-2.72(m,3H,H-3′,H-10,H-2),2.71-2.60(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.55-2.44(m,1H,H-8),2.30(s,6H,-N(CH ₃ ) ₂ ),2.02-1.73(m,7H,H-4,H-14eq,CH ₂ ,-N-(CH ₂ -CH ₂ ) ₂ ,H-4′a),1.58-1.37(m,6H,H-7a,H-4′a,H-7b,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ),1.33(s,3H,12-CH ₃ ),1.31-1.22(m,7H,6-CH ₃ ,5′-CH ₃ ,H-4′b),1.17-1.04(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.83(t,J＝7.4Hz,3H,15-CH ₃ ),0.76(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 55

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 28 (0.602 g, 2.214 mmol) were used. After the reaction was completed, the BOC protecting group was removed and purified by column chromatography (dichloromethane/ethanol/ammonia water = 10/0.6/0.1) to obtain about 0.300 g (0.327 mmol, 22.16%) of compound 55. HRMS (ESI) (M+H) ⁺ m/z 917.5472, calculated for C ₄₈ H ₇₇ N ₄ O ₁₃ 917.5482. ¹ H NMR (CDCl ₃ , 400 MHz) 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), 5.39 (t, J=5.5 Hz, 1H, 3-O-CO-NH-CH ₂ ),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＝11.0Hz,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-CH ₂ ),3.48-3.39(m,4H,H-5′,3-O-CO-NH-CH ₂ ),3.36-3.23(m,3H,3-O-CO-NH-CH ₂ ,O-CH ₂ ),3.15-3.04(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.96(s,3H,6-O-CH ₃ ),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-(CH ₂ -CH ₂ ) ₂ ),2.54-2.42(m,1H,H-8),2.28(s,6H,-N(CH ₃ ) ₂ ),1.99-1.78(m,4H,H-4,H-14eq,CH,H-4′a),1.78-1.68(m,4H,-N-(CH ₂ -CH ₂ ) ₂ ,CH ₂ ),1.64(s,1H,NH),1.56-1.35(m,4H,H-7a,H-4′a,H-7b,H-14eq),1.31(s,3H,12-CH ₃ ),1.29-1.23(m,6H,6-CH ₃ ,5′-CH ₃ ),1.23-1.14(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),1.14-1.03(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.74(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 56

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 29 (0.629 g, 2.214 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 about 0.334 g (0.358 mmol, 24.25%) of compound 56. HRMS (ESI) (M+H) ⁺ m/z 931.5648, calculated for C ₄₉ H ₇₉ N ₄ O ₁₃ 931.5638. ¹ H NMR (CDCl ₃ , 400 MHz) δ: 8.09-8.00 (m, 2H, 2H-Bz), 7.62-7.54 (m, 1H, H-Bz), 7.50-7.41 (m, 2H, 2H-Bz), 5.78 (s, 1H, 11-NH), 5.34 (t, J=5.6 Hz, 1H, 3-O-CO-NH-CH ₂ ),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,CH ₂ OCH ₂ ,H-5′,3-O-CO-NH-CH ₂ ),3.33-3.21(m,1H,3-O-CO-NH-CH ₂ ),3.11-3.02(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.97(s,3H,6-O-CH ₃ ), 2.87-2.70(m,3H,H-3′,H-10,H-2),2.66-2.53(m,2H,-N-(CH ₂ -CH ₂ ) ₂ ),2.53-2.41(m,1H,H-8),2.28(s,6H,-N(CH ₃ ) ₂ ),1.99-1.61(m,9H,H-4,H-14eq,CH,H-4′a,2(CH ₂ ),H-7a,),1.61-1.36(m,7H,-N-(CH ₂ -CH ₂ ) ₂ CH,NH,H-4′a,H-7b,H-14eq),1.32(s,3H,12-CH ₃ ),1.30-1.22(m,6H,6-CH ₃ ,5′-CH ₃ ),1.23-1.03(m,11H,-N-(CH ₂ -CH ₂ ) ₂ ,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.75(d,J＝7.4Hz,3H,4-CH ₃ ).

Synthesis of compound 57

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 30 (0.540 g, 2.214 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 about 0.382 g (0.430 mmol, 29.13%) of compound 57. HRMS (ESI) (M+H) ⁺ m/z 889.5169, calculated for C ₄₆ H ₇₃ N ₄ O ₁₃ 889.5169. ¹ H NMR (CDCl ₃ , 400 MHz) 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, 1H, 11-NH), 5.36 (t, J=5.6 Hz, 1H, 3-O-CO-NH-CH ₂ ), 5.18 (dd, J = 2.2 Hz, 10.9 Hz, 1H, H-13), 4.99 (dd, J = 7.4 Hz, 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-CH ₂ , 2H-tetrahydropyrrole), 3.29-3.18 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.15-2.99 (m, 2H, H-5′, H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH ₃ ), 2.94-2.70 (m, 5H, 3-O-CO-NH-CH ₂ , H-tetrahydropyrrole, H-10, H-2, H-3′), 2.52-2.41 (m, 1H, H-8), 2.28 (s, 6H, -N(CH ₃ ) ₂ ), 2.08-1.98 (m, 2H, CH ₂ ),1.97-1.70(m,6H,H-4,H-14eq,2H-tetrahydropyrrole,H-4′a,H-7a),1.59-1.36(m,4H,NH,H-4′a,H-7b,H-14eq),1.31(s,3H,12-CH ₃ ),1.29-1.22(m,6H,6-CH ₃ ,5′-CH ₃ ),1.17-1.03(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.75(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 58

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 31 (0.540 g, 2.214 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 about 0.400 g (0.450 mmol, 30.48%) of compound 58. HRMS (ESI) (M+H) ⁺ m/z 889.5166, calculated for C ₄₆ H ₇₃ N ₄ O ₁₃ 889.5169. ¹ H NMR (CDCl ₃ , 400 MHz) 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, 1H, 11-NH), 5.41 (t, J=5.6 Hz, 1H, 3-O-CO-NH-CH ₂ ), 5.18 (dd, J = 2.2 Hz, 10.9 Hz, 1H, H-13), 4.99 (dd, J = 7.4 Hz, 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-CH ₂ , 2H-tetrahydropyrrole), 3.29-3.19 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.18-2.99 (m, 2H, H-5′, H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH ₃ ), 2.94-2.70 (m, 5H, 3-O-CO-NH-CH ₂ , H-tetrahydropyrrole, H-10, H-2, H-3′), 2.53-2.40 (m, 1H, H-8), 2.28 (s, 6H, -N(CH ₃ ) ₂ ), 2.08-1.98 (m, 2H, CH ₂ ),1.97-1.71(m,6H,H-4,H-14eq,2H-tetrahydropyrrole,H-4′a,H-7a),1.61-1.35(m,4H,NH,H-4′a,H-7b,H-14eq),1.32(s,3H,12-CH ₃ ),1.29-1.21(m,6H,6-CH ₃ ,5′-CH ₃ ),1.15-1.02(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.75(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 59

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 32 (0.578 g, 2.214 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 about 0.200 g (0.221 mmol, 14.97%) of compound 59. HRMS (ESI) (M+H) ⁺ m/z 903.5338, calculated for C ₄₇ H ₇₅ N ₄ O ₁₃ 903.5325. ¹ H NMR (CDCl ₃ , 400 MHz) 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=5.3 Hz, 1H, 3-O-CO-NH-CH ₂ ),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,1H,H-1′),3.83(d,J＝3.2Hz,1H,H-5),3.69(s,1H,H-11),3.56(t,J＝5.7Hz,2H,O-CH ₂ ),3.50-3.38(m,3H,H-5′,O-CH ₂ ),3.39-3.32(m,1H,H-tetrahydropyrrole),3.30-3.20(m,1H,3-O-CO-NH-CH ₂ ), 3.14-2.99 (m, 2H, 3-O-CO-NH-CH ₂ , H-tetrahydropyrrole), 2.96 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 1.99-1.72 (m, 6H, H-4, H-14eq, H-tetrahydropyrrole, H-4′a, CH ₂ ), 1.58-1.36 (m, 5H, NH, H-7a, H-4′a, H-7b, H-14eq), 1.31 (s, 3H, 12-CH ₃ ), 1.29-1.22 (m, 6H, 6-CH ₃ , 5′-CH ₃ ), 1.16-1.01 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.4Hz, 3H, 15-CH ₃ ), 0.75 (d, J＝7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 60

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 33 (0.578 g, 2.214 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 about 0.328 g (0.363 mmol, 24.60%) of compound 60. HRMS (ESI) (M+H) ⁺ m/z 903.5327, calculated for C ₄₇ H ₇₅ N ₄ O ₁₃ 903.5325. ¹ H NMR (CDCl ₃ , 400 MHz) 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=5.6 Hz, 1H, 3-O-CO-NH-CH ₂ ),5.18(dd,J＝2.3Hz,10.9Hz,1H,H-13),5.00(dd,J＝7.4Hz,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),3.56(t,J＝5.8Hz,2H,O-CH ₂ ),3.51-3.41(m,3H,H-5′,O-CH ₂ ),3.39-3.32(m,2H,H-tetrahydropyrrole),3.31-3.20(m,1H,3-O-CO-NH-CH ₂ ), 3.12-2.99 (m, 2H, 3-O-CO-NH-CH ₂ , H-tetrahydropyrrole), 2.97 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 1.98-1.71 (m, 6H, H-4, H-14eq, H-tetrahydropyrrole, H-4′a, CH ₂ ), 1.61-1.34 (m, 5H, NH, H-7a, H-4′a, H-7b, H-14eq), 1.31 (s, 3H, 12-CH ₃ ),1.29-1.21(m,6H,6-CH ₃ ,5′-CH ₃ ),1.15-1.00(m,9H,2-CH ₃ ,10-CH ₃ ,8-CH ₃ ),0.81(t,J＝7.3Hz,3H,15-CH ₃ ),0.75(d,J＝7.5Hz,3H,4-CH ₃ ).

Synthesis of compound 61

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 34 (0.571 g, 2.214 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 about 0.368 g (0.407 mmol, 27.57%) of compound 61. HRMS (ESI) (M+H) ⁺ m/z 903.5330, calculated for C ₄₇ H ₇₅ N ₄ O ₁₃ 903.5325. ¹ H NMR (CDCl ₃ , 400 MHz) 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, 1H, 11-NH), 5.69 (t, J=5.6 Hz, 1H, 3-O-CO-NH-CH ₂ ),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-CH ₂ ),3.54-3.38(m,2H,3-O-CO-NH-CH ₂ ,H-5′),3.37-3.31(m,1H,CH),3.30-3.22(m,1H,3-O-CO-NH-CH ₂ ), 3.12-3.05 (m, 1H, H-piperidinyl), 2.97 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 1.98-1.71 (m, 8H, CH ₂ , 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-CH ₃ ), 1.30-1.22 (m, 6H, 6-CH _3,5′ -CH ₃ ), 1.16-1.01 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.3Hz, 3H, 15-CH ₃ ), 0.74 (d, J＝7.5Hz, 3H, 4-CH ₃ ).

Synthesis of compound 62

According to the general synthesis method, compound 37 (1.200 g, 1.476 mmol) and compound 35 (0.571 g, 2.214 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 about 0.391 g (0.433 mmol, 29.33%) of compound 62. HRMS (ESI) (M+H) ⁺ m/z 903.5329, calculated for C ₄₇ H ₇₅ N ₄ O ₁₃ 903.5325. ¹ H NMR (CDCl ₃ , 400 MHz) 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=5.7 Hz, 1H, 3-O-CO-NH-CH ₂ ),5.77(s,1H,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＝11.0 Hz,1H,H-3),4.31(d,J＝7.5Hz,1H,H-1′),3.84(d,J＝3.2Hz,1H,H-5),3.69(s,1H,H-11),3.60(t,J＝3.6Hz,2H,O-CH ₂ ),3.49-3.40(m,2H,3-O-CO-NH-CH ₂ , H-5′), 3.39-3.33 (m, 1H, CH), 3.33-3.26 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.07-3.00 (m, 1H, H-piperidinyl), 2.97 (s, 3H, 6-O-CH ₃ ), 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 3H, -N(CH ₃ ) ₂ ), 2.11-1.71 (m, 8H, CH ₂ , 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-CH ₃ ), 1.29-1.22 (m, 6H, 6-CH ₃ , 5′-CH ₃ ), 1.16-1.02 (m, 9H, 2-CH ₃ , 10-CH ₃ , 8-CH ₃ ), 0.81 (t, J＝7.3 Hz, 3H, 15-CH ₃ ), 0.75 (d, J＝7.5 Hz, 3H, 4-CH ₃ ).

3. Preparation of compounds of general formula

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

General Synthesis Method of Compound 63 and 64 Series

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 about 10-20 min. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was washed with water twice and with saturated brine once. The organic phase was spin-dried and purified by column chromatography.

Disperse the intermediate (1 eq) and the quinolone with piperazine (5 eq) in anhydrous acetonitrile and stir at 70°C for 72 h. After the reaction is completed, spin dry the reaction solution, add 50 mL of dichloromethane, wash with water 3 times, and wash with saturated brine once. Spin dry the organic phase, add 20 mL of methanol and reflux to remove the protecting group. After the reaction is completed, monitor the reaction by TLC and spin dry the reaction solution and purify it by column chromatography.

Synthesis of compound 63a

According to the synthesis method, compound 40 (0.412 g, 0.488 mmol) and methanesulfonyl chloride (0.044 mL, 0.533 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: petroleum ether/dichloromethane/ethanol/ammonia water = 7/3/0.05/0.05) was performed to obtain about 0.253 g (0.253 mmol, 51.84%) of compound 87.

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 the general formula compound 63a. Melting point: 162.3-165.8°C. HRMS (ESI) (M+H) ⁺ m/z 1059.5662, calculated for C ₅₃ H ₈₀ FN ₆ O ₁₅ 1059.5660. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₂ -CH ₂ -piperazinyl), 3.62-3.48 (m, 5H, 1H-cyclopropyl, 3-O-CO-NH-CH ₂ -CH ₂ ), 3.47-3.31 (m, 5H, H-5′, 4H-piperazinyl), 3.29-3.22 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.18 (dd, J = 7.3 Hz, 10.0 Hz, 1H, H-2'), 2.98 (s, 3H, 6-O-CH ₃ ), 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-CH ₂ -CH ₂ -piperazinyl), 2.57-2.38 (m, 2H, H-8, H-3'), 2.30 (s, 6H, -N(CH ₃ ) 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-CH ₃ , 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH ₃ , H-4′b, 5′-CH ₃ , 2H-cyclopropyl), 1.17-1.07 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.83 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.63,177.11,174.33,167.00,158.42,156.48,147.43,139.11,108.17, 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.

Synthesis of compound 64a

According to the synthesis method, compound 41 (0.294 g, 0.340 mmol) and methanesulfonyl chloride (0.029 mL, 0.357 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: petroleum ether/dichloromethane/ethanol/ammonia water = 3/7/0.1/0.05) was performed to obtain about 0.233 g (0.247 mmol, 72.60%) of compound 88.

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/ammonia water = 10/1/0.5) was performed to obtain about 41.7 mg (0.0388 mmol, 15.73%) of the general formula compound 64a. Melting point: 163.6-164.7°C. HRMS (ESI) (M+H) ⁺ m/z 1073.5814, calculated for C ₅₄ H ₈₂ FN ₆ O ₁₅ 1073.5817. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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 = 7.2 Hz, 1H, H-1′), 3.85-3.73 (m, 2H, H-5, H-11), 3.68-3.51 (m, 4H, -CH ₂ -O-CH ₂ -CH ₂ -piperazinyl)), 3.48-3.27 (m, 7H, H-5′, 1H-cyclopropyl, 4H-piperazinyl, 3-O-CO-NH-CH ₂ -), 3.25-3.13 (m, 2H, H-2′, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.93-2.79 (m, 2H, H-10, H-2), 2.79-2.62 (m, 6H, 4H-piperazinyl, -O-CH ₂ -CH ₂ -piperazinyl), 2.58-2.39 (m, 2H, H-8, H-3′), 2.28 (s, 6H, -N(CH ₃ ) ₂ ), 2.12-2.01 (m, 1H, H-4), 1.98-1.86 (m, 1H, H-14eq), 1.85-1.71 (m, 3H, H-7a, -CH ₂ -), 1.69-1.49 (m, 3H, H-7b, H-14eq, H-4′a), 1.47-1.35 (m, 5H, 12-CH ₃ ,2H-cyclopropyl), 1.31-1.17 (m,9H,6-CH ₃ ,H-4′b,5′-CH ₃ ,2H-cyclopropyl), 1.18-1.06 (m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.83 (t, J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.62,177.05,174.37,166.96,158.40,156.43,152.37,147.37,139.11,119.72, 112.43,112.20,108.10,104.77,103.15,83.88,81.46,78.09,77.88,77.25,75.76,70.48,69.4 5,69.26,68.44,66.05,58.11,57.63,53.16,52.84,49.81,49.68,45.29,43.38,40.31,39.13,3 7.27,35.83,35.31,29.69,22.03,21.19,19.29,18.27,15.06,13.84,13.27,10.23,9.10,8.23.

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.

General Synthesis Method of Compounds 65-73 Series

Compounds 42-44, 46-51 (1 eq) were dissolved in 20 mL of dichloromethane, and triethylamine (2 eq) was added. Methanesulfonyl chloride (1.5 eq) was added dropwise at room temperature, or p-toluenesulfonyl chloride (2 eq) was added and stirred for about 10-20 min. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was washed with water twice and with saturated brine once. The organic phase was spin-dried and purified by column chromatography.

Disperse the intermediate (1 eq) and the quinolone with piperazine (5 eq) in anhydrous acetonitrile and stir at 70°C for 72 h. After the reaction is completed, spin dry the reaction solution, add 50 mL of dichloromethane, wash with water 3 times, and wash with saturated brine once. Spin dry the organic phase, add 20 mL of methanol and reflux to remove the protecting group. After the reaction is completed, monitor the reaction by TLC and spin dry the reaction solution and purify it by column chromatography.

Synthesis of compound 65a

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 white fluffy solid compound 89.

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/ammonia water = 10/1/0.5) to obtain about 71.5 mg (0.0675 mmol, 31.11%) of white fluffy solid compound 65a. Melting point: 182.9-184.0°C. HRMS (ESI) (M+H) ⁺ m/z 1059.5666, calculated for C ₅₃ H ₈₀ FN ₆ O ₁₅ 1059.5660. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₃ ), 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-CH ₂ , 4H-piperazinyl), 3.25-3.15 (m, 1H, H-2′, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ),2.88-2.80(m,1H,H-2),2.75-2.62(m,4H,4H-piperazinyl),2.60-2.51(m,2H,-CH ₂ -piperazinyl),2.50-2.37(m,2H,H-3′,H-10)2.30(s,6H,-N(CH ₃ ) ₂ ),2.11-2.02(m,1H,H-4),1.94-1.85(m,1H,H-14eq),1.84-1.70(m,2H,CH ₂ ),1.70-1.62(m,1H,H-4′a),1.60-1.50(m,1H,H-14ax)1.47(s,3H,12-CH ₃ ), 1.45-1.34 (m, 3H, 2H-cyclopropyl, H-4′b), 1.33 (s, 3H, 6-CH ₃ ), 1.30-1.17 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH ₃ , 10-CH ₃ ), 1.15 (d, J＝6.8 Hz, 3H, 2-CH ₃ ), 1.06 (d, J＝7.5 Hz, 3H, 4-CH ₃ ), 0.94 (d, J＝7.0 Hz, 3H, 8-CH ₃ ), 0.85 (t, J＝7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:177.06,174.05,167.00,164.54,156.35,154.66,147.41,139.10 ,104.88,84.99,83.19,78.36,77.27,75.49,70.46,69.49,66.25,61.42,56.4 4,52.84,49.82,43.42,40.39,37.32,35.99,35.36,32.72,29.69,28.66,26.4 4,25.60,22.22,21.21,19.34,18.86,15.59,14.97,13.02,10.18,8.96,8.25.

Synthesis of compound 66a

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 white fluffy solid compound 90.

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, dichloromethane/methanol/ammonia water = 10/1/0.5 developing solvent) to obtain about 72.6 mg (0.0676 mmol, 32.52%) of white fluffy solid compound 66a. Melting point: 185.4-186.2°C. HRMS (ESI) (M+H) ⁺ m/z 1073.5828, calculated for C ₅₄ H ₈₂ FN ₆ O ₁₅ 1073.5817. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),5.18(dd,J＝2.6Hz,10.5Hz,1H,H-13),4.90(d,J＝11.1Hz,1H,H-3),4.87(s,1H,H-11),4.04(d,J＝7.2Hz,1H,H-1′),3.83(s,3H,9-O-CH ₃ ),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-CH ₂ , 4H-piperazinyl), 3.24-3.16 (m, 1H, H-2′), 3.15-3.06 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl), 2.30 (s, 6H, -N(CH ₃ ) ₂ ), 2.13-2.04 (m, 1H, H-4), 1.95-1.83 (m, 1H, H-14eq), 1.73-1.53 (m, 6H, 2(-CH ₂ -), H-4'a, H-14ax), 1.49 (s, 3H, 12-CH ₃ ), 1.46-1.36 (m, 3H, 2H-cyclopropyl, H-4'b), 1.34 (s, 3H, 6-CH ₃ ), 1.31-1.19 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5'-CH ₃ , 10-CH ₃ ), 1.16 (d, J＝6.8 Hz, 3H, 2-CH ₃ ), 1.07 (d, J＝7.6 Hz, 3H, 4-CH ₃ ), 0.94 (d, J＝7.0 Hz, 3H, 8-CH ₃ ), 0.84 (t, J＝7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:174.04,167.02,164.49,154.66,147.42,139.12,112.56,108.19 ,104.78,84.98,83.20,78.34,77.25,75.46,70.44,69.45,66.23,61.43,57.8 6,52.80,49.83,43.37,41.07,40.40,37.34,35.98,35.32,32.72,28.10,25.6 0,24.22,22.24,21.21,19.33,18.87,15.61,14.96,13.03,10.21,9.05,8.25.

Synthesis of compound 66g

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.

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, dichloromethane/methanol/ammonia water = 10/0.9/0.5 developing solvent) to obtain white fluffy solid compound 66g (about 13.9 mg) (0.0129 mmol, 5.18%). Melting point: 165.6-165.9°C. HRMS (ESI) (M+2H) ²⁺ m/z (z＝2) 537.7910, calculated for C ₅₃ H ₈₂ FN ₇ O ₁₅ 537.7921. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),5.18(dd,J＝2.5Hz,10.7Hz,1H,H-13),4.89(d,J＝11.2Hz,1H,H-3),4.87(s,1H,H-11),4.03(d,J＝7.3Hz,1H,H-1′), 3.99-3.91 (m, 4H, 4H-piperazinyl), 3.83 (s, 3H, 9-O-CH ₃ ), 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-CH ₂ ), 3.21 (dd, J=7.3 Hz, 10.1 Hz, 1H, H-2′), 3.15-3.08 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ),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,-CH ₂ -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(-CH ₂ -),H-4′a,H-14ax),1.49(s,3H,12-CH ₃ ),1.44-1.36(m,1H,H-4′b),1.34(s,3H,6-CH ₃ ), 1.30-1.19 (m, 10H, H-7a, H-7b, 5′-CH ₃ , 2H-cyclopropyl, 10-CH ₃ ), 1.16 (d, J＝6.8Hz, 3H, 2-CH ₃ ), 1.09 (d, J＝4.2Hz, 2H, 2H-cyclopropyl), 1.08 (d, J＝7.4Hz, 3H, 4-CH ₃ ), 0.94 (d, J＝7.0Hz, 3H, 8-CH ₃ ), 0.87 (t, J＝7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:177.15,174.00,166.81,164.48,154.65,146.55,120.24,108.9 7,84.98,83.21,78.34,78.34,77.24,75.55,70.44,61.44,57.84,53.00,49 .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.

Synthesis of compound 66h

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.

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, dichloromethane/methanol/ammonia water = 10/1/0.5 developing solvent) to obtain about 17.8 mg (0.0161 mmol, 9.01%) of white fluffy solid compound 66h. Melting point: 153.0-154.1°C. HRMS (ESI) (M+H) ⁺ m/z 1103.5912, calculated for C ₅₅ H ₈₄ FN ₆ O ₁₆ 1103.5922. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₃ ), 3.79 (s, 3H, O-CH ₃ ), 3.78 (d, J = 3.0 Hz, 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-CH ₂ ), 3.21 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2'), 3.16-3.09 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ), 2.89-2.81 (m, 1H, H-2), 2.62 (br, 4H, 4H-piperazinyl), 2.53-2.40 (m, 4H, H-3', H-10, -CH ₂ -piperazinyl), 2.31 (s, 6H, -N(CH ₃ ) ₂ ), 2.12-2.04 (m, 1H, H-4), 1.96-1.87 (m, 1H, H-14eq), 1.72-1.53 (m, 6H, 2(-CH ₂ 1H, 14-CH 3 ), 1.50 (s, 3H, 12-CH ₃ ), 1.43-1.35 (m, 1H, H-4′b), 1.34 (s, 3H, 6-CH ₃ ), 1.31-1.19 (m, 10H, H-7a, H-7b, 5′-CH ₃ , 2H-cyclopropyl, 10-CH ₃ ), 1.17 (d, J＝6.8 Hz, 3H, 2-CH ₃ ), 1.08 (d, J＝7.5 Hz, 3H, 4-CH ₃ ), 1.01 (d, J＝4.0 Hz, 2H, 2H-cyclopropyl), 0.94 (d, J＝7.0 Hz, 3H, 8-CH ₃ ), 0.87 (t, J＝7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:177.05,174.05,166.73,164.51,156.40,154.67,149.94,145.38,139.44,133.92,121 .90,108.41,108.17,107.82,103.30,85.00,83.21,81.32,78.34,78.15,77.24,75.53,70.46,69.4 6,66.19,62.33,61.44,58.12,53.79,50.66,49.81,43.40,41.07,40.54,40.37,37.35,36.00,32.7 3,28.70,28.04,25.60,24.24,22.25,21.23,19.34,18.86,15.61,14.97,13.04,10.20,9.56,8.98.

Synthesis of compound 66i

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.

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, dichloromethane/methanol/ammonia water = 10/1/0.5 developing solvent) to obtain about 19.0 mg (0.0174 mmol, 9.74%) of white fluffy solid compound 66i. Melting point: 163.7-163.9°C. HRMS (ESI) (M+H) ⁺ m/z 1089.5768, calculated for C ₅₄ H ₈₂ FN ₆ O ₁₆ 1089.5766. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),5.18(dd,J＝2.5Hz,10.8Hz,1H,H-13),4.90(d,J＝11.0Hz,1H,H-3),4.87(s,1H,H-11),4.55(s,1H,N-CH),4.47(d,J＝12.3Hz,O-CH ₂ -),4.37(d,J＝11.3Hz,O-CH ₂ -),4.05(d,J＝7.3Hz,1H,H-1′),3.83(s,3H,9-O-CH ₃ ), 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-CH ₂ ), 3.21 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2'), 3.17-3.10 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl),2.31(s,6H,-N(CH ₃ ) ₂ ),2.12-2.05(m,1H,H-4),1.96-1.87(m,1H,H-14eq),1.72-1.53(m,9H,2(-CH ₂ -),H-4′a,H-14ax,N-CH-CH ₃ ),1.50(s,3H,12-CH ₃ ),1.45-1.36(m,1H,H-4′b),1.34(s,3H,6-CH ₃ ),1.30-1.20(m,8H,H-7a,H-7b,5′-CH ₃ ,10-CH ₃ ),1.17(d,J＝6.8Hz,3H,2-CH ₃ ), 1.08 (d, J = 7.5Hz, 3H, 4-CH ₃ ), 0.94 (d, J = 7.0Hz, 3H, 8-CH ₃ ), 0.87 (t, J = 7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:177.14,174.08,167.14,164.52,156.38,154.67,144.68,139.34,133.06,124.72,10 7.90,105.46,105.22,103.22,85.01,83.22,81.17,78.34,78.06,78.06,77.24,75.51,70.44,69 .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.

Synthesis of compound 67a

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.

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, dichloromethane/methanol/ammonia water = 10/1/0.5 developing solvent) to obtain about 68.5 mg (0.0630 mmol, 27.27%) of white fluffy solid compound 67a. Melting point: 153.9-154.5°C. HRMS (ESI) (M+H) ⁺ m/z 1087.5970, calculated for C ₅₅ H ₈₄ FN ₆ O ₁₅ 1087.5973. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),4.91-4.81(m,2H,H-3,H-11),4.02(br,1H,H-1′),3.82(s, 3H, 9-O-CH ₃ ), 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-CH ₂ ), 3.23-3.17 (m, 1H, H-2′), 3.12-3.05 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.03 (s, 3H, 6-O-CH ₃ ), 2.90-2.80 (m, 1H, H-2), 2.75-2.58 (m, 4H, 4H-piperazinyl), 2.53-2.38 (m, 4H, -CH ₂ -piperazinyl, H-3′, H-10), 2.30 (s, 6H, -N(CH ₃ ) 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(-CH ₂ -), H-14ax), 1.49 (s, 3H, 12-CH ₃ ), 1.46-1.36 (m, 5H, 2H-cyclopropyl, H-4′b, CH ₂ ), 1.33 (s, 3H, 6-CH ₃ ), 1.30-1.18 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH ₃ , 10-CH _{3 13 C NMR ​} ^​ _​ ,100MHz)δ:177.10,174.08,167.04,164.56,154.67,152.43,147.41,139.11, 108.15,104.76,85.03,83.21,78.34,77.25,75.50,70.47,61.42,58.30,52.8 7,49.83,43.35,41.06,40.37,37.33,35.97,35.30,32.72,30.10,26.47,25.6 1,24.63,22.23,21.21,19.33,18.87,15.61,14.91,13.02,10.20,8.94,8.25.

Synthesis of compound 68a

According to the synthesis method, compound 46 (0.282 g, 0.371 mmol) and methanesulfonyl chloride (0.033 mL, 0.408 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.241 g (0.268 mmol, 72.24%) of compound 92.

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 the general formula compound 68a. Melting point: 162.2-164.4°C. HRMS (ESI) (M+H) ⁺ m/z 1029.5548, calculated for C ₅₂ H ₇₈ FN ₆ O ₁₄ 1029.5555. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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), 4.06 (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-CH ₂ ), 3.24-3.12 (m, 2H, H-2′, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.93-2.80 (m, 2H, H-10, H-2), 2.69 (s, 4H, 4H-piperazinyl), 2.60-2.46 (m, 3H, H-8, -CH ₂ -piperazinyl), 2.46-2.37 (m, 1H, H-3′), 2.30 (s, 6H, -N(CH ₃ ) ₂ ), 2.11-2.01 (m, 1H, H-4), 1.97-1.85 (m, 1H, H-14eq), 1.84-1.72 (m, 3H, -CH ₂ -CH ₂ -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-CH ₃ , 2H-cyclopropyl), 1.32-1.21 (m, 7H, 6-CH ₃ , H-4′b, 5′-CH ₃ ), 1.21-1.18 (m, 2H, 2H-cyclopropyl), 1.17-1.07 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.64,174.36,167.05,158.43,156.34,147.47,108.19,83.87,77.87,77.24,75.82,70.49,66.24,58.13,56.38,52.85,49 .83,45.29,43.44,40.36,40.17,39.13,37.30,35.82,35.34,29.70, 22.04,21.22,19.32,18.27,15.09,13.88,13.31,10.25,9.10,8.27.

Synthesis of compound 69a

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.210 g (0.231 mmol, 58.78%) of compound 93.

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/ammonia water = 10/1/0.5) was performed to obtain about 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 for C ₅₃ H ₈₀ FN ₆ O ₁₄ 1043.5711. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₂ ), 3.23-3.15 (m, 1H, H-2′), 3.14-3.04 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.94-2.79 (m, 2H, H-10, H-2), 2.68 (s, 4H, 4H-piperazinyl), 2.56-2.37 (m, 4H, H-8, -CH ₂ -piperazinyl, H-3′), 2.29 (s, 6H, -N(CH ₃ ) 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, 7H, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH ₃ ), 1.40 (br, 2H, 2H-cyclopropyl), 1.32-1.18 (m, 9H, 6-CH ₃ , H-4′b, 5′-CH ₃ , 2H-cyclopropyl), 1.18-1.04 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.62,177.13,174.35,167.00,158.41,156.37,147.43,139.11,112.56,11 2.32,108.18,104.78,103.19,83.87,81.67,78.19,77.85,77.24,75.82,70.46,69.51,66 .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.

Synthesis of compound 69b

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.210 g (0.231 mmol, 58.78%) of compound 93.

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/ammonia water = 10/1/0.5) was performed to obtain about 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 for C ₅₂ H ₈₀ FN ₆ O ₁₄ 1031.5711. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),5.23(dd,J＝2.3Hz,10.9Hz,1H,H-13),4.93(d,J＝11.0Hz,1H,H-3),4.35(br,2H,N-CH ₂ CH ₃ ), 4.05 (d, J = 7.2 Hz, 1H, H-1'), 3.80 (d, J = 2.9 Hz, 1H, H-5), 3.77 (s, 1H, H-11), 3.44-3.29 (m, 6H, H-5', 4H-piperazinyl, 3-O-CO-NH-CH ₂ ), 3.19 (dd, J = 7.2 Hz, 10.1 Hz, 1H, H-2'), 3.13-3.03 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.94-2.79 (m, 2H, H-10, H-2), 2.68 (s, 4H, 4H-piperazinyl), 2.56-2.38 (m, 4H, H-8, -CH ₂ 2-CH 3 ), 1.26 (s, 3H, 10-CH ₃ ), 1.13 (s, 4H, -CH ₃ ), 1.25 (s, 5H, -CH 3 ), 1.19 (s, 1H, -CH 3 ), 1.30 (s, 6H, -N(CH 3 ) 2 ), 2.11-2.01 (m, 1H, H-4), 1.96-1.86 (m, 1H, H-14eq), 1.82-1.72 (m, 1H, H-7a), 1.71-1.48 (m, 10H, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a, N-CH ₂ CH ₃ ), 1.42 (s, 3H, 12-CH ₃ ), 1.28 (s, 3H, 6-CH ₃ ), 1.23 (d, J＝6.1 Hz, 3H, 5′-CH ₃ ), 1.19 (s, 13H, H-4′b, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J = 7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.63,176.99,174.37,167.22,158.43,156.37,154.78,152.28,147.15,146.05,145. 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. 80,70.47,69.49,66.26,58.13,57.82,52.76,49.81,49.75,45.29,43.39,41.08,40.37,39.11,37.2 9,35.79,28.68,28.05,24.23,22.04,21.22,19.31,18.27,15.06,14.49,13.87,13.31,10.26,9.20.

Synthesis of compound 69c

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

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 about 58.8 mg (0.0578 mmol, 38.54%) of compound 69c. HRMS (ESI) (M+2H) ²⁺ m/z (z＝2) 509.2821, calculated for C ₅₁ H ₇₉ FN ₆ O ₁₄ 509.2813. ¹ H NMR (CD ₃ OD, 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-CH ₃ ), 3.87 (d, J = 3.1 Hz, 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-CH ₂ ), 3.12-3.02 (m, 2H, H-10, 3-O-CO-NH-CH ₂ ), 2.99 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl), 2.40 (s, 6H, -N(CH ₃ ) 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(-CH ₂ -),H-7b,H-14eq),1.47(s,3H,12-CH _{3 13 C NMR ​ ​ ​ ​} ^​ _​ OD,100MHz)δ:217.98,174.82,159.44,157.38,101.75,84.49,78.66,77.89,77.47,75.50,70.73,68.76,64.55,58.05,57.79,52.61,49.22 ,48.94,45.35,43.20,40.40,39.53,38.66,37.42,35.71,30.89,27.6 0,23.40,21.80,20.03,18.43,17.17,14.04,12.93,12.22,9.43,8.14.

Synthesis of compound 69d

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain compound 93 0.210 g (0.231 mmol, 58.78%).

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 for C ₅₄ H ₈₂ FN ₆ O ₁₄ 1057.5868. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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 Hz, 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-CH ₂ ), 3.30-3.14 (m, 2H, H-2′, 1H-piperazinyl), 3.11-3.03 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.02-2.94 (m, 4H, 6-O-CH ₃ , 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, -CH ₂ -piperazinyl), 2.29 (s, 6H, -N(CH ₃ ) 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, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH ₃ ), 1.42-1.36 (m, 2H, 2H-cyclopropyl), 1.28 (s, 3H, 6-CH ₃ ), 1.26-1.18 (m, 9H, H-4′b, 5′-CH ₃ , 2H-cyclopropyl, -piperazinyl-CH ₃ ), 1.18-1.06 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.64,177.08,174.37,167.02,158.42,156.38,147.36,139.14,112.46,112.22, 108.10,104.71,103.17,83.88,81.65,78.20,77.85,77.25,75.80,70.45,69.48,66.18,58.13 ,56.59,54.64,52.98,50.01,49.81,45.30,43.40,41.13,40.32,39.12,37.28,35.79,35.33,2 8.65,28.23,23.68,22.03,21.22,19.31,18.27,15.28,15.08,13.87,13.30,10.26,9.20,8.24.

Synthesis of compound 69e

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.210 g (0.231 mmol, 58.78%) of compound 93.

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/ammonia water = 10/1/0.5) was performed to obtain about 13.5 mg (0.0128 mmol, 7.79%) of the general formula compound 69e. Melting point: 162.5-163.6°C. HRMS (ESI) (M+H) ⁺ m/z 1057.5859, calculated for C ₅₄ H ₈₂ FN ₆ O ₁₄ 1057.5868. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₂ ), 3.25-3.14 (m, 2H, H-2′, 1H-piperazinyl), 3.13-3.04 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.02-2.67 (m, 9H, 6-O-CH ₃ ,H-10,H-2,4H-piperazinyl), 2.59-2.46 (m, 2H, H-8, H-3′), 2.44-2.34 (m, 2H, -CH ₂ -piperazinyl), 2.28 (s, 6H, -N(CH ₃ ) 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, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a), 1.42 (s, 3H, 12-CH ₃ ), 1.41-1.35 (m, 2H, 2H-cyclopropyl), 1.28 (s, 3H, 6-CH ₃ ), 1.27-1.18 (m, 9H, H-4′b, 5′-CH ₃ , 2H-cyclopropyl, -piperazinyl-CH ₃ ), 1.18-1.07 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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 .14,119.73,112.53,112.40,108.19,104.63,103.23,83.87,81.65,78.27,77.86,75.82,70.48,69.55,66 .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.

Synthesis of compound 69f

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.210 g (0.231 mmol, 58.78%) of compound 93.

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 the general formula compound 69f. Melting point: 161.8-164.2°C HRMS (ESI) (M+H) ⁺ m/z 1052.5785, calculated for C ₅₃ H ₈₁ N ₆ O ₁₄ 1025.5805. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₂ ), 3.19 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2'), 3.14-3.06 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.89 (q, J = 6.4 Hz, 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, -CH ₂ -piperazinyl, H-3′), 2.30 (s, 6H, -N(CH ₃ ) 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, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a), 1.41 (s, 3H, 12-CH ₃ ), 1.40-1.33 (m, 2H, 2H-cyclopropyl), 1.30-1.20 (m, 9H, 6-CH ₃ , H-4′b, 5′-CH ₃ , 2H-cyclopropyl), 1.20-1.06 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.83 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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 ,66.16,58.12,57.88,52.66,49.82,47.21,45.31,43.38,41.07,40.35,39.11,37.28,35.78,3 4.92,28.66,28.09,24.27,22.03,21.24,19.32,18.28,15.10,13.89,13.29,10.27,9.18,8.18.

Synthesis of compound 69g

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for the reaction. After completion, 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 0.210 g (0.231 mmol, 58.78%) of compound 93.

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 about 104.5 mg (0.100 mmol, 40.21%) of the general formula compound 69g. Melting point: 187.0-188.1°C. HRMS (ESI) (M+H) ⁺ m/z 1044.5668, calculated value C ₅₂ H ₇₉ FN ₇ O ₁₄ 1044.5664. ¹ H NMR (CD ₃ OD, 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-CH ₂ ),3.16-3.03(m,2H,H-10,3-O-CO-NH-CH ₂ ),3.01(m,3H,6-O-CH ₃ ),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,-CH ₂ -piperazinyl,-N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq), 1.49 (s, 3H, 12-CH ₃ ), 1.37-1.25 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH ₃ ), 1.22 (d, J＝6.0 Hz, 3H, 5′-CH ₃ ), 1.20-1.02 (m, 14H, 2H-cyclopropyl, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.88 (t, J＝7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.70,180.59,174.33,166.84,161.69,158.46,156.34, 146.27,103.17,83.88,77.84,75.80,70.51,69.58,66.25,58.13,53.4 7,53.00,49.83,46.87,45.32,43.38,40.40,39.12,37.27,35.80,34.6 6,22.03,21.25,19.32,18.30,15.10,13.90,13.30,10.28,9.12,7.48.

Synthesis of Compound 69j

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain compound 93 0.210 g (0.231 mmol, 58.78%).

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 about 79.2 mg (0.0767 mmol, 38.95%) of compound 69j of the general formula. Melting point: 152.2-153.7°C HRMS (ESI) (M+H) ⁺ m/z 1032.5683, calculated for C ₅₁ H ₇₉ FN ₇ O ₁₄ 1032.5664. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),5.23(dd,J＝2.3Hz,10.9Hz,1H,H-13),4.93(d,J＝11.0Hz,1H,H-3),4.41(q,J＝7.2Hz,2H,N-CH ₂ CH ₃ ),4.03(d,J＝7.3Hz,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-CH ₂ ),3.19(dd,J＝7.3Hz,10.1Hz,1H,H-2′),3.13-3.04(m,1H,3-O-CO-NH-CH ₂ ),2.98(s,3H,6-O-CH ₃ ),2.90(q,J＝6.6Hz,1H,H-10),2.87-2.79(m,1H,H-2),2.60(t,J＝4.9Hz,4H,4H-piperazinyl),2.56-2.47(m,1H,H-8),2.48-2.35(m,3H,-CH ₂ -Piperazinyl,H-3′),2.30(s,6H,-N(CH ₃ ) 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,7H,-CH ₂ -CH ₂ -CH ₂ -Piperazinyl, H-7b, H-14eq, H-4′a), 1.51 (t, J＝7.2Hz, 3H, N-CH ₂ CH ₃ ), 1.43 (s, 3H, 12-CH ₃ ), 1.28 (m, 3H, 6-CH ₃ ), 1.23 (d, J＝6.2Hz, 3H, 5′-CH ₃ ), 1.18-1.06 (m, 13H, H-4′b, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.85 (t, J＝7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

Synthesis of compound 69k

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain compound 93 0.210 g (0.231 mmol, 58.78%).

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/ammonia water = 10/1/0.5) was performed to obtain about 36.9 mg (0.0363 mmol, 22.26%) of compound 69k. HRMS (ESI) (M+H) ⁺ m/z 1015.5708, calculated for C ₅₀ H ₇₉ N ₈ O ₁₄ 1015.5710. ¹ H NMR (CD ₃ OD, 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-CH ₂ CH ₃ ), 4.15 (d, J = 7.2 Hz, 1H, H-1'), 4.00 (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-CH ₂ ), 3.11-3.02 (m, 2H, H-10, 3-O-CO-NH-CH ₂ ), 2.99 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq), 1.47 (s, 3H, 12-CH ₃ ), 1.43 (t, J＝7.1 Hz, N-CH ₂ CH _{3 13 C NMR ​ ​ ​ ​} ^​ ₃ OD,100MHz)δ:217.89,174.80,159.42,157.37,101.65,84.49,78.75,77.88,77.47,75.52,70.58,68.69,64.66,58.06,57.67,52.48,48.94 ,45.34,43.56,43.21,40.36,39.45,38.68,37.42,35.70,27.55,23.4 1,21.82,19.99,18.42,17.17,14.03,13.55,12.92,12.23,9.44,8.09.

Synthesis of compound 69p

According to the synthesis method, compound 47 (0.328 g, 0.393 mmol) and methanesulfonyl chloride (0.035 mL, 0.432 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.210 g (0.231 mmol, 58.78%) of compound 93.

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 FN ₆ O ₁₄ 1071.6024. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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, OCH ₂ CH ₃ ), 4.04 (d, J = 7.3 Hz, 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-CH ₂ ), 3.17 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2'), 3.13-3.05 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 2.89 (q, J = 6.8 Hz, 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, -CH ₂ -piperazinyl), 2.42-2.32 (m, 1H, H-3′), 2.27 (s, 6H, -N(CH ₃ ) 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), 1.69-1.48 (m, 7H, -CH ₂ -CH ₂ -CH ₂ -piperazinyl, H-7b, H-14eq, H-4′a), 1.45-1.36 (m, 6H, 12-CH ₃ , OCH ₂ CH ₃ ), 1.35-1.29 (m, 2H, 2H-cyclopropyl, 1.29-1.18 (m, 7H, 6-CH ₃ , H-4′b, 5′-CH ₃ ), 1.19-1.05 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.84 (t, J＝7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.65,174.34,173.15,165.88,158.43,156.35,148.12,138.05,113.48,113.25, 110.54,104.68,103.18,83.88,81.61,78.15,77.85,77.25,75.81,70.44,69.54,66.27,60.92 ,58.13,57.89,52.92,49.82,45.30,43.41,41.12,40.38,39.12,37.29,35.80,34.48,29.70,2 8.57,28.08,24.29,22.04,21.24,19.31,18.27,15.09,14.45,13.88,13.31,10.26,9.17,8.17.

Synthesis of compound 70a

According to the synthesis method, compound 48 (0.540 g, 0.637 mmol) and methanesulfonyl chloride (0.057 mL, 0.701 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.512 g (0.552 mmol, 86.66%) of compound 94.

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/ammonia water = 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 for C ₅₄ H ₈₂ FN ₆ O ₁₄ 1057.5868. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 4.92 (d, J = 11.0 Hz, 1H, H-3), 4.03 (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-CH ₂ ), 3.19 (dd, J = 7.2 Hz, 10.0 Hz, 1H, H-2′), 3.12-3.02 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl, H-3′), 2.29 (s, 6H, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq, H-4′a), 1.43 (s, 3H, 12-CH ₃ ), 1.40 (br, 4H, -CH ₂ -,2H-cyclopropyl), 1.28 (s, 3H, 6-CH ₃ ), 1.25-1.18 (m, 6H, H-4′b, 5′-CH ₃ , 2H-cyclopropyl), 1.18-1.05 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.85 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.67,177.08,174.40,167.01,158.43,156.40,154.93,152.43,147.39,145.95,145.86, 139.11,119.77,119.69,112.47,112.23,108.11,104.76,103.23,83.91,81.63,78.26,77.86,77.26,75 .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.

Synthesis of compound 70b

According to the synthesis method, compound 48 (0.540 g, 0.637 mmol) and methanesulfonyl chloride (0.057 mL, 0.701 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain compound 94 0.512 g (0.552 mmol, 86.66%).

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/ammonia water = 10/1/0.5) was performed to obtain about 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 for C ₅₃ H ₈₂ FN ₆ O ₁₄ 1045.5868. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),4.92(d,J＝11.0Hz,1H,H-3),4.34(br,2H,N-CH ₂ CH ₃ ),4.04(d,J＝7.2Hz,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-CH ₂ ),3.19(dd,J＝7.3Hz,10.1Hz,1H,H-2′),3.12-3.03(m,1H,3-O-CO-NH-CH ₂ ),2.98(s,3H,6-O-CH ₃ ), 2.94-2.81 (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, -CH ₂ -piperazinyl, H-3′), 2.29 (s, 6H, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq, H-4′a, N-CH ₂ CH ₃ ), 1.43 (s, 3H, 12-CH ₃ ),1.41-1.36(m,2H,-CH ₂ -),1.28(s,3H,6-CH ₃ ),1.23(d,J＝6.1Hz,3H,5′-CH ₃ ),1.19-1.06(m,13H,H-4′b,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.84 (t, J=7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.69,176.96,174.43,167.24,158.45,156.41,147.12,137.15,112.76,11 2.53,108.29,103.17,83.92,81.53,78.20,77.86,77.27,75.74,70.49,69.50,66.09,58. 25,58.12,52.84,49.86,49.82,45.31,43.36,41.07,40.36,39.11,37.27,35.78,30.05,2 8.63,26.44,24.61,22.02,21.21,19.30,18.28,15.02,14.44,13.87,13.29,10.25,9.06.

Synthesis of compound 71a

According to the synthesis method, compound 49 (0.332 g, 0.385 mmol) and methanesulfonyl chloride (0.038 mL, 0.462 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.163 g (0.174 mmol, 54.19%) of compound 95.

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 about 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 for C ₅₅ H ₈₄ FN ₆ O ₁₄ 1071.6024. ¹ H NMR (CDCl ₃ , 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-CH ₂ ),4.92(d,J＝11.1Hz,1H,H-3),4.04(d,J＝7.3Hz,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-CH ₂ ), 3.19 (dd, J=7.3 Hz, 10.2 Hz, 1H, H-2′), 3.11-3.01 (m, 1H, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl, H-3′), 2.29 (s, 6H, -N(CH ₃ ) 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), 1.68-1.48 (m, 7H, 2(-CH ₂ -), H-7b, H-14eq, H-4′a), 1.43 (s, 3H, 12-CH ₃ ), 1.42-1.32 (m, 6H, 2(-CH ₂ -), 2H-cyclopropyl), 1.28 (s, 3H, 6-CH ₃ ), 1.26-1.18 (m, 6H, H-4′b, 5′-CH ₃ ,2H-cyclopropyl), 1.18-1.06 (m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.85 (t,J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.68,177.10,174.43,167.04,158.44,156.41,154.93,152.43,147.39,145.98,145.87,13 9.11,119.75,119.67,112.45,112.22,108.10,104.75,103.18,83.92,81.59,78.20,77.86,77.26,75.75 ,70.50,69.48,66.06,58.40,58.13,52.87,49.82,45.32,43.37,41.07,40.35,39.13,37.28,35.79,35.3 0,30.17,28.64,27.16,26.78,26.70,22.03,21.21,19.30,18.29,15.02,13.87,13.29,10.25,9.05,8.23.

Synthesis of compound 71j

According to the synthesis method, compound 49 (0.300 g, 0.348 mmol) and p-toluenesulfonyl chloride (0.0995 g, 0.522 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.265 g (0.261 mmol, 75.00%) of compound 96.

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 about 16.5 mg (0.0156 mmol, 5.96%) of compound 71j. HRMS (ESI) (M+H) ⁺ m/z 1060.5978, calculated for C ₅₃ H ₈₃ FN ₇ O ₁₄ 1060.5977. ¹ H NMR (CD ₃ OD, 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-CH ₂ CH ₃ ), 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-CH ₂ ), 3.14-3.00 (m, 2H, H-10, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq), 1.50-1.43 (m, 6H, 12-CH ₃ , N-CH ₂ CH ₃ ), 1.42-1.28 (m, 5H, 2(-CH ₂ -),H-4′b),1.26(s,3H,6-CH ₃ ),1.20(d,J＝6.1Hz,3H,5′-CH ₃ ),1.17-1.09(m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ),0.86(t,J＝7.4Hz,3H,15-CH ₃ ). ¹³ C NMR(CD ₃ OD,100MHz)δ:217.96,174.83,159.43,157.39,101.74,84.50,78.76,7 7.90,77.44,75.50,70.76,68.72,64.52,58.07,52.71,48.92,45.35,43 .25,40.41,39.53,38.69,37.42,35.71,30.91,29.51,26.83,26.32,26. 02,21.82,20.01,18.43,17.17,14.01,13.89,12.92,12.23,9.42,8.07.

Synthesis of compound 71k

According to the synthesis method, compound 49 (0.300 g, 0.348 mmol) and p-toluenesulfonyl chloride (0.0995 g, 0.522 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.265 g (0.261 mmol, 75.00%) of compound 96.

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 the general formula compound 71k. HRMS (ESI) (M+H) ⁺ m/z 1043.6017, calculated for C ₅₂ H ₈₃ FN ₈ O ₁₄ 1043.6023. ¹ H NMR (CD ₃ OD, 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-CH ₂ CH ₃ ), 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-CH ₂ ), 3.14-3.01 (m, 2H, H-10, 3-O-CO-NH-CH ₂ ), 2.99 (s, 3H, 6-O-CH ₃ ), 2.96-2.87 (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, -CH ₂ -piperazinyl, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq), 1.48 (s, 3H, 12-CH ₃ ), 1.47 (t, J＝7.1 Hz, 3H, N-CH ₂ CH ₃ ),1.41-1.17(m,11H,2(-CH ₂ -),H-4′b,6-CH ₃ ,5′-CH ₃ ),1.17-1.09(m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ),0.86(t,J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR(CD ₃ OD,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.

Synthesis of compound 72a

According to the synthesis method, compound 50 (0.235 g, 0.268 mmol) and p-toluenesulfonyl chloride (0.0492 g, 0.403 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.182 g (0.177 mmol, 65.91%) of compound 97.

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 about 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 FN ₆ O ₁₄ 1085.6181. ¹ H NMR (CD ₃ OD, 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 H z, 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-CH ₂ ), 3.12-3.01 (m, 2H, H-10, 3-O-CO-NH-CH ₂ ), 2.98 (s, 3H, 6-O-CH ₃ ), 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, -CH ₂ -piperazinyl, -N(CH ₃ ) 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(-CH ₂ -), H-7b, H-14eq), 1.47 (s, 3H, 12-CH ₃ ), 1.43-1.27 (m, 9H, 3(-CH ₂ -), 2H-cyclopropyl, H-4'b), 1.25 (s, 3H, 6-CH ₃ ), 1.19 (d, J=6.1 Hz, 3H, 5'-CH ₃ ), 1.17-1.07 (m, 14H, 2H-cyclopropyl, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.85 (t, J=7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CD ₃ OD,100MHz)δ:217.97,174.83,159.39,157.38,101.69,84.49,78.78,77.90, 77.41,75.49,70.75,68.68,64.52,58.19,58.07,52.61,49.16,48.95,45.35 ,43.24,40.48,39.55,38.69,37.41,35.69,30.97,29.53,28.88,27.17,26.4 5,25.94,21.82,20.03,18.44,17.19,14.03,12.95,12.25,9.45,8.10,7.17.

Synthesis of compound 73a

According to the synthesis method, compound 51 (0.167 g, 0.188 mmol) and p-toluenesulfonyl chloride (0.0460 g, 0.376 mmol) were used for reaction. After the reaction was completed, column chromatography purification (100-200 mesh silica gel, mobile phase: dichloromethane/ethanol/ammonia water = 10/0.1/0.05) was performed to obtain about 0.120 g (0.115 mmol, 61.12%) of compound 98.

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 about 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 FN ₆ O ₁₄ 1099.6337. ¹ H NMR (CD ₃ OD, 400MHz)δ:8.75(s,1H,2″-quinolyl),7.84(s,1H,5″-quinolyl),7.51(s,1H,8″-quinolyl),5.18(dd,J＝2.4Hz,10.8Hz,1H,H-13),4.88(d,J＝11.1Hz,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-CH ₂ ),3.13-3.00(m,2H,H-10,3-O-CO-NH-CH ₂ ),2.98(s,3H,6-O-CH ₃ ),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,-CH ₂ -piperazinyl,-N(CH ₃ ) 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(-CH ₂ -),H-7b,H-14eq),1.47(s,3H,12-CH ₃ ), 1.43-1.28 (m, 9H, 3 (-CH ₂ -), 2H-cyclopropyl, H-4'b), 1.25 (s, 3H, 6-CH ₃ ), 1.20 (d, J = 6.0 Hz, 3H, 5'-CH ₃ ), 1.17-1.08 (m, 14H, 2H-cyclopropyl, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.86 (t, J = 7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CD ₃ OD,100MHz)δ:217.96,174.83,159.41,157.39,101.72,84.49,78.80,77.90,7 7.43,75.50,70.73,68.70,64.54,58.26,58.07,52.63,49.16,48.93,45.35,43 .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.

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

General Synthesis Method of Compound 74-75 Series

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

The intermediate (1 eq) and compound 100 (5 eq) were dispersed in anhydrous acetonitrile and stirred at 80°C for 72 h. After the reaction was completed, the reaction solution was dried by spin drying, 50 mL of dichloromethane was added, and the mixture was washed with water 3 times and once with saturated brine. The organic phase was dried by spin drying, and 20 mL of methanol was added to reflux to remove the protecting group. After the reaction was completed under TLC monitoring, the reaction solution was dried by spin drying and purified by column chromatography.

Synthesis of compound 74a

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

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 the general formula compound 74a. Melting point: 163.4-164.9°C. HRMS (ESI) (M+H) ⁺ m/z 1058.5786, calculated for C ₅₃ H ₈₁ FN ₇ O ₁₄ 1058.5802. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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-CH ₂ -), 3.40-3.28 (m, 5H, H-5′, 4H-piperazinyl), 3.24-3.13 (m, 2H, 3-O-CO-NH-CH ₂ , H-2′), 2.98 (s, 3H, 6-O-CH ₃ ), 2.93-2.79 (m, 6H, H-10, H-2, -CH ₂ -N-CH ₂ -CH ₂ -piperazinyl), 2.69 (s, 4H, 4H-piperazinyl), 3.64-2.57 (m, 2H, -N-CH ₂ -CH ₂ -piperazinyl), 2.56-2.44 (m, 2H, H-8, H-3′), 2.30 (s, 6H, -N(CH ₃ ) ₂ ), 2.12-2.03 (m, 1H, H-4), 1.98-1.88 (m, 1H, H-14eq), 1.83-1.74 (m, 1H, H-7a), 1.68-1.50 (m, 3H, H-7b, H-14eq, H-4′a), 1.46-1.35 (m, 5H, 12-CH ₃ , 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH ₃ ,H-4′b,5′-CH ₃ ,2H-cyclopropyl), 1.17-1.07 (m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.84 (t,J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.67,177.02,158.44,147.47,139.05,103.06,83.89,78.36,77.87,77.25,75.80,70.53,58.14,52.88,49. 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.

Synthesis of compound 75a

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

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 the general formula compound 75a. Melting point: 163.6-164.2°C. HRMS (ESI) (M+H) ⁺ m/z 1072.5975, calculated for C ₅₄ H ₈₃ FN ₇ O ₁₄ 1072.5977. ¹ H NMR (CDCl ₃ , 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-CH ₂ ), 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 = 7.2 Hz, 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-CH ₂ -), 3.23-3.12 (m, 2H, H-2′, 3-O-CO-NH-CH ₂ ), 2.97 (s, 3H, 6-O-CH ₃ ), 2.93-2.83 (m, 2H, H-10, H-2), 2.82-2.73 (m, 4H, -CH ₂ -N-CH ₂ -CH ₂ -piperazinyl), 2.72-2.57 (m, 6H, 4H-piperazinyl, -N-CH ₂ -CH ₂ -piperazinyl), 2.55-2.41 (m, 2H, H-8, H-3′), 2.30 (s, 6H, -N(CH ₃ ) 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, -CH ₂ -), 1.68-1.51 (m, 3H, H-7b, H-14eq, H-4′a), 1.45-1.35 (m, 5H, 12-CH ₃ , 2H-cyclopropyl), 1.31-1.17 (m, 9H, 6-CH ₃ , H-4′b, 5′-CH ₃ , 2H-cyclopropyl), 1.18-1.07 (m, 12H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ), 0.84 (t, J＝7.2Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

General Synthesis Method of Compound 76-86 Series

Compound 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 the reaction was completed, the reaction solution was 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 the reaction was completed, dichloromethane was added for extraction. The organic phase was dried and methanol was added to reflux for 12-14 hours. After the reaction was completed, column chromatography was performed to purify to obtain compound 76-86 series.

Synthesis of compound 76o

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 about 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 for C ₅₃ H ₈₀ FN ₆ O ₁₆ 1075.5609. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ ),4.14(d,J＝7.3Hz,1H,H-1′),3.88-3.80(m 4H,H-5,9-O-CH ₃ ),3.79-3.65(m,5H,1H-cyclopropyl,-N-(CH ₂ -CH ₂ ) ₂ -CH,H-8),3.62(d,J＝6.0Hz,2H,O-CH ₂ )3.51-3.36(m,2H,3-O-CO-NH-CH ₂ ,H-5′),3.28(dd,J＝7.3Hz,10.2Hz,1H,H-2′),3.21-3.12(m,1H,3-O-CO-NH-CH ₂ ),3.05(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.16-1.99(m,1H,H-4,CH ₂ ),1.91-1.62(m,1H,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ,H-4′a,H-14eq),1.56(s,3H,12-CH ₃ ),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 ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:177.08,174.01,166.87,165.97,164.53,156.34,154.67,150.22,150.17,148.17,146.93,146.69,146.47,13 4.24,129.49,119.99,119.87,113.22,108.87,103.34,85.00,83.20,81.25,78.34,78.22,75.54,74.05,70.45,69.52,66 .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.

Synthesis of compound 77l

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 about 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 for C ₅₄ H ₈₁ FN ₅ O ₁₄ 1042.5759. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ ,1H-cyclopropyl),3.50-3.39(m,1H,H-5′),3.29-3.21(m,2H,H-2′,3-O-CO-NH-CH ₂ ),3.14-3.01(m,2H,H-10,3-O-CO-NH-CH ₂ ),2.99(s,3H,6-O-CH ₃ ),2.95-2.70(m,4H,H-2,H-3′,-N-(CH ₂ -CH ₂ ) ₂ ),2.54-2.47(m,1H,H-8),2.43(s,6H,-N(CH ₃ ) ₂ ),2.17-2.06(m,1H,H-4),1.92-1.75(m,5H,-CH-(CH ₂ -CH ₂ ) ₂ , H-14eq, H-7a), 1.60-1.45 (m, 8H, H-7b, H-4′a, H-14eq, -CH-(CH ₂ -CH ₂ ) ₂ , 12-CH ₃ ), 1.44-1.28 (m, 9H, 3(-CH ₂ -), 2H-cyclopropyl, H-4′b), 1.25 (m, 3H, 6-CH ₃ ), 1.20 (d, J＝6.1 Hz, 3H, 5′-CH ₃ ), 1.18-1.06 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.86 (t, J＝7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.69,177.09, 167.17,158.45,147.28,146.42,139.19,108.04,104.73,83.93,77. 87,77.25,75.78,70.54,58.14,50.53,49.85,45.33,43.36,41.05,4 0.38,39.15,37.28,36.08,35.80,35.49,35.28,32.09,30.53,23.84 ,22.05,21.22,19.30,18.30,15.01,13.88,13.29,10.26,9.07,8.22.

Synthesis of compound 77o

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 about 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 for C ₅₃ H ₈₀ FN ₆ O ₁₄ 1043.5711. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ ),4.13(d,J＝7.3Hz,1H,H-1′),3.85(d,J＝3.1Hz,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-CH ₂ ),3.15(td,J＝2.7Hz,13.2Hz,2H,-N-(CH ₂ -CH ₂ ) ₂ ),3.11-3.01(m,2H,H-10,3-O-CO-NH-CH ₂ ),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(CH ₃ ) ₂ ),2.16-2.08(m,1H,H-4),1.93-1.80(m,4H,H-14eq,H-7a,CH ₂ ),1.80-1.71(m,1H,H-4′a),1.71-1.50(m,5H,H-7b,H-14eq,-CH-(CH ₂ -CH ₂ ) ₂ ,CH ₂ ),1.47(s,3H,12-CH ₃ ),1.45-1.27(m,9H,3(-CH ₂ -), 2H-cyclopropyl, H-4'b), 1.25 (m, 3H, 6-CH ₃ ), 1.20 (d, J＝6.1Hz, 3H, 5'-CH ₃ ), 1.17-1.06 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.86 (t, J＝7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

Synthesis of compound 78l

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 about 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 for C ₅₃ H ₇₉ FN ₅ O ₁₅ 1044.55512. ¹ H NMR (CD ₃ OD, 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 = 3.0 Hz, 1H, H-5), 3.79 (s, 1H, H-11), 3.75-3.65 (m, 1H, 1H-cyclopropyl), 3.64-3.50 (m, 5H, -N-(CH ₂ -CH ₂ ) ₂ -CH-O-CH ₂ ),3.49-3.41(m,1H,H-5′),3.41-3.33(m,1H,3-O-CO-NH-CH ₂ ),3.27(dd,J＝7.4Hz,10.1Hz, 1H,H-2′),3.22-3.11(m,3H,3-O-CO-NH-CH ₂ ,-N-(CH ₂ -CH ₂ ) ₂ ),3.08(q,J＝6.7Hz,H-10),2.98(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.16-2.00(m,3H,H-4,CH ₂ ),1.92-1.70(m,7H,-N-(CH ₂ -CH ₂ ) ₂ , H-14eq, H-7a, H-4′a), 1.66-1.54 (m, 2H, H-7b, H-14eq), 1.47 (s, 3H, 12-CH ₃ ), 1.42-1.27 (m, 3H, 2H-cyclopropyl, H-4′b), 1.25 (m, 3H, 6-CH ₃ ), 1.20 (d, J＝6.1 Hz, 3H, 5′-CH ₃ ), 1.17-1.07 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.85 (t, J＝7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:220.00,178.75,163.36,161.27,105.62,88.42,82.65,81.82,81 .39,79.44,79.42,77.72,74.61,72.64,69.01,68.44,61.98,52.89,49.28,4 7.14,43.44,42.58,41.94,41.35,39.63,34.88,34.73,34.65,33.93,25.74, 23.99,22.39,22.37,21.11,18.02,16.88,16.18,16.16,13.39,12.03,11.11.

Synthesis of Compound 78m

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 about 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 for C ₅₂ H ₇₉ FN ₅ O ₁₅ 1032.5551. ¹ H NMR (CD ₃ OD, 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, NCH ₂ CH ₃ ),4.16(d,J＝7.3Hz,1H,H-1′),3.87(d,J＝3.1Hz,1H,H-5),3.81(s,1H,H-11),3.85-3.76(m,3H,-N-(CH ₂ -CH ₂ ) ₂ -CH),3.69-3.52(m,5H,O-CH ₂ ,N-(CH ₂ -CH ₂ ) ₂ CH),3.49-3.36(m,5H,H-5′,3-O-CO-NH-CH ₂ ),N-(CH ₂ -CH ₂ ) ₂ ),3.27(dd,J＝7.3Hz,10.2Hz,1H,H-2′),3.25-3.04(m,4H,3-O-CO-NH-CH ₂ ,H-10,N-(CH ₂ -CH ₂ ) ₂ ),3.00(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.19-2.00(m,3H,H-4,CH ₂ ),1.94-1.63(m,7H,-N-(CH ₂ -CH ₂ ) ₂ ,H-14eq,H-7a,H-4′a),1.69-1.58(m,2H,H-7b,H-14eq),1.58-1.51(m,3H,NCH ₂ CH ₃ ),1.49(s,3H,12-CH ₃ ),1.39-1.30(m,1H,H-4′b),1.28(s,3H,6-CH ₃ ),1.22(d,J＝6.1Hz,3H,5′-CH ₃ ),1.19-1.09(m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.87 (t, J=7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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 ,58.12,49.83,49.73,47.38,45.31,43.37,40.36,39.12,37.28,35.80,30.89,30.15,29.7 0,22.03,21.21,19.31,18.29,15.06,14.53,14.47,13.88,13.84,13.29,10.26,9.24,9.06.

Synthesis of compound 78n

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 about 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 for C ₅₃ H ₈₀ N ₅ O ₁₅ 1026.5645. ¹ H NMR (CD ₃ OD, 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-11,1H-cyclopropyl,-N-(CH ₂ -CH ₂ ) ₂ -CH),3.74-3.56(m,4H,O-CH ₂ ,N-(CH ₂ -CH ₂ ) ₂ ),3.48-3.36(m,4H,H-5′,3-O-CO-NH-CH ₂ ,N-(CH ₂ -CH ₂ ) ₂ ),3.27(dd,J＝7.2Hz,10.1Hz,1H,H-2′),3.21-3.04(m,2H,3-O-CO-NH-CH ₂ ,H-10),3.00(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.18-2.09(m,1H,H-4),2.09-2.00(m,2H,CH ₂ ),1.95-1.69(m,7H,-N-(CH ₂ -CH ₂ ) ₂ ,H-14eq,H-7a,H-4′a),1.68-1.56(m,2H,H-7b,H-14eq),1.49(s,3H,12-CH ₃ ), 1.45-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.27 (s, 3H, 6-CH ₃ ), 1.21 (d, J＝6.1Hz, 3H, 5′-CH ₃ ), 1.19-1.09 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.86 (t, J＝7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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 ,58.12,49.82,45.30,44.82,44.79,43.35,40.33,39.35,39.10,37.28,35.77,34.87,30.41,30.23,3 0.12,29.70,28.68,22.02,21.20,19.30,18.28,18.25,15.06,13.88,13.27,10.26,10.24,9.04,8.15.

Synthesis of compound 78o

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 about 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 for C ₅₂ H ₇₈ FN ₆ O ₁₅ 1045.55037. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ ), 3.84 (d, J = 3.0Hz, 1H, H-5), 3.79 (s, 1H, H-11), 3.37-3.61 (m, 4H, 1H-cyclopropyl, -N- (CH ₂ -CH ₂ ) ₂ -CH), 6.01 (t, J = 3.6Hz, 1H, O-CH ₂ ),3.51-3.41(m,1H,H-5′),3.40-3.32(m,1H,3-O-CO-NH-CH ₂ ),3.30-3.24(m,1H,H-2′),3.20-3.04(m,2H,3-O-CO-NH-CH ₂ ,H-10),2.98(s,3H,6-O-CH ₃ ),2.92-2.78(m,2H,H-2,H-3′),2.54-2.40(m,7H,H-8,-N(CH ₃ ) ₂ ),2.16-2.06(m,1H,H-4),2.05-1.94(m,2H,CH ₂ ),1.90-1.74(m,5H,-N-(CH ₂ -CH ₂ ) ₂ ,H-14eq,H-7a,H-4′a),1.74-1.54(m,4H,H-7b,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ),1.46(s,3H,12-CH ₃ ),1.35-1.22(m,6H,2H-cyclopropyl,H-4′b,6-CH ₃ ), 1.19 (d, J = 6.0 Hz, 3H, 5′-CH ₃ ), 1.16-0.98 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.85 (t, J = 7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:220.00,180.44,178.73,163.32,161.25,105.53,88.41,82.63,81.81,8 1.33,79.42,79.40,77.94,74.54,72.57,69.10,68.48,61.98,52.92,51.93,49.29,4 8.23,48.18,47.12,43.59,43.45,42.57,41.91,41.34,39.61,34.92,34.84,33.97, 25.75,23.98,22.40,22.39,21.14,18.04,16.92,16.21,16.19,13.43,12.04,10.45.

Synthesis of compound 79l

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 FN ₅ O ₁₅ 1058.5708. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ -), 3.55 (t, J = 6.0 Hz, 2H, O-CH ₂ ),3.51-3.43(m,1H,H-5′),3.44-3.35(m,1H,3-O-CO-NH-CH ₂ ,O-CH ₂ ),3.29(dd,J＝7.3Hz,10.3Hz,1H,H-2′),3.22-3.03(m,1H,3-O-CO-NH-CH ₂ ),3.09(q,J＝6.5Hz,1H,H-10),2.99(s,3H,6-O-CH ₃ ),2.97-2.86(m,3H,H-2,N-(CH ₂ -CH ₂ ) ₂ ),2.83-2.69(m,1H,H-3′),2.56-2.38(m,7H,H-8,-N(CH ₃ ) ₂ ),2.18-2.07(m,1H,H-4),1.98-1.74(m,7H,-N-(CH ₂ -CH ₂ ) ₂ -CH-CH ₂ -O-CH ₂ CH ₂ ,H-14eq,H-4′a),1.69-1.50(m,4H,H-7a,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ),1.45(s,3H,12-CH ₃ ),1.43-1.29(m,4H,2H-cyclopropyl,H-4′b,H-7b),1.27(s,3H,6-CH ₃ ),1.22(d,J＝6.1Hz,3H,5′-CH ₃ ),1.19-1.06(m,14H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ,2H-cyclopropyl), 0.86 (t, J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.65,177.08,174.38,173.69,167.08,158.43,147.32,146.37,139.16,104.85,104.82,103.12,83.89,81.42,77.86,75.79,70.46,69.55,58. 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.

Synthesis of compound 79o

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 about 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 for C ₅₃ H ₈₀ FN ₆ O ₁₅ 1059.5660. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ -),4.15(d,J＝7.2Hz,1H,H-1′),3.86(d,J＝3.0Hz,1H,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-CH ₂ ),3.48-3.40(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.39-3.34(m,1H,O-CH ₂ ),3.28(dd,J＝7.3Hz,10.3Hz,1H,H-2′),3.24-3.06(m,4H,3-O-CO-NH-CH ₂ ,N-(CH ₂ -CH ₂ ) ₂ ,H-10),3.00(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.17-2.08(m,1H,H-4),2.06-1.74(m,8H,-N-(CH ₂ -CH ₂ ) ₂ -CH-CH ₂ -O-CH ₂ CH ₂ ,H-14eq,H-4′a,H-7a),1.69-1.54(m,4H,H-14eq,H-7b),1.53-1.38(m,5H,12-CH ₃ ,N-(CH ₂ -CH ₂ ) ₂ ), 1.36-1.24 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH ₃ ), 1.19 (d, J＝6.2Hz, 3H, 5′-CH ₃ ), 1.17-1.04 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.87 (t, J＝7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,100MHz)δ:217.67,177.06,176.59,174.39,166.92,158.43,150.30,146. 99,146.36,108.80,83.90,81.48,77.85,75.58,70.49,69.54,58.11,49.8 3,47.26,45.31,43.37,40.36,39.13,37.26,36.66,35.81,34.64,29.33,2 9.26,22.02,21.19,19.29,18.29,15.05,13.87,13.26,10.26,8.99,7.44.

Synthesis of compound 801

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 about 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 FN ₅ O ₁₅ 1072.5864. ¹ H NMR (CD ₃ OD, 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, 1H, H-11), 3.79-3.63 (m, 3H, 1H-cyclopropyl, -N-(CH ₂ -CH ₂ ) ₂ -), 3.61-3.48 (m, 4H, CH ₂ -O-CH ₂ ),3.48-3.43(m,1H,H-5′),3.41-3.35(m,1H,3-O-CO-NH-CH ₂ ),3.29(dd,J＝7.3Hz,10.3Hz,1H,H-2′),3.20-3.05(m,2H,3-O-CO-NH-CH ₂ ,H-10),2.99(s,3H,6-O-CH ₃ ),2.97-2.86(m,3H,H-2,N-(CH ₂ -CH ₂ ) ₂ ),2.84-2.69(m,1H,H-3′),2.55-2.40(m,7H,H-8,-N(CH ₃ ) ₂ ),2.18-2.09(m,1H,H-4),1.99-1.69(m,9H,-N-(CH ₂ -CH ₂ ) ₂ -CH,H-14eq,2(CH ₂ ),H-4′a),1.68-1.56(m,5H,H-7a,H-7b,H-14eq,-N-(CH ₂ -CH ₂ ) ₂ ),1.48(s,3H,12-CH ₃ ),1.46-1.29(m,5H,2H-cyclopropyl,H-4′b,CH ₂ ),1.27(s,3H,6-CH ₃ ),1.23(d,J＝6.1Hz,3H,5′-CH ₃ ),1.19-1.10(m,14H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ,2H-cyclopropyl), 0.86 (t, J＝7.4Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

Synthesis of compound 80o

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 about 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 for C ₅₄ H ₈₂ FN ₆ O ₁₅ 1073.5817. ¹ H NMR (CD ₃ OD, 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-(CH ₂ -CH ₂ ) ₂ -),4.16(d,J＝7.2Hz,1H,H-1′),3.88(d,J＝3.2Hz,1H,H-5),3.81(s,1H,H-11),3.75-3.66(m,1H,1H-cyclopropyl),3.57-3.48(m,4H,CH ₂ OCH ₂ ),3.48-3.36(m,2H,H-5′,3-O-CO-NH-CH ₂ ),3.29(dd,J＝7.3Hz,10.2Hz,1H,H-2′),3.24-3.06(m,4H,3-O-CO-NH-CH ₂ ,N-(CH ₂ -CH ₂ ) ₂ ,H-10),3.00(s,3H,6-O-CH ₃ ),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(CH ₃ ) ₂ ),2.18-2.09(m,1H,H-4),1.97-1.74(m,8H,-N-(CH ₂ -CH ₂ ) ₂ -CH-CH ₂ O-CH ₂ CH ₂ ,H-14eq,H-4′a,H-7a),1.69-1.54(m,4H,CH ₂ ,H-14eq,H-7b),1.49(s,3H,12-CH ₃ ),1.45-1.29(m,5H,N-(CH ₂ -CH ₂ ) ₂ ,2H-cyclopropyl,H-4′b), 1.27(s,3H,6-CH ₃ ),1.23(d,J＝6.1Hz,3H,5′-CH ₃ ),1.20-1.07(m,14H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ,2H-cyclopropyl),0.88(t,J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR(CDCl ₃ ,176MHz)δ:217.66,177.05,177.03,174.38,166.95,158.43,156.32,150.2 0,150.15,148.15,147.02,146.67,146.34,119.82,119.69,112.92,112.90, 108.79,103.23,83.88,81.59,78.21,77.86,75.79,70.45,69.54,69.1 9,68.49,66.12,58.12,49.83,47.64,47.59,45.31,43.39,40.36,39.3 2,39.13,37.28,36.18,35.82,34.63,33.17,32.42,32.39,29.94,28.5 2,22.03,21.22,19.31,18.28,15.05,13.88,13.29,10.26,9.05,7.45.

Synthesis of compound 811

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 about 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 FN ₅ O ₁₅ 1030.5395. ¹ H NMR (CD ₃ OD, 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-CH ₂ , 2H-tetrahydropyrrole), 3.62-3.53 (m, 1H, H-tetrahydropyrrole), 3.46-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.25 (dd, J＝7.3 Hz, 10.2 Hz, 1H, H-2′), 3.18-3.04 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 2.97 (s, 3H, 6-O-CH ₃ ), 2.80-2.59 (m, 2H, H-2, H-3′), 2.54-2.45 (m, 1H, H-8), 2.38 (s, 6H, -N(CH ₃ ) 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, CH ₂ , H-14eq, H-7a, H-4′a), 1.67-1.55 (m, 2H, H-7b, H-14eq), 1.45 (s, 3H, 12-CH ₃ ), 1.43-1.27 (m, 3H, 2H-cyclopropyl, H-4′b), 1.25 (s, 3H, 6-CH ₃ ), 1.17 (d, J＝6.2Hz, 3H, 5′-CH ₃ ), 1.16-1.02 (m, 14H, 2-CH ₃ , 10-CH ₃ ,4-CH ₃ ,8-CH ₃ ,2H-cyclopropyl), 0.84 (t, J＝7.4Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.68,176.40,174.35,167.33,158.45,156.36,151.19,149.78,146.81,142.02,141.95,139.73,11 5.47,115.43,111.75,111.61,107.39,103.21,99.47,99.44,83.91,81.62,78.20,78.06,77.84,75.78,70.44,69 .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.

Synthesis of compound 81o

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 about 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 for C ₅₁ H ₇₆ FN ₆ O ₁₅ 1031.5347. ¹ H NMR (CD ₃ OD, 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-CH ₂ ), 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-CH ₂ ), 3.26 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2′), 3.18-3.05 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 2.97 (s, 3H, 6-O-CH ₃ ), 2.82-2.64 (m, 2H, H-2, H-3′), 2.55-2.44 (m, 1H, H-8), 2.40 (s, 6H, -N(CH ₃ ) ₂ ), 2.32-2.21 (m, 1H, H-tetrahydropyrrole), 2.18-2.05 (m, 2H, H-tetrahydropyrrole 1H, 2-CH ₃ , 5′-CH 3 , 10-CH 3 , 4-CH ₃ , 8-CH ₃ , _2H -cyclopropyl), 0.84 (t, _J =7.3 _Hz , 3H, ₁₅ -CH _{3 )} . ¹³ C NMR (CDCl ₃ ,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.

Synthesis of compound 821

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 about 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 FN ₅ O ₁₅ 1030.5395. ¹ H NMR (CD ₃ OD, 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-CH ₂ , 3H-tetrahydropyrrole), 3.46-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.24 (dd, J＝7.3 Hz, 10.2 Hz, 1H, H-2′), 3.17-3.05 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) 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, CH ₂ , H-14eq, H-7a, H-4′a), 1.67-1.56 (m, 2H, H-7b, H-14eq), 1.47 (s, 3H, 12-CH ₃ ), 1.43-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.26 (s, 3H, 6-CH ₃ ), 1.24-1.06 (m, 17H, 2-CH ₃ , 10-CH ₃ , 5′-CH ₃ , 4-CH ₃ , 8-CH ₃ ,2H-cyclopropyl), 0.85 (t, J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.68,176.35,176.33,174.38,167.30,158.44,156.40,151.20,149.79,146.75,142.07,142.00,139.72,115.38,115.34,111.64,111.50,107.33,103.15,99.48,99.45,83.90,81.47,78.24,78.16,77.84,75.78 ,70.45,69.51,66.89,66.07,58.11,55.39,55.35,49.81,48.03,48.01,45.31,43.32,40.33,39.10,38.82,37.2 7,35.75,35.12,30.69,29.98,28.50,22.02,21.19,19.29,18.28,15.02,13.88,13.27,10.26,8.94,8.09,8.06.

Synthesis of compound 82o

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 about 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 FN ₆ O ₁₅ 1031.5347. ¹ H NMR (CD ₃ OD, 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-CH ₂ ), 3.45-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.26 (dd, J＝7.2 Hz, 10.2 Hz, 1H, H-2′), 3.18-3.05 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) 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, CH ₂ , H-14eq, H-7a, H-4′a), 1.68-1.54 (m, 2H, H-7b, H-14eq), 1.48 (s, 3H, 12-CH ₃ ), 1.35-1.27 (m, 3H, 2H-cyclopropyl, H-4′b), 1.26 (s, 3H, 6-CH ₃ ), 1.20-1.07 (m, 17H, 2-CH ₃ , 5′-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ,2H-cyclopropyl), 0.85 (t, J＝7.3Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.67,176.93,174.32,167.00,158.44,156.37,149.25,149.18,147.49,147.25,145.99,145.78,118.11,118.00,111.75,108.69,103.29,83.89,81.70,78.31,77.85,77.22,75.83, 70.44,69.54,67.00,66.12,58.13,49.80,45.31,43.35,40.34,40.31,39.11,38.94,37.28,35.7 6,34.65,30.06,28.48,22.02,21.19,19.30,18.27,15.03,13.88,13.29,10.27,8.97,7.43,7.41.

Synthesis of compound 831

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 about 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 FN ₅ O ₁₅ 1044.5551. ¹ H NMR (CD ₃ OD, 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-CH ₂ , H-tetrahydropyrrole), 3.55-3.47 (m, 2H, O-CH ₂ ), 3.46-3.36 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.26 (dd, J＝7.3 Hz, 10.2 Hz, 1H, H-2′), 3.20-3.12 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.09 (q, J＝6.5 Hz, 1H, H-10), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) 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,CH ₂ ,H-14eq,H-4′a,H-7a,),1.68-1.55(m,2H,H-14eq,H-7a),1.47(s,3H,12-CH ₃ ),1.44-1.29(m,3H,2H-cyclopropyl,H-4′b),1.27(s,3H,6-CH ₃ ),1.24-1.18(m,5H,5′-CH ₃ ,2H-cyclopropyl),1.17-1.07(m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ ,8-CH ₃ ), 0.86 (t, J = 7.4Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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 .74,115.33,111.70,111.57,107.40,103.18,99.38,83.90,81.60,78.24,77.85,75.79,72.56,70.46,69. 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.

Synthesis of compound 83o

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 about 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 FN ₆ O ₁₅ 1045.5504. ¹ H NMR (CD ₃ OD, 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-CH ₂ ), 3.27 (dd, J＝7.3 Hz, 10.1 Hz, 1H, H-2′), 3.20-3.05 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 3.00 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 2.24-2.08 (m, 1H, H-tetrahydropyrrole, H-4), 1.96-1.73 (m, 6H, H-tetrahydropyrrole, CH ₂ , H-14eq, H-4′a, H-7a,), 1.69-1.53 (m, 2H, H-14eq, H-7a), 1.48 (s, 3H, 12-CH ₃ ), 1.38-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.28 (s, 3H, 6-CH ₃ ), 1.21 (d, J＝6.1 Hz, 3H, 5′-CH ₃ ), 1.17-1.07 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ,2H-cyclopropyl), 0.86 (t, J＝7.4Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.69,176.84,174.38,167.04,158.44,156.34,149.15,149.08,147.50,147.24,145.85,145.76,117.86,117.74,111.52,108.55,103.19,83.91,81.57,78.22,77.85, 75.77,72.37,70.46,69.49,66.10,58.12,49.82,45.31,43.38,40.35,39.11,37.27,35.7 9,34.65,29.90,22.02,21.20,19.30,18.28,15.04,13.88,13.28,10.26,9.00,7.44,7.34.

Synthesis of compound 841

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 about 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 FN ₅ O ₁₅ 1044.5551. ¹ H NMR (CD ₃ OD, 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-CH ₂ , H-tetrahydropyrrole), 3.56-3.48 (m, 2H, O-CH ₂ ), 3.48-3.35 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.27 (dd, J＝7.3 Hz, 10.2 Hz, 1H, H-2′), 3.22-3.12 (m, 1H, 3-O-CO-NH-CH ₂ ), 3.09 (q, J＝6.4 Hz, 1H, H-10), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) 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,CH ₂ ,H-14eq,H-4′a,H-7a),1.67-1.53(m,2H,H-14eq,H-7a),1.46(s,3H,12-CH ₃ ),1.42-1.30(m,3H,2H-cyclopropyl,H-4′b),1.28(s,3H,6-CH ₃ ),1.24-1.17(m,5H,5′-CH ₃ ,2H-cyclopropyl),1.18-1.08(m,12H,2-CH ₃ ,10-CH ₃ ,4-CH ₃ , 8-CH ₃ ), 0.85 (t, J = 7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.68,176.35,176.33,174.38,167.32,158.44,156.33,151.16,149.75,146.68,142.08,142.01,1 39.72,115.24,115.20,111.59,111.46,107.33,103.15,99.38,99.34,83.90,81.52,78.19,77.85,72.37,70.45 ,69.52,69.45,66.09,58.11,52.84,52.81,49.82,49.57,49.54,45.31,43.37,40.34,39.20,39.11,38.74,37.2 7,35.77,35.12,29.84,28.58,28.08,22.01,21.21,19.30,18.28,15.05,13.88,13.25,10.26,8.99,8.08,8.05.

Synthesis of compound 84o

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 about 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 FN ₆ O ₁₅ 1045.5504. ¹ H NMR (CD ₃ OD, 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-CH ₂ ), 3.27 (dd, J＝7.3 Hz, 10.1 Hz, 1H, H-2′), 3.21-3.06 (m, 2H, 3-O-CO-NH-CH ₂ , H-10), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 2.27-2.06 (m, 1H, H-tetrahydropyrrole, H-4), 1.98-1.72 (m, 6H, H-tetrahydropyrrole, CH ₂ , H-14eq, H-4′a, H-7a), 1.69-1.53 (m, 2H, H-14eq, H-7a), 1.47 (s, 3H, 12-CH ₃ ), 1.35-1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.27 (s, 3H, 6-CH ₃ ), 1.21 (d, J＝6.1 Hz, 3H, 5′-CH ₃ ), 1.18-1.07 (m, 14H, 2-CH ₃ , 10-CH ₃ , 4-CH ₃ , 8-CH ₃ ,2H-cyclopropyl), 0.85 (t, J＝7.4Hz,3H,15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.66,176.90,174.34,167.04,158.43,156.31,149.15,149.08,147.51,147.24,145.89,145.76,117.97,117.85,111.60,111.59,108.63,103.20,83.88,81.61,78.25,77.85,72.21 ,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.

Synthesis of compound 85l

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 about 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 FN ₅ O ₁₅ 1044.5551. ¹ H NMR (CD ₃ OD, 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-CH ₂ , H-piperidinyl, CH), 3.52-3.37 (m, 2H, H-5′, 3-O-CO-NH-CH ₂ ), 3.31-3.18 (m, 3H, H-2′, 3-O-CO-NH-CH ₂ , H-piperidinyl), 3.16-3.04 (m, 2H, H-10, H-piperidinyl), 2.99 (s, 3H, 6-O-CH ₃ ), 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(CH ₃ ) ₂ ), 2.15-1.96 (m, 3H, H-4, CH ₂ ), 1.95-1.54 (m, 9H, 4H-piperidinyl, H-14eq, H-7a, H-4′a, H-7b, H-14eq), 1.48 (s, 3H, 12-CH ₃ ), 1.45-1.28 (m, 3H, 2H-cyclopropyl, H-4′b), 1.26 (s, 3H, 6-CH ₃ ), 1.25-0.99 (m, 17H, 2-CH ₃ , 10-CH ₃ , 5′-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.84 (t, J＝7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.69,177.07,174.36,167.02,158.44,156.34,154.33,15 2.91,147.42,146.27,146.22,139.18,119.63,119.58,112.48,112.35, 108.11,105.06,103.21,83.90,81.59,78.22,77.85,75.78,73.87,70.4 5,69.52,66.77,66.10,58.11,54.38,54.35,50.31,49.81,45.31,43.38, 40.34,39.34,39.11,37.28,35.77,35.30,30.12,29.52,28.48,22.37,2 2.02,21.21,19.31,18.28,15.03,13.88,13.28,10.26,8.94,8.28,8.24.

Synthesis of compound 85o

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 about 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 FN ₆ O ₁₅ 1045.5504. ¹ H NMR (CD ₃ OD, 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-CH ₂ , H-piperidinyl), 3.45-3.36 (m, 1H, H-5'), 3.31-3.14 (m, 2H, H-2', 3-O-CO-NH-CH ₂ ), 3.10 (q, J = 6.5 Hz, 1H, H-10), 3.05-2.94 (s, 4H, 6-O-CH ₃ , 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(CH ₃ ) ₂ ), 2.15-2.07 (m, 1H, H-4), 2.07-1.94 (m, 2H, CH ₂ ), 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-CH ₃ ), 1.37-1.23 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH ₃ ), 1.23-1.02 (m, 17H, 2-CH ₃ , 10-CH ₃ , 5′-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.86 (t, J＝7.4 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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.

Synthesis of compound 86l

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 about 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 FN ₅ O ₁₅ 1044.5551. ¹ H NMR (CD ₃ OD, 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, 1H, 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-CH ₂ ,CH), 3.59-3.50 (m, 1H, H-piperidinyl), 3.49-3.36 (m, 3H, H-5′, 3-O-CO-NH-CH ₂ , H-piperidinyl), 3.30-3.21 (m, 3H, H-2′, 3-O-CO-NH-CH ₂ ), 3.17-3.03 (m, 2H, H-10, H-piperidinyl), 2.98 (s, 3H, 6-O-CH ₃ ), 2.78-2.66 (m, 2H, H-2, H-3′), 2.54-2.37 (m, 7H, H-8, -N(CH ₃ ) ₂ ), 2.13-1.95 (m, 3H, H-4, CH ₂ ),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-CH ₃ ),1.43-1.27(m,3H,2H-cyclopropyl,H-4′b),1.26(s,3H,6-CH ₃ ),1.24-1.09(m,12H, 2-CH ₃ ,10-CH ₃ ,5′-CH ₃ ,8-CH ₃ ), 1.08-0.95 (m, 5H, 4-CH ₃ , 2H-cyclopropyl), 0.84 (t, J=7.3Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,176MHz)δ:217.68,177.05,174.31,167.00,158.45,156.27,154.34,152.92,147.39,146.35,139.16,119.65,119.60,1 12.49,112.36,108.12,105.10,103.01,83.90,81.26,78.09,77.82,77.79,75.76,73.61,70.46,69.52,66.77,66.11,58 .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.

Synthesis of compound 86o

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 about 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 FN ₆ O ₁₅ 1045.5504. ¹ H NMR (CD ₃ OD, 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-CH ₂ , H-piperidinyl), 3.39-3.34 (m, 1H, H-5'), 3.31-3.14 (m, 2H, H-2', 3-O-CO-NH-CH ₂ ), 3.10 (q, J = 6.5 Hz, 1H, H-10), 3.05-2.94 (s, 4H, 6-O-CH ₃ , 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(CH ₃ ) ₂ ), 2.17-2.08 (m, 1H, H-4), 2.08-1.93 (m, 2H, CH ₂ ), 1.92-1.74 (m, 3H, 2H-piperidinyl, H-14eq), 1.77-1.56 (m, 6H, H-4′a, 2H-piperidinyl, H-7a, H-7b, H-14eq), 1.48 (s, 3H, 12-CH ₃ ), 1.37-1.22 (m, 6H, 2H-cyclopropyl, H-4′b, 6-CH ₃ ), 1.22-1.04 (m, 17H, 2-CH ₃ , 10-CH ₃ , 5′-CH ₃ , 4-CH ₃ , 8-CH ₃ , 2H-cyclopropyl), 0.86 (t, J＝7.3 Hz, 3H, 15-CH ₃ ). ¹³ C NMR (CDCl ₃ ,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, 53.44,51.24,51.18,49.81,47.65,45.31,43.37,40.34,39.11,39.03,37.28,35.75,34.68,33.86,30.12,2 9.92,29.70,28.47,22.13,22.02,21.18,19.30,18.28,15.00,13.88,13.27,10.27,8.96,7.52,7.49,7.46.

Test Example 1 In vitro antibacterial activity experiment

According to the standards recommended by 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-type (c-erm)-resistant Streptococcus pneumoniae 07P390, induced ermB-type (i-ermB)-resistant Streptococcus pyogenes, constitutively ermA-type (c-ermA)-resistant Streptococcus pyogenes 12-206, Staphylococcus aureus ATCC29213, induced ermA-type (i-ermA)-resistant Staphylococcus aureus PU32, constitutively resistant Staphylococcus aureus 19D052, 19B133, 19B130, 19E131, 15B196, Haemophilus influenzae ATCC49247 and catarrhalis 13L332 were determined by broth dilution method. Each bacterial strain was plated and purified before the test, and fresh bacteria were used for the test. Standard strains were used as sensitive test quality control bacteria in each experiment; bacterial solution without antimicrobial drugs was used as the growth control of the test strain. The minimum inhibitory concentration (MIC) was determined by the broth double dilution method. The concentration range of antimicrobial drugs was 256-0.008μg/mL, and the final concentration of the test bacterial solution was about 5×10 ⁵ CFU/ml.

The measurement results are shown in the following table:

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

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

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

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

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

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

cMLS _B : constitutive resistance to macrolide-lincosamide-streptogramin B.

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

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

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

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 represent the phenotypes of the strains' resistance to erythromycin; Ery<8 and Ery>8 represent the MIC (μg/mL) range of erythromycin for the test strains, and so on.

The statistical results of MIC ₅₀ and MIC ₉₀ data of compounds 78o and 84o against different species of resistant bacteria 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.

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

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

Table 9. MIC (μg/mL) of 78o, 84o and control drugs against different species of resistant bacteria

The antibacterial activities of compounds 78o and 84o against different species of drug-resistant bacteria were superior to those of first-, second- and third-generation macrolides.

The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

The compound represented by formula I, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug:
Wherein, W is an oxygen atom O or a NOC _1-12 alkyl group; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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, and m2 is 0, 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, and Ra is a halogen, a C _1-12 alkyl group, a halogenated C _1-12 alkyl group or a C _1-12 alkoxy group; ^R1 is a hydrogen atom, an amino group, a halogen, unsubstituted or optionally substituted by one, two or more Rb: a _C1-12 alkyl group, a _C3-20 cycloalkyl group, a 3-20 membered heterocyclyl group, a _C6-20 aryl group or a 5-20 membered heteroaryl group; Rb is selected from halogen, an amino group, a _C1-12 alkyl group, a halogenated _C1-12 alkyl group or a _C1-12 alkoxy group; ^R2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb as follows: _C1-12 alkyl, _C3-20 cycloalkyl, 3-20 membered heterocyclyl, _C6-20 aryl or 5-20 membered heteroaryl; Rb is selected from halogen, _C1-12 alkyl, halogenated _C1-12 alkyl or _C1-12 alkoxy; Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, it is connected to N connected to ^R2 to form a ring, wherein the connecting part between Z and N is _-OCH2- CH( _CH3 )-, in which case ^R2 is absent; Rc is halogen, nitrile, amino, _C1-12 alkyl, halogenated _C1-12 alkyl, _C1-12 alkoxy or halogenated _C1-12 alkoxy. The compound according to claim 1, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, characterized in that W is an oxygen atom O or a NOC _1-6 alkyl group; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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, and m2 is 1 or 2; Q is a methine CH, CRa or a nitrogen atom N, and Ra is a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group; ^R1 is a hydrogen atom, a halogen, unsubstituted or optionally substituted by one, two or more Rb: a _C1-6 alkyl group, a _C3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a _C6-12 aryl group or a 5-12 membered heteroaryl group; Rb is selected from halogen, a _C1-6 alkyl group or a _C1-6 alkoxy group; ^R2 is absent, a hydrogen atom, unsubstituted or optionally substituted by one, two or more Rb as follows: _C1-6 alkyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-12 aryl or 5-12 membered heteroaryl; Rb is selected from halogen, _C1-6 alkyl or _C1-6 alkoxy; Z is a methine CH, CRc, a nitrogen atom N, or when Z is C, it is connected to N connected to R ² to form a ring, wherein the connecting part between Z and N is -OCH ₂ -CH(CH ₃ )-, and R ² does not exist at this time; Rc is a halogen, a C _1-6 alkyl or a C _1-6 alkoxy. The compound according to claim 2, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, characterized in that W is an oxygen atom O or NOCH ₃ ; V is an oxygen atom O or a secondary amine NH, X is a methylene CH ₂ , 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; ^R1 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, or a fluorocyclopropyl group; Z is a methine group CH, a carbon atom CF substituted with fluorine, a nitrogen atom N, a carbon atom C-OCH ₃ substituted with methoxy, or when Z is C, it is connected to N connected to R ² to form a ring, wherein the connecting part between Z and N is -OCH ₂ -CH(CH ₃ )-, and R ² is absent at this time. The compound according to any one of claims 1 to 3, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, characterized in that the compound represented by formula I is selected from the following:

Use of the compound according to any one of claims 1 to 4, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug in the preparation of an antibacterial drug. The use according to claim 5 is 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. The use according to claim 5 or 6 is characterized in that the antibacterial drug is used to inhibit or kill at least one of the following bacteria that are sensitive to erythromycin or have different types of resistance: sensitive Streptococcus pneumoniae, constitutively resistant Streptococcus pneumoniae, exudative resistant Streptococcus pneumoniae, sensitive Staphylococcus aureus, inducible resistant Staphylococcus aureus, constitutively resistant Staphylococcus aureus, sensitive Streptococcus pyogenes, exudative resistant Streptococcus pyogenes, inducible resistant Streptococcus pyogenes, constitutively resistant Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 4, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 8 is characterized in that the pharmaceutical composition is used to prepare an antibacterial drug. The method for preparing the compound according to any one of claims 1 to 4, characterized in that it comprises the following steps:
Wherein, W, V, X, Y, n1, n2, m1, m2, R ¹ , R ² , Z, Q have the definitions as described in any one of claims 1-4; R is Ac or Bz.