Clarithromycin derivative, pharmaceutical composition and application thereof

Abstract

The invention provides a clarithromycin derivative, a pharmaceutical composition and application of the clarithromycin derivative, and relates to the technical field of pharmaceutical chemistry, the clarithromycin derivative has a general formula structure as shown in the following formula I. In the formula I, W is selected from any one group of oxygen atom and NOCH2C = C-Ar, and the structural formula is shown in the description. Ar is selected from any one of pyridyl, quinolyl, isoquinolyl, substituted pyridyl, substituted quinolyl and substituted isoquinolyl; v is selected from any one of oxygen atoms and 11-site side chains of telithromycin; x is selected from any one of-C is equivalent to C-,-OCH2CH2C is equivalent to C-and piperazinyl; q is selected from any one of methylene and fluorine-substituted carbon atoms; z is selected from any one of methylene, fluorine-substituted carbon atoms, nitrogen atoms and methoxyl carbon atoms; r1 and R2 are respectively and independently selected from any one of hydrogen atoms, C1-C3 alkyl groups, halogen-substituted C1-3 alkyl groups, C3-4 cycloalkyl groups, halogen-substituted C3-4 cycloalkyl groups and halogen-substituted phenyl groups; and the value range of n is an integer between 3 and 6. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a clarithromycin derivative, a pharmaceutical composition and their applications. Background Art

[0002] Macrolide-lincosamide-streptogramin B (MLS B ) has the same ribosomal binding site A2058 and has cross-resistance. Among them, the 14-membered macrolide antibiotic - erythromycin is a very important therapeutic drug for treating upper and lower respiratory tract infections. The main mechanism of action is that its 5-position deoxysugar amine acts on the ribosomal bases A2058 / A2059 (E. coli numbering) in the form of hydrogen bonds. The second-generation erythromycins - clarithromycin and azithromycin, which emerged in the 1980s, are widely used in the treatment of bacterial pneumonia, mycoplasma pneumonia, etc. They have the advantages of high acid resistance (gastric) and good pharmacokinetic properties, but they have no activity against bacteria and mycoplasmas resistant to erythromycin. [[ID=,12]]

[0003] The drug resistance mechanism of bacteria is that strains containing the erm gene express methylase, resulting in N6 methylation of A2058, leading to a sharp decline in the affinity of erythromycin drugs. As the third-generation erythromycin, ketolide macrolides with a structural feature of removing cladinose at the 3-position and modifying it into a carbonyl group emerged. The representative marketed drug is telithromycin. The aryl group at the end of its 11-position side chain acts on the new sites A752 and U2609 (E. coli numbering) of the bacterial ribosome, and has good antibacterial activity against drug-resistant Streptococcus pneumoniae and Streptococcus pyogenes. It is the only erythromycin derivative approved for marketing to treat community-acquired bacterial pneumonia infections so far. Although telithromycin has activity against sensitive Mycoplasma pneumoniae, it has no activity against Mycoplasma with mutations in A2058 or A2059 (E. coli numbering) (minimum inhibitory concentration MIC = 256 μg / mL), which shows the particularity of drug-resistant mycoplasmas.

[0004] Mycoplasmas are a class of minimal prokaryotic microorganisms that lack cell walls, are highly pleomorphic, can pass through bacteria filters, and can be cultured and multiplied in artificial culture media. Mycoplasma pneumoniae is the pathogen that causes mycoplasma pneumonia, and can also cause upper respiratory tract infections and chronic bronchitis. It is primarily transmitted through the respiratory tract and can occur year-round. For example, in 2023, China experienced an outbreak of drug-resistant mycoplasma pneumoniae infections that lasted for six months. Mycoplasma resistance occurs through mutations of ribosomal bases A2058 / A2059 (Escherichia coli numbering) to G2058 / G2059 / T2058, among others. Currently, the G2058 mutation is the most common mycoplasma found in clinical practice. Currently, new-generation macrolides, including telithromycin, are primarily screened based on their minimum inhibitory concentration (MIC) against resistant bacteria, and activity against mycoplasmas with A2058 or A2059 (E. coli numbering) mutations is rarely tested. Because mycoplasmas and bacteria have distinct resistance mechanisms to macrolides and belong to different species, it is impossible to predict whether a drug will have activity against resistant mycoplasmas based solely on data from anti-resistant bacteria unless there is clear data to support this. Telithromycin, a marketed macrolide with excellent activity against resistant bacteria, is a prime counterexample. It is only active against susceptible Mycoplasma pneumoniae and has no activity against the major clinically resistant mycoplasmas.

[0005] The current structural characteristics of the modification of 3-position non-ketolide are that the 3-position modification is mostly connected to a side chain pharmacophore through an ester group. The ester group is a very unstable group that is easily metabolized and hydrolyzed, thereby losing its activity.

[0006] Therefore, what needs to be solved is to find a new broad-spectrum macrolide antibiotic with pharmacokinetic and stable structural characteristics for clinical use in the treatment of infections caused by pathogenic microorganisms such as erythromycin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, and drug-resistant mycoplasma. Summary of the Invention

[0007] The present invention provides a clarithromycin derivative, a pharmaceutical composition and applications thereof to solve the above problems.

[0008] In a first aspect of an embodiment of the present invention, a clarithromycin derivative is provided. The clarithromycin derivative has the general structure shown in the following formula I:

[0009]

[0010] In the formula I, W is selected from any one of an oxygen atom and NOCH2C≡C-Ar, and Ar is selected from any one of a pyridyl group, a quinolinyl group, an isoquinolinyl group, a substituted pyridyl group, a substituted quinolinyl group, and a substituted isoquinolinyl group. Among them, the substituents of the substituted pyridyl group, the substituted quinolinyl group, and the substituted isoquinolinyl group are independently selected from at least one group among an acetyl group, a methoxycarbonyl group, a carbamoyl group, an N-(methyl)carbamoyl group, an N,N-(dimethyl)carbamoyl group, an N-(ethyl)carbamoyl group, an N-(cyclopropyl)carbamoyl group, an oxazolyl group, an oxadiazolyl group, a phenyl group, a pyridyl group, a nitro group, a halogen, a cyano group, a hydroxyl group, and an amino group;

[0011] V is selected from any one of an oxygen atom and the 11-side chain of telithromycin. Among them, the 11-side chain of telithromycin is 4-[4-(pyridin-3-yl)imidazol-1-yl]butylamine;

[0012] X is selected from any one of -C≡C-, -OCH2CH2C≡C-, and a piperazinyl group;

[0013] Q is selected from any one of a methylene group and a fluorine-substituted carbon atom;

[0014] Z is selected from any one of a methylene group, a fluorine-substituted carbon atom, a nitrogen atom, and a methoxycarbon atom;

[0015] R 1 and R 2 are each independently selected from a hydrogen atom, a C1-C3 alkyl group, a halogen-substituted C 1-3 alkyl group, a C 3-4 cycloalkyl group, a halogen-substituted C 3-4 cycloalkyl group, and a halogen-substituted phenyl group;

[0016] The value range of n is an integer from 3 to 6.

[0017] Optionally, W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as a piperazinyl group, and n = 4.

[0018] Optionally, W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as -OCH2CH2C≡C-, and n = 3.

[0019] Optionally, W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as -C≡C-, and n = 5 or 6.

[0020] Optionally, W is selected as an oxygen atom, V is selected as the 11-side chain of telithromycin, X is selected as a piperazinyl group, and n = 4.

[0021] Optionally, W is selected as an oxygen atom, V is selected as the 11-position side chain of telithromycin, X is selected as -OCH2CH2C≡C-, and n = 3.

[0022] Optionally, W is selected as an oxygen atom, V is selected as the 11-position side chain of telithromycin, X is selected as -C≡C-, and n = 5 or 6.

[0023] Optionally, the specific structural formula of the clarithromycin derivative is:

[0024]

[0025]

[0026] In the second aspect of the embodiments of the present invention, a clarithromycin derivative pharmaceutical composition is provided. The clarithromycin derivative pharmaceutical composition includes at least one of the clarithromycin derivatives described in any item of the first aspect, its isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt, or its prodrug compound.

[0027] In the third aspect of the embodiments of the present invention, there is provided an application of a clarithromycin derivative described in any item of the first aspect, or the clarithromycin derivative pharmaceutical composition described in the second aspect in the preparation of antibacterial drugs and anti-drug-resistant mycoplasma drugs.

[0028] The present invention has the following advantages:

[0029] 1. Macrolide antibiotics have inhibitory activity against sensitive bacteria and sensitive mycoplasmas. The screening of new macrolide antibiotics represented by telithromycin is basically carried out by testing the activity against drug-resistant bacteria. Through structure-activity relationship research and repeated iterative screening, preferred compounds with high activity against drug-resistant bacteria are obtained; however, compounds with high anti-drug-resistant bacterial activity do not necessarily have high activity against drug-resistant Mycoplasma pneumoniae. The reason is that different species have different numbers of operons. In bacteria with multiple operons, the drug resistance mechanism is the methylation of A2058 catalyzed by erm-mediated erythromycin methylase, while in mycoplasmas with a single operon, it is the mutation of the A2058 base. The former has less impact on the decrease in affinity than the mutation of A2058 to G in mycoplasmas. Therefore, the preferred compounds obtained from antibacterial activity screening have no necessary guiding significance and predictability for improving the activity against drug-resistant Mycoplasma pneumoniae, such as the counterexample - telithromycin. Therefore, the design and screening of compounds against drug-resistant Mycoplasma pneumoniae need to be carried out by analyzing the structure-activity relationship through testing the activity against drug-resistant Mycoplasma pneumoniae. The compounds in the present invention are obtained through structure-activity relationship analysis by testing the activity against drug-resistant Mycoplasma pneumoniae and further testing and screening to obtain compounds that can resist drug-resistant Mycoplasma pneumoniae.

[0030] 2. The preferred compounds obtained after the anti-resistant Mycoplasma pneumoniae activity test screening of the compounds of the present invention also have good antibacterial activity against drug-resistant bacteria in the antibacterial spectrum of erythromycin, and the antibacterial activity is better than that of the second-generation macrolide clarithromycin.

[0031] 3. The compounds of the present invention are connected with side chains through carbamate at the 3-position. Compared with the compounds with ester side chains, they are easily metabolized and hydrolyzed by esterase, and the compounds of the present invention have high stability. Detailed implementation mode

[0032] The following embodiments are provided to better understand the present invention further. They are not limited to the best implementation mode, and do not limit the content and protection scope of the present invention. Any product that is the same as or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior art features falls within the protection scope of the present invention.

[0033] If the specific experimental steps or conditions are not indicated in the embodiments, the operations or conditions of the conventional experimental steps described in the prior art in this field can be carried out. All kinds of chemical drugs used in the present invention are commercially available, and the nuclear magnetic resonance and mass spectrometers used to determine the structures of the following compounds are provided by the Analysis and Testing Center of Beijing Institute of Technology.

[0034] The first aspect of the present invention provides a clarithromycin derivative, and the clarithromycin derivative has a general formula structure shown in the following formula I:

[0035]

[0036] In the formula I, W is selected from any one of an oxygen atom and NOCH2C≡C-Ar, and Ar is selected from any one of a pyridyl group, a quinolinyl group, an isoquinolinyl group, a substituted pyridyl group, a substituted quinolinyl group, and a substituted isoquinolinyl group. Among them, the substituents of the substituted pyridyl group, the substituted quinolinyl group, and the substituted isoquinolinyl group are independently selected from at least one of an acetyl group, a methoxycarbonyl group, a carbamoyl group, an N-(methyl)carbamoyl group, an N,N-(dimethyl)carbamoyl group, an N-(ethyl)carbamoyl group, an N-(cyclopropyl)carbamoyl group, an oxazolyl group, an oxadiazolyl group, a phenyl group, a pyridyl group, a nitro group, a halogen, a cyano group, a hydroxyl group, and an amino group;

[0037] V is selected from any one of an oxygen atom and the 11-position side chain of telithromycin;

[0038] X is selected from any one of -C≡C-, -OCH2CH2C≡C-, and a piperazinyl group;

[0039] Q is selected from any one of a methylene group and a fluorine-substituted carbon atom;

[0040] Z is selected from any one of a methylene group, a fluorine-substituted carbon atom, a nitrogen atom, and a methoxy-substituted carbon atom;

[0041] R 1 and R 2 are each independently selected from a hydrogen atom, a C1-C3 alkyl group, a halogen-substituted C 1-3 alkyl group, a C 3-4 cycloalkyl group, a halogen-substituted C 3-4 cycloalkyl group, and a halogen-substituted phenyl group;

[0042] n ranges from 3 to 6 and is an integer.

[0043] In this article, the term "halogen" means fluorine, chlorine, bromine, and / or iodine. Accordingly, the term "halogenated" means fluorinated, chlorinated, brominated, and / or iodinated. Within the scope of this article, when an atom, residue, group, or moiety is halogenated, the atom at the halogenated position can be mono-substituted, di-substituted, or poly-substituted with halogen atoms up to full substitution. For example, "halogenated C 1-3 alkyl" and "halogenated C 1-3 alkoxy".

[0044] The term "C1-C3 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 3 carbon atoms, a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. The alkyl group is, for example, methyl, ethyl, n-propyl, or isopropyl.

[0045] The term "C 3-4 cycloalkyl" should be understood to mean a saturated monovalent monocyclic ring having 3 to 4 carbon atoms. Such as cyclopropyl, cyclobutyl.

[0046] The above definition of the term "C 1-3 alkyl" also applies to other terms containing "C 1-3 alkyl", such as the term "halogenated C 1-3 alkyl" or "C 1-3 alkoxy" or "halogenated C 1-3 alkoxy", etc.

[0047] The compounds in the examples of the present invention may exist in the form of a solvate (such as a hydrate), wherein the compounds in this article contain a polar solvent, especially water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, may be present in a stoichiometric ratio or a non-stoichiometric ratio.

[0048] Embodiments of the present invention can also provide the use of a compound having a general formula or a pharmaceutically acceptable salt thereof as an antibacterial drug. The present invention can also provide a pharmaceutical composition having antibacterial activity, which composition can include a compound having the aforementioned general formula, or a pharmaceutically acceptable salt formed from a compound having the aforementioned general formula, and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents for pharmaceutically active substances, which are well known in the art. The use of any conventional medium or reagent in the pharmaceutical composition can be considered, except for any conventional medium or reagent that is incompatible with the compound. Supplementary compounds can also be added to the composition.

[0049] Embodiments of the present invention also include prodrugs of the compounds of the present invention, that is, they are administered in a structure that is not disclosed, but are metabolized or transformed into the compounds disclosed in the present invention in the human body and exert pharmacological effects as active pharmaceutical ingredients. For the present invention, various pharmaceutically acceptable acids can form salts on the nitrogen of 5-O-desosaminyl dimethylamine in the general formula or on the nitrogen of the side chain piperazine; the prodrug is esterified at the 3-carboxyl group of quinolone, such as methyl ester, ethyl ester, isopropyl ester, or other (cyclic) alkyl esters containing heteroatoms, etc., and the ester group is hydrolyzed in vivo to release the active group 3-carboxyl. For the conventional methods of preparing prodrugs, see "Design of Prodrugs" (H. Bundgaard, Elsevier, 1985). In this embodiment, preferably, the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, or phosphoric acid; the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, malic acid, or citric acid.

[0050] The quinolone in the embodiments of the present invention refers to benzopyridone or hydroxyquinoline, such as quinolin-4(1H)-one or 4-hydroxyquinoline. In the embodiments of the present invention, due to the presence of the 3-carboxyl group, the quinolone has the general formula structure shown in Formula 1 below:

[0051]

[0052] The quinolone in the embodiments of the present invention also refers to pipemidic acid or nalidixic acid. By changing C-6 of the quinolone of Formula 1 above to N-6, and changing C-8 to N-8, or only changing C-8 to N-8, it has the general formula structures shown in Formula 2 or Formula 3 below:

[0053]

[0054] Among them, the N-1 substituents in Formula 1 - Formula 3 include alkyl, cycloalkyl, aryl substitution, or haloalkyl, halocycloalkyl, haloaryl, such as methyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, 2,4-difluorophenyl, etc. The 6-position in Formula 1 and Formula 3 can be substituted by halogen, such as chlorine, fluorine. The 7-position in Formula 1 - Formula 3 can be substituted by the corresponding heterocycloalkyl, benzheterocycloalkyl at the 7-position in quinolone antibiotics, such as piperazine, methylpiperazine, piperidine, hydroxypiperidine, aminotetrahydropyrrolidine, aminomethyltetrahydropyrrolidine, (1R)-1-methyl-2,3-dihydro-1H-isoindol-5-yl, etc. The 5-position, 6-position and 8-position in Formula 1 can be independently substituted by alkyl, halogen, amino, alkoxy respectively, specifically such as methyl, chlorine, fluorine, amino, methoxy, etc. In addition, the 8-substituent can form a ring with the 1-substituent. As an example, in this case, the heterocycle formed between the 8-position and the 1-position in levofloxacin, for example, the quinolone in the present invention can include 7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine ring.

[0055] The patients in the embodiments of the present invention refer to any animals including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0056] The therapeutically effective amount in the embodiments of the present invention refers to the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are seeking in tissues, systems, animals, individuals or humans to cause a biological or medical response, and it includes one or more of the following: (1) Preventing diseases: For example, preventing diseases, disorders or conditions in an individual who is susceptible to diseases, disorders or conditions but has not yet experienced or shown the pathology or symptoms of the disease. (2) Suppressing diseases: For example, suppressing diseases, disorders or conditions in an individual who is experiencing or showing the pathology or symptoms of the disease, disorder or condition (i.e., preventing the further development of the pathology and / or symptoms). (3) Alleviating diseases: For example, alleviating diseases, disorders or conditions in an individual who is experiencing or showing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0057] To enable those skilled in the art to further understand the technical solutions of the present invention, the following further illustrates a clarithromycin derivative, a pharmaceutical composition and their applications provided by the present invention in a specific embodiment manner.

[0058] The following is a brief description of the synthesis method of the clarithromycin derivative of the present invention. In the synthesis examples listed below, the synthesis of intermediates mainly involves Sonogashira reaction, substitution reaction, nucleophilic addition-elimination reaction, etc. Since the clarithromycin derivative prepared by the present invention is a double-side chain derivative obtained by introducing double side chains at the 9th or 11th position and the 3rd position, after the 9th position reacts with an aryl group through the Sonogashira reaction to obtain a compound with an aryl group introduced at the 9th position, when the hydroxyl group at the 3rd position reacts with carbonyldiimidazole, some active groups such as amide groups on the aryl group at the 9th position will react with carbonyldiimidazole to produce side reactions, resulting in by-products with substituents on the aryl group at the 9th position and double modification of the imidazole carbonyl group at the 3rd position, which is not conducive to the purification of the product and the synthesis of the final product.

[0059] Therefore, in order to avoid the above situation, when synthesizing the double-side chain compound at the 9th and 3rd positions, first react the hydroxyl group at the 3rd position with carbonyldiimidazole, and then introduce aryl modification at the 9th position. Further, the side chain and aryl group are introduced at the 3rd position through stepwise reactions. By the above synthesis method, the generation of by-products on the aryl group at the 9th position can be avoided. When synthesizing the double-side chain compound at the 11th and 3rd positions, after introducing the telithromycin side chain at the 11th position, the hydroxyl group at the 3rd position reacts with carbonyldiimidazole to introduce an imidazole carbonyl group. Further, the side chain and aryl group are introduced at the 3rd position through stepwise reactions. By connecting different quinolone side chains at the 3rd position through carbamate, a clarithromycin derivative more stable than the side chain connected by an ester group is obtained.

[0060] Specifically, the following gives the synthesis methods of representative specific compounds of the present invention.

[0061] Example 1 is the synthesis route of the clarithromycin derivative having the formula II, which is specifically as follows:

[0062]

[0063] The reaction conditions and reagents of the above synthesis route are as follows: a. Acetic anhydride, dichloromethane, room temperature; b. Propargyl bromide, potassium tert-butoxide, DMSO / THF = 1:1; c. Triphosgene, pyridine, dichloromethane, -15 °C; d. CDI (carbonyldiimidazole), DMAP (4-dimethylaminopyridine), dichloromethane; e. Haloaryl, CuI, Pd(PPh3)2Cl2, triethylamine, acetonitrile, 70 °C, f. Butanolamine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DMF, room temperature; g. p-Toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature; h. Ciprofloxacin or enoxacin, etc., acetonitrile, 70 °C; i. Reflux in methanol.

[0064] The steps for preparing the clarithromycin derivative of formula II are as follows:

[0065] Step 1: Dissolve Compound 1 in dichloromethane, then add acetic anhydride dropwise. Stir at room temperature to obtain a mixed solution, and perform post-treatment on the mixed solution to obtain a first solid;

[0066] Step 2: Dissolve the first solid in a mixed solution of DMSO and THF, add potassium tert-butoxide, then add propargyl bromide dropwise. Stir at room temperature, and perform post-treatment after the reaction is completed to obtain Compound 2;

[0067] Step 3: Dissolve Compound 2 in dichloromethane. At low temperature, add a mixed solution of pyridine and triphosgene. After the reaction at low temperature is completed, react the solid obtained by post-treatment with carbonyldiimidazole. After the reaction is completed, perform post-treatment to obtain Compound 3;

[0068] Step 4: Add Compound 3, bis(triphenylphosphine)palladium dichloride, bromoaryl, copper(I) iodide, and triethylamine in sequence, and react under anaerobic conditions. After the reaction is completed, perform post-treatment to obtain Compound 4;

[0069] Step 5: Dissolve Compound 4 in DMF, add butanolamine and DBU, and react at room temperature. After the reaction is completed, perform post-treatment to obtain Compound 5;

[0070] Step 6: Dissolve Compound 5 in dichloromethane, add p-toluenesulfonyl chloride, DMAP, and triethylamine, and react at room temperature. After the reaction is completed, perform post-treatment to obtain Intermediate 27;

[0071] Step 7: Disperse Intermediate 27, ciprofloxacin, enoxacin, or Compound 28 in anhydrous acetonitrile, stir until the reaction is completed, and then perform post-treatment to obtain Compound 6. Example 2 is a synthesis method of Compound 2 and Compound 3:

[0072] Specifically, the synthesis method of Compound 2 is as follows:

[0073] Compound 1 (10.000 g, 16.530 mmol) was dissolved in 50 mL of dichloromethane, and acetic anhydride (4.687 mL, 49.590 mmol) was added dropwise. The mixture was stirred at room temperature for 30 - 60 min. After the reaction monitoring was completed, it was washed 5 times with 50 mL of saturated sodium bicarbonate solution for 30 min each time to remove the excess acetic anhydride. Then it was washed successively with water and saturated sodium chloride solution, and the organic phase was dried by rotary evaporation and placed in a vacuum oven to obtain 11.343 g (16.466 mmol, 99.61%) of a pale yellow fluffy solid. The obtained pale yellow fluffy solid (2.799 g, 4.063 mmol) was dissolved in a mixed solution of 50 mL of THF and 50 mL of DMSO, potassium tert-butoxide (0.684 g, 6.094 mmol) was added, and the mixture was stirred at room temperature for 15 min to remove the acetyl group at the 9th position. Then potassium tert-butoxide (0.456 g, 4.063 mmol) was added and 80% propargyl bromide (0.48 mL, 4.466 mmol) was added dropwise. The reaction was carried out at room temperature for 15 min. After the reaction monitoring was completed, 50 mL of ethyl acetate and 50 mL of distilled water were added to the reaction system. The aqueous layer was washed 3 times with ethyl acetate and the organic phases were combined. The organic layer was washed 3 times with water and once with saturated brine, and the organic phase was dried by rotary evaporation to obtain 2.325 g (3.395 mmol, 83.56%) of a fluffy vesicular pale yellow solid (Compound 2).

[0074] Specifically, the synthesis method of Compound 3 is as follows:

[0075] Dissolve compound 2 (9.300 g, 13.623 mmol) in 40 mL of dichloromethane and place it in an ice-salt bath at -15 °C. After the temperature stabilizes, add pyridine (9.92 mL, 122.607 mmol). Dissolve triphosgene (6.064 g, 20.434 mmol) in 30 mL of dichloromethane and slowly add it dropwise to the above reaction system. After the addition is complete, maintain the reaction at -15 °C for 4 h, and then transfer it to room temperature for 10 h. After the reaction monitoring is completed, transfer the system to an ice-water bath and slowly add 40 mL of saturated sodium chloride solution dropwise. The organic phase is washed successively with saturated sodium bicarbonate, water, and saturated sodium chloride. The organic phase is dried by rotary evaporation, and column chromatography is carried out on silica gel of 100 - 200 mesh, with the mobile phase being dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05, to obtain 4.201 g (5.910 mmol, 43.38%) of a yellow fluffy solid compound. Disperse the yellow fluffy solid compound (6.012 g, 8.458 mmol), DMAP (2.066 g, 16.915 mmol), and CDI (4.114 g, 25.373 mmol) in 10 mL of dry dichloromethane and react at room temperature for 12 - 14 h. After the reaction monitoring is completed, add 50 mL of dichloromethane, wash twice with saturated ammonium chloride, once with water, and once with saturated brine. The organic phase is dried by rotary evaporation and purified by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05) to obtain 4.530 g (5.631 mmol, 66.58%) of a white fluffy solid (compound 3).

[0076] Example 3 is the general synthesis method of compounds 4a - 4n:

[0077] Add compound 3 (1 eq), bis(triphenylphosphine)palladium(II) dichloride (0.05 eq), aryl bromide (1.2 eq), copper(I) iodide (0.1 eq), and triethylamine (1.5 eq) to a pressure-resistant flask. After purging with gas, seal and transfer it to a 70 °C water bath and react for 4 h. After the reaction monitoring is completed, add 30 mL of dichloromethane to the reaction system, wash successively with water, saturated sodium bicarbonate, and saturated sodium chloride solution, dry the organic phase by rotary evaporation, and purify by column chromatography to obtain compounds 4a - 4n.

[0078] Specifically, the synthesis method of compound 4a is as follows:

[0079] React compound 3 (3.500 g, 4.351 mmol) with 3-bromopyridine (0.46 mL, 4.786 mmol) according to the synthesis method of Example 3, and purify the product by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 1.000 g (1.268 mmol, 29.14%) of compound 4a.

[0080] Specifically, the synthesis method of compound 4b is as follows:

[0081] According to the synthesis method of Example 3, compound 3 (3.500 g, 4.351 mmol) was reacted with 5-bromo-3-acetylpyridine (0.870 g, 4.351 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 1.526 g (1.652 mmol, 37.97%) of compound 4b.

[0082] Specifically, the synthesis method of compound 4c is as follows:

[0083] According to the synthesis method of Example 3, compound 3 (1.800 g, 2.238 mmol) was reacted with methyl 5-bromonicotinate (0.532 g, 2.461 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.877 g (0.946 mmol, 42.27%) of compound 4c.

[0084] Specifically, the synthesis method of compound 4d is as follows:

[0085] According to the synthesis method of Example 3, compound 3 (4.000 g, 4.972 mmol) was reacted with 5-bromo-nicotinamide (1.199 g, 5.967 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 1.404 g (1.481 mmol, 29.78%) of compound 4d.

[0086] Specifically, the synthesis method of compound 4e is as follows:

[0087] According to the synthesis method of Example 3, compound 3 (4.000 g, 4.972 mmol) was reacted with 5-bromo-N-methylnicotinamide (1.283 g, 5.967 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.2 / 0.1) to obtain 1.324 g (1.410 mmol, 28.36%) of compound 4e.

[0088] Specifically, the synthesis method of compound 4f is as follows:

[0089] Using the synthetic method of Example 3, compound 3 (4.500 g, 5.594 mmol) was reacted with 5-bromo-N,N-dimethylnicotinamide (1.483 g, 6.154 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 2.412 g (2.494 mmol, 44.58%) of compound 4f.

[0090] Specifically, the synthetic method of compound 4g is as follows:

[0091] Using the synthetic method of Example 3, compound 3 (4.500 g, 5.594 mmol) was reacted with 5-bromo-N-cyclopropylnicotinamide (1.483 g, 6.154 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.2 / 0.1) to obtain 2.658 g (2.757 mmol, 49.29%) of compound 4g.

[0092] Specifically, the synthetic method of compound 4h is as follows:

[0093] Using the synthetic method of Example 3, compound 3 (3.613 g, 4.490 mmol) was reacted with 4-bromopyridine-2-carboxamide (1.078 g, 5.388 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 2.423 g (2.661 mmol, 59.27%) of compound 4h.

[0094] Specifically, the synthetic method of compound 4i is as follows:

[0095] Using the synthetic method of Example 3, compound 3 (5.800 g, 7.220 mmol) was reacted with 5-bromopyridine-2-carboxamide (1.739 g, 8.652 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 2.000 g (2.162 mmol, 29.94%) of compound 4i.

[0096] Specifically, the synthetic method of compound 4j is as follows:

[0097] According to the synthesis method of Example 3, compound 3 (4.500 g, 5.594 mmol) was reacted with 2-(5-bromopyridin-3-yl)-1,3,4-oxadiazole (1.391 g, 6.154 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 2.692 g (2.833 mmol, 50.64%) of compound 4j.

[0098] Specifically, the synthesis method of compound 4k is as follows:

[0099] According to the synthesis method of Example 3, compound 3 (1.500 g, 1.865 mmol) was reacted with 5-bromo-2,2′-bipyridine (0.526 g, 2.238 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.733 g (0.764 mmol, 40.96%) of compound 4k.

[0100] Specifically, the synthesis method of compound 4l is as follows:

[0101] According to the synthesis method of Example 3, compound 3 (3.000 g, 3.729 mmol) was reacted with 7-bromoisoquinolin-1(2H)-one (1.003 g, 4.475 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.2 / 0.1) to obtain 0.605 g (0.638 mmol, 17.11%) of compound 4l.

[0102] Specifically, the synthesis method of compound 4m is as follows:

[0103] According to the synthesis method of Example 3, compound 3 (1.800 g, 2.238 mmol) was reacted with 3-bromoquinoline (0.36 mL, 2.686 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.989 g (1.061 mmol, 47.40%) of compound 4m.

[0104] Specifically, the synthesis method of compound 4n is as follows:

[0105] According to the synthesis method of Example 3, compound 3 (2.000 g, 2.486 mmol) was reacted with 4-bromoisoquinoline (0.620 g, 2.983 mmol), and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.496 g (0.532 mmol, 21.40%) of compound 4n.

[0106] Example 4 is the synthesis method of the compound 5a-5n series:

[0107] Compound 4a-4n (1 eq) was dissolved in DMF, and butanolamine (2 eq) and DBU (1 eq) were added dropwise, and the reaction was carried out at room temperature for 12-15 h. After the reaction monitoring was completed, ethyl acetate was added. It was washed three times with water and once with saturated brine, and the organic phase was dried by evaporation and purified by column chromatography to obtain compound 5a-5n.

[0108] Specifically, the synthesis method of compound 5a is as follows:

[0109] According to the synthesis method of Example 4, compound 4a (0.500 g, 0.634 mmol) was reacted, and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.247 g (0.274 mmol, 43.14%) of compound 5a. HRMS(ESI)(M+H) + m / z 903.4958, calcd for C 46 H 71 N4O 14 903.4961.

[0110] Specifically, the synthesis method of compound 5b is as follows:

[0111] According to the synthesis method of Example 4, compound 4b (0.763 g, 0.826 mmol) was reacted, and the product was purified by column chromatography (silica gel 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.274 g (0.290 mmol, 35.11%) of compound 5b. HRMS(ESI)(M+H) + m / z 945.5063, calcd for C 48 H 73 N4O 15 945.5067.

[0112] Specifically, the synthesis method of compound 5c is as follows:

[0113] Using compound 4c (0.877 g, 0.946 mmol) in the synthesis method according to Example 4, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.222 g (0.228 mmol, 24.10%) of compound 5c. HRMS (ESI) (M+H) + m / z 961.4993, calcd for C 48 H 73 N4O 16 961.5016.

[0114] Specifically, the synthesis method of compound 5d is as follows:

[0115] Using compound 4d (0.904 g, 1.442 mmol) in the synthesis method according to Example 4, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.354 g (0.373 mmol, 25.87%) of compound 5d. HRMS (ESI) (M+H) + m / z 946.5028, calcd for C 47 H 72 N5O 15 946.5019.

[0116] Specifically, the synthesis method of compound 5e is as follows:

[0117] Using compound 4e (0.958 g, 1.036 mmol) in the synthesis method according to Example 4, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.258 g (0.268 mmol, 25.87%) of compound 5e. HRMS (ESI) (M+H) + m / z 960.5156, calcd for C 48 H 74 N5O 15 960.5176. 11H NMR (CDCl3, 400 MHz) δ: 9.04 (d, J = 2.2 Hz, 1H, 6″′-pyridyl), 8.74 (d, J = 1.9 Hz, 1H, 2″′-pyridyl), 8.14 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 6.78 (d, J = 5.1 Hz, 1H, NH-CH3), 5.19 - 5.10 (m, 2H, H-13, NH), 4.92 - 4.82 (m, 4H, H-11, 9-O-CH2, H-3), 4.73 (dd, J = 7.5 Hz, 10.5 Hz, 1H, H-2′), 4.12 (d, J = 7.5 Hz, 1H, H-1′), 3.75 (d, J = 3.2 Hz, 1H, H-5), 3.73 - 3.65 (m, 3H, -CH2-OH, H-8), 3.42 - 3.29 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.22 - 3.12 (m, 1H, 3-O-CO-NH-CH2), 3.07 - 2.97 (s, 6H, 6-O-CH3, NH-CH3), 2.89 - 2.79 (m, 1H, H-2), 2.76 - 2.65 (m, 1H, H-3′), 2.54 (q, J = 6.8 Hz, 1H, H-10), 2.29 (s, 6H, -N(CH3)2), 2.09 (s, 3H, 2′-OAc), 2.07 - 1.99 (m, 1H, H-4), 1.97 - 1.86 (m, 1H, H-14eq), 1.78 - 1.55 (m, 6H, H-7a, H-4′a, H-14ax, H-7b, -CH2-), 1.52 (s, 3H, 12-CH3), 1.39 - 1.30 (m, 6H, -CH2-, 6-CH3, H-4′a), 1.28 (d, J = 6.8 Hz, 3H, 10-CH3), 1.24 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.15 (d, J = 6.7 Hz, 3H, 2-CH3), 0.98 (d, J = 7.0 Hz, 3H, 4-CH3), 0.94 (d, J = 7.5 Hz, 3H, 8-CH3), 0.89 (t, J = 7.4 Hz, 3H, 15-CH3).

[0118] Specifically, the synthesis method of compound 5f is as follows:

[0119] React according to the synthesis method of Example 4 using compound 4f (0.800 g, 0.827 mmol). The product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.372 g (0.375 mmol, 45.34%) of compound 5f. HRMS (ESI) (M + H)+ m / z 974.5296, calcd for C 49 H 76 N5O 15 974.5332.

[0120] Specifically, the synthesis method of compound 5g is as follows:

[0121] React according to the synthesis method of Example 4 using compound 4g (0.800 g, 0.829 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.296 g (0.299 mmol, 36.07%) of compound 5g. HRMS(ESI)(M + H) + m / z 986.5302, calcd for C 50 H 76 N5O 15 986.5332.

[0122] Specifically, the synthesis method of compound 5h is as follows:

[0123] React according to the synthesis method of Example 4 using compound 4h (1.305 g, 1.582 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.374 g (0.394 mmol, 24.91%) of compound 5h. HRMS(ESI)(M + H) + m / z 946.5020, calcd for C 47 H 72 N5O 15 946.5019.

[0124] Specifically, the synthesis method of compound 5i is as follows:

[0125] React according to the synthesis method of Example 4 using compound 4i (1.000 g, 1.081 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.413 g (0.435 mmol, 40.24%) of compound 5i. HRMS(ESI)(M + H) + m / z 946.5028, calcd for C 47 H 72 N5O 15 946.5019.

[0126] Specifically, the synthesis method of compound 5j is as follows:

[0127] The reaction was carried out using compound 4j (0.800 g, 0.842 mmol) according to the synthesis method of Example 4, and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.513 g (0.526 mmol, 62.74%) of compound 5j. HRMS(ESI)(M + H) + m / z 971.4929, calcd for C 48 H 71 N6O 15 971.4972.

[0128] Specifically, the synthesis method of compound 5k is as follows:

[0129] The reaction was carried out using compound 4k (0.733 g, 0.764 mmol) according to the synthesis method of Example 4, and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.353 g (0.364 mmol, 47.64%) of compound 5k.

[0130] Specifically, the synthesis method of compound 5l is as follows:

[0131] The reaction was carried out using compound 4l (0.668 g, 0.688 mmol) according to the synthesis method of Example 4, and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.327 g (0.337 mmol, 48.98%) of compound 5l. HRMS(ESI)(M + H) + m / z 969.5087, calcd for C 50 H 73 N4O 15 969.5067.

[0132] Specifically, the synthesis method of compound 5m is as follows:

[0133] The reaction was carried out using compound 4m (0.989 g, 1.061 mmol) according to the synthesis method of Example 4, and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.420 g (0.441 mmol, 41.56%) of compound 5m. HRMS(ESI)(M + H) + m / z 953.5122, calcd for C 50 H 73 N4O 14953.5118.

[0134] Specifically, the synthesis method of compound 5n is as follows:

[0135] React according to the synthesis method of Example 4 using compound 4n (0.977 g, 1.048 mmol). The product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.425 g (0.446 mmol, 42.56%) of compound 5n. HRMS (ESI)(M+H) + m / z 953.5117, calcd for C 50 H 73 N4O 14 953.5118.

[0136] The following Examples 5 - 21 are the synthetic routes and methods for the compound 6 series, and the synthetic method for the compound 6 series is as shown in Example 5 - 1:

[0137] Dissolve compound 5a - 5n (1 eq) in dry dichloromethane, add p - toluenesulfonyl chloride (2 eq), DMAP (2 eq), and triethylamine (2 eq) to the system, and react at room temperature for 1 - 2 h. After the reaction monitoring is completed, wash with saturated ammonium chloride, water, and saturated brine respectively, spin - dry the organic phase, and obtain intermediates 27a - 27n after column chromatography.

[0138] Disperse the intermediate 27a - 27n (1 eq) from the above - step reaction, and ciprofloxacin, enoxacin, or compound 28 (5 eq) in anhydrous acetonitrile, and stir at 75 °C for 72 h. After the reaction monitoring is completed, spin - dry the reaction solution, add 50 mL of dichloromethane, wash with water 3 times and with saturated brine once, spin - dry the organic phase, add 20 mL of methanol to de - acetylate, and after the reaction monitoring is completed, spin - dry the reaction solution and purify by column chromatography to obtain the general formula compound 6 series.

[0139] The synthetic route of Example 5 - compound 6aA is as follows:

[0140]

[0141] React according to the synthesis method of Example 5 - 1 using compound 5a (0.247 g, 0.274 mmol), and obtain 0.188 g (0.178 mmol, 64.96%) of intermediate 27a after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1).

[0142] Intermediate 27a (0.188 g, 0.178 mmol) was reacted with ciprofloxacin (0.177 g, 0.533 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 20.2 mg (0.0172 mmol, 9.66%) of compound 6aA was obtained. Melting point: 170.0 - 170.4 °C. HRMS(ESI)(M + H) + m / z 1174.6047, calcd for C 61 H 85 FN7O 15 1174.6082. 11H NMR (CDCl3, 400 MHz) δ: 8.69 (s, 1H, 2″-quinolyl), 8.58 (s, 1H, 2″′-pyridyl), 8.45 (d, J = 4.8 Hz, 1H, 5″′-pyridyl), 7.94 (d, J = 13.0 Hz, 1H, 5″-quinoly), 7.65 (dd, J = 2.0 Hz, 8.0 Hz, 1H, 4″′-pyridyl), 7.29 (d, J = 7.6 Hz, 1H, 8″-quinolyl), 7.17 (dd, J = 4.9 Hz, 7.9 Hz, 1H, 5″′-pyridyl), 5.51 (s, 1H, 3-O-CO-NH-CH2), 5.09 (d, J = 11.0 Hz, 1H, H-13), 4.89 - 4.72 (m, 4H, H-11, 9-O-CH2, H-3), 3.95 (d, J = 7.5 Hz, 1H, H-1′), 3.75 - 3.61 (m, 2H, H-5, H-8), 3.55 - 3.44 (m, 1H, H-cyclopropyl), 3.38 - 3.23 (m, 5H, H-5′, 4H-piperazinyl), 3.23 - 3.16 (m, 1H, 3-O-CO-NH-CH2), 3.15 - 3.06 (m, 1H, H-2′), 3.06 - 2.99 (m, 1H, 3-O-CO-NH-CH2), 2.98 (s, 3H, 6-O-CH3), 2.80 - 2.69 (m, 1H, H-2), 2.66 - 2.49 (m, 4H, 4H-piperazinyl), 2.48 - 2.26 (m, 4H, H-10, -CH2-quinolyl, H-3′), 2.20 (s, 6H, -N(CH3)2), 2.05 - 1.93 (m, 1H, H-4), 1.89 - 1.74 (m, 1H, H-14eq), 1.63 - 1.44 (m, 7H, H-4′a, H-14ax, H-7b, 2(-CH2-)), 1.41 (s, 3H, 12-CH3), 1.38 - 1.21 (m, 6H, H-7a, H-4′b, 6-CH3, 2H-cyclopropyl), 1.24 - 1.10 (m, 8H, 10-CH3, 5′-CH3, 2H-cyclopropyl), 1.10 - 1.02 (m, 3H, 2-CH3), 0.98 (d, J = 7.0 Hz, 3H, 4-CH3), 0.89 (d, J = 6.9 Hz, 3H, 8-CH3), 0.78 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR (CDCl3, 176 MHz) δ: 177.11, 174.06, 167.04, 166.13, 156.37, 154.67, 154.65, 152.36, 152.35, 148.63, 147.41, 145.80, 139.11, 138.77, 138.54, 123.02, 120.12, 112.50, 112.36, 108.16, 104.79, 104.19, 103.25, 89.37, 89.36, 85.05, 85.01, 82.96, 82.94, 82.42, 78.36, 75.43, 70.44, 69.52, 66.21, 61.85, 61.84, 57.86, 52.86, 52.79, 49.92, 49.71, 43.36, 41.05, 40.40, 37.33, 35.97, 35.32, 32.98, 29.70, 29.66, 28.56, 28.07, 26.04, 24.19, 22.69, 22.21, 21.24, 19.40, 18.85, 15.61, 15.56, 14.94, 13.00, 10.20, 9.02, 8.25, 8.12.

[0143] Synthetic route of Example 6 - Compound 6bA is as follows:

[0144]

[0145] According to the synthesis method of Example 5 - 1, using Compound 5b (0.274 g, 0.290 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27b 0.259 g (0.235 mmol, 81.03%) was obtained.

[0146] Using intermediate 27b (0.259 g, 0.235 mmol) and ciprofloxacin (0.234 g, 0.707 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6bA 27.6 mg (0.0227 mmol, 9.66%) was obtained. Melting point: 169.3 - 170.4 °C. HRMS (ESI) (M + H) + m / z 1216.6179, calcd for C 63 H 87 FN7O 16 1216.6188. 11H NMR (CDCl3, 400 MHz) δ: 8.98 (t, J = 1.9 Hz, 1H, 2″′-pyridyl), 8.72 (t, J = 1.9 Hz, 1H, 4″′-pyridyl), 8.70 (s, 1H, 2″-quinolyl), 8.19 (q, J = 1.9 Hz, 1H, 6″′-pyridyl), 7.95 (d, J = 13.0 Hz, 1H, 5″-quinoly), 7.29 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.49 (s, 1H, 3-O-CO-NH-CH2), 5.09 (d, J = 9.1 Hz, 1H, H-13), 4.87 - 4.71 (m, 4H, H-11, 9-O-CH2, H-3), 3.94 (d, J = 7.4 Hz, 1H, H-1′), 3.73 - 3.62 (m, 2H, H-5, H-8), 3.53 - 3.44 (m, 1H, H-cyclopropyl), 3.37 - 3.23 (m, 5H, H-5′, 4H-piperazinyl), 3.23 - 3.16 (m, 1H, 3-O-CO-NH-CH2), 3.15 - 3.06 (m, 1H, H-2′), 3.06 - 2.99 (m, 1H, 3-O-CO-NH-CH2), 2.96 (s, 3H, 6-O-CH3), 2.80 - 2.71 (m, 1H, H-2), 2.64 - 2.57 (m, 4H, 4H-piperazinyl), 2.56 (s, 3H, pyridyl-CO-CH3), 2.50 - 2.25 (m, 4H, H-10, -CH2-quinolyl, H-3′), 2.20 (s, 6H, -N(CH3)2), 2.02 - 1.93 (m, 1H, H-4), 1.91 - 1.77 (m, 1H, H-14eq, H-7a), 1.62 - 1.45 (m, 8H, H-4′a, H-14ax, H-7b, 2(-CH2-)), 1.42 (s, 3H, 12-CH3), 1.38 - 1.22 (m, 6H, H-4′b, 6-CH3, 2H-cyclopropyl), 1.24 - 1.10 (m, 8H, 10-CH3, 5′-CH3, 2H-cyclopropyl), 1.10 - 1.01 (m, 3H, 2-CH3), 0.98 (d, J = 7.2 Hz, 3H, 4-CH3), 0.90 (d, J = 6.9 Hz, 3H, 8-CH3), 0.78 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 176 MHz) δ: 196.21, 177.13, 174.05, 167.04, 166.20, 155.59, 155.58, 154.65, 148.38, 139.11, 138.31, 131.54, 120.41, 108.20, 104.76, 103.23, 90.78, 90.75, 85.03, 82.89, 81.49, 78.36, 75.39, 70.44, 69.53, 66.21, 61.70, 61.68, 57.87, 52.80, 49.94, 49.72, 43.35, 41.05, 40.40, 37.30, 35.97, 35.30, 33.01, 29.70, 28.55, 28.07, 26.82, 26.05, 24.20, 22.19, 21.24, 19.41, 18.86, 15.62, 14.94, 12.97, 10.17, 9.01, 8.26.

[0147] Synthetic route of Example 7 - Compound 6cB is as follows:

[0148]

[0149] According to the synthesis method of Example 5 - 1, react with Compound 5c (0.222 g, 0.228 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27c 0.210 g (0.188 mmol, 82.46%) is obtained.

[0150] React intermediate 27c (0.210 g, 0.188 mmol) with enoxacin (0.181 g, 0.565 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6cB 79.8 mg (0.0653 mmol, 34.75%) is obtained. Melting point: 156.1 - 156.5 °C. HRMS(ESI)(M + H) + m / z 1221.6046, calcd for C 61 H 86 FN8O 17 1221.6089. 11H NMR (CD3OD, 400 MHz) δ: 9.03 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.83 (s, 1H, 2″-quinolyl), 8.78 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.43 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 8.07 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.13 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.99 - 4.88 (m, 3H, H-11, 9-O-CH2), 4.83 (d, J = 11.2 Hz, 1H, H-3), 4.48 (s, 2H, N-CH2CH3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.96 (s, 3H, OCH3), 3.90 (s, 4H, 4H-piperazinyl), 3.85 (d, J = 3.3 Hz, 1H, H-5), 3.80 - 3.72 (m, 1H, H-8), 3.47 - 3.39 (m, 1H, H-5′), 3.31 - 3.23 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.10 - 3.00 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.96 - 2.87 (m, 1H, H-2), 2.77 - 2.59 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.37 (m, 8H -CH2-C≡C-quinolyl, -N(CH3)2), 2.15 - 2.05 (m, 1H, H-4), 1.94 - 1.74 (m, 2H, H-14eq, H-7a), 1.72 - 1.59 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.57 (s, 3H, 12-CH3), 1.53 - 1.42 (m, 5H, -CH2-, N-CH2CH3), 1.35 (s, 3H, 6-CH3), 1.33 - 1.29 (m, 1H, H-4′b), 1.27 (d, J = 6.7 Hz, 3H, 10-CH3), 1.21 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.18 - 1.07 (m, 6H, 2-CH3, 4-CH3), 1.02 (d, J = 7.0 Hz, 3H, 8-CH3), 0.91 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR (CDCl3, 100 MHz) δ: 165.14, 155.63, 154.62, 149.52, 146.41, 145.08, 139.64, 125.57, 120.14, 120.14, 109.35, 103.25, 90.56, 85.00, 82.93, 81.44, 78.37, 77.25, 75.35, 70.45, 61.73, 57.82, 52.95, 52.54, 49.92, 47.74, 46.92, 43.38, 40.41, 37.33, 35.98, 33.02, 28.06, 26.05, 22.22, 21.22, 19.39, 18.87, 15.62, 14.98, 14.93, 12.98, 10.16, 8.97.

[0151] Synthetic route of Example 8 - Compound 6dA is as follows:

[0152]

[0153] According to the synthesis method of Example 5 - 1, react with Compound 5d (0.354 g, 0.373 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27d 0.270 g (0.245 mmol, 65.79%) is obtained.

[0154] React intermediate 27d (0.135 g, 0.123 mmol) with ciprofloxacin (0.122 g, 0.368 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6dA 33.8 mg (0.0278 mmol, 22.57%) is obtained. Melting point: 173.9 - 174.3 °C. HRMS (ESI) (M + H) + m / z 1217.6140, calcd for C 62 H 86 FN8O 16 1217.6140. 11H NMR (CD3OD, 400 MHz) δ: 8.93 (d, J = 2.1 Hz, 1H, 2″′-pyridyl), 8.77 (s, 1H, 2″-quinolyl), 8.72 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.29 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 7.89 (d, J = 10.8 Hz, 1H, 5″-quinolyl), 7.54 (s, 1H, 8″-quinolyl), 5.14 (dd, J = 2.4 Hz, 10.7 Hz, 1H, H-13), 4.95 - 4.79 (m, 4H, H-11, 9-O-CH2, H-3), 4.12 (d, J = 7.3 Hz, 1H, H-1′), 3.84 (d, J = 3.2 Hz, 1H, H-5), 3.79 - 3.69 (m, 2H, H-8, H-cyclopropyl), 3.49 - 3.33 (m, 5H, H-5′, 4H-piperazinyl), 3.29 - 3.21 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.08 - 2.99 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.96 - 2.85 (m, 1H, H-2), 2.78 - 2.63 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.53 - 2.45 (m, 2H-CH2-quinolyl), 2.41 (s, 6H, -N(CH3)2), 2.14 - 2.04 (m, 1H, H-4), 1.90 - 1.72 (m, 2H, H-14eq, H-7a), 1.96 - 1.57 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.55 (s, 3H, 12-CH3), 1.52 - 1.42 (m, 2H, -CH2-), 1.42 - 1.35 (m, 2H, 2H-cyclopropyl), 1.34 (s, 3H, 6-CH3), 1.30 - 1.26 (m, 3H, H-4′a, 2H-cyclopropyl), 1.24 (d, J = 6.5 Hz, 3H, 10-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.15 - 1.06 (m, 6H, 2-CH3, 4-CH3), 1.00 (d, J = 7.0 Hz, 3H, 8-CH3), 0.88 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR (CD3OD, 176 MHz) δ: 174.58, 167.54, 167.04, 157.40, 154.92, 153.62, 147.17, 138.05, 129.64, 120.28, 101.80, 90.57, 85.44, 83.04, 80.88, 78.36, 78.08, 77.31, 75.22, 70.62, 68.72, 64.56, 60.93, 57.74, 52.55, 49.32, 49.22, 43.19, 40.34, 39.47, 36.88, 35.92, 32.96, 30.86, 27.60, 26.05, 23.34, 21.85, 20.04, 18.63, 17.65, 14.66, 13.94, 11.77, 9.26, 7.96, 7.15.

[0155] The synthetic route of Example 9 - Compound 6dB is as follows:

[0156]

[0157] According to the synthesis method of Example 5 - 1, reacting with Compound 5d (0.354 g, 0.373 mmol), after purification by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27d 0.270 g (0.245 mmol, 65.79%) was obtained.

[0158] Reacting intermediate 27d (0.135 g, 0.123 mmol) with enoxacin (0.118 g, 0.368 mmol), after purification by column chromatography (silica gel of 100 - 200 mesh, developing agent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6dB 63.5 mg (0.0526 mmol, 42.79%) was obtained. Melting point: 181.6 - 182.5 °C. HRMS (ESI) (M + H) + m / z 1206.6102, calcd for C 60 H 85 FN9O 16 1206.6093. 11H NMR (CD3OD, 400 MHz) δ: 8.94 (d, J = 2.1 Hz, 1H, 2″′-pyridyl), 8.79 (s, 1H, 2″-quinolyl), 8.72 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.29 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 8.00 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.13 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.94 - 4.79 (m, 4H, H-11, 9-O-CH2, H-3), 4.54 (s, 2H, N-CH2CH3), 4.12 (d, J = 7.2 Hz, 1H, H-1′), 3.93 - 3.79 (m, 5H, 4H-piperazinyl, H-5), 3.79 - 3.70 (m, 1H, H-8), 3.46 - 3.37 (m, 1H, H-5′), 3.29 - 3.21 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.08 - 2.99 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.95 - 2.84 (m, 1H, H-2), 2.78 - 2.66 (m, 2H, H-3′, H-10), 3.63 (br, 4H, 4H-piperazinyl), 2.50 - 2.37 (m, 8H -CH2-quinolyl, -N(CH3)2), 2.12 - 2.03 (m, 1H, H-4), 1.89 - 1.73 (m, 2H, H-14eq, H-7a), 1.96 - 1.56 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.55 (s, 3H, 12-CH3), 1.49 - 1.39 (m, 5H, -CH2-, N-CH2CH3), 1.33 (s, 3H, 6-CH3), 1.30 - 1.26 (m, 1H, H-4′b), 1.24 (d, J = 6.7 Hz, 3H, 10-CH3), 1.19 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.15 - 1.05 (m, 6H, 2-CH3, 4-CH3), 1.00 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 100MHz) δ: 174.57, 167.52, 167.05, 157.38, 154.92, 153.63, 147.19, 138.04, 129.63, 120.27, 101.81, 90.59, 85.44, 83.05, 80.89, 78.36, 78.11, 77.32, 75.22, 70.66, 68.72, 64.55, 60.95, 57.65, 52.62, 49.32, 46.51, 43.19, 40.33, 39.51, 36.89, 35.92, 32.97, 30.93, 27.56, 26.06, 23.33, 21.85, 20.05, 18.64, 17.66, 14.67, 13.94, 11.78, 9.28, 7.96.

[0159] Synthetic route of Example 10 - Compound 6eA is as follows:

[0160]

[0161] According to the synthesis method of Example 5 - 1, react with compound 5e (0.258 g, 0.268 mmol), and after purification by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27e 0.205 g (0.184 mmol, 68.66%) is obtained.

[0162] React intermediate 27e (0.185 g, 0.178 mmol) with ciprofloxacin (0.295 g, 0.890 mmol), and purify the product with silica gel of 100 - 200 mesh and the developing agent of dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5 to obtain 25.3 mg (0.0205 mmol, 11.54%) of white fluffy solid compound 6eA. HRMS(ESI)(M + H) + m / z 1231.6309, calcd for C 63 H 88 FN8O 161231.6297.1H NMR (CDCl3, 700 MHz) δ: 9.03 (d, J = 2.2 Hz, 1H, 6″′-pyridyl), 8.76 (s, 1H, 2″-quinolyl), 8.72 (d, J = 1.9 Hz, 1H, 2″′-pyridyl), 8.14 (s, 1H, 4″′-pyridyl), 8.00 (d, J = 12.91 Hz, 1H, 5″-quinolyl), 7.36 (d, J = 6.9 Hz, 1H, 8″-quinolyl), 6.82 (br, 1H, NH-CH3), 5.64 (t, J = 5.8 Hz, 1H, 3-O-CO-NH-CH2), 5.15 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.90 (s,17(m, 2H, 2H-cyclopropyl), 1.15(d, J=6.8 Hz, 3H, 2-CH3), 1.07(d, J=7.5 Hz, 3H, 4-CH3), 0.97(d, J=7.0 Hz, 3H, 8-CH3), 0.87(t, J=7.4 Hz, 3H, 15-CH3). 13 13C NMR(CDCl3, 100 MHz) δ: 177.12, 174.24, 167.04, 165.87, 165.44, 156.37, 154.97, 154.06, 152.41, 148.04, 147.42, 139.11, 136.91, 129.40, 119.89, 112.53, 112.30, 108.14, 104.79, 103.25, 90.51, 85.24, 83.15, 81.83, 80.94, 78.37, 77.92, 77.25, 75.44, 71.81, 70.43, 69.51, 66.21, 61.57, 57.85, 52.78, 50.05, 49.70, 43.37, 41.08, 40.36, 37.33, 36.04, 35.32, 33.04, 28.07, 26.86, 26.03, 24.18, 22.18, 21.24, 19.43, 18.88, 15.69, 14.97, 12.94, 10.20, 9.01, 8.25.

[0163] Example 11 - The synthetic route of compound 6eB is as follows:

[0164]

[0165] According to the synthesis method of Example 5 - 1, using compound 5e (0.258 g, 0.268 mmol) for reaction, after purification by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27e 0.205 g (0.184 mmol, 68.66%) was obtained.

[0166] Using intermediate 27e (0.205 g, 0.184 mmol) and enoxacin (0.177 g, 0.552 mmol) for reaction, after purification by column chromatography (silica gel of 100 - 200 mesh, developing agent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), compound 6eB 80.0 mg (0.0656 mmol, 35.65%) was obtained. Melting point: 180.3 - 181.7 °C. HRMS(ESI)(M + H) + m / z 1220.6216, calcd for C61 H 87 FN9O 16 1220.6249. 1 1H NMR (CD3OD, 400 MHz) δ: 8.90 (d, J = 2.1 Hz, 1H, 2′″-pyridyl), 8.83 (s, 1H, 2″-quinolyl), 8.73 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.25 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 8.06 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.16 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.97 - 4.80 (m, 4H, H-11, 9-O-CH2, H-3), 4.48 (s, 2H, N-CH2CH3), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 3.90 (s, 4H, 4H-piperazinyl), 3.86 (d, J = 3.3 Hz, 1H, H-5), 3.81 - 3.71 (m, 1H, H-8), 3.49 - 3.38 (m, 1H, H-5′), 3.32 - 3.23 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.10 - 3.01 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.97 - 2.84 (m, 4H, H-2, NCH3), 2.79 - 2.58 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.36 (m, 8H -CH2-C≡C-quinolyl, -N(CH3)2), 2.16 - 2.06 (m, 1H, H-4), 1.92 - 1.75 (m, 2H, H-14eq, H-7a), 1.72 - 1.58 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.57 (s, 3H, 12-CH3), 1.54 - 1.42 (m, 5H, -CH2-, N-CH2CH3), 1.36 (s, 3H, 6-CH3), 1.34 - 1.28 (m, 1H, H-4′b), 1.26 (d, J = 6.7 Hz, 3H, 10-CH3), 1.22 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.19 - 1.08 (m, 6H, 2-CH3, 4-CH3), 1.02 (d, J = 7.0 Hz, 3H, 8-CH3), 0.91 (t, J = 7.3 Hz, 3H, 15-CH3). 13CNMR (CDCl3, 176 MHz) δ: 177.07, 167.02, 165.93, 165.45, 154.97, 154.02, 153.93, 150.41, 150.36, 148.03, 146.60, 146.42, 145.07, 136.95, 129.42, 120.30, 120.18, 119.87, 113.79, 109.30, 90.49, 85.26, 83.15, 81.84, 78.35, 75.41, 75.41, 70.44, 69.51, 61.57, 57.81, 53.45, 52.94, 50.06, 47.77, 46.97, 46.92, 43.36, 41.01, 40.38, 37.32, 36.02, 33.02, 29.70, 28.03, 26.85, 26.03, 24.12, 22.16, 21.22, 19.43, 18.88, 15.68, 14.98, 14.96, 12.92, 10.20, 8.97.

[0167] Example 12 - The synthetic route of compound 6eC is as follows:

[0168]

[0169] According to the synthesis method of Example 5 - 1, using compound 5e (0.258 g, 0.268 mmol) for reaction, after purification by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27e 0.205 g (0.184 mmol, 68.66%) was obtained.

[0170] Using intermediate 27e (0.260 g, 0.250 mmol) and compound 28 (0.452 g, 1.250 mmol) for reaction, the product was purified with silica gel of 100 - 200 mesh and eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5 to obtain white fluffy solid compound 6eC 45.5 mg (0.0361 mmol, 14.43%). Melting point: 144.2 - 146.0 °C. HRMS (ESI) (M + H) + m / z 1261.6405, calcd for C 64 H 90 FN8O 17 1261.6402. 11H NMR (CDCl3, 700 MHz) δ: 9.03 (d, J = 2.2 Hz, 1H, 6″′-pyridyl), 8.81 (s, 1H, 2″-quinolyl), 8.71 (d, J = 1.9 Hz, 1H, 2′″-pyridyl), 8.14 (s, 1H, 4′″-pyridyl), 7.86 (d, J = 12.0 Hz, 1H, 5″-quinolyl), 6.87 (br, 1H, NH-CH3), 5.79 (br, 1H, 3-O-CO-NH-CH2), 5.15 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.90 (s, 1H, H-11), 4.88 (d, J = 11.1 Hz, 1H, H-3), 4.84 (s, 2H, 9-O-CH2), 4.07 - 4.00 (m, 2H, H-1′, 1H-cyclopropyl), 3.79 (s, 3H, OCH3), 3.79 - 3.76 (m, 1H, H-5), 3.75 - 3.68 (m, 1H, H-8), 3.50 - 3.41 (m, 4H, 4H-piperazinyl), 3.41 - 3.31 (m, 2H, H-5′, -O-CO-NH-CH2), 3.28 - 3.23 (m, 1H, 2′-OH), 3.20 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.15 - 3.08 (m, 1H, 3-O-CO-NH-CH2), 3.04 (s, 3H, 6-O-CH3), 3.00 (d, J = 4.7 Hz, 3H, NH-CH3), 2.90 - 2.83 (m, 1H, H-2), 2.61 (br, 4H, 4H-piperazinyl), 2.54 (q, J = 6.9 Hz, 1H, H-10), 2.46 (t, J = 6.7 Hz, 2H, -CH2-piperazinyl), 2.44 - 2.39 (m, 1H, H-3′), 2.30 (s, 6H, -N(CH3)2), 2.10 - 2.02 (m, 1H, H-4), 1.94 - 1.87 (m, 1H, H-14eq), 1.69 - 1.55 (m, 6H, 2(-CH2-), H-4′a, H-14ax), 1.51 (s, 3H, 12-CH3), 1.46 - 1.36 (m, 1H, H-4′b), 1.35 (s, 3H, 6-CH3), 1.29 - 1.18 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 10-CH3, 5′-CH3), 1.15 (d, J = 6.8 Hz, 3H, 2-CH3), 1.08 (d, J = 7.5 Hz, 3H, 4-CH3), 1.03 - 0.99(m, 2H, 2H-cyclopropyl), 0.96 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3). 13 13C NMR (CDCl3, 100 MHz) δ: 177.00, 174.29, 166.78, 165.92, 165.45, 156.39, 154.99, 154.04, 149.94, 148.06, 145.44, 136.91, 133.91, 129.41, 119.88, 108.37, 108.13, 107.79, 103.21, 90.50, 85.28, 83.17, 81.83, 80.96, 78.37, 77.90, 77.26, 75.41, 70.44, 69.46, 66.14, 62.32, 61.56, 58.12, 53.79, 50.63, 50.04, 46.45, 43.39, 41.07, 40.56, 40.32, 37.34, 36.06, 33.04, 28.67, 28.03, 26.86, 26.03, 24.24, 22.18, 21.24, 20.22, 19.44, 18.88, 15.69, 14.98, 12.94, 10.20, 9.56, 8.97.

[0171] Synthetic route of Example 13 - Compound 6fB is as follows:

[0172]

[0173] According to the synthesis method of Example 5 - 1, using Compound 5f (0.372 g, 0.375 mmol) for reaction, after purification by column chromatography (silica gel of 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27f 0.230 g (0.204 mmol, 54.40%) was obtained.

[0174] Using intermediate 27f (0.230 g, 0.204 mmol) and enoxacin (0.196 g, 0.612 mmol) for reaction, after purification by column chromatography (silica gel of 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6fB 94.9 mg (0.0769 mmol, 37.70%) was obtained. Melting point: 162.5 - 162.7 °C. HRMS (ESI) (M + H) + m / z 1234.6372, calcd for C 62 H 89 FN9O 161234.6406. 1 1H NMR (CD3OD, 400 MHz) δ: 8.83 (s, 1H, 2″-quinolyl), 8.69 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.57 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.08 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 7.97 (t, J = 2.0 Hz, 1H, 4″′-pyridyl), 5.14 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.97 - 4.82 (m, 4H, H-11, 9-O-CH2, H-3), 4.50 (d, J = 7.3 Hz, 2H, N-CH2CH3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.91 (s, 4H, 4H-piperazinyl), 3.86 (d, J = 3.3 Hz, 1H, H-5), 3.80 - 3.73 (m, 1H, H-8), 3.47 - 3.40 (m, 1H, H-5′), 3.31 - 3.23 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.15 - 2.99 (m, 10H, 3-O-CO-NH-CH2, 6-O-CH3, -N(CH3)2), 2.97 - 2.88 (m, 1H, H-2), 2.77 - 2.60 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.38 (m, 8H -CH2-C≡C-quinolyl, -N(CH3)2), 2.16 - 2.07 (m, 1H, H-4), 1.91 - 1.75 (m, 2H, H-14eq, H-7a), 1.73 - 1.58 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.57 (s, 3H, 12-CH3), 1.53 - 1.44 (m, 5H, -CH2-, N-CH2CH3), 1.36 (s, 3H, 6-CH3), 1.34 - 1.29 (m, 1H, H-4′b), 1.26 (d, J = 6.9 Hz, 3H, 10-CH3), 1.22 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.18 - 1.08 (m, 6H, 2-CH3, 4-CH3), 1.02 (d, J = 7.0 Hz, 3H, 8-CH3), 0.91 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 100 MHz) δ: 177.05, 168.16, 166.96, 166.30, 154.63, 152.93, 146.86, 146.41, 146.05, 145.08, 137.28, 134.24, 131.58, 129.48, 119.92, 109.32, 90.41, 85.03, 82.93, 81.63, 78.37, 75.41, 70.45, 67.77, 61.73, 57.82, 52.94, 49.95, 47.75, 46.92, 43.35, 40.39, 39.53, 38.91, 37.33, 35.98, 35.44, 33.00, 30.57, 28.98, 28.05, 26.05, 24.14, 23.99, 22.96, 22.20, 21.23, 19.38, 18.86, 15.61, 14.97, 14.04, 12.97, 11.09, 10.18, 8.97.

[0175] Synthetic route of Example 14 - Compound 6gB is as follows:

[0176]

[0177] According to the synthesis method of Example 5 - 1, reacting with Compound 5g (0.296 g, 0.299 mmol), after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27g 0.284 g (0.249 mmol, 83.28%) was obtained.

[0178] Reacting intermediate 27g (0.284 g, 0.249 mmol) with enoxacin (0.239 g, 0.747 mmol), after purification by column chromatography (silica gel 100 - 200 mesh, developing agent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6gB 95.2 mg (0.0764 mmol, 30.68%) was obtained. Melting point: 175.5 - 176.3 °C. HRMS(ESI)(M + H) + m / z 1246.6358, calcd for C 63 H 89 FN9O 16 1246.6406. 11H NMR (CD3OD, 400 MHz) δ: 8.88 (d, J = 2.1 Hz, 1H, 2″′-pyridyl), 8.84 (s, 1H, 2″-quinolyl), 8.73 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.24 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 8.08 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.16 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.96 - 4.83 (m, 4H, H-11, 9-O-CH2, H-3), 4.50 (s, 2H, N-CH2CH3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.91 (s, 4H, 4H-piperazinyl), 3.86 (d, J = 3.3 Hz, 1H, H-5), 3.81 - 3.72 (m, 1H, H-8), 3.48 - 3.40 (m, 1H, H-5′), 3.31 - 3.24 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.10 - 3.01 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.97 - 2.84 (m, 2H, H-2, H-cyclopropyl), 2.78 - 2.62 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.53 - 2.37 (m, 8H -CH2-C≡C-quinolyl, -N(CH3)2), 2.16 - 2.07 (m, 1H, H-4), 1.91 - 1.74 (m, 2H, H-14eq, H-7a), 1.71 - 1.59 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.57 (s, 3H, 12-CH3), 1.54 - 1.44 (m, 5H, -CH2-, N-CH2CH3), 1.36 (s, 3H, 6-CH3), 1.34 - 1.28 (m, 1H, H-4′b), 1.26 (d, J = 6.8 Hz, 3H, 10-CH3), 1.22 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.18 - 1.07 (m, 6H, 2-CH3, 4-CH3), 1.02 (d, J = 7.0 Hz, 3H, 8-CH3), 0.91 (t, J = 7.3 Hz, 3H, 15-CH3), 0.86 - 0.78 (m, 2H, 2H-cyclopropyl), 0.71 - 0.64 (m, 2H, 2H-cyclopropyl). 1313C NMR(CDCl3, 176 MHz) δ: 177.06, 174.08, 167.01, 166.24, 165.83, 156.35, 154.97, 154.17, 150.41, 150.36, 148.08, 147.94, 146.60, 146.42, 145.07, 144.44, 137.04, 129.29, 120.30, 120.18, 119.85, 113.79, 109.30, 103.25, 90.37, 85.27, 83.04, 81.80, 81.08, 78.36, 78.07, 75.30, 70.42, 69.53, 66.22, 61.59, 57.80, 52.94, 49.95, 47.77, 46.98, 46.93, 43.38, 41.03, 40.39, 37.32, 36.01, 33.03, 29.69, 28.57, 28.03, 26.02, 24.15, 23.33, 23.30, 22.21, 21.23, 19.41, 18.86, 15.67, 14.98, 14.95, 14.13, 12.88, 10.20, 8.98, 6.47, 6.45, 6.40.

[0179] Example 15 - The synthetic route of compound 6hA is as follows:

[0180]

[0181] According to the synthetic method of Example 5 - 1, using compound 5h (0.374 g, 0.394 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27h was obtained with a yield of 0.164 g (0.149 mmol, 37.82%).

[0182] Using intermediate 27h (0.164 g, 0.149 mmol) and ciprofloxacin (0.148 g, 0.447 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), compound 6hA was obtained with a yield of 42.0 mg (0.0345 mmol, 23.15%). Melting point: 172.1 - 172.8 °C. HRMS(ESI)(M + H) + m / z 1217.6140, calcd for C 62 H 86 FN8O 16 1217.6140. 11H NMR (CDCl3, 400 MHz) δ: 8.69 (s, 1H, 2″-quinolyl), 8.44 (d, J = 4.9 Hz, 1H, 6″′-pyridyl), 8.11 (s, 1H, 3″′-pyridyl), 7.93 (d, J = 13.0 Hz, 1H, 5″-quinoly), 7.74 (d, J = 4.3 Hz, 1H, NH2), 8.38 (dd, J = 5.0 Hz, 1.7 Hz, 1H, 5″′-pyridyl), 7.28 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.86 (s, 1H, 3-O-CO-NH-CH2), 5.5 (s, 1H, NH2), 5.10 (dd, J = 2.5 Hz, 10.6 Hz, 1H, H-13), 4.89 - 4.72 (m, 4H, H-11, 9-O-CH2, H-3), 3.95 (d, J = 7.9 Hz, 1H, H-1′), 3.74 - 3.61 (m, 2H, H-5, H-8), 3.53 - 3.44 (m, 1H, H-cyclopropyl), 3.39 - 3.23 (m, 5H, H-5′, 4H-piperazinyl), 3.24 - 3.16 (m, 1H, 3-O-CO-NH-CH2), 3.16 - 3.07 (m, 1H, H-2′), 3.07 - 2.98 (m, 1H, 3-O-CO-NH-CH2), 2.96 (s, 3H, 6-O-CH3), 2.81 - 2.71 (m, 1H, H-2), 2.68 - 2.52 (m, 4H, 4H-piperazinyl), 2.48 - 2.27 (m, 4H, H-10, -CH2-quinolyl, H-3′), 2.21 (s, 6H, -N(CH3)2), 2.03 - 1.93 (m, 1H, H-4), 1.90 - 1.77 (m, 1H, H-14eq), 1.64 - 1.43 (m, 8H, H-4′a, H-14ax, H-7b, H-7a, 2(-CH2-)), 1.41 (s, 3H, 12-CH3), 1.39 - 1.20 (m, 6H, H-4′b, 6-CH3, 2H-cyclopropyl), 1.23 - 1.09 (m, 8H, 10-CH3, 5′-CH3, 2H-cyclopropyl), 1.07 (d, J = 6.7 Hz, 3H, 2-CH3), 0.99 (d, J = 7.4 Hz, 3H, 4-CH3), 0.89 (d, J = 6.9 Hz, 3H, 8-CH3), 0.79 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 176 MHz) δ: 174.08, 167.06, 166.38, 166.15, 154.64, 149.61, 148.32, 139.11, 132.80, 128.39, 128.36, 124.52, 108.13, 104.79, 92.13, 85.02, 82.90, 82.73, 78.37, 75.43, 70.45, 61.66, 57.85, 52.78, 49.92, 49.69, 43.37, 41.04, 40.38, 37.32, 35.95, 35.33, 33.01, 28.06, 26.05, 24.16, 22.21, 21.24, 19.42, 18.86, 15.62, 14.94, 12.99, 10.18, 9.03, 8.24.

[0183] Synthesis route of Example 16 - Compound 6iA is as follows:

[0184]

[0185] According to the synthesis method of Example 5 - 1, using Compound 5i (0.413 g, 0.435 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27i 0.190 g (0.173 mmol, 39.77%) was obtained.

[0186] Using intermediate 27i (0.190 g, 0.173 mmol) and ciprofloxacin (0.172 g, 0.518 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6iA 59.9 mg (0.0492 mmol, 28.44%) was obtained. Melting point: 178.9 - 179.8 °C. HRMS(ESI)(M + H) + m / z 1217.6145, calcd for C 62 H 86 FN8O 16 1217.6140. 11H NMR (CD3OD, 400 MHz) δ: 8.75 (s, 1H, 2″-quinolyl), 8.63 (s, 1H, 2″′-pyridyl), 8.06 (d, J = 8.1 Hz, 1H, 5″′-pyridyl), 7.96 (d, J = 2.1 Hz, 8.1 Hz, 1H, 4″′-pyridyl), 7.84 (s, 1H, 5″-quinolyl), 7.48 (s, 1H, 8″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.94 - 4.78 (m, 4H, H-11, 9-O-CH2, H-3), 4.13 (d, J = 7.2 Hz, 1H, H-1′), 3.84 (d, J = 3.2 Hz, 1H, H-5), 3.80 - 3.63 (m, 2H, H-8, H-cyclopropyl), 3.50 - 3.33 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.27 (dd, J = 7.3 Hz, 10.3 Hz, 1H, H-2′), 3.10 - 3.01 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.94 - 2.86 (m, 1H, H-2), 2.77 - 2.63 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.38 (m, 8H, -CH2-C≡C-quinolyl, -N(CH3)2), 2.14 - 2.05 (m, 1H, H-4), 1.87 - 1.76 (m, 2H, H-14eq, H-7a), 1.69 - 1.57 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.55 (s, 3H, 12-CH3), 1.52 - 1.37 (m, 2H, -CH2-), 1.39 - 1.32 (m, 5H, 6-CH3, 2H-cyclopropyl), 1.32 - 1.26 (m, 3H, 2H-cyclopropyl, H-4′b), 1.23 (d, J = 6.8 Hz, 3H, 10-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.13 (d, J = 6.8 Hz, 3H, 2-CH3), 1.09 (d, J = 7.4 Hz, 3H, 4-CH3), 1.00 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 176 MHz) δ: 174.64, 167.11, 167.06, 157.40, 156.65, 154.88, 150.68, 148.40, 139.76, 122.83, 121.38, 101.78, 91.69, 85.42, 83.02, 81.45, 78.38, 78.07, 77.28, 75.22, 70.64, 68.71, 64.55, 61.01, 57.73, 52.55, 49.34, 49.21, 49.19, 43.18, 40.33, 39.51, 36.87, 35.93, 32.95, 30.92, 27.60, 26.06, 23.31, 21.86, 20.06, 18.65, 17.65, 14.68, 13.96, 11.79, 9.33, 7.98, 7.17.

[0187] Example 17 - The synthetic route of compound 6jB is as follows:

[0188]

[0189] According to the synthesis method of Example 5 - 1, using compound 5j (0.513 g, 0.526 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27j 0.398 g (0.353 mmol, 67.24%) was obtained.

[0190] Using intermediate 27j (0.200 g, 0.178 mmol) and enoxacin (0.170 g, 0.533 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), compound 6jB 70.6 mg (0.0573 mmol, 32.19%) was obtained. Melting point: 163.4 - 163.8 °C. HRMS(ESI)(M + H) + m / z 1231.5993, calcd for C 61 H 84 FN 10 O 16 1231.6045. 11H NMR (CD3OD, 400 MHz) δ: 9.16 (s, 1H, H-oxadiazolyl), 9.12 (s, 1H, 2″′-pyridyl), 8.83 (s, 1H, 2″-quinolyl), 8.81 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.52 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 8.06 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 5.17 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.99 - 4.79 (m, 4H, H-11, 9-O-CH2, H-3), 4.49 (s, 2H, N-CH2CH3), 4.13 (d, J = 7.3 Hz, 1H, H-1′), 3.91 (s, 4H, 4H-piperazinyl), 3.85 (d, J = 3.3 Hz, 1H, H-5), 3.81 - 3.73 (m, 1H, H-8), 3.47 - 3.39 (m, 1H, H-5′), 3.31 - 3.22 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.12 - 3.01 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.97 - 2.87 (m, 1H, H-2), 2.78 - 2.66 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.38 (m, 8H -CH2-C≡C-quinolyl, -N(CH3)2), 2.15 - 2.06 (m, 1H, H-4), 1.94 - 1.75 (m, 2H, H-14eq, H-7a), 1.72 - 1.59 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.57 (s, 3H, 12-CH3), 1.53 - 1.44 (m, 5H, -CH2-, N-CH2CH3), 1.36 (s, 3H, 6-CH3), 1.34 - 1.29 (m, 1H, H-4′b), 1.27 (d, J = 6.7 Hz, 3H, 10-CH3), 1.21 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.16 - 1.08 (m, 6H, 2-CH3, 4-CH3), 1.03 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR (CDCl3, 100 MHz) δ: 177.05, 174.16, 166.96, 162.24, 154.84, 154.63, 153.28, 153.18, 146.61, 146.41, 136.69, 120.74, 119.65, 113.80, 109.31, 91.39, 85.07, 82.91, 81.11, 78.37, 75.41, 70.45, 61.69, 57.82, 53.46, 52.94, 49.97, 47.75, 46.93, 40.40, 37.32, 35.99, 33.03, 28.06, 26.07, 24.14, 22.20, 21.21, 19.40, 18.88, 15.63, 14.98, 14.92, 12.97, 10.17, 8.98.

[0191] Synthetic route of Example 18 - Compound 6kA is as follows:

[0192]

[0193] According to the synthesis method of Example 5 - 1, using Compound 5k (0.353 g, 0.364 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / .1), intermediate 27k 0.211 g (0.186 mmol, 51.10%) was obtained.

[0194] Using intermediate 27k (0.211 g, 0.186 mmol) and ciprofloxacin (0.185 g, 0.558 mmol) for reaction, after purification by column chromatography (silica gel 100 - 200 mesh, developing agent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6kA 35.3 mg (0.0282 mmol, 15.16%) was obtained. Melting point: 187.9 - 188.4 °C. HRMS (ESI) (M + H) + m / z 1251.6313, calcd for C 66 H 88 FN8O 15 1251.6348. 11H NMR (CDCl3, 400 MHz) δ: 8.70 (s, 1H, 2″-quinolyl), 8.66 - 8.57 (m, 2H, Ar), 8.34 - 8.25 (m, 2H, Ar), 7.95 (d, J = 13.0 Hz, 1H, 5″-quinoly), 7.81 - 7.69 (m, 2H, Ar), 7.28 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 7.26 - 7.21 (m, 1H, Ar), 5.49 (s, 1H, 3-O-CO-NH-CH2), 5.10 (d, J = 9.9 Hz, 1H, H-13), 4.93 - 4.72 (m, 4H, H-11, 9-O-CH2, H-3), 3.95 (d, J = 7.4 Hz, 1H, H-1′), 3.76 - 3.64 (m, 2H, H-5, H-8), 3.52 - 3.42 (m, 1H, H-cyclopropyl), 3.37 - 3.23 (m, 5H, H-5′, 4H-piperazinyl), 3.23 - 3.15 (m, 1H, 3-O-CO-NH-CH2), 3.15 - 3.03 (m, 2H, H-2′, 3-O-CO-NH-CH2), 2.99 (s, 3H, 6-O-CH3), 2.81 - 2.70 (m, 1H, H-2), 2.65 - 2.49 (m, 4H, 4H-piperazinyl), 2.48 - 2.52 (m, 4H, H-10, -CH2-quinolyl, H-3′), 2.20 (s, 6H, -N(CH3)2), 2.05 - 1.89 (m, 2H, H-4, H-7a), 1.88 - 1.75 (m, 1H, H-14eq), 1.62 - 1.46 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.42 (s, 3H, 12-CH3), 1.38 - 1.22 (m, 10H, H-4′b, 6-CH3, 2H-cyclopropyl, 2(-CH2-)), 1.23 - 1.01 (m, 8H, 10-CH3, 5′-CH3, 2H-cyclopropyl), 1.10 - 1.02 (m, 3H, 2-CH3), 1.02 - 0.94 (m, 3H, 4-CH3), 0.90 (d, J = 7.0 Hz, 3H, 8-CH3), 0.78 (t, J = 6.9 Hz, 3H, 15-CH3). 13C NMR(CDCl3,176MHz)δ:177.15,174.05,167.05,166.26,155.52,155.51,154.90,154.65,151.80,149.24,139.64,139. 11,138.57,136.94,123.88,121.35,120.29,119.97,108.20,104.77,103.25,90.12,85.03,82.95,82.76,78.38,75.46 ,70.46,69.53,66.22,61.94,57.87,52.84,49.93,49.73,43.38,41.05,40.41,37.35,35.98,35.30,34.52,33.00,29.70,28.56,28.08,26.07,26.05,24.19,22.21,21.25,19.41,18.87,15.62,14.95,14.13,13.02,10.20,9.03,8.25,8.12.

[0195] The synthetic route of Example 19-Compound 61A is as follows:

[0196]

[0197] According to the synthesis method of Example 5-1, compound 51 (0.327 g, 0.337 mmol) was reacted and purified by column chromatography (100-200 mesh silica gel, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.184 g (0.164 mmol, 48.56%) of intermediate 271.

[0198] Intermediate 271 (0.184 g, 0.164 mmol) was reacted with ciprofloxacin (0.163 g, 0.492 mmol) and purified by column chromatography (100-200 mesh silica gel, developing solvent: dichloromethane / methanol / aqueous ammonia = 10 / 0.9 / 0.5) to give 20.3 mg (0.0164 mmol, 10.00%) of compound 61A.

[0199] The synthetic route of Example 20-Compound 6mA is as follows:

[0200]

[0201] According to the synthesis method of Example 5-1, using compound 5m (0.420 g, 0.441 mmol) for reaction, after purification by column chromatography (silica gel of 100-200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27m 0.189 g (0.171 mmol, 38.78%) was obtained.

[0202] Using intermediate 27m (0.189 g, 0.171 mmol) and ciprofloxacin (0.170 g, 0.513 mmol) for reaction, after purification by column chromatography (silica gel of 100-200 mesh, developing agent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), compound 6mA 36.3 mg (0.0296 mmol, 17.31%) was obtained. Melting point: 168.7-169.5 °C. HRMS(ESI)(M+H) + m / z 1224.6254, calcd for C 65 H 87 FN7O 15 1224.6239. 11H NMR (CD3OD, 400 MHz) δ: 8.82 (s, 1H, 2″′-Ar), 8.76 (s, 1H, 2″-quinolyl), 8.46 (s, 1H, 4″′-Ar), 7.99 (d, J = 8.3 Hz, 1H, 8″′-Ar), 7.94 - 7.83 (m, 2H, 5″′-Ar, 5″-quinolyl), 7.76 (t, J = 7.8 Hz, 1H, 6″′-Ar), 7.61 (t, J = 7.8 Hz, 1H, 7″′-Ar), 8.52 (s, 1H, 8″-quinolyl), 5.13 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.97 - 4.81 (m, 4H, H-11, 9-O-CH2, H-3), 4.12 (d, J = 7.3 Hz, 1H, H-1′), 3.84 (d, J = 3.2 Hz, 1H, H-5), 3.81 - 3.74 (m, 1H, H-8), 3.73 - 3.64 (m, 1H, H-cyclopropyl), 3.46 - 3.37 (m, 6H, H-5′, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.26 (dd, J = 7.3 Hz, 10.2 Hz, 1H, H-2′), 3.11 - 2.98 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.95 - 2.86 (m, 1H, H-2), 2.77 - 2.61 (m, 6H, H-3′, H-10, 4H-piperazinyl), 2.52 - 2.35 (m, 8H, -CH2-C≡C-quinolyl, -N(CH3)2), 2.15 - 2.07 (m, 1H, H-4), 1.90 - 1.73 (m, 2H, H-14eq, H-7a), 1.69 - 1.57 (m, 5H, H-4′a, H-14ax, H-7b, -CH2-), 1.55 (s, 3H, 12-CH3), 1.50 - 1.41 (m, 3H, H-4′b, -CH2-), 1.41 - 1.27 (m, 7H, 6-CH3, 4H-cyclopropyl), 1.26 (d, J = 6.8 Hz, 3H, 10-CH3), 1.22 - 1.06 (m, 9H, 5′-CH3, 2-CH3, 4-CH3), 1.01 (d, J = 6.9 Hz, 3H, 8-CH3), 0.87 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 176 MHz) δ: 174.61, 166.92, 157.42, 154.92, 151.43, 146.11, 139.23, 130.43, 127.82, 127.73, 127.42, 117.18, 101.8, 89.6, 85.43, 83.07, 82.11, 78.39, 78.08, 77.3, 75.24, 70.67, 68.73, 64.54, 61.1, 57.71, 52.54, 49.38, 49.22, 43.18, 39.49, 36.9, 35.95, 32.97, 30.87, 29.35, 27.6, 26.06, 21.86, 20.05, 18.67, 17.66, 14.67, 13.94, 11.77, 9.29, 7.97, 7.14.

[0203] Synthetic route of Example 21 - Compound 6pA is as follows:

[0204]

[0205] According to the synthesis method of Example 5 - 1, reacting with Compound 5p (0.425 g, 0.446 mmol), after purification by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), intermediate 27p 0.201 g (0.211 mmol, 47.28%) was obtained.

[0206] Reacting intermediate 27p (0.201 g, 0.211 mmol) with ciprofloxacin (0.209 g, 0.633 mmol), after purification by column chromatography (silica gel 100 - 200 mesh, eluent dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), Compound 6pA 40.9 mg (0.0334 mmol, 15.83%) was obtained. Melting point: 170.3 - 171.2 °C. HRMS(ESI)(M + 2H) 2+ m / z(z = 2) 612.8175, calcd for C 65 H 88 FN7O 15 612.8156. 11H NMR (CDCl3, 400 MHz) δ: 9.10 (s, 1H, 1″′-Ar), 8.69 (s, 1H, 2″-quinolyl), 8.59 (s, 1H, 3″′-Ar), 8.24 (d, J = 8.4 Hz, 1H, 5″′-Ar), 7.94 (d, J = 13.1 Hz, 1H, 5″-quinoly), 7.90 (d, J = 8.2 Hz, 1H, 8″′-Ar), 7.73 (t, J = 7.7 Hz, 1H, 6″′-Ar), 7.57 (t, J = 7.6 Hz, 1H, 7″′-Ar), 7.28 (d, J = 7.0 Hz, 1H, 8″-quinolyl), 5.50 (t, J = 5.9 Hz, 1H, 3-O-CO-NH-CH2), 5.10 (d, J = 10.6 Hz, 1H, H-13), 5.01 - 4.73 (m, 4H, H-11, 9-O-CH2, H-3), 3.94 (d, J = 7.4 Hz, 1H, H-1′), 3.78 - 3.65 (m, 2H, H-5, H-8), 3.53 - 3.43 (m, 1H, H-cyclopropyl), 3.37 - 3.23 (m, 5H, H-5′, 4H-piperazinyl), 3.23 - 3.16 (m, 1H, 3-O-CO-NH-CH2), 3.11 (dd, J = 7.1 Hz, 9.9 Hz, 1H, H-2′), 3.06 - 3.00 (m, 1H, 3-O-CO-NH-CH2), 2.96 (s, 3H, 6-O-CH3), 2.81 - 2.69 (m, 1H, H-2), 2.65 - 2.51 (m, 4H, 4H-piperazinyl), 2.48 (q, J = 6.8 Hz, 1H, H-10), 2.42 - 2.35 (m, 2H, -CH2-quinolyl), 2.33 - 2.25 (m, 1H, H-3′), 2.19 (s, 6H, -N(CH3)2), 2.05 - 1.94 (m, 1H, H-4), 1.90 - 1.78 (m, 2H, H-14eq, H-7a), 1.62 - 1.47 (m, 7H, H-4′a, H-14ax, H-7b, 2(-CH2-)), 1.43 (s, 3H, 12-CH3), 1.39 - 1.23 (m, 8H, H-4′b, 6-CH3, 4H-cyclopropyl), 1.24 - 1.09 (m, 6H, 10-CH3, 5′-CH3), 1.06 (d, J = 6.7 Hz, 3H, 2-CH3), 0.99 (d, J = 7.3 Hz, 3H, 4-CH3), 0.90 (d, J = 6.9 Hz, 3H, 8-CH3), 0.79 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR (CD3OD, 176 MHz) δ: 174.52, 167.08, 157.38, 154.93, 151.69, 144.90, 135.72, 131.77, 128.23, 127.97, 127.88, 124.77, 116.06, 101.84, 94.16, 85.44, 83.08, 79.65, 78.37, 78.10, 77.30, 75.27, 70.68, 68.73, 64.52, 61.12, 57.73, 52.54, 49.31, 49.22, 43.16, 40.33, 39.52, 36.90, 35.91, 32.97, 30.90, 27.59, 26.07, 21.91, 20.06, 18.69, 17.65, 14.75, 13.91, 11.82, 9.36, 7.97, 7.15.

[0207] Example 22 is the synthetic route of clarithromycin derivative with formula Ⅲ, which is specifically as follows:

[0208]

[0209] The reaction conditions and reagents of the above synthetic route are as follows: a. propanediamine, DMF, room temperature; b. formic acid, NaNO2, 3-butyn-1-ol, -15 °C; c. compound 30 (see Example 25 for the chemical structure of compound 30), CuI, Pd(PPh3)2Cl2, triethylamine / acetonitrile (1:1), 45 °C; d. reflux in methanol.

[0210] The steps for preparing the clarithromycin derivative of formula Ⅲ are as follows:

[0211] Step 1: Dissolve compound 4 in DMF, then dropwise add propanediamine and react at room temperature. After the reaction is completed, perform post-treatment to obtain compound 7; Step 2: Dissolve compound 7 in butynol, then dropwise add formic acid at low temperature, slowly add NaNO2, and react at low temperature. After the reaction is completed, perform post-treatment to obtain compound 8;

[0212] Step 3: Stir the mixed solution containing compound 8, copper(I) iodide, triethylamine and acetonitrile at room temperature, add bis(triphenylphosphine)palladium(II) dichloride and compound 30, and react under an argon atmosphere. After the reaction is completed, perform post-treatment to obtain compound 9.

[0213] Example 23 is the synthetic method of compounds 7d - 7j:

[0214] Dissolve compounds 4d, 4e, 4f, 4g, 4j (1 eq) in DMF, add propanediamine (5 eq) dropwise to the system, and react at room temperature for 4 - 8 h. After the reaction monitoring is completed, add ethyl acetate. Wash three times with water and once with saturated brine, and rotary evaporate the organic phase. Purify by column chromatography to obtain compounds 7d, 7e, 7f, 7g, 7j.

[0215] Specifically, the synthesis method of compound 7d is as follows:

[0216] React using compound 4d (2.624 g, 2.836 mmol) according to the synthesis method of Example 23, and purify the product by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 1.259 g (1.312 mmol, 46.26%) of compound 7d.

[0217] Specifically, the synthesis method of compound 7e is as follows:

[0218] React using compound 4e (2.099 g, 2.235 mmol) according to the synthesis method of Example 23, and purify the product by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 1.451 g (1.535 mmol, 68.68%) of compound 7e.

[0219] Specifically, the synthesis method of compound 7f is as follows:

[0220] React using compound 4f (1.612 g, 1.666 mmol) according to the synthesis method of Example 23, and purify the product by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.1) to obtain 1.305 g (1.341 mmol, 80.49%) of compound 7f.

[0221] Specifically, the synthesis method of compound 7g is as follows:

[0222] React using compound 4g (1.858 g, 1.926 mmol) according to the synthesis method of Example 23, and purify the product by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 1.064 g (1.096 mmol, 56.90%) of compound 7g.

[0223] Specifically, the synthesis method of compound 7j is as follows:

[0224] Using compound 4j (1.892 g, 1.992 mmol) in the synthesis method according to Example 23, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 1.412 g (1.477 mmol, 74.14%) of compound 7j.

[0225] Example 24 is a synthesis method of compounds 8d - 7j:

[0226] Dissolve compounds 7d, 7e, 7f, 7g, 7j (1 eq) in butynol (50 eq). After complete dissolution, cool the temperature to -15 °C, add formic acid (4.5 eq) dropwise, slowly add NaNO2 (6 eq), and maintain the reaction at -15 °C for 24 - 48 h. After the reaction monitoring is completed, add 50 mL of dichloromethane to the system, wash with saturated sodium bicarbonate, water, and saturated brine respectively, and the organic phase is dried by rotary evaporation and then purified by column chromatography to obtain compounds 8d, 8e, 8f, 8g, 8j.

[0227] Specifically, the synthesis method of compound 8d is as follows:

[0228] Using compound 7d (1.259 g, 1.312 mmol) in the synthesis method according to Example 24, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.213 g (0.216 mmol, 16.46%) of compound 8d. HRMS (ESI) (M + H) + m / z 984.5169, calcd for C 50 H 74 N5O 15 984.5176.

[0229] Specifically, the synthesis method of compound 8e is as follows:

[0230] Using compound 7e (1.451 g, 1.535 mmol) in the synthesis method according to Example 24, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.283 g (0.284 mmol, 18.50%) of compound 8e. HRMS (ESI) (M + H) + m / z 998.5346, calcd for C 61 H 76 N5O 15 998.5332.

[0231] Specifically, the synthesis method of compound 8f is as follows:

[0232] Using compound 7f (1.305 g, 1.341 mmol) in the synthesis method according to Example 24, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.262 g (0.255 mmol, 19.02%) of compound 8f. HRMS (ESI) (M+H)+ m / z 1012.5456, calcd for C 52 H 78 N5O 15 1012.5489.

[0233] Specifically, the synthesis method of compound 8g is as follows:

[0234] Using compound 7g (1.064 g, 1.096 mmol) in the synthesis method according to Example 24, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.201 g (0.196 mmol, 17.88%) of compound 8g. HRMS (ESI) (M+H) + m / z 982.5338, calcd for C 51 H 76 N5O 14 982.5383.

[0235] Specifically, the synthesis method of compound 8j is as follows:

[0236] Using compound 7j (1.412 g, 1.477 mmol) in the synthesis method according to Example 24, the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.232 g (0.230 mmol, 15.57%) of compound 8j. HRMS (ESI) (M+H) + m / z 1009.5104, calcd for C 51 H 73 N6O 15 1009.5128.

[0237] The following Examples 25 - 29 are the synthetic routes and methods for the compound 9 series, and the general synthetic method for the compound 9 series is as shown in Example 25 - 1:

[0238] The mixture of compound 30 (1.2 eq), copper(I) iodide (0.1 eq), 5 mL of triethylamine and 5 mL of acetonitrile was stirred at room temperature for 20 min. Then, bis(triphenylphosphine)palladium(II) dichloride (0.05 eq) and compound 30 (1 eq) were added to the system, and the reaction was carried out at 45 °C for 12 h under argon protection. After the reaction monitoring was completed, 30 mL of ethyl acetate was added to the reaction system, and it was washed successively with water, saturated sodium bicarbonate, and saturated sodium chloride solutions. The organic phase was dried by rotary evaporation, and then methanol was added and refluxed at 65 °C for 2 h to remove the acetyl protection at the 2'-position. After the reaction monitoring was completed, the reaction solution was dried by rotary evaporation and purified by column chromatography to obtain the compound 9 series.

[0239] The synthetic route of Example 25 - Compound 9dE is as follows:

[0240]

[0241] Using compound 8d (0.213 g, 0.216 mmol), the reaction was carried out according to the synthetic method of Example 25 - 1. After column chromatography of the product (silica gel 100 - 200 mesh, mobile phase dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 57.0 mg (0.0498 mmol, 23.08%) of compound 9dE was obtained. Melting point: 182.8 - 183.5 °C. HRMS(ESI)(M + H) + m / z1143.54992, calcd for C 59 H 79 N6O 17 1143.54962. 11H NMR (CD3OD, 400 MHz) δ: 8.94 (d, J = 2.4 Hz, 1H, 2″′-pyridyl), 8.82 (s, 1H, 2″-quinolyl), 8.71 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.32 (d, J = 8.8 Hz, 1H, 5″-quinolyl), 8.29 (d, J = 2.1 Hz, 1H, 6″′-pyridyl), 7.78 (s, 1H, 8″-quinolyl), 7.48 (s, 1H, 6″-quinolyl), 5.10 (dd, J = 2.5 Hz, 10.5 Hz, 1H, H-13), 4.94 - 4.86 (m, 3H, H-11, 9-O-CH2), 4.78 (d, J = 11.1 Hz, 1H, H-3), 4.19 (d, J = 7.2 Hz, 1H, H-1′), 4.01 (s, 3H, N-CH3), 3.81 (d, J = 3.2 Hz, 1H, H-5), 3.77 - 3.70 (m, 1H, H-8), 3.66 (t, J = 6.4 Hz, 2H, O-CH2-CH2-C≡C-quinolyl), 3.62 - 3.54 (m, 2H, CH2-O-CH2-CH2-C≡C-quinolyl), 3.44 - 3.33 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.25 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.21 - 3.12 (m, 1H, 3-O-CO-NH-CH2), 3.02 (s, 3H, 6-O-CH3), 2.83 - 2.64 (m, 5H, H-2, H-3′, -CH2-C≡C-quinolyl, H-10), 2.41 (s, 6H, -N(CH3)2), 2.08 - 2.00 (m, 1H, H-4), 1.90 - 1.70 (m, 4H, H-14eq, H-7a, -CH2-), 1.64 - 1.57 (m, 1H, H-14ax), 1.52 (s, 3H, 12-CH3), 1.50 - 1.38 (m, 2H, H-7b, H-4′b), 1.32 (s, 3H, 6-CH3), 1.30 - 1.25 (m, 1H, H-4′a), 1.22 (d, J = 6.3 Hz, 3H, 10-CH3), 1.16 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.08 - 1.01 (m, 6H, 2-CH3, 4-CH3), 0.99 (d, J = 6.9 Hz, 3H, 8-CH3), 0.84 (t, J = 7.2 Hz, 3H, 15-CH3). 1313C NMR (CD3OD, 176 MHz) δ: 174.54, 167.53, 167.04, 157.28, 154.91, 153.62, 147.19, 138.05, 129.63, 120.27, 101.78, 90.59, 85.42, 83.04, 80.89, 79.91, 78.35, 78.11, 77.31, 75.19, 70.59, 68.70, 68.52, 68.18, 64.55, 60.95, 49.33, 43.17, 41.04, 39.48, 38.07, 36.87, 35.87, 32.95, 30.77, 29.55, 26.04, 21.82, 20.26, 20.02, 18.65, 17.66, 14.66, 13.92, 11.77, 9.26, 7.92.

[0242] Synthetic route of Example 26 - Compound 9eE is as follows:

[0243]

[0244] Compound 8e (0.283 g, 0.284 mmol) was reacted according to the synthetic method of Example 25 - 1. After column chromatography of the product (silica gel 100 - 200 mesh, mobile phase dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 134.2 mg (0.116 mmol, 40.83%) of compound 9eE was obtained. Melting point: 174.7 - 175.2 °C. HRMS (ESI) (M + H) + m / z 1157.5647, calcd for C 60 H 81 N6O 17 1157.5653. 11H NMR (CD3OD, 400 MHz) δ: 8.87 (s, 1H, 2″′-pyridyl), 8.83 (s, 1H, 2″-quinolyl), 8.70 (s, 1H, 4″′-pyridyl), 8.34 (s, 1H, 5″-quinolyl), 8.33 (s, 1H, 6″′-pyridyl), 7.74 (s, 1H, 8″-quinolyl), 7.45 (s, 1H, 6″-quinolyl), 5.09 (dd, J = 2.6 Hz, 10.7 Hz, 1H, H-13), 4.92 - 4.82 (m, 3H, H-11, 9-O-CH2), 4.78 (d, J = 11.1 Hz, 1H, H-3), 4.11 (d, J = 7.1 Hz, 1H, H-1′), 3.97 (s, 3H, N-CH3), 3.80 (d, J = 3.0 Hz, 1H, H-5), 3.76 - 3.69 (m, 1H, H-8), 3.65 (t, J = 5.8 Hz, 2H, O-CH2-CH2-C≡C-quinolyl), 3.61 - 3.52 (m, 2H, CH2-O-CH2-CH2-C≡C-quinolyl), 3.46 - 3.32 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.29 - 3.21 (m, 1H, H-2′), 3.21 - 3.12 (m, 1H, 3-O-CO-NH-CH2), 3.01 (s, 3H, 6-O-CH3), 2.90 (s, 3H, NH-CH3), 2.84 - 2.70 (m, 4H, H-2, H-3′, -CH2-C≡C-quinolyl) 2.67 (q, J = 6.4 Hz, 1H, H-10), 2.44 (s, 6H, -N(CH3)2), 2.08 - 1.99 (m, 1H, H-4), 1.87 - 1.71 (m, 4H, H-14eq, H-7a, -CH2-), 1.67 - 1.59 (m, 1H, H-14ax), 1.51 (s, 3H, 12-CH3), 1.49 - 1.37 (m, 2H, H-7b, H-4′b), 1.31 (s, 3H, 6-CH3), 1.29 - 1.26 (m, 1H, H-4′a), 1.22 (d, J = 6.6 Hz, 3H, 10-CH3), 1.16 (d, J = 5.8 Hz, 3H, 5′-CH3), 1.09 - 1.01 (m, 6H, 2-CH3, 4-CH3), 0.98 (d, J = 6.8 Hz, 3H, 8-CH3), 0.83 (t, J = 7.3 Hz, 3H, 15-CH3). 13CNMR(CD3OD, 176 MHz) δ: 174.53, 167.04, 165.92, 157.28, 154.88, 153.35, 146.80, 137.60, 130.06, 120.24, 101.73, 90.62, 85.41, 83.03, 80.94, 79.95, 78.34, 78.11, 77.27, 75.17, 70.57, 68.65, 68.54, 68.18, 64.57, 60.97, 49.35, 43.16, 40.99, 39.51, 38.04, 36.87, 35.86, 32.94, 29.57, 26.04, 25.61, 21.83, 20.28, 20.05, 18.67, 17.68, 14.70, 13.97, 11.79, 9.30, 7.94.

[0245] Synthetic route of Example 27 - Compound 9fE is as follows:

[0246]

[0247] Compound 8f (0.262 g, 0.255 mmol) was reacted according to the synthetic method of Example 25 - 1. After column chromatography of the product (silica gel of 100 - 200 mesh, mobile phase dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 103.8 mg (0.088 mmol, 34.75%) of Compound 9fE was obtained. Melting point: 160.1 - 161.2 °C. HRMS(ESI)(M + H) + m / z 1171.5754, calcd for C 61 H 83 N6O 17 1171.5809. 11H NMR (CD3OD, 400 MHz) δ: 8.86 (s, 1H, 2″-quinolyl), 8.68 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.37 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.37 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 7.95 (t, J = 2.0 Hz, 1H, 6″′-pyridyl), 7.81 (s, 1H, 8″-quinolyl), 7.50 (s, 1H, 6″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.96 - 4.88 (m, 3H, H-11, 9-O-CH2), 4.80 (d, J = 11.1 Hz, 1H, H-3), 4.11 (d, J = 7.2 Hz, 1H, H-1′), 4.03 (s, 3H, N-CH3), 3.83 (d, J = 3.3 Hz, 1H, H-5), 3.79 - 3.72 (m, 1H, H-8), 3.69 (t, J = 6.4 Hz, 2H, O-CH2-CH2-C≡C-quinolyl), 3.65 - 3.58 (m, 2H, CH2-O-CH2-CH2-C≡C-quinolyl), 3.46 - 3.36 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.26 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.22 - 3.13 (m, 1H, 3-O-CO-NH-CH2), 3.11 (s, 3H, N(CH3)2), 3.04 (s, 3H, 6-O-CH3), 3.02 (s, 3H, N(CH3)2), 2.86 - 2.64 (m, 5H, H-2, H-3′, -CH2-C≡C-quinolyl, H-10), 2.42 (s, 6H, -N(CH3)2), 2.13 - 2.02 (m, 1H, H-4), 1.89 - 1.71 (m, 4H, H-14eq, H-7a, -CH2-), 1.71 - 1.59 (m, 1H, H-14ax), 1.55 (s, 3H, 12-CH3), 1.53 - 1.41 (m, 2H, H-7b, H-4′b), 1.34 (s, 3H, 6-CH3), 1.33 - 1.27 (m, 1H, H-4′a), 1.24 (d, J = 6.7 Hz, 3H, 10-CH3), 1.18 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.12 - 1.04 (m, 6H, 2-CH3, 4-CH3), 1.01 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 101MHz) δ: 178.27, 174.09, 168.16, 154.63, 152.92, 146.87, 137.27, 131.60, 119.93, 90.43, 85.03, 82.93, 81.63, 78.37, 70.50, 61.72, 49.98, 40.38, 39.53, 37.30, 35.95, 35.44, 33.00, 26.05, 22.17, 21.20, 21.00, 19.39, 18.88, 15.62, 14.91, 12.93, 10.17, 8.86.

[0248] Example 28 - The synthetic route of Compound 9gE is as follows:

[0249]

[0250] Using Compound 8g (0.201 g, 0.196 mmol), the reaction was carried out according to the synthetic method of Example 25 - 1. After column chromatography of the product (silica gel 100 - 200 mesh, mobile phase dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 55.2 mg (0.0466 mmol, 23.80%) of Compound 9gE was obtained. Melting point: 171.6 - 172.8 °C. HRMS(ESI)(M + H) + m / z 1183.5789, calcd for C 62 H 83 N6O 17 1183.5809. 11H NMR (CD3OD, 400 MHz) δ: 8.88 (s, 1H, 2″′-pyridyl), 8.87 (s, 1H, 2″-quinolyl), 8.71 (s, 1H, 4″′-pyridyl), 8.36 (d, J = 8.2 Hz, 1H, 5″-quinolyl), 8.23 (s, 1H, 6″′-pyridyl), 7.80 (s, 1H, 8″-quinolyl), 7.50 (s, 1H, 6″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.96 - 4.88 (m, 3H, H-11, 9-O-CH2), 4.81 (d, J = 11.1 Hz, 1H, H-3), 4.11 (d, J = 7.2 Hz, 1H, H-1′), 4.03 (s, 3H, N-CH3), 3.83 (d, J = 3.2 Hz, 1H, H-5), 3.80 - 3.72 (m, 1H, H-8), 3.69 (t, J = 6.4 Hz, 2H, O-CH2-CH2-C≡C-quinolyl), 3.65 - 3.56 (m, 2H, CH2-O-CH2-CH2-C≡C-quinolyl), 3.48 - 3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.27 (dd, dd, J = 7.3 Hz, 10.9 Hz, 1H, H-2′), 3.23 - 3.13 (m, 1H, 3-O-CO-NH-CH2), 3.04 (s, 3H, 6-O-CH3), 2.92 - 2.82 (m, 1H, H-cyclopropyl), 2.83 - 2.73 (m, 4H, H-2, H-3′, -CH2-C≡C-quinolyl) 2.70 (q, J = 6.9 Hz, 1H, H-10), 2.45 (s, 6H, -N(CH3)2), 2.13 - 2.00 (m, 1H, H-4), 1.91 - 1.71 (m, 4H, H-14eq, H-7a, -CH2-), 1.71 - 1.59 (m, 1H, H-14ax), 1.54 (s, 3H, 12-CH3), 1.52 - 1.39 (m, 2H, H-7b, H-4′b), 1.34 (s, 3H, 6-CH3), 1.33 - 1.28 (m, 1H, H-4′a), 1.24 (d, J = 6.8 Hz, 3H, 10-CH3), 1.19 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.14 - 1.03 (m, 6H, 2-CH3, 4-CH3), 1.01 (d, J = 7.0 Hz, 3H, 8-CH3), 0.87 (t, J = 7.4 Hz, 3H, 15-CH3), 0.84 - 0.77 (m, 2H, 2H-cyclopropyl), 0.71 - 0.63 (m, 2H, 2H-cyclopropyl). 13 C NMR (CDCl3, 176 MHz) δ: 178.06, 174.15, 166.91, 166.26, 165.87, 156.47, 154.96, 154.15, 149.55, 147.90, 140.15, 137.09, 129.87, 129.35, 126.99, 126.68, 125.21, 120.18, 119.89, 119.43, 109.00, 103.00, 92.68, 90.41, 85.28, 83.04, 81.78, 80.52, 80.32, 78.45, 78.35, 75.30, 75.19, 70.45, 69.06, 68.71, 61.59, 49.99, 43.30, 42.10, 40.32, 37.27, 35.99, 33.03, 31.93, 29.85, 29.70, 29.66, 29.36, 26.01, 23.32, 22.69, 22.17, 21.18, 20.99, 19.41, 18.87, 15.69, 15.64, 15.06, 14.91, 14.13, 12.85, 10.18, 9.04, 8.88, 6.46, 6.44, 6.39.

[0251] Synthetic route of Example 29 - Compound 9jE is as follows:

[0252]

[0253] Using compound 8j (0.232 g, 0.230 mmol), reacting according to the synthetic method of Example 25 - 1, after column chromatography of the product (silica gel of 100 - 200 mesh, mobile phase dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), compound 9jE 75.3 mg (0.0644 mmol, 28.02%) was obtained. Melting point: 168.1 - 169.7 °C. HRMS (ESI) (M + H) + m / z 1168.5386, calcd for C 60 H 78 N7O 17 1168.5449. 11H NMR (CD3OD, 400 MHz) δ: 9.15 (d, J = 2.1 Hz, 1H, 2″′-pyridyl), 9.10 (s, 1H, H-oxadiazolyl), 8.87 (s, 1H, 2″-quinolyl), 8.80 (d, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.50 (s, 1H, 6″′-pyridyl), 8.37 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 7.82 (s, 1H, 8″-quinolyl), 7.52 (s, 1H, 6″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.96 - 4.88 (m, 3H, H-11, 9-O-CH2), 4.80 (d, J = 11.1 Hz, 1H, H-3), 4.10 (d, J = 7.3 Hz, 1H, H-1′), 4.05 (s, 3H, N-CH3), 3.83 (d, J = 3.3 Hz, 1H, H-5), 3.80 - 3.73 (m, 1H, H-8), 3.69 (t, J = 6.4 Hz, 2H, O-CH2-CH2-C≡C-quinolyl), 3.66 - 3.57 (m, 2H, CH2-O-CH2-CH2-C≡C-quinolyl), 3.45 - 3.35 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.27 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.22 - 3.13 (m, 1H, 3-O-CO-NH-CH2), 3.05 (s, 3H, 6-O-CH3), 2.84 - 2.67 (m, 5H, H-2, H-3′, -CH2-C≡C-quinolyl, H-10), 2.42 (s, 6H, -N(CH3)2), 2.12 - 2.01 (m, 1H, H-4), 1.90 - 1.72 (m, 4H, H-14eq, H-7a, -CH2-), 1.69 - 1.60 (m, 1H, H-14ax), 1.55 (s, 3H, 12-CH3), 1.54 - 1.40 (m, 2H, H-7b, H-4′b), 1.35 (s, 3H, 6-CH3), 1.34 - 1.29 (m, 1H, H-4′a), 1.24 (d, J = 6.9 Hz, 3H, 10-CH3), 1.18 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.12 - 1.03 (m, 6H, 2-CH3, 4-CH3), 1.02 (d, J = 7.0 Hz, 3H, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR (CDCl3, 101 MHz) δ: 174.10, 162.25, 154.84, 154.63, 153.30, 153.19, 146.62, 136.70, 120.74, 119.65, 91.40, 85.04, 82.90, 81.12, 78.37, 70.48, 61.69, 50.00, 43.30, 40.35, 37.29, 35.95, 33.03, 26.07, 22.17, 21.18, 20.98, 19.41, 18.89, 15.63, 14.90, 12.93, 10.16, 8.87.

[0254] Example 30 is the synthetic route of clarithromycin derivatives with formula IV, which is as follows:

[0255]

[0256] The reaction conditions and reagents for the above synthetic route are as follows: a. hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride, DBU, DMF, room temperature; b. compounds 29, 30, 31, CuI, Pd(PPh3)2Cl2, triethylamine / acetonitrile (1:1), 45 °C; c. reflux in methanol.

[0257] The steps for preparing the clarithromycin derivative of formula IV are as follows:

[0258] Step 1: Dissolve compound 4 in DMF, add DBU dropwise, then add hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride, and react at room temperature. After the reaction is completed, perform post-treatment to obtain compound 10 or compound 11;

[0259] Step 2: Stir a mixed solution containing compound 29 or compound 30 or compound 31, copper(I) iodide, triethylamine and acetonitrile at room temperature, add bis(triphenylphosphine)palladium(II) dichloride and compound 10 or compound 11, change the gas, and react in an oil bath. After the reaction is completed, perform post-treatment to obtain compound 12 or compound 13. Synthetic methods for Examples 31 - compound 10 series and compound 11 series:

[0260] According to the synthetic method of Example 31, dissolve compound 4 (1 eq) in 20 mL of DMF, add DBU (3.6 eq) dropwise, and then add hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride (1.2 eq) to the system. React at room temperature for 12 h. After the reaction monitoring is completed, add 50 mL of ethyl acetate to the system, wash three times with water, and then wash successively with saturated sodium bicarbonate and saturated sodium chloride solutions. Rotavap the organic phase and purify by column chromatography to obtain compounds 10 and 11.

[0261] Specifically, the synthetic method of compound 10d is as follows:

[0262] Using compound 4d (0.573 g, 0.649 mmol) and heptynylamine hydrochloride (0.191 g, 1.298 mmol) according to the synthesis method of Example 31, the obtained product was purified by column chromatography on silica gel (100 - 200 mesh) with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. A pale yellow fluffy solid, compound 10d, 0.349 g (0.377 mmol, 58.09%) was obtained.

[0263] Specifically, the synthesis method of compound 10e is as follows:

[0264] Using compound 4e (0.600 g, 0.939 mmol) and heptynylamine hydrochloride (0.166 g, 1.127 mmol) according to the synthesis method of Example 31, the obtained product was purified by column chromatography on silica gel (100 - 200 mesh) with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. A pale yellow fluffy solid, compound 10e, 0.221 g (0.225 mmol, 23.96%) was obtained.

[0265] Specifically, the synthesis method of compound 10k is as follows:

[0266] Using compound 4k (0.904 g, 0.940 mmol) and heptynylamine hydrochloride (0.166 g, 1.128 mmol) according to the synthesis method of Example 31, the obtained product was purified by column chromatography on silica gel (100 - 200 mesh) with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. A pale yellow fluffy solid, compound 10k, 0.470 g (0.469 mmol, 49.89%) was obtained.

[0267] Specifically, the synthesis method of compound 10m is as follows:

[0268] Using compound 4m (0.428 g, 0.460 mmol) and heptynylamine hydrochloride (0.0815 g, 0.552 mmol) according to the synthesis method of Example 31, the obtained product was purified by column chromatography on silica gel (100 - 200 mesh) with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. A pale yellow fluffy solid, compound 10m, 0.260 g (0.267 mmol, 66.75%) was obtained.

[0269] Specifically, the synthesis method of compound 10n is as follows:

[0270] According to the synthesis method of Example 31, compound 4n (0.574 g, 0.615 mmol) was used with heptynylamine hydrochloride (0.109 g, 0.738 mmol). The resulting product was purified by column chromatography on silica gel (100 - 200 mesh), with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. A pale yellow fluffy solid, compound 10n, 0.318 g (0.326 mmol, 53.01%) was obtained.

[0271] Specifically, the synthesis method of compound 11a is as follows:

[0272] According to the synthesis method of Example 31, compound 4a (0.500 g, 0.634 mmol) was reacted with octynylamine hydrochloride (0.205 g, 1.269 mmol). The product was purified by column chromatography (silica gel, 100 - 200 mesh, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain compound 11a 0.100 g (0.106 mmol, 16.72%). HRMS(ESI)(M + H) + m / z939.5315, calcd for C 50 H 75 N4O 13 939.5325.

[0273] Specifically, the synthesis method of compound 11b is as follows:

[0274] According to the synthesis method of Example 31, compound 4b (0.763 g, 0.826 mmol) was reacted with octynylamine hydrochloride (0.267 g, 1.651 mmol). The product was purified by column chromatography (silica gel, 100 - 200 mesh, mobile phase: dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain compound 11b 0.259 g (0.264 mmol, 31.96%). HRMS(ESI)(M + H) + m / z981.5425, calcd for C 52 H 77 N4O 14 981.5431.

[0275] Specifically, the synthesis method of compound 11d is as follows:

[0276] Using the synthetic method of Example 31, compound 4d (0.993 g, 1.073 mmol) was reacted with octynylamine hydrochloride (0.347 g, 1.073 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.4 / 0.1) to obtain 0.255 g (0.260 mmol, 24.23%) of compound 11d. HRMS (ESI) (M + H) + m / z 982.5405, calcd for C 51 H 76 N5O 14 982.5383.

[0277] Specifically, the synthetic method of compound 11e is as follows:

[0278] Using the synthetic method of Example 31, compound 4e (0.761 g, 1.191 mmol) was reacted with octynylamine hydrochloride (0.231 g, 1.429 mmol), and the resulting product was purified by column chromatography on silica gel 100 - 200 mesh with dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.05. 0.349 g (0.350 mmol, 29.39%) of pale yellow fluffy solid compound 11e was obtained. HRMS (ESI) (M + H) + m / z 996.5555, calcd for C 52 H 78 N5O 14 996.5540.

[0279] Specifically, the synthetic method of compound 11h is as follows:

[0280] Using the synthetic method of Example 31, compound 4h (1.118 g, 1.230 mmol) was reacted with octynylamine hydrochloride (0.240 g, 1.476 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.371 g (0.380 mmol, 30.89%) of compound 11h.

[0281] Specifically, the synthetic method of compound 11i is as follows:

[0282] Using the synthesis method of Example 31, compound 4i (1.000 g, 1.081 mmol) was reacted with octynylamine hydrochloride (0.349 g, 2.162 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.249 g (0.254 mmol, 23.50%) of compound 11i. HRMS(ESI)(M + H) + m / z982.5395,calcd for C 51 H 76 N5O 14 982.5383.

[0283] Specifically, the synthesis method of compound 11l is as follows:

[0284] Using the synthesis method of Example 31, compound 4l (0.605 g, 0.638 mmol) was reacted with octynylamine hydrochloride (0.210 g, 1.275 mmol), and the product was purified by column chromatography (silica gel 100 - 200 mesh, mobile phase dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.143 g (0.142 mmol, 22.26%) of compound 11l. HRMS(ESI)(M + H) + m / z1005.5445,calcd for C 54 H 77 N4O 14 1005.5431.

[0285] The following Examples 32 - 45 are the synthesis routes and methods of compound 12 series and compound 13 series, and the general synthesis method of compound 12 series and compound 13 series is as shown in Example 32 - 1:

[0286] A mixture of compounds 29, 30, 31 (1.2 eq), copper(I) iodide (0.1 eq), and a mixture of 5 mL of triethylamine and 5 mL of acetonitrile was stirred at room temperature for 20 min, then bis(triphenylphosphine)palladium(II) dichloride (0.05 eq) and compound 10 or 11 (1 eq) were added to the system. After changing the gas, it was sealed and transferred to an oil bath at 45 °C and reacted for 12 h. After the reaction was completed, 30 mL of dichloromethane was added to the reaction system, and it was washed successively with water, saturated sodium bicarbonate, and saturated sodium chloride solutions. The organic phase was dried by evaporation, then methanol was added and refluxed at 65 °C for 2 h to remove the acetyl protection at the 2'-position. After the reaction monitoring was completed, the reaction solution was dried by evaporation and purified by column chromatography to obtain compound 12 series and compound 13 series.

[0287] The synthesis route of Example 32 - compound 12dD is as follows:

[0288]

[0289] According to the synthesis method of Example 32-1, compound 10d (0.349 g, 0.377 mmol) and compound 29 (0.201 g, 0.566 mmol) were used. The column chromatography conditions were silica gel of 100-200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and compound 12dD 15.1 mg (0.0131 mmol, 3.47%) was obtained. Melting point: 138.3-138.5 °C. HRMS (ESI) (M+H) + m / z 1153.5714, calcd for C 61 H 81 N6O 16 1153.5704. 11H NMR (CD3OD, 400 MHz) δ: 8.96 (d, J = 2.0 Hz, 1H, 6″′-pyridyl), 8.82 (s, 1H, 2″-quinolyl), 8.72 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.36 - 8.27 (m, 2H, 5″-quinolyl, 4″′-pyridyl), 8.18 (s, 1H, 8″-quinolyl), 7.53 (dd, J = 8.3 Hz, 1H, 6″-quinolyl), 5.10 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.94 - 4.76 (m, 4H, H-3, H-11, 9-O-CH2), 4.11 (d, J = 7.3 Hz, 1H, H-1′), 3.82 (d, J = 3.3 Hz, 1H, H-5), 3.79 - 3.68 (m, 2H, H-8, 1H-cyclopropyl), 3.51 - 3.36 (m, 1H, H-5′), 3.30 - 3.23 (m, 2H, 3-O-CO-NH-CH2, H-2′), 3.08 - 3.04 (m, 1H, 3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 2.84 - 2.46 (m, 3H, H-2, H-3′, H-10), 2.53 (t, J = 6.8 Hz, 2H, -CH2-C≡C-quinolyl), 2.44 (s, 6H, -N(CH3)2), 2.11 - 2.00 (m, 1H, H-4), 1.88 - 1.73 (m, 2H, H-4′a, H-14eq), 1.72 - 1.55 (m, 7H, 3(-CH2-), H-14ax), 1.53 (s, 3H, 12-CH3), 1.50 - 1.35 (m, 3H, 2H-cyclopropyl, H-4′b), 1.33 (s, 3H, 6-CH3), 1.32 - 1.11 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 10-CH3, 5′-CH3), 1.07 (d, J = 7.6 Hz, 3H, 4-CH3), 1.03 (d, J = 6.7 Hz, 3H, 2-CH3), 0.99 (d, J = 7.3 Hz, 3H, 8-CH3), 0.81 (t, J = 7.3 Hz, 3H, 15-CH3). 13CNMR(CD3OD, 100MHz) δ: 174.51, 167.55, 167.04, 157.38, 154.92, 153.63, 148.68, 147.18, 141.24, 138.06, 129.65, 128.69, 126.13, 120.29, 120.13, 101.72, 94.82, 90.57, 85.43, 83.04, 80.88, 79.63, 78.34, 78.15, 77.29, 75.17, 70.53, 68.67, 64.61, 60.94, 49.48, 49.31, 47.89, 43.18, 40.36, 39.42, 36.88, 35.86, 35.28, 32.96, 30.78, 29.06, 27.77, 26.04, 25.72, 21.82, 20.00, 18.69, 18.62, 18.06, 17.65, 14.66, 13.90, 11.76, 9.23, 7.93, 7.20.

[0290] Example 33 - The synthetic route of Compound 12eD is as follows:

[0291]

[0292] According to the synthetic method of Example 32 - 1, using Compound 10e (0.549 g, 0.559 mmol) and 29 (0.238 g, 0.671 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.5, and Compound 12eD 24.0 mg (0.0206 mmol, 3.67%) was obtained. Melting point: 126.0 - 127.8 °C. HRMS(ESI)(M + H) + m / z 1167.5862, calcd for C 62 H 83 N6O 16 1167.5860. 11H NMR (CDCl3, 500 MHz) δ: 9.02 (d, J = 2.2 Hz, 1H, 6″′-pyridyl), 8.85 (s, 1H, 2″-quinolyl), 8.71 (d, J = 2.2 Hz, 1H, 2″′-pyridyl), 8.40 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.14 (s, 1H, 4″′-pyridyl), 8.06 (d, J = 1.4 Hz, 1H, 8″-quinolyl), 7.54 (dd, J = 1.4 Hz, 8.3 Hz, 1H, 6″-quinolyl), 6.86 (d, J = 5.1 Hz, 1H, NH-CH3), 5.21 (br, 1H, 3-O-CO-NH-CH2), 5.13 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.91 - 4.81 (m, 4H, H-3, H-11, 9-O-CH2), 4.03 (d, J = 7.2 Hz, 1H, H-1′), 3.74 (d, J = 3.0 Hz, 1H, H-5), 3.73 - 3.66 (m, 1H, H-8), 3.59 (tt, J = 4.0 Hz, 7.3 Hz, 1H, 1H-cyclopropyl), 3.43 - 3.31 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.21 (dd, J = 7.2 Hz, 10.1 Hz, 1H, H-2′), 3.12 - 3.04 (m, 1H, 3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 3.00 (d, J = 4.7 Hz, 1H, NH-CH3), 2.86 - 2.78 (m, 1H, H-2), 2.57 - 2.46 (m, 4H, H-3′, H-10, -CH2-C≡C-quinolyl), 2.34 (s, 6H, -N(CH3)2), 2.10 - 2.00 (m, 1H, H-4), 1.94 - 1.84 (m, 1H, H-14eq), 1.74 - 1.52 (m, 8H, 3(-CH2-), H-4′a, H-14ax), 1.51 (s, 3H, 12-CH3), 1.46 - 1.37 (m, 3H, 2H-cyclopropyl, H-4′b), 1.34 (s, 3H, 6-CH3), 1.26 (d, J = 6.6 Hz, 3H, 10-CH3), 1.24 - 1.17 (m, 7H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH3), 1.11 (d, J = 6.8 Hz, 3H, 2-CH3), 1.06 (d, J = 7.5 Hz, 3H, 4-CH3), 0.96 (d, J = 7.0 Hz, 3H, 8-CH3), 0.84 (t, J = 7.4Hz, 3H, 15-CH3). 13 13C NMR (CDCl3, 125 MHz) δ: 178.19, 174.26, 166.79, 165.91, 165.44, 156.48, 154.97, 154.03, 148.48, 148.00, 141.07, 136.95, 130.04, 129.43, 129.40, 126.87, 124.84, 119.90, 119.86, 108.98, 103.22, 95.50, 90.52, 85.28, 83.16, 81.83, 81.14, 80.01, 78.36, 77.99, 77.25, 75.42, 70.45, 69.36, 65.99, 61.57, 50.04, 43.34, 40.95, 40.22, 37.34, 36.00, 35.39, 33.04, 29.76, 28.87, 28.00, 26.85, 26.06, 26.02, 22.16, 21.18, 19.53, 19.42, 18.88, 15.69, 14.88, 12.92, 10.17, 8.92, 8.35.

[0293] Synthetic route of Example 34 - Compound 12kD is as follows:

[0294]

[0295] According to the synthesis method of Example 32 - 1, using Compound 10k (0.470 g, 0.469 mmol) and Compound 29 (0.200 g, 0.563 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.5, and Compound 12kD 40.5 mg (0.0341 mmol, 7.27%) was obtained. Melting point: 157.3 - 158.6 °C. HRMS (ESI)(M + H) + m / z 1187.5898, calcd for C 65 H 83 N6O 15 1187.5911. 11H NMR (CDCl3, 400 MHz) δ: 8.78 (s, 1H, 2″-quinolyl), 8.67 - 8.56 (m, 2H, 6″′-pyridyl, 6″″-pyridyl), 8.36 - 8.25 (m, 3H, 3″′-pyridyl, 3″″-pyridyl, 5″-quinolyl), 7.99 (s, 1H, 8″-quinolyl), 7.81 - 7.70 (m, 2H, 4″′-pyridyl, 4″′-pyridyl), 7.46 (d, J = 8.3 Hz, 1H, 6″-quinolyl), 7.76 - 7.21 (m, 1H, 5″″-pyridyl), 5.20 (br, 1H, 3-O-CO-NH-CH2), 5.09 (d, J = 9.3 Hz, 1H, H-13), 4.92 - 4.72 (m, 4H, H-3, H-11, 9-O-CH2), 3.98 (br, 1H, H-1′), 3.76 - 3.60 (m, 2H, H-8, H-5), 3.55 - 3.47 (m, 1H, 1H-cyclopropyl), 3.38 - 3.21 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.21 - 3.10 (m, 1H, H-2′), 3.06 - 3.00 (m, 1H, 3-O-CO-NH-CH2), 2.99 (s, 3H, 6-O-CH3), 2.79 - 2.67 (m, 1H, H-2), 2.61 - 2.37 (m, 3H, H-10, -CH2-C≡C-quinolyl), 2.32 (s, 6H, -N(CH3)2), 2.27 - 2.17 (m, 1H, H-3′), 2.06 - 1.94 (m, 1H, H-4), 1.89 - 1.76 (m, 1H, H-14eq), 1.96 - 1.44 (m, 8H, 3(-CH2-), H-4′a, H-14ax), 1.42 (s, 3H, 12-CH3), 1.40 - 1.31 (m, 3H, 2H-cyclopropyl, H-4′b), 1.30 (s, 3H, 6-CH3), 1.27 - 1.09 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 10-CH3, 5′-CH3), 1.04 (d, J = 6.5 Hz, 3H, 2-CH3), 0.99 (d, J = 7.0 Hz, 3H, 4-CH3), 0.90 (d, J = 6.7 Hz, 3H, 8-CH3), 0.77 (t, J = 7.2 Hz, 3H, 15-CH3). 13CNMR(CDCl3, 100MHz) δ: 178.18, 174.08, 166.76, 166.25, 156.53, 155.51, 154.91, 154.66, 151.80, 149.25, 148.47, 141.06, 139.64, 136.94, 129.40, 126.87, 124.84, 123.89, 121.35, 120.29, 119.97, 119.85, 108.99, 95.55, 90.12, 85.05, 82.96, 82.76, 79.98, 78.35, 78.08, 77.26, 75.42, 70.46, 61.96, 49.94, 43.35, 40.89, 40.14, 37.35, 35.94, 35.38, 33.01, 29.78, 28.03, 26.06, 22.21, 21.19, 19.54, 19.39, 18.87, 15.63, 14.87, 13.00, 10.17, 8.97, 8.35.

[0296] Example 35 - The synthetic route of Compound 12mD is as follows:

[0297]

[0298] According to the synthesis method of Example 32 - 1, using Compound 10m (0.260 g, 0.267 mmol) and Compound 29 (0.114 g, 0.320 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.5, and Compound 12mD 51.2 mg (0.0441 mmol, 16.52%) was obtained. Melting point: 139.9 - 140.0 °C. HRMS(ESI)(M + H) + m / z 1160.5786, calcd for C 64 H 82 N5O 15 1160.5802. 11H NMR (CDCl3, 400 MHz) δ: 8.90 (d, J = 2.1 Hz, 1H, 2″′-quinolyl), 8.85 (s, 1H, 2″-quinolyl), 8.40 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.26 (d, J = 2.1 Hz, 1H, 4″′-quinolyl), 8.10 - 8.03 (m, 2H, 5″′-quinolyl, 8″-quinolyl), 7.80 (dd, J = 1.4 Hz, 8.2 Hz, 1H, 6″-quinolyl), 7.74 - 7.67 (m, 1H, 7″′-quinolyl), 7.59 - 7.51 (m, 2H, 6″′-quinolyl, 8″′-quinolyl), 5.17 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 5.06 - 4.83 (m, 5H, 3-O-CO-NH-CH2, H-3, H-11, 9-O-CH2), 4.02 (d, J = 7.3 Hz, 1H, H-1′), 3.85 - 3.70 (m, 2H, H-5, H-8), 3.58 (tt, J = 3.9 Hz, 7.3 Hz, 1H, 1H-cyclopropyl), 3.44 - 3.30 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.19 (dd, J = 7.2 Hz, 10.1 Hz, 1H, H-2′), 3.14 - 3.08 (m, 1H, 3-O-CO-NH-CH2), 3.07 (s, 3H, 6-O-CH3), 2.88 - 2.77 (m, 1H, H-2), 2.58 - 2.46 (m, 3H, H-10, -CH2-C≡C-quinolyl), 2.46 - 2.36 (m, 1H, H-3′), 2.29 (s, 6H, -N(CH3)2), 2.14 - 2.03 (m, 1H, H-4), 1.97 - 1.85 (m, 1H, H-14eq), 1.75 - 1.52 (m, 8H, 3(-CH2-), H-4′a, H-14ax), 1.50 (s, 3H, 12-CH3), 1.48 - 1.40 (m, 3H, 2H-cyclopropyl, H-4′b), 1.38 (s, 3H, 6-CH3), 1.35 - 1.16 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 5′-CH3, 10-CH3), 1.12 (d, J = 6.7 Hz, 3H, 2-CH3), 1.07 (d, J = 7.5 Hz, 3H, 4-CH3), 0.98 (d, J = 7.0 Hz, 3H, 8-CH3), 0.85 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 100 MHz) δ: 173.43, 169.30, 161.97, 161.45, 151.68, 149.92, 147.46, 143.72, 142.16, 136.30, 134.02, 125.28, 125.25, 124.64, 124.60, 122.95, 122.50, 122.43, 122.15, 120.12, 115.06, 112.35, 104.28, 98.56, 90.71, 84.50, 80.28, 78.28, 78.24, 76.44, 75.25, 73.64, 73.46, 72.50, 70.72, 65.71, 64.73, 61.37, 57.21, 45.20, 38.61, 36.19, 35.61, 32.61, 31.22, 30.60, 28.27, 25.04, 24.95, 23.28, 21.32, 17.46, 16.47, 14.79, 14.67, 14.14, 10.89, 10.13, 8.26, 5.42, 4.17, 3.60.

[0299] Synthetic route of Example 36 - Compound 12pD is as follows:

[0300]

[0301] According to the synthesis method of Example 32 - 1, using Compound 10p (0.318 g, 0.326 mmol) and Compound 29 (0.139 g, 0.391 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.7 / 0.5, and Compound 12pD 50.2 mg (0.0433 mmol, 13.27%) was obtained. Melting point: 152.2 - 154.1 °C. HRMS(ESI)(M + H) + m / z 1160.5776, calcd for C 64 H 82 N5O 15 1160.5802. 11H NMR (CDCl3, 400 MHz) δ: 9.11 (s, 1H, 1″′-isoquinolyl), 8.78 (s, 1H, 2″-quinolyl), 8.58 (s, 1H, 3″′-isoquinolyl), 8.33 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.24 (d, J = 8.4 Hz, 1H, 8″′-isoquinolyl), 7.98 (s, 1H, 8″-quinolyl), 7.90 (d, J = 8.2 Hz, 1H, 5′″-isoquinolyl), 7.73 (t, J = 7.2 Hz, 1H, 7″′-isoquinolyl), 7.57 (t, J = 7.2 Hz, 1H, 6″′-isoquinolyl), 7.46 (dd, J = 1.3 Hz, 8.4 Hz, 1H, 6″-quinolyl), 5.19 (br, 1H, 3-O-CO-NH-CH2), 5.09 (dd, J = 2.6 Hz, 10.7 Hz, 1H, H-13), 5.01 - 4.71 (m, 4H, H-3, H-11, 9-O-CH2), 3.97 (br, 1H, H-1′), 3.78 - 3.67 (m, 1H, H-8), 3.64 (br, 1H, H-5), 3.51 (tt, J = 4.0 Hz, 7.2 Hz, 1H, 1H-cyclopropyl), 3.39 - 3.22 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.15 (t, J = 8.6 Hz, 1H, H-2′), 3.05 - 2.97 (m, 1H, 3-O-CO-NH-CH2), 2.96 (s, 3H, 6-O-CH3), 2.79 - 2.67 (m, 1H, H-2), 2.54 - 2.38 (m, 4H, H-3′, H-10, -CH2-C≡C-quinolyl), 2.31 (s, 6H, -N(CH3)2), 2.06 - 1.94 (m, 1H, H-4), 1.90 - 1.7 (m, 1H, H-14eq), 1.69 - 1.45 (m, 8H, 3(-CH2-), H-4′a, H-14ax), 1.43 (s, 3H, 12-CH3), 1.40 - 1.32 (m, 3H, 2H-cyclopropyl, H-4′b), 1.31 (s, 3H, 6-CH3), 1.25 - 1.09 (m, 7H, 2H-cyclopropyl, H-7a, H-7b, 10-CH3, 5′-CH3), 1.03 (d, J = 6.7 Hz, 3H, 2-CH3), 0.99 (d, J = 7.3 Hz, 3H, 4-CH3), 0.90 (d, J = 6.9 Hz, 3H, 8-CH3), 0.78 (t, J = 7.4 Hz, 3H, 15-CH3). 13 C NMR(CDCl3,100MHz)δ:178.18,174.05,166.76,166.27,156.51,154.68,152.08,148.48,146.48,141.06,135 .87,131.22,130.03,129.40,127.90,127.74,126.88,125.32,124.84,119.84,115.65,109.00,95.53,93.46 ,85.07,82.99,80.77,79.99,78.35,77.25,75.45,70.44,62.00,49.94,43.34,40.88,40.15,37.35,35.93,35.38,33.03,29.77,28.02,26.06,22.24,21.18,19.54,19.41,18.87,15.65,14.85,13.01,10.21,8.96,8.35.

[0302] The synthetic route of Example 37-Compound 13aE is as follows:

[0303]

[0304] According to the synthesis method of Example 32-1, compound 11a (0.100 g, 0.106 mmol) and compound 30 (0.0386 g, 0.117 mmol) were used. Column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, to obtain 34.4 mg (0.0313 mmol, 29.55%) of compound 13aE. Melting point: 156.0-157.5°C. HRMS (ESI) (M+H) + m / z 1098.5636,calcd for C 59 H 80 N5O 15 1098.5645. 11H NMR (CDCl3, 400 MHz) δ: 8.68 (s, 1H, 2″-quinolyl), 8.58 (s, 1H, 2″′-pyridyl), 8.45 (dd, J = 2.0 Hz, 5.0 Hz, 1H, 5″′-pyridyl), 8.36 (d, J = 8.1 Hz, 1H, 5″-quinoly), 7.65 (dd, J = 2.1 Hz, 7.9 Hz, 1H, 4′″-pyridyl), 7.52 (s, 1H, 8″-quinoly), 7.47 (d, J = 7.6 Hz, 1H, 6″-quinolyl), 7.17 (dd, J = 4.9 Hz, 7.9 Hz, 1H, 5′″-pyridyl), 5.09 (dd, J = 3.0 Hz, 10.8 Hz, 1H, H-13), 4.90 - 4.70 (m, 4H, H-11, 9-O-CH2, H-3), 3.92 (s, 1H, N-CH3), 3.78 (br, 1H, H-1′), 3.73 - 3.62 (m, 2H, H-5, H-8), 3.36 - 3.18 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.17 - 3.06 (m, 1H, H-2′), 3.04 - 2.99 (m, 1H, 3-O-CO-NH-CH2), 2.97 (s, 3H, 6-O-CH3), 2.83 - 2.70 (m, 1H, H-2), 2.51 - 2.27 (m, 4H, H-10, -CH2-C≡C-quinolyl, H-3′), 2.20 (s, 6H, -N(CH3)2), 2.04 - 1.93 (m, 1H, H-4), 1.90 - 1.75 (m, 1H, H-14eq), 1.63 - 1.44 (m, 6H, H-4′a, H-14ax, H-7a, H-7b, -CH2-), 1.41 (s, 3H, 12-CH3), 1.39 - 1.21 (m, 8H, H-4′b, 2(-CH2-), 6-CH3), 1.22 - 1.09 (m, 8H, 10-CH3, 5′-CH3, -CH2-), 1.06 (d, J = 6.7 Hz, 3H, 2-CH3), 0.99 (d, J = 7.0 Hz, 3H, 4-CH3), 0.89 (d, J = 6.9 Hz, 3H, 8-CH3), 0.79 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 176 MHz) δ: 178.10, 174.09, 166.85, 166.16, 154.67, 152.37, 152.34, 149.47, 148.64, 140.16, 138.77, 130.34, 129.39, 127.02, 125.08, 123.01, 120.12, 119.08, 109.06, 96.02, 89.39, 89.37, 85.06, 85.03, 82.96, 82.42, 79.66, 78.35, 75.41, 70.46, 61.86, 61.84, 49.94, 43.34, 42.01, 41.04, 40.37, 37.32, 35.95, 32.98, 30.08, 29.70, 29.66, 29.36, 28.67, 28.59, 28.45, 28.28, 26.29, 26.03, 22.70, 22.20, 21.21, 19.49, 19.40, 19.33, 18.87, 15.62, 14.89, 14.13, 13.03, 12.99, 10.19, 10.18, 8.92.

[0305] Synthetic route of Example 38 - Compound 13bE is as follows:

[0306]

[0307] According to the synthesis method of Example 32 - 1, using Compound 11b (0.259 g, 0.264 mmol) and Compound 30 (0.0955 g, 0.290 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and Compound 13bE 94.0 mg (0.0824 mmol, 31.22%) was obtained. Melting point: 163.2 - 163.8 °C. HRMS(ESI)(M + H) + m / z 1140.5751, calcd for C 61 H 82 N5O 16 1140.5751. 11H NMR (CDCl3, 400 MHz) δ: 8.98 (d, J = 2.2 Hz, 1H, 2″′-pyridyl), 8.72 (d, J = 2.2 Hz, 1H, 4″′-pyridyl), 8.69 (s, 1H, 2″-quinolyl), 8.37 (d, J = 8.3 Hz, 1H, 5″-quinoly), 8.19 (d, J = 2.3 Hz, 1H, 6″′-pyridyl), 7.52 (s, 1H, 8″-quinolyl), 7.48 (d, J = 8.3 Hz, 1H, 6″-quinolyl), 5.09 (d, J = 3.3 Hz, 11.4 Hz, 1H, H-13), 4.92 - 4.72 (m, 4H, H-11, 9-O-CH2, H-3), 3.92 (s, 1H, N-CH3), 3.78 (br, 1H, H-1′), 3.73 - 3.61 (m, 2H, H-5, H-8), 3.35 - 3.17 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.15 - 3.06 (m, 1H, H-2′), 3.05 - 2.97 (m, 1H, 3-O-CO-NH-CH2), 2.96 (s, 3H, 6-O-CH3), 2.82 - 2.70 (m, 1H, H-2), 2.56 (s, 3H, pyridyl-CO-CH3), 2.49 - 2.37 (m, 3H, H-10, -CH2-C≡C-quinolyl), 2.35 - 2.26 (m, 1H, H-3′), 2.19 (s, 6H, -N(CH3)2), 2.03 - 1.93 (m, 1H, H-4), 1.89 - 1.77 (m, 1H, H-14eq), 1.64 - 1.45 (m, 6H, H-4′a, H-14ax, H-7a, H-7b, -CH2-), 1.42 (s, 3H, 12-CH3), 1.40 - 1.30 (m, 7H, H-4′b, 3(-CH2-)), 1.28 (s, 3H, 6-CH3), 1.19 (d, J = 6.1 Hz, 3H, 10-CH3), 1.14 (d, J = 5.9 Hz, 3H, 5′-CH3), 1.06 (d, J = 6.6 Hz, 3H, 2-CH3), 0.99 (d, J = 7.1 Hz, 3H, 4-CH3), 0.89 (d, J = 6.9 Hz, 3H, 8-CH3), 0.79 (t, J = 7.2 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 176 MHz) δ: 196.52, 174.59, 166.88, 157.38, 154.92, 154.37, 147.84, 138.52, 132.13, 120.61, 101.78, 90.97, 85.44, 83.05, 80.93, 78.33, 78.11, 77.22, 75.16, 70.63, 68.66, 64.52, 60.91, 49.34, 43.18, 40.45, 39.51, 36.85, 35.87, 32.96, 30.87, 29.40, 28.27, 28.09, 26.03, 25.99, 21.84, 20.05, 18.69, 18.65, 17.68, 14.67, 13.90, 11.77, 9.22, 7.92.

[0308] Synthetic route of Example 39 - Compound 13dE is as follows:

[0309]

[0310] According to the synthesis method of Example 32 - 1, using Compound 11d (0.255 g, 0.260 mmol) and Compound 30 (0.102 g, 0.312 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and Compound 13dE 25.9 mg (0.0824 mmol, 31.67%) was obtained. HRMS(ESI)(M + H) + m / z 1141.5709, calcd for C 60 H 81 N6O 16 1141.5704. 11H NMR (CD3OD, 400 MHz) δ: 8.94 (d, J = 2.1 Hz, 1H, 6″′-pyridyl), 8.84 (s, 1H, 2″-quinolyl), 8.72 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.34 (d, J = 8.3 Hz, 1H, 5″-quinolyl), 8.29 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 7.76 (s, 1H, 8″-quinolyl), 7.47 (s, 1H, 6″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.94 - 4.86 (m, 3H, H-11, 9-O-CH2), 4.81 (d, J = 11.1 Hz, 1H, H-3), 4.10 (d, J = 7.3 Hz, 1H, H-1′), 4.01 (s, 3H, N-CH3), 4.82 (d, J = 3.3 Hz, 1H, H-5), 3.77 - 3.70 (m, 1H, H-8), 3.44 - 3.36 (m, 1H, H-5′), 3.28 - 3.19 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.09 - 2.99 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.91 - 2.81 (m, 1H, H-2), 2.75 - 2.61 (m, 2H, H-3′, H-10), 2.50 (d, J = 6.7 Hz, 2H, -CH2-C≡C-quinolyl), 2.39 (s, 6H, -N(CH3)2), 2.11 - 2.02 (m, 1H, H-4), 1.87 - 1.78 (m, 1H, H-14eq), 1.77 - 1.69 (m, 1H, H-7a), 1.68 - 1.55 (m, 3H, H-4′a, H-14ax, H-7b), 1.58 - 1.49 (s, 7H, 2(-CH2-), 12-CH3), 1.48 - 1.36 (m, 4H, 2(-CH2-)), 1.33 (s, 3H, 6-CH3), 1.30 - 1.25 (m, 1H, H-4′a), 1.23 (d, J = 6.7 Hz, 3H, 10-CH3), 1.17 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.12 - 1.04 (m, 6H, 2-CH3, 4-CH3), 0.99 (d, J = 7.0 Hz, 3H, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 176 MHz) δ: 174.57, 167.55, 167.03, 157.39, 154.92, 153.62, 147.18, 138.05, 129.64, 120.28, 101.80, 90.57, 85.43, 83.05, 80.88, 79.47, 78.35, 78.14, 77.27, 75.19, 70.62, 68.68, 64.52, 60.94, 49.31, 43.20, 40.46, 39.48, 36.88, 35.89, 32.95, 30.81, 29.40, 28.26, 28.08, 26.04, 25.99, 21.83, 20.03, 18.67, 18.64, 17.65, 14.65, 13.89, 11.76, 9.24, 7.92.

[0311] Synthetic route of Example 40 - Compound 13eD is as follows:

[0312]

[0313] According to the synthesis method of Example 32 - 1, using Compound 11e (0.349 g, 0.350 mmol) and Compound 29 (0.149 g, 0.420 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.5, and Compound 13eD 28.5 mg (0.0241 mmol, 6.89%) was obtained. Melting point: 129.6 - 130.1 °C. HRMS(ESI)(M + H) + m / z 1181.5999, calcd for C 63 H 85 N6O 16 1181.6017. 11H NMR (CDCl3, 400 MHz) δ: 9.02 (d, J = 2.0 Hz, 1H, 6′″-pyridyl), 8.85 (s, 1H, 2″-quinolyl), 8.71 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.40 (d, J = 8.3 Hz, 1H, 5″-quinolyl), 8.13 (t, J = 2.0 Hz, 1H, 4″′-pyridyl), 8.06 (d, J = 1.4 Hz, 1H, 8″-quinolyl), 7.54 (dd, J = 1.4 Hz, 8.3 Hz, 1H, 6″-quinolyl), 6.86 (d, J = 5.1 Hz, 1H, NH-CH3), 5.21 (br, 1H, 3-O-CO-NH-CH2), 5.14 (dd, J = 2.6 Hz, 10.7 Hz, 1H, H-13), 4.92 - 4.79 (m, 4H, H-3, H-11, 9-O-CH2), 4.04 (br, 1H, H-1′), 3.82 - 3.63 (m, 2H, H-5, H-8), 3.59 (tt, J = 4.0 Hz, 7.2 Hz, 1H, 1H-cyclopropyl), 3.49 - 3.25 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.26 - 3.14 (m, 1H, H-2′), 3.12 - 3.04 (m, 1H, 3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 2.99 (d, J = 4.7 Hz, 1H, NH-CH3), 2.90 - 2.78 (m, 1H, H-2), 2.58 - 2.41 (m, 4H, H-3′, H-10, -CH2-C≡C-quinolyl), 2.32 (s, 6H, -N(CH3)2), 2.10 - 1.97 (m, 1H, H-4), 1.95 - 1.83 (m, 1H, H-14eq), 1.73 - 1.53 (m, 8H, 3(-CH2-), H-4′a, H-14ax), 1.50 (s, 3H, 12-CH3), 1.47 - 1.36 (m, 5H, 2H-cyclopropyl, H-4′b, CH2), 1.34 (s, 3H, 6-CH3), 1.29 - 1.16 (m, 10H, 2H-cyclopropyl, H-7a, H-7b, 10-CH3, 5′-CH3), 1.13 (d, J = 6.7 Hz, 3H, 2-CH3), 1.06 (d, J = 7.2 Hz, 3H, 4-CH3), 0.96 (d, J = 6.9 Hz, 3H, 8-CH3), 0.84 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 100 MHz) δ: 178.20, 174.28, 166.80, 165.94, 165.45, 154.96, 154.02, 148.47, 147.99, 141.07, 136.94, 130.12, 129.43, 126.89, 124.84, 119.89, 119.79, 109.01, 90.50, 85.27, 83.17, 81.84, 79.89, 78.37, 77.24, 75.42, 70.48, 61.58, 50.06, 43.36, 41.06, 40.29, 37.35, 36.03, 35.37, 33.05, 30.10, 28.61, 28.31, 26.84, 26.30, 26.03, 22.18, 21.18, 19.53, 19.42, 18.89, 15.69, 14.89, 12.92, 10.18, 8.91, 8.34.

[0314] Example 41 - The synthetic route of Compound 13eE is as follows:

[0315]

[0316] According to the synthesis method of Example 32 - 1, using Compound 11e (0.306 g, 0.307 mmol) and Compound 30 (0.121 g, 0.368 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and Compound 13eE 110.3 mg (0.0955 mmol, 31.10%) was obtained. Melting point: 175.8 - 176.7 °C. HRMS(ESI)(M + H) + m / z 1155.5883, calcd for C 61 H 83 N6O 16 1155.5860. 11H NMR (CD3OD, 400 MHz) δ: 8.87 (d, J = 2.2 Hz, 1H, 6″′-pyridyl), 8.83 (s, 1H, 2″-quinolyl), 8.70 (d, J = 2.0 Hz, 1H, 2″′-pyridyl), 8.34 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.33 (t, J = 2.1 Hz, 1H, 4″′-pyridyl), 7.74 (s, 1H, 8″-quinolyl), 7.45 (s, 1H, 6″-quinolyl), 5.12 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.92 - 4.86 (m, 3H, H-11, 9-O-CH2), 4.81 (d, J = 11.2 Hz, 1H, H-3), 4.09 (d, J = 7.3 Hz, 1H, H-1′), 4.00 (s, 3H, N-CH3), 4.81 (d, J = 3.3 Hz, 1H, H-5), 3.77 - 3.70 (m, 1H, H-8), 3.44 - 3.34 (m, 1H, H-5′), 3.28 - 3.19 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.07 - 2.97 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.91 (s, 3H, NH-CH3), 2.90 - 2.82 (m, 1H, H-2), 2.78 - 2.62 (m, 2H, H-3′, H-10), 2.50 (d, J = 6.8 Hz, -CH2-C≡C-quinolyl), 2.38 (s, 6H, -N(CH3)2), 2.11 - 2.01 (m, 1H, H-4), 1.88 - 1.78 (m, 1H, H-14eq), 1.77 - 1.69 (m, 1H, H-7a), 1.68 - 1.55 (m, 3H, H-4′a, H-14ax, H-7b), 1.55 - 1.48 (s, 7H, 2(-CH2-), 12-CH3), 1.49 - 1.36 (m, 4H, 2(-CH2-)), 1.33 (s, 3H, 6-CH3), 1.30 - 1.26 (m, 1H, H-4′a), 1.23 (d, J = 6.8 Hz, 3H, 10-CH3), 1.17 (d, J = 6.5 Hz, 3H, 5′-CH3), 1.13 - 1.03 (m, 6H, 2-CH3, 4-CH3), 0.99 (d, J = 7.0 Hz, 3H, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 100 MHz) δ: 174.57, 167.03, 165.99, 154.92, 153.36, 146.76, 137.64, 130.10, 120.32, 110.19, 90.60, 85.43, 80.89, 78.36, 78.16, 77.29, 75.19, 68.71, 60.94, 49.31, 43.21, 39.51, 36.88, 32.96, 29.41, 28.26, 28.10, 26.00, 25.57, 21.84, 20.04, 18.64, 17.65, 14.66, 13.89, 11.77, 9.25, 7.92.

[0317] Synthetic route of Example 42 - Compound 13eF is as follows:

[0318]

[0319] According to the synthesis method of Example 32 - 1, using Compound 11e (0.200 g, 0.201 mmol) and Compound 31 (0.0860 g, 0.241 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and Compound 13eF 36.8 mg (0.0311 mmol, 15.47%) was obtained. Melting point: 140.3 - 140.9 °C. HRMS(ESI)(M + H) + m / z 1183.6160, calcd for C 63 H 87 N6O 16 1183.6173. 11H NMR (CDCl3, 400 MHz) δ: 9.03 (d, J = 2.2 Hz, 1H, 2″′-pyridyl), 8.71 (d, J = 1.9 Hz, 1H, 4″′-pyridyl), 8.47 (s, 1H, 2″-quinolyl), 8.42 (d, J = 8.3 Hz, 1H, 5″-quinolyl), 8.14 (d, J = 2.1 Hz, 1H, 6″′-pyridyl), 7.78 (s, 1H, 8″-quinolyl), 7.42 (d, J = 8.3 Hz, 1H, 6″-quinolyl), 6.89 (d, J = 4.9 Hz, NH-CH3), 5.14 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.94 (t, J = 6.0 Hz, 1H, 3-O-CO-NH-CH2), 4.91 - 4.80 (m, 3H, H-11, 9-O-CH2, H-3), 4.39 (q, J = 7.1 Hz, 2H, -OCH2CH3), 4.00 (d, J = 7.3 Hz, 1H, H-1′), 3.87 (s, 3H, N-CH3), 3.75 (d, J = 3.0 Hz, 1H, H-5), 3.74 - 3.66 (m, 1H, H-8), 3.40 - 3.23 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.17 (dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.13 - 3.05 (m, 1H, 3-O-CO-NH-CH2), 3.03 (s, 3H, 6-O-CH3), 3.00 (d, J = 4.8 Hz, 1H, NH-CH3), 2.90 - 2.80 (m, 5H, H-2), 2.53 (q, J = 6.8 Hz, 1H, H-10), 2.46 (t, J = 7.0 Hz, 2H, -CH2-C≡C-quinolyl), 2.41 - 2.32 (m, 1H, H-3′), 2.26 (s, 6H, -N(CH3)2), 2.09 - 2.00 (m, 1H, H-4), 1.95 - 1.84 (m, 1H, H-14ax), 1.68 - 1.43 (m, 4H, H-14eq, H-7a, 2(-CH2-), 12-CH3, H-7b, H-4′b), 1.44 - 1.36 (m, 5H, -CH2-, -OCH2CH3), 1.35 (s, 3H, 6-CH3), 1.32 - 1.28 (m, 1H, H-4′a), 1.26 (d, J = 6.4 Hz, 3H, 10-CH3), 1.20 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.13 (d, J = 6.7 Hz, 3H, 2-CH3), 1.07 (d, J = 7.5 Hz, 3H, 4-CH3), 0.96 (d, J = 7.0 Hz, 3H, 8-CH3), 0.86 (t, J = 7.3 Hz, 3H). 13 13C NMR (CDCl3, 176 MHz) δ: 174.29, 173.99, 165.93, 165.63, 165.49, 156.39, 154.99, 154.03, 149.99, 148.07, 139.69, 136.95, 129.43, 128.63, 128.36, 127.84, 127.78, 119.85, 118.47, 111.23, 103.30, 94.19, 90.40, 85.27, 83.18, 81.87, 80.93, 80.03, 78.37, 78.00, 75.42, 70.45, 69.54, 66.12, 61.58, 60.94, 50.06, 43.35, 41.35, 41.09, 40.36, 37.33, 36.03, 33.03, 30.08, 28.52, 28.35, 26.87, 26.29, 26.03, 22.16, 21.21, 19.43, 18.88, 15.70, 14.91, 14.44, 12.94, 10.19, 8.91.

[0320] Example 43 - The synthetic route of compound 13hE is as follows:

[0321]

[0322] According to the synthesis method of Example 32 - 1, using compound 11h (0.200 g, 0.210 mmol) and compound 30 (0.082 g, 0.252 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and compound 13hE 20.1 mg (0.0176 mmol, 8.39%) was obtained.

[0323] Example 44 - The synthetic route of compound 13iE is as follows:

[0324]

[0325] According to the synthesis method of Example 32 - 1, using compound 11i (0.249 g, 0.254 mmol) and compound 30 (0.100 g, 0.304 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and compound 13iE 72.8 mg (0.0638 mmol, 25.11%) was obtained. Melting point: 172.3 - 172.8 °C. HRMS (ESI) (M + H)+ m / z 1141.5718, calcd for C 60 H 81 N6O 16 1141.5704. 11H NMR (CD3OD, 400 MHz) δ: 8.84 (s, 1H, 2″-quinolyl), 8.64 (d, J = 1.2 Hz, 1H, 6″′-pyridyl), 8.34 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.06 (d, J = 8.1 Hz, 1H, 3″′-pyridyl), 7.96 (dd, J = 2.1 Hz, 8.1 Hz, 1H, 4″′-pyridyl), 7.76 (s, 1H, 8″-quinolyl), 7.48 (s, 1H, 6″-quinolyl), 5.11 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.93 - 4.87 (m, 3H, H-11, 9-O-CH2), 4.83 - 4.79 (m, 1H, H-3), 4.10 (d, J = 7.3 Hz, 1H, H-1′), 4.01 (s, 3H, N-CH3), 3.82 (d, J = 3.3 Hz, 1H, H-5), 3.79 - 3.70 (m, 1H, H-8), 3.43 - 3.32 (m, 1H, H-5′), 3.29 - 3.19 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.07 - 2.98 (m, 4H, 3-O-CO-NH-CH2, 6-O-CH3), 2.91 - 2.84 (m, 1H, H-2), 2.74 - 2.61 (m, 2H, H-3′, H-10), 2.50 (d, J = 6.8 Hz, 2H, -CH2-C≡C-quinolyl), 2.37 (s, 6H, -N(CH3)2), 2.11 - 2.02 (m, 1H, H-4), 1.87 - 1.78 (m, 1H, H-14eq), 1.76 - 1.68 (m, 1H, H-7a), 1.68 - 1.59 (m, 3H, H-4′a, H-14ax, H-7b), 1.59 - 1.49 (s, 7H, 2(-CH2-), 12-CH3), 1.49 - 1.37 (m, 4H, 2(-CH2-)), 1.33 (s, 3H, 6-CH3), 1.30 - 1.25 (m, 1H, H-4′a), 1.23 (d, J = 6.8 Hz, 3H, 10-CH3), 1.17 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.13 - 1.05 (m, 6H, 2-CH3, 4-CH3), 1.00 (d, J = 7.0 Hz, 3H, 8-CH3), 0.86 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR(CD3OD, 176 MHz) δ: 174.62, 167.16, 167.04, 157.40, 154.90, 150.70, 148.39, 139.77, 122.85, 121.38, 101.84, 91.66, 85.41, 83.02, 81.44, 79.47, 78.37, 78.13, 77.28, 75.20, 70.69, 68.71, 64.48, 60.99, 49.31, 43.21, 40.46, 39.50, 36.88, 35.90, 32.95, 30.82, 29.40, 28.25, 28.08, 26.05, 25.99, 21.84, 20.03, 18.66, 18.64, 17.63, 14.64, 13.88, 11.75, 9.27, 7.91.

[0326] Example 45 - The synthetic route of compound 13lE is as follows:

[0327]

[0328] According to the synthetic method of Example 32 - 1, using compound 11l (0.143 g, 0.142 mmol) and compound 30 (0.0562 g, 0.171 mmol), the column chromatography conditions were silica gel of 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 1 / 0.5, and compound 13lE 23.2 mg (0.0199 mmol, 14.03%) was obtained. HRMS(ESI)(M + H) + m / z 1164.5751, calcd for C 63 H 82 N5O 16 1164.5751. 11H NMR (Acetone-d6, 400 MHz) δ: 8.90 (s, 1H, 2″-quinolyl), 8.39 (d, J = 8.3 Hz, 1H, 5″-quinolyl), 8.35 (d, J = 1.8 Hz, 1H, 5″′-quinolyl), 7.93 (d, J = 1.3 Hz, 1H, 8″-quinolyl), 7.71 (dd, J = 1.8 Hz, 8.2 Hz, 1H, 2″′-quinolyl), 7.67 - 7.58 (m, 2H, 6″-quinolyl, 1″′-quinolyl), 7.27 (d, J = 7.2 Hz, 1H, 7″′-quinolyl), 6.62 (t, J = 5.8 Hz, 1H, NH), 6.55 (d, J = 7.2 Hz, 1H, 8″′-quinolyl), 5.18 (dd, J = 2.5 Hz, 10.7 Hz, 1H, H-13), 4.95 - 4.85 (m, 4H, 9-O-CH2, H-11, H-3), 4.14 (d, J = 7.3 Hz, 1H, H-1′), 3.85 (d, J = 3.4 Hz, 1H, H-5), 3.81 (s, 3H, N-CH3), 3.79 - 3.74 (m, 1H, H-8), 3.53 - 3.44 (m, 1H, H-5′), 3.34 - 3.24 (m, 1H, 3-O-CO-NH-CH2), 3.17 - 3.05 (m, 6H, 3-O-CO-NH-CH2, H-2′, 6-O-CH3), 2.95 - 2.84 (m, 2H, H-2, H-3′), 2.78 (q, J = 6.8 Hz, 1H, H-10), 2.54 (t, J = 6.97 Hz, 2H, -CH2-C≡C-quinolyl), 2.27 (s, 6H, -N(CH3)2), 1.89 - 1.80 (m, 1H, H-4, H-14eq), 1.72 - 1.59 (m, 4H, H-7a, H-4′a, H-14ax, H-7b), 1.72 - 1.40 (s, 12H, 4(-CH2-), 12-CH3, H-4′a), 1.37 (s, 3H, 6-CH3), 1.25 (d, J = 6.8 Hz, 3H, 10-CH3), 1.17 (d, J = 6.1 Hz, 3H, 5′-CH3), 1.14 - 1.06 (m, 6H, 2-CH3, 4-CH3), 1.03 (d, J = 7.1 Hz, 3H, 8-CH3), 0.87 (t, J = 7.3 Hz, 3H, 15-CH3).

[0329] Example 46 is the synthetic route of clarithromycin derivatives with formula V, which is as follows:

[0330]

[0331] The reaction conditions and reagents for the above synthetic route are as follows: a. benzoic anhydride, DMAP, THF, N,N-dimethylethylenediamine, at room temperature; b. CDI, NaHMDS, THF / DMF = 1.5 / 1, at room temperature; c. telithromycin side chain, DBU, acetonitrile, 55 °C; d. 4M HCl solution, ethanol, 45 °C; e. CDI, DMAP, dichloromethane; f. butanolamine, DBU, DMF, at room temperature; g. p-toluenesulfonyl chloride, triethylamine, dichloromethane, at room temperature; h. ciprofloxacin or enoxacin, acetonitrile, 70 °C; i. reflux in methanol.

[0332] The steps for preparing the clarithromycin derivative of formula V are as follows:

[0333] Step 1: Dissolve clarithromycin, DMAP and benzoic anhydride in anhydrous tetrahydrofuran, add triethylamine, stir at room temperature until the reaction is complete, and perform post-treatment to obtain compound 14;

[0334] Step 2: Disperse compound 14 and CDI in a mixed solution of THF / DMF, dropwise add a solution of NaHMDS with stirring, stir at room temperature until the reaction is complete, and perform post-treatment to obtain compound 15;

[0335] Step 3: Dissolve compound 15 in acetonitrile, add the telithromycin side chain and DBU, react until the reaction is complete, spin-dry the reaction solution, add ethanol, raise the temperature, and dropwise add 4M HCl until the reaction is complete, and perform post-treatment to obtain compound 16;

[0336] Step 4: Disperse compound 16, DMAP and CDI in dichloromethane, react at room temperature until the reaction is complete, and perform post-treatment to obtain compound 17;

[0337] Step 5: Dissolve compound 17 in dry DMF, dropwise add butanolamine and DBU at room temperature, stir until the reaction is complete, and perform post-treatment to obtain compound 18;

[0338] Step 6: React the compound with p-toluenesulfonyl chloride to obtain intermediate 32;

[0339] Step 7: Disperse intermediate 32, ciprofloxacin or enoxacin in anhydrous acetonitrile, stir until the reaction is complete, and perform post-treatment to obtain compound 19.

[0340] Example 47 is the synthetic method of compounds 14 - 18:

[0341] Specifically, the synthetic method of compound 14 is as follows:

[0342] Clarithromycin (20.000 g, 26.740 mmol), DMAP (3.267 g, 26.740 mmol), and benzoic anhydride (18.148 g, 80.219 mmol) were dissolved in 150 mL of anhydrous tetrahydrofuran. Triethylamine (11.12 mL, 80.219 mmol) was added, and the mixture was stirred at room temperature while monitoring the reaction progress by TLC. After about 48 h when the reaction was complete, N,N-dimethylethylenediamine (5.84 mL, 53.480 mmol) was added dropwise under an ice bath. After reacting for half an hour, the reaction solution was concentrated by rotary evaporation. 200 mL of dichloromethane was added to the system, and the organic phase was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and saturated brine successively. The organic phase was dried by rotary evaporation and recrystallized with anhydrous ethanol to obtain 22.440 g (23.469 mmol, 87.77%) of white crystalline compound 14.

[0343] Specifically, the synthesis method of compound 15 is as follows:

[0344] Compound 14 (10.000 g, 10.458 mmol) and CDI (6.783 g, 41.832 mmol) were dispersed in a mixed solution of THF / DMF (42 mL / 15 mL). While stirring, a 2 mol / L NaHMDS solution (8.37 mL, 16.733 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for about 2 h. After the reaction was completed, 100 mL of ethyl acetate was added, and then it was washed with saturated sodium bicarbonate solution, water, and saturated brine successively and dried by rotary evaporation to obtain 10.660 g (10.327 mmol, 98.75%) of white solid compound 15.

[0345] Specifically, the synthesis method of compound 16 is as follows:

[0346] Dissolve compound 15 (5.628 g, 5.452 mmol) in 10 mL of acetonitrile, add the telithromycin side chain (1.202 g, 5.563 mmol) and DBU (0.83 mL, 5.563 mmol), heat to 55 °C, monitor the reaction progress by TLC, and the reaction is complete in about 1 - 2 h. After the reaction is completed, evaporate the reaction solution to dryness, add 50 mL of dichloromethane, wash with water and saturated brine respectively, evaporate the organic phase to dryness without further purification, dissolve it in 20 mL of ethanol, heat the system to 45 °C, slowly add 20 mL of 4 M HCl dropwise, and react for about 1 - 1.5 h. After the reaction is completed, add 20 mL of water and 40 mL of methyl tert-butyl ether, stir well and separate the layers. Discard the organic layer. Adjust the pH of the aqueous layer to 10 - 11 with ammonia water after adding 40 mL of ethyl acetate. Wash the ethyl acetate layer once with water and once with saturated brine, evaporate the organic layer to dryness, and purify by column chromatography (100 - 200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 2.831 g (3.084 mmol, 55.44%) of compound 16. HRMS(ESI)(M + H) + m / z 918.5233, calcd for C 50 H 72 N5O 11 918.5223.

[0347] Specifically, the synthesis method of compound 17 is as follows:

[0348] Disperse compound 16 (2.831 g, 3.084 mmol), DMAP (0.753 g, 6.167 mmol), and CDI (1.500 g, 9.251 mmol) in 5 mL of dichloromethane, and react at room temperature for 12 - 18 h. After the reaction is completed, add 50 mL of dichloromethane, wash twice with saturated ammonium chloride, once with water, and once with saturated brine, and evaporate the organic phase to dryness to obtain 3.003 g (2.967 mmol, 96.20%) of compound 17.

[0349] Specifically, the synthesis method of compound 18 is as follows:

[0350] Dissolve compound 17 (1.000 g, 0.988 mmol) in dry DMF, add butanolamine (0.18 mL, 1.976 mmol) and DBU (0.15 mL, 0.988 mmol) dropwise at room temperature, and stir for about 12 h. After the reaction is completed, add 50 mL of ethyl acetate, wash three times with water and once with saturated brine, evaporate the organic phase to dryness, and purify by column chromatography (100 - 200 mesh silica gel, dichloromethane / ethanol / ammonia water = 10 / 0.3 / 0.1) to obtain 0.503 g (0.487 mmol, 50.91%) of compound 18. HRMS(ESI)(M + H) +m / z 1033.5863, calcd for C 55 H 81 N6O 13 1033.5856.

[0351] The following Examples 48 and 49 are the synthetic routes and methods for the compound 19 series, and the synthetic method for the compound 19 series is as follows:

[0352] Disperse the intermediate 32 (1 eq) from the previous step reaction and ciprofloxacin or enoxacin (3 eq) in anhydrous acetonitrile, and stir at 75 °C for 72 h. After the reaction is completed, evaporate the reaction solution to dryness, add 50 mL of dichloromethane, wash with water three times, and wash once with saturated brine. Evaporate the organic phase to dryness, add 20 mL of methanol to remove the acetyl group. After the reaction monitoring is completed, evaporate the reaction solution to dryness and purify by column chromatography to obtain compounds 19A and 19B.

[0353] The synthetic route for Example 48 - compound 19A is as follows:

[0354]

[0355] React intermediate 32 (0.230 g, 0.194 mmol) with ciprofloxacin (0.192 g, 0.581 mmol), and after purification by column chromatography (silica gel of 100 - 200 mesh, dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 45.6 mg (0.0367 mmol, 18.92%) of compound 19A is obtained. Melting point: 147.7 - 148.7 °C. HRMS(ESI)(M + H) + m / z 1242.6819, calcd for C 65 H 93 FN9O 14 1242.6821. 11H NMR (CD3OD, 400 MHz) δ: 8.88 (d, J = 2.2 Hz, 1H, H-pyridyl), 8.76 (s, 1H, 2″-quinolyl), 8.37 (dd, J = 1.6 Hz, 4.9 Hz, 1H, H-pyridyl), 8.14 (dt, J = 1.9 Hz, 7.7 Hz, 1H, H-pyridyl), 7.88 (d, J = 12.8 Hz, 1H, 5″-quinolyl), 7.80 (s, 1H, H-imidazolyl), 7.73 (s, 1H, H-imidazolyl), 7.43 (dd, J = 4.9 Hz, 8.0 Hz, 1H, H-pyridyl), 5.07 (dd, J = 2.4 Hz, 10.8 Hz, 1H, H-13), 4.87 (d, J = 13.8 Hz, 1H, H-3), 4.26 - 4.10 (m, 3H, H-1′, CH2), 3.91 (d, J = 3.4 Hz, 1H, H-5), 3.85 - 3.76 (m, 1H, CONCH2), 3.75 (s, 1H, H-11), 3.71 - 3.59 (m, 1H, CONCH2), 3.53 - 3.44 (m, 1H, H-5′), 3.44 - 3.36 (m, 5H, 4H-piperazinyl, 3-O-CO-NH-CH2), 3.30 - 3.22 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.12 - 3.01 (m, 4H, H-10, 6-O-CH3), 3.00 - 3.92 (m, 1H, H-2), 2.84 - 2.66 (m, 5H, H-3′, 4H-piperazinyl), 2.61 - 2.48 (m, 3H, H-8, -CH2-quinolyl), 2.46 (s, 6H, -N(CH3)2), 2.23 - 2.11 (m, 1H, H-4), 2.00 - 1.54 (m, 13H, H-14ax, 4(CH2), H-7a, H-14eq, H-4′a, H-7b), 1.50 (m, 3H, 12-CH3), 1.44 - 1.29 (m, 3H, 2H-cyclopropyl, H-4′b), 1.28 (s, 3H, 6-CH3), 1.24 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.21 - 1.11 (m, 12H, 2-CH3, 8-CH3, 10-CH3), 1.03 (d, J = 6.7 Hz, 4-CH3), 0.80 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 176 MHz) δ: 215.79, 177.11, 174.79, 167.01, 157.42, 156.48, 154.36, 152.94, 147.57, 147.42, 146.40, 145.77, 139.09, 139.04, 137.80, 131.97, 130.33, 129.49, 123.51, 119.86, 115.61, 112.51, 112.38, 108.16, 104.76, 103.11, 82.79, 80.12, 78.38, 70.44, 69.60, 66.17, 60.13, 57.87, 52.79, 50.17, 49.71, 46.93, 45.80, 43.16, 42.70, 40.35, 38.83, 38.51, 35.79, 35.29, 29.70, 28.84, 28.05, 24.34, 24.22, 22.10, 21.24, 19.50, 18.99, 14.91, 14.35, 14.19, 10.36, 9.02, 8.24.

[0356] Example 49 - The synthetic route of Compound 19B is as follows:

[0357]

[0358] Intermediate 32 (0.230 g, 0.194 mmol) was reacted with enoxacin (0.186 g, 0.581 mmol), and after purification by column chromatography (silica gel 100 - 200 mesh, dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5), 52.0 mg (0.0422 mmol, 21.76%) of Compound 19B was obtained. Melting point: 153.4 - 154.3 °C. HRMS(ESI)(M + H) + m / z 1231.6756, calcd for C 63 H 92 FN 10 O 14 1231.6773. 11H NMR (CD3OD, 400 MHz) δ: 8.89 (d, J = 2.2 Hz, 1H, H-pyridyl), 8.81 (s, 1H, 2″-quinolyl), 8.37 (dd, J = 1.6 Hz, 4.9 Hz, 1H, H-pyridyl), 8.14 (dt, J = 2.0 Hz, 8.0 Hz, 1H, H-pyridyl), 8.03 (d, J = 13.6 Hz, 1H, 5″-quinolyl), 7.81 (s, 1H, H-imidazolyl), 7.72 (s, 1H, H-imidazolyl), 7.43 (dd, J = 4.8 Hz, 8.1 Hz, 1H, H-pyridyl), 5.07 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.84 (d, J = 11.1 Hz, 1H, H-3), 4.48 (s, 2H, NCH2CH3), 4.23 - 4.10 (m, 3H, H-1′, CH2), 4.01 - 4.83 (s, 5H, 4H-piperazinyl, H-5), 3.85 - 3.76 (m, 1H, CONCH2), 3.75 (s, 1H, H-11), 3.69 - 3.59 (m, 1H, CONCH2), 3.51 - 3.42 (m, 1H, H-5′), 3.40 - 3.35 (m, 1H, 3-O-CO-NH-CH2), 3.31 - 3.21 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.14 - 3.07 (m, 1H, H-10), 3.04 (s, 3H, 6-O-CH3), 3.00 - 2.92 (m, 1H, H-2), 2.79 - 2.70 (m, 1H, H-3′), 2.66 (s, 4H, 4H-piperazinyl), 2.61 - 2.46 (m, 3H, H-8, -CH2-quinolyl), 2.44 (s, 6H, -N(CH3)2), 2.21 - 2.10 (m, 1H, H-4), 2.00 - 1.55 (m, 13H, H-14ax, 4(CH2), H-7a, H-14eq, H-4′a, H-7b), 1.55 - 1.42 (m, 6H, NCH2CH3, 12-CH3), 1.35 - 1.29 (m, 1H, H-4′b), 1.27 (s, 3H, 6-CH3), 1.23 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.20 - 1.11 (m, 12H, 2-CH3, 8-CH3, 10-CH3), 1.03 (d, J = 6.7 Hz, 4-CH3), 0.80 (t, J = 7.4 Hz, 3H, 15-CH3). 1313C NMR (CDCl3, 100 MHz) δ: 215.77, 177.06, 166.93, 157.42, 147.58, 146.43, 145.07, 139.08, 137.80, 131.96, 130.34, 123.49, 115.59, 109.36, 82.79, 78.40, 70.45, 60.16, 57.83, 52.97, 50.16, 47.73, 46.92, 45.80, 43.18, 42.70, 40.39, 38.84, 38.54, 35.81, 28.84, 28.03, 24.35, 22.13, 21.24, 19.50, 18.99, 14.98, 14.91, 14.35, 14.19, 10.37, 8.98.

[0359] Example 50 is the synthetic route of clarithromycin derivatives with formula VI, which is as follows:

[0360]

[0361] The reaction conditions and reagents for the above synthetic route are: a. propanediamine, DMF, room temperature; b. formic acid, NaNO2, 3-butyn-1-ol, -15 °C; c. compound 30, CuI, Pd(PPh3)2Cl2, triethylamine / acetonitrile (1:1), 45 °C; d. reflux in methanol.

[0362] The steps for preparing clarithromycin derivatives of formula VI are as follows:

[0363] Step 1: Dissolve compound 17 in DMF, then add propanediamine dropwise, stir at room temperature until the reaction is complete, and perform post-treatment to obtain compound 20;

[0364] Step 2: Dissolve compound 20 in 3-butyn-1-ol, add formic acid dropwise at low temperature, then slowly add sodium nitrite, keep the temperature for reaction until the reaction is complete, and perform post-treatment to obtain compound 21;

[0365] Step 3: Dissolve compound 30 and CuI in a mixed solution of acetonitrile and triethylamine, stir at room temperature, add compound 21 and bis(triphenylphosphine)palladium dichloride, displace the air with argon and seal, stir until the reaction is complete, and perform post-treatment to obtain compound 22.

[0366] Example 51 is the synthesis method of compound 20 and compound 21:

[0367] Specifically, the synthesis method of compound 20 is as follows:

[0368] Compound 17 (1.462 g, 1.445 mmol) was dissolved in 20 mL of DMF, and propanediamine (0.36 mL, 4.334 mmol) was added dropwise. The reaction was carried out at room temperature for 4 h. After the reaction was completed, 50 mL of ethyl acetate was added. The mixture was washed three times with water and once with saturated brine, and the organic phase was dried by rotary evaporation and purified by column chromatography (silica gel 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.1) to obtain 1.103 g (1.092 mmol, 75.57%) of compound 20.

[0369] Specifically, the synthesis method of compound 21 is as follows:

[0370] Compound 20 (1.103 g, 1.092 mmol) was dissolved in 3-butyn-1-ol (4.13 mL, 54.590 mmol). The system was placed at -15 °C, formic acid (0.23 mL, 4.913 mmol) was added dropwise to the system, and then sodium nitrite (0.452 g, 6.551 mmol) was slowly added. The reaction was carried out with heat preservation for 36 h. After the reaction was completed, 50 mL of dichloromethane was added. The mixture was washed three times with saturated sodium bicarbonate and once with saturated brine, and the organic phase was dried by rotary evaporation and purified by column chromatography (silica gel 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1) to obtain 0.189 g (0.176 mmol, 16.12%) of compound 21. HRMS (ESI) (M + H) + m / z 1071.6016, calcd for C 58 H 83 N6O 13 1071.6013.

[0371] Example 52 is the synthesis method of compound 22E:

[0372]

[0373] Compound 30 (0.0553 g, 0.168 mmol), CuI (0.00335 g, 0.0176 mmol) were dissolved in a mixture of acetonitrile and triethylamine (4 mL / 4 mL), stirred at room temperature for 20 min, then compound 21 (0.189 g, 0.176 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.00576 g, 0.00882 mmol) were added. After replacing the air with argon, the system was sealed and transferred to an oil bath at 45 °C for reaction for 12 h. After the reaction was completed, 50 mL of dichloromethane was added, washed with saturated sodium chloride, and the organic layer was dried by rotary evaporation. 20 mL of methanol was added and refluxed overnight to remove the benzoyl protecting group. The reaction solution was dried by rotary evaporation and purified by column chromatography (100 - 200 mesh silica gel, dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5) to obtain 62.2 mg (0.0536 mmol, 30.44%) of compound 22E. Melting point: 156.7 - 157.7 °C. HRMS(ESI)(M + H) + m / z 1168.6179, calcd for C 62 H 86 N7O 15 1168.6176. 1H NMR(CD3OD,400MHz)δ:8.85(d,J=2.2Hz,1H,H-pyridyl),8.83(s,1H,2″-quinolyl),8.37(dd,J=1.6Hz,4.9Hz,1H,H-pyridyl),8.33(d,J=8.4Hz,1H,5″-quinolyl),8.10(dt,J=1.9Hz,8.0Hz,1H,H-pyridyl),7.79(s,1H,8″-quinolyl),7.75(s,1H,H-imidazolyl),7.67(s,1H,H-imidazolyl),7.54(s,1H,6″-quinolyl),7.42(dd,J=4.8Hz,8.0Hz,1H,H-pyridyl),5.03(dd,J=2.5Hz,10.9Hz,1H,H-13),4.82(d,J=11.1Hz,1H,H-3),4.22-4.06(m,3H,H-1′,CH2),4.01(s,3H,N-CH3),3.88(d,J=3.4Hz,1H,H-5),3.81-3.66(m,4H,H-11,OCH2,CONCH2),3.66-3.56(m,3H,OCH2,CONCH2),3.49-3.38(m,2H,H-5′,3-O-CO-NH-CH2),3.31-3.12(m,3H,H-2′,3-O-CO-NH-CH2,H-10),3.02(s,3H,6-O-CH3),2.92-2.82(m,1H,H-2),3.83-3.71(m,3H,H-3′,-CH2-C≡C-),2.59-2.49(m,1H,H-8),2.44(s,6H,-N(CH3)2),2.19-2.08(m,1H,H-4),1.99-1.51(m,11H,H-14ax,H-7a,H-14eq,3(CH2),H-4′a,H-7b),1.48(m,3H,12-CH3),1.38-1.27(m,1H,H-4′b),1.25(s,3H,6-CH3),1.20(d,J=6.1Hz,3H,5′-CH3),1.16(d,J=7.2Hz,3H,2-CH3),1.19-1.10(m,6H,8-CH3,10-CH3),1.01(d,J=6.6Hz,4-CH3),0.76(t,J=7.3Hz,3H,15-CH3). 1313C NMR (CDCl3, 176 MHz) δ: 215.80, 178.04, 176.99, 174.78, 166.78, 157.43, 149.50, 147.57, 146.39, 140.11, 139.02, 137.80, 131.94, 130.33, 123.50, 115.67, 115.63, 82.81, 82.79, 78.38, 70.47, 69.58, 69.13, 68.82, 60.10, 50.18, 46.92, 45.80, 43.10, 42.71, 40.35, 38.82, 38.49, 35.76, 29.82, 29.70, 28.84, 24.33, 22.08, 21.20, 20.99, 20.91, 19.49, 19.01, 14.87, 14.36, 14.34, 14.14, 10.37, 10.35, 8.89.

[0374] Example 53 is the synthetic route of clarithromycin derivatives with formula VII, which is as follows:

[0375]

[0376] The reaction conditions and reagents for the above synthetic route are as follows: a. hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride, DBU, DMF, room temperature; b. compounds 29, 30, CuI, Pd(PPh3)2Cl2, triethylamine / acetonitrile (1:1), 45 °C; c. reflux in methanol.

[0377] The steps for preparing the clarithromycin derivative of formula VII are as follows:

[0378] Step 1: Dissolve compound 17 in DMF, add hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride, dropwise add DBU, and react at room temperature until the reaction is complete. After work-up, compound 23 or compound 24 is obtained;

[0379] Step 2: Stir a mixture of compound 29 or compound 30, copper(I) iodide, 5 mL of triethylamine and 5 mL of acetonitrile at room temperature, add bis(triphenylphosphine)palladium(II) dichloride and compound 23 or compound 24, seal the reaction after purging with gas, and after the reaction is complete, perform work-up to obtain compound 25 or compound 26.

[0380] Example 54 is the synthetic method for the series of compounds 23 and 24:

[0381] Dissolve compound 17 (1 eq) in 20 mL of dry DMF. Add hept-1-yn-1-amine hydrochloride or oct-1-yn-1-amine hydrochloride (1.2 eq) to the system and dropwise add DBU (3 eq). React at room temperature for about 12 - 18 h. After the reaction is completed, add 50 mL of ethyl acetate, wash three times with water and once with saturated brine, and rotary evaporate the organic phase and purify by column chromatography to obtain compounds 23 and 24.

[0382] Specifically, the synthesis method of compound 23 is as follows:

[0383] Using compound 17 (2.692 g, 2.660 mmol) and hept-1-yn-1-amine hydrochloride (0.471 g, 3.190 mmol), according to the synthesis method of Example 54, after purification by column chromatography (silica gel 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), 1.200 g (1.137 mmol, 42.75%) of 23 was obtained.

[0384] Specifically, the synthesis method of compound 24 is as follows:

[0385] Using compound 17 (0.700 g, 0.691 mmol) and oct-1-yn-1-amine hydrochloride (0.168 g, 1.037 mmol), according to the synthesis method of Example 54, after purification by column chromatography (silica gel 100 - 200 mesh, dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1), 0.228 g (0.213 mmol, 30.82%) of 24 was obtained. HRMS (ESI) (M + H) + m / z 1069.6220, calcd for C 59 H 85 N6O 12 1069.6220.

[0386] Example 55 is the synthesis method of compound 25 and compound 26:

[0387] Stir a mixture of compounds 29 and 30 (1.2 eq), copper(I) iodide (0.1 eq), and a mixture of 5 mL of triethylamine and 5 mL of acetonitrile at room temperature for 20 min. Then add bis(triphenylphosphine)palladium(II) dichloride (0.05 eq) and compound 23 or 24 (1 eq) to the system. After changing the gas, seal and transfer to an oil bath at 45 °C and react for 12 h. After the reaction is completed, add 30 mL of dichloromethane to the reaction system, wash successively with water, saturated sodium bicarbonate, and saturated sodium chloride solutions, rotary evaporate the organic phase, then add methanol and reflux at 65 °C overnight to remove the benzoyl protecting group at the 2'-position. Monitor the reaction process by TLC. After the reaction is completed, rotary evaporate the reaction solution and purify by column chromatography to obtain compounds 25 and 26.

[0388] Specifically, the synthetic route and synthesis method of compound 25D are as follows:

[0389]

[0390] Compound 25D (95.6 mg, 0.081 mmol, 12.9%) was synthesized from compound 23 (0.620 g, 0.63 mmol) and compound 29 (0.268 g, 0.70 mmol) according to the synthesis method of Example 55. HRMS (ESI) (M+H) + m / z 1178.6384, calcd for C 64 H 88 N7O 14 1178.6452. m.p. 92.5 - 94.5 °C. 11H NMR (CDCl3, 400 MHz) δ: 8.96 (d, J = 2.2 Hz, 1H, H-2-pyridine), 8.86 (s, 1H, H-quinolyl), 8.45 (dd, J = 4.8, 1.7 Hz, 1H, H-6-pyridine), 8.41 (d, J = 8.3 Hz, 1H, H-quinolyl), 8.11 - 8.04 (m, 2H, H-4-pyridine, H-quinolyl), 7.60 - 7.50 (m, 2H, H-quinolyl, H-2-imidazole), 7.36 (d, J = 1.3 Hz, 1H, H-5-imidazole), 7.31 - 7.24 (m, 1H, H-5-pyridine), 5.99 (s, 1H, NHCO), 5.03 (dd, J = 11.0, 2.4 Hz, 1H, H-13), 4.85 (d, J = 11.0 Hz, 1H, H-3), 4.15 (d, J = 7.0 Hz, 1H, H-1′), 4.04 (dt, J = 7.3, 2.7 Hz, 2H, -CH2-), 3.82 - 3.56 (m, 5H, H-5, -CH2-NCO, H-11, H-cyclopropyl), 3.49 - 3.31 (m, 3H, -CH2-NHCO, H-5′), 3.30 - 3.24 (m, 1H, H-2′), 3.14 - 2.99 (m, 5H, H-10, 2′-OH, 6-O-CH3), 2.85 - 2.77 (m, 1H, H-2), 6.03 - 5.94 (m, 10H, H-8, H-3′, N(CH3)2, -CH2-C≡C-), 2.15 - 2.07 (m, 1H, H-4), 1.98 - 1.84 (m, 3H, H-14eq, -CH2-CH2), 1.81 - 1.65 (m, 6H, H-7a, H-4′a, -CH2-CH2-C≡C-, -CH2-CH2-NCO), 1.64 - 1.49 (m, 6H, H-7b, -CH2-CH2-CH2-NHCO, H-14ax), 1.42 (s, 5H, 12-CH3, 2H-cyclopropyl), 1.31 - 1.23 (m, 6H, 6-CH3, 5′-CH3), 1.21 - 1.09 (m, 12H, 2H-cyclopropyl, 2-CH3, 4-CH3, 8-CH3, H-4′b), 1.03 (d, J = 6.7 Hz, 3H, 10-CH3), 0.77 (t, J = 7.3 Hz, 3H, 15-CH3). 1313C NMR(CDCl3, 100 MHz) δ: 215.8, 178.2, 174.9, 166.8, 157.4, 156.7, 148.5, 147.5, 146.3, 141.0, 139.0, 137.8, 132.0, 130.3, 130.1, 129.4, 126.8, 124.8, 123.5, 119.9, 115.7, 108.9, 103.0, 95.6, 82.9, 81.3, 80.0, 78.3, 77.3, 76.4, 70.4, 68.8, 65.3, 60.2, 50.1, 46.9, 45.8, 43.2, 42.7, 40.9, 39.6, 38.8, 38.5, 35.8, 35.4, 29.7, 28.8, 28.0, 26.0, 24.3, 22.1, 21.1, 19.5, 19.4, 19.2, 19.0, 14.8, 14.4, 14.2, 10.3, 9.0, 8.4, 8.3。

[0391] Specifically, the synthetic route and method for compound 26E are as follows:

[0392]

[0393] Compound 24 (0.228 g, 0.213 mmol) and compound 30 (0.0736 g, 0.224 mmol) were reacted according to the synthetic method of Example 55 and purified by column chromatography (silica gel 100 - 200 mesh, dichloromethane / methanol / ammonia water = 10 / 0.9 / 0.5) to obtain 77.8 g (0.0667 mmol, 31.31%) of compound 26E. Melting point: 160.8 - 161.8 °C. HRMS(ESI)(M + H) + m / z 1166.6388, calcd for C 63 H 88 N7O 14 1166.6384. 11H NMR (CD3OD, 400 MHz) δ: 8.86 (d, J = 2.2 Hz, 1H, H-pyridyl), 8.81 (s, 1H, 2″-quinolyl), 8.37 (dd, J = 1.6 Hz, 4.9 Hz, 1H, H-pyridyl), 8.31 (d, J = 8.4 Hz, 1H, 5″-quinolyl), 8.10 (dt, J = 2.0 Hz, 8.0 Hz, 1H, H-pyridyl), 7.74 (s, 1H, H-imidazolyl), 7.71 (s, 1H, 8″-quinolyl), 7.66 (s, 1H, H-imidazolyl), 7.48 (s, 1H, 6″-quinolyl), 7.42 (dd, J = 4.9 Hz, 8.0 Hz, 1H, H-pyridyl), 5.03 (dd, J = 2.5 Hz, 10.8 Hz, 1H, H-13), 4.84 (d, J = 11.1 Hz, 1H, H-3), 4.17 (d, J = 7.2 Hz, 1H, H-1′), 4.15 - 4.03 (m, 2H, CH2), 3.99 (s, 3H, N-CH3), 3.89 (d, J = 3.3 Hz, 1H, H-5), 3.82 - 3.73 (m, 1H, CONCH2), 3.71 (m, 1H, H-11), 3.66 - 3.56 (m, 1H, CONCH2), 3.51 - 3.42 (m, 1H, H-5′), 3.38 - 3.34 (m, 1H, 3-O-CO-NH-CH2), 3.31 - 3.17 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.11 - 3.04 (m, 1H, H-10), 3.02 (s, 3H, 6-O-CH3), 2.96 - 2.85 (m, 1H, H-2), 3.82 - 3.70 (m, 1H, H-3′), 2.60 - 2.47 (m, 3H, H-8, -CH2-C≡C-), 2.43 (s, 6H, -N(CH3)2), 2.18 - 2.09 (m, 1H, H-4), 1.96 - 1.73 (m, 5H, H-14ax, 2(CH2)), 1.73 - 1.52 (m, 10H, H-7a, H-14eq, 3(CH2), H-4′a, H-7b), 1.50 - 1.40 (m, 5H, CH2, 12-CH3), 1.36 - 1.27 (m, 1H, H-4′b), 1.26 (s, 3H, 6-CH3), 1.21 (d, J = 6.0 Hz, 3H, 5′-CH3), 1.19 - 1.10 (m, 9H, 2-CH3, 8-CH3, 10-CH3), 1.01 (d, J = 6.6 Hz, 4-CH3), 0.76 (t, J = 7.3 Hz, 3H, 15-CH3).13 13C NMR (CDCl3, 100 MHz) δ: 215.78, 157.43, 150.56, 149.42, 147.58, 146.42, 137.80, 131.94, 130.33, 129.41, 123.49, 115.62, 82.80, 78.39, 70.45, 50.18, 46.93, 45.81, 42.71, 40.36, 38.84, 38.53, 28.85, 28.58, 28.30, 24.34, 22.11, 21.21, 19.50, 19.00, 14.85, 14.36, 14.18, 10.36, 8.94.

[0394] In the characterization of the above exemplary compounds, Agilent Q-TOF6520 LC / MS was used for high-resolution mass spectrometry (HRMS), and Bruker Ascend 400M and Bruker Ascend 700M nuclear magnetic resonance spectrometers were used for nuclear magnetic resonance, which were determined by the Analysis and Testing Center of Liangxiang Campus, Beijing Institute of Technology.

[0395] Example 56: Anti-resistant Mycoplasma pneumoniae activity test

[0396] Resuscitate the cryopreserved strains ATCC29342 (sensitive strain), W-003-1 (mutation of base A2063 in 23S rDNA ribosome to G, corresponding to A2058G in E. coli 23S rRNA), W-034-1 (mutation of base A2063 in 23S rDNA ribosome to T, corresponding to A2058T in E. coli 23S rRNA), BCH-388 (mutation of base A2064 in 23S rDNA ribosome to G, corresponding to A2059G in E. coli 23S rRNA) with known CFU, and dilute them to a final concentration of 10 4 ~10 5 CFU / mL with a liquid medium (without antibiotics and thallium salts), place them at 37 °C for 2 hours to restore vitality, and prepare the stock solution of the test drug to 2048 μg / mL with DMSO. In a 96-well plate, use the blank liquid medium to prepare the drug by two-fold dilution to 25 μL per well, and then add 175 μL of the resuscitated mycoplasma solution to the corresponding wells to a final concentration of 10 4 ~10 5 CFU / mL, the drug concentration is 256 - 0.008 μg / mL, each well is repeated 3 times, and the mycoplasma solution without the drug is used as the growth control of the test strain. Seal the culture wells with sterile paraffin oil, culture at 37 °C for 7 days and observe the results.

[0397] Table 1 Anti-resistant Mycoplasma pneumoniae activity of the compounds in the examples

[0398]

[0399]

[0400]

[0401] Among them, the structural formulas of compounds MCX-91 and LXM-17 are shown as follows:

[0402]

[0403] As can be seen from Table 1, the compounds prepared in the present invention all have good anti-mycoplasma activity against drug-resistant mycoplasma. Compared with the second-generation and third-generation erythromycins, the antibacterial activity of the compounds in the examples of the present invention is better because the compounds prepared in the present invention introduce double side chains at the 9th and 3rd positions or the 11th, 12th and 3rd positions, and the 3rd position is connected to different quinolone side chains through carbamate. The crystal structure of the complex of compound 6eA in the examples of the present invention and the ribosome of T. thermophilus shows that the aryl groups of the double side chains of the compounds in the examples of the present invention form a ternary stacking interaction mode with the bases C1782-C2586 in the ribosome, making the compounds in the examples of the present invention bind stronger to the ribosome, and thus having better anti-drug-resistant bacteria and anti-drug-resistant mycoplasma activity.

[0404] Mycoplasma pneumoniae has only one set of rRNA operons, so it is easy to produce base mutations and then develop drug resistance, which is different from the drug resistance mode mediated by the erm resistance gene through methylation of ribosomal A2058 (E. coli number). Although telithromycin has antibacterial activity in erm-mediated drug-resistant bacteria (as shown in Tables 2 and 3), it has no activity against drug-resistant mycoplasma caused by base mutations at A2058 (E. coli number) (as shown in Table 1). In addition, compounds MCX-91 and LXM-17 have good antibacterial activity against drug-resistant bacteria, but have poor activity against drug-resistant Mycoplasma pneumoniae. Therefore, compounds developed using the antibacterial activity structure-activity relationship do not necessarily have anti-drug-resistant mycoplasma activity, and the preferred compounds screened from antibacterial activity have no necessary guiding significance and predictability for improving the activity against drug-resistant Mycoplasma pneumoniae in bacteria, and new macrolide compounds need to be developed specifically based on the anti-mycoplasma structure-activity relationship. The compounds in the present invention are obtained by analyzing the structure-activity relationship through testing the activity against drug-resistant Mycoplasma pneumoniae and further testing and screening to obtain compounds capable of resisting drug-resistant Mycoplasma pneumoniae.

[0405] Example 57: Antibacterial Activity Test

[0406] According to the standards recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010), the in vitro antibacterial activities of some target compounds against sensitive Streptococcus pneumoniae ATCC49619, mef-type resistant Streptococcus pneumoniae PU-09, constitutive erm-type resistant Streptococcus pneumoniae 07P390, ermA-type resistant Streptococcus pyogenes 12-206, and inducible resistant Streptococcus pyogenes 01-968 were determined by the broth dilution method. Each strain of bacteria was subcultured and purified on a plate before the experiment, and fresh bacterial cells were used for the experiment. In each experiment, a standard strain was used as the quality control bacterium for the sensitivity test; a bacterial solution without antibacterial drugs was used as the growth control for the test strains. The minimum inhibitory concentration (MIC) was determined by the broth two-fold dilution method. The concentration range of the antibacterial drugs tested was 256 - 0.008 μg / mL, and the final concentration of the test bacterial solution was approximately 5×10 5 CFU / mL.

[0407] Table 2 Antibacterial activities of compounds 6eA, 6eC, 12dD, 12eD, 12kD, 12mD, 12pD, 13eD, and 25D in the examples

[0408]

[0409] Table 3 Antibacterial activities of compounds 6cB, 6dB, 6eB, 6fB, 6gB, 6jB, 9eE, 13eE, 19A, 19B, 22E, and 26E in the examples

[0410]

[0411]

[0412] The compounds of the present invention not only have good activities against drug-resistant Mycoplasma pneumoniae, but also have better antibacterial activities against drug-resistant bacteria in the antibacterial spectrum of erythromycin (see Tables 2 - 3) as tested.

[0413] Example 58: Metabolic stability test of compound 12eD with MCX-66 liver microsomes

[0414] Determine the intrinsic clearance (CL) of the compound in rat liver microsomes int(liver))。Incubate 0.1 M potassium phosphate buffer (pH 7.4) containing 0.5 mg microsomal protein with cofactor (NADPH) at 37 °C for 5 minutes. Then add the test compound (1.0 μm) to the incubation solution, and continue to incubate the mixture at 37 °C. At 0, 10, 20, 30, 45, and 60 minutes respectively, take 100 μL of the incubation mixture and add it to 300 μL of acetonitrile containing the internal standard solution to terminate the reaction. Analyze the sample by LC-MS / MS (liquid chromatography-tandem mass spectrometry), and calculate the ratio of the peak area of the compound to the peak area of the internal standard in the positive ion mode. The intrinsic clearance rate is determined by the first-order elimination constant through non-linear regression, and the incubation volume is corrected, assuming that the microsomal protein content is 45 mg / g liver and the liver weight-body weight ratio of rats is 40 g / kg. The value of CL int(liver) is expressed as ml / min / kg liver. In the experiment, 7-ethoxycoumarin was used as the control group for detection. Among them, compound MCX-66 is a similar compound of compound 12eD, and its side chain group is connected through an ester group at the 3-position. The specific structure is as follows:

[0415]

[0416] Table 4 Liver microsomal metabolism results of compound 12eD and MCX-66

[0417]

[0418]

[0419] In Table 4 a CL int(liver) : Intrinsic clearance rate CL int(liver) : 0.693 / T 1 / 2 / mg amount of microsomal protein per ml of liver microsomal solution × mg microsomal protein / g liver weight × g liver weight / kg body weight.

[0420] Compound 12eD in the examples of the present invention has a longer half-life in the liver microsomes of rats than the analogue MCX-66. The ester side chain (analogue MCX-66) is more easily hydrolyzed and metabolized by esterase compared to the 3-carbamate side chain (compound 12eD). Therefore, the 3-carbamate side chain (compound 12eD) in the macrolide has higher pharmacokinetic stability than the 3-ester side chain (analogue MCX-66). Since the compounds in the examples of the present invention all have side chain groups connected by carbamate at the 3-position, the clarithromycin derivatives prepared in the examples of the present invention are more stable than the similar compounds connected by ester side chains.

Claims

1. A clarithromycin derivative, characterized in that, The clarithromycin derivative has a general formula structure as shown in the following formula I: In the formula I, W is selected from any one of an oxygen atom and NOCH2C≡C-Ar; Ar is selected from any one of a pyridyl group, a quinolinyl group, an isoquinolinyl group, a substituted pyridyl group, a substituted quinolinyl group, and a substituted isoquinolinyl group, wherein the substituents of the substituted pyridyl group, the substituted quinolinyl group, and the substituted isoquinolinyl group are independently selected from at least one of an acetyl group, a methoxycarbonyl group, a carbamoyl group, an N-(methyl)carbamoyl group, an N,N-(dimethyl)carbamoyl group, an N-(ethyl)carbamoyl group, an N-(cyclopropyl)carbamoyl group, an oxazolyl group, an oxadiazolyl group, a phenyl group, a pyridyl group, a nitro group, a halogen, a cyano group, a hydroxyl group, and an amino group; V is selected from any one of an oxygen atom and the 11-position side chain of telithromycin; X is selected from any one of -C≡C-, -OCH2CH2C≡C-, and a piperazinyl group; Q is selected from any one of a methylene group and a fluorine-substituted carbon atom; Z is selected from any one of a methylene group, a fluorine-substituted carbon atom, a nitrogen atom, and a methoxycarbon atom; R 1 and R 2 are each independently selected from any one of a hydrogen atom, a C1-C3 alkyl group, a halogen-substituted C 1-3 alkyl group, a C 3-4 cycloalkyl group, a halogen-substituted C 3-4 cycloalkyl group, and a halogen-substituted phenyl group; The value of n ranges from 3 to 6 and is an integer.

2. The clarithromycin derivative according to claim 1, wherein W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as a piperazinyl group, and n = 4.

3. The clarithromycin derivative according to claim 1, wherein W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as -OCH2CH2C≡C-, and n = 3.

4. The clarithromycin derivative according to claim 1, characterized in that W is selected as NOCH2C≡C-Ar, V is selected as an oxygen atom, X is selected as -C≡C-, and n = 5 or 6.

5. The clarithromycin derivative according to claim 1, wherein W is selected as an oxygen atom, V is selected as the 11-position side chain of telithromycin, X is selected as a piperazinyl group, and n = 4.

6. The clarithromycin derivative according to claim 1, characterized in that, W is selected as an oxygen atom, V is selected as the 11-position side chain of telithromycin, X is selected as -OCH2CH2C≡C-, and n = 3.

7. The clarithromycin derivative according to claim 1, characterized in that, W is selected as an oxygen atom, V is selected as the 11-position side chain of telithromycin, X is selected as -C≡C-, and n = 5 or 6.

8. The clarithromycin derivative according to claim 1, wherein The specific structural formula of the clarithromycin derivative is:

9. A clarithromycin derivative pharmaceutical composition, characterized in that, The clarithromycin derivative pharmaceutical composition comprises at least one of the clarithromycin derivatives described in any one of claims 1-8, its isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt, or its prodrug compound.

10. Use of a clarithromycin derivative as described in any one of claims 1-8, or the clarithromycin derivative pharmaceutical composition described in claim 9, in the preparation of antibacterial drugs and anti-resistant mycoplasma drugs.

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