A macrocyclic lactone-quinolone derivative, its preparation method and application

Abstract

This article provides a macrolide-quinolone compound of formula (I) which has good antibacterial and anti-inflammatory effects and can be used as an antibiotic, especially for the treatment of infections caused by erythromycin-resistant pathogens in clinical practice.

Description

Technical Field

[0001] This invention relates to the fields of chemical synthesis and pharmaceuticals, and in particular to a macrolide-quinolone derivative, its preparation method, and its application. Background Technology

[0002] Erythromycin, a fourteen-membered macrolide antibiotic, is a crucial therapeutic agent for upper and lower respiratory tract infections. Its target is the 50S large subunit of the microbial ribosome, and its mechanism of action is to inhibit microbial protein export. Clinically, it is used to treat upper and lower respiratory tract infections, as well as skin and soft tissue infections caused by pathogenic microorganisms. It has mild side effects and has provided a highly effective and safe route of administration for humans, especially children, for half a century. Currently, an increasing number of pathogenic microorganisms isolated clinically show drug resistance, such as *Streptococcus pneumoniae*, *Staphylococcus aureus*, *Streptococcus pyogenes*, and *Mycoplasma pneumoniae*. Second-generation erythromycins—clarithromycin and azithromycin—which emerged in the 1980s, while exhibiting high acid resistance and good pharmacokinetic properties, are inactive against erythromycin-resistant microorganisms. The main reason is that cladinose at the 3-position can induce drug resistance in pathogenic microorganisms, such as when the key target A2058 is modified or pumped out of the cell by efflux pumps.

[0003]

[0004] The main pathogens causing community-acquired and hospital-acquired bacterial pneumonia include Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Among these, constitutively resistant Streptococcus pneumoniae is a common, highly drug-resistant pathogen causing bacterial pneumonia in clinical practice in China. It can modify its A2058 antigen independently of erythromycin, clarithromycin, azithromycin, etc. This leads to a significant decrease in the bacteria's affinity for antibiotics, resulting in drug resistance.

[0005] Currently, the structures of macrolides used to combat drug-resistant bacteria mainly involve modifying the cladinose glycoside structure or replacing the cladinose with other groups such as carbonyl (ketolide), acyl (acylide), or alkylide (alkylide). Structure-activity relationship analysis shows that most macrolides have low activity against constitutively resistant bacteria. Targeting novel binding sites is key to improving their effectiveness against constitutively resistant bacteria. Telithromycin, the only erythromycin derivative approved for the treatment of community-acquired bacterial pneumonia, exhibits excellent antibacterial activity against inducible and efflux resistant bacteria. Furthermore, it acts on the base pairs A752 and U2609 of the microbial ribosome, thus showing good antibacterial activity against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes, but has no activity against constitutively resistant Staphylococcus aureus and drug-resistant Mycoplasma. Telithromycin is metabolically unstable in the human body. Its side chain structure has a terminal aryl group, namely "pyridylimidazole", which is similar in structure to "nicotine" (1-methyl-2-(3-pyridyl)pyrrolidine). Moreover, the off-target effects (acting on nicotine cholinergic receptors) caused by the unstable metabolism of the side chain imidazole are highly correlated with various toxic side effects.

[0006] Therefore, it is necessary to find a new type of macrolide antibiotic to treat infections caused by erythromycin-resistant pathogens in clinical practice. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a compound of formula (I), its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0008]

[0009] Where A represents O or N-OC 1-6 alkyl;

[0010] B represents O or NH;

[0011] X represents CH2, NH, or O;

[0012] Y represents H, no substitution, or optional substitution by one, two, or more Rs. 1 The following groups are substituted: C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl; each R 1 They are either the same or different, and are independently selected from halogens, OH, CN, NO2, NH2, COOH, and C. 1-20 Alkyl, C 3-20 cycloalkyl;

[0013] Z represents H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0014] Alternatively, Y and Z are linked by their terminal groups to form a 6-8 membered heterocycle fused with the quinolone ring, wherein the 6-8 membered heterocycle is unsubstituted or optionally surrounded by one, two or more R groups. 2 Replace, each R 2 They are either the same or different, and are independently selected from halogens, OH, CN, NO2, NH2, COOH, and C. 1-20 Alkyl, C 3-20 cycloalkyl;

[0015] R represents H, halogen, amino, C. 1-6 Alkyl or C 1-6 Alkoxy;

[0016] m is selected from integers from 0 to 10; for example, integers selected from 0 to 8, such as 1, 2, 3, 4 or 5;

[0017] n is an integer selected from 0 to 10, such as an integer selected from 0 to 6, like 1, 2, or 3.

[0018] According to some implementation schemes, A can be selected from O or N-OCH3.

[0019] According to some implementation schemes, Y can be selected from H, without substitution, or optionally by one, two, or more R. 1 The following groups are substituted: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R 1 They are the same or different, and are independently selected from halogens and C. 1-12 alkyl.

[0020] According to some implementation schemes, Y is selected from H and C. 1-6 Alkyl, C 3-8 cycloalkyl, halogenated C 1-6 Alkyl or halophenyl.

[0021] According to some implementation schemes, Y can be selected from H and C. 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 1-3 Alkyl, Halogenated C 3-6 Cycloalkyl or fluorophenyl.

[0022] According to some implementation schemes, Y can be selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2-fluoroethyl, cyclopropyl, fluorocyclopropyl, or 2,4-difluorophenyl.

[0023] According to some implementation schemes, Z can be selected from H, F, methyl or methoxy.

[0024] According to some embodiments, the compound of formula (I) can have the structure of formula (IA):

[0025]

[0026]

[0027]

[0028]

[0029] According to some embodiments, the prodrug compound has the structure shown in formula (II):

[0030]

[0031] Wherein, G is selected from C 1-20 Alkyl, C 3-20 Cycloalkyl groups, 5-20 membered heterocyclic groups, such as C 1-6 Alkyl groups, such as those selected from methyl, ethyl, or isopropyl; A, B, X, Y, Z, R, m, and n each have the definitions described above independently.

[0032] This article also provides a method for preparing the compound shown in formula (I), including the following steps: deprotecting compound I-1 R 0 The compound shown in formula (I) was obtained;

[0033]

[0034] Among them, R 0 Selected from hydroxyl protecting groups, such as methyl, triphenylmethyl, acetyl, neopentanoyl, benzoyl, benzyl, etc.; A, B, X, Y, Z, R, m, n independently have the definitions described above;

[0035] According to some implementation schemes, the preparation method of formula (I-1) includes the following scheme 1 or scheme 2:

[0036] Scheme 1: Compound I-2 reacts with compound I-3 to obtain compound I-1;

[0037]

[0038] Among them, Z 0 Selected from halogens, such as chlorine, bromine, or iodine; R 0 Selected from hydroxyl protecting groups, such as acetyl, methyl, triphenylmethyl, benzoyl, neopentyl, benzyl, etc.; A, B, X, Y, Z, R, m, n independently have the definitions described above;

[0039] Option 2: Compound I-4 reacts with compound I-5 to give compound I-1;

[0040]

[0041] Wherein, X' is selected from the protected form of the hydroxyl group, such as methanesulfonate group or p-toluenesulfonate group; R 0 Selected from hydroxyl protecting groups, such as methyl, triphenylmethyl, acetyl, neopentanoyl, benzoyl, benzyl, etc.; A, B, X, Y, Z, R, m, n independently have the definitions described above.

[0042] This article also provides intermediate compounds or prodrugs of formula (I):

[0043]

[0044] Among them, A, B, R, R 0 X, X', Y, Z, m, and n each have the definitions described above independently.

[0045] This article also provides a pharmaceutical composition comprising at least one of the following: a therapeutically effective amount of a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0046] According to some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0047] According to some embodiments, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0048] This document also provides the use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof, in the preparation of pharmaceuticals.

[0049] According to some implementation schemes, the drug is an antimicrobial drug, such as an antibiotic.

[0050] According to some implementation schemes, the pathogenic microorganism can be bacteria or other non-bacterial pathogenic microorganisms; such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Mycoplasma, Chlamydia, etc.

[0051] According to some implementation schemes, the bacteria may be drug-resistant.

[0052] This article also provides the use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds as antibiotics.

[0053] This article also provides a method for preventing and / or treating diseases associated with bacterial infection, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, its prodrug compound, or the pharmaceutical composition thereof.

[0054] According to some implementation schemes, the bacteria may be streptococci, staphylococci, or Haemophilus influenzae; for example, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae.

[0055] In some implementations, the patient is a mammal, preferably a human.

[0056] This document also provides at least one of the following: a compound of formula (I) for use in diseases associated with bacterial infection, a racemic mixture, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof, or a pharmaceutical composition thereof.

[0057] Beneficial effects

[0058] This article provides a macrolide-quinolone compound of formula (I) which has good antibacterial and anti-inflammatory effects and can be used as an antibiotic, especially for the treatment of infections caused by erythromycin-resistant pathogens in clinical practice.

[0059] The compounds of this invention are characterized by a nitrogen atom in the 3-position of the carbamate functional group of the macrolide being attached to a side chain of suitable length, with the terminal alkynyl group of the side chain linked to a quinolone-7'-yl group, thereby replacing the 3-O-claridose of clarithromycin; the 9-position is a carbonyl group or an alkoxyoxime, while the 11,12-OH groups are cyclized into cyclic carbonates or cyclic carbamates. Experimental verification shows that the quinolone-7'-yl group in the compounds of this invention has significant advantages over the corresponding quinolone-6'-yl substitution, and the alkyne-linked 7-quinolone is also generally more advantageous than the corresponding alkane-linked 6-quinolone.

[0060] Terminology Definitions and Explanations

[0061] Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this specification and / or claims.

[0062] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each of the specific integer values. For example, the numerical range "1-20" is equivalent to describing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0063] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0064] Term "C" 1-20 "Alkyl" should be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0065] Term "C" 3-20 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon rings or tricyclic alkanes, having 3 to 20 carbon atoms, preferably "C". 3-10 "Cycloalkyl", more preferably "C" 3-8 cycloalkyl. The term "C" 3-10 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0066] The term "3-20 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrolo-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazinolo-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroloyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is linked to other groups to form the compounds described herein, the carbon atom on the 3-20-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20-membered heterocyclic ring can be linked to other groups.

[0067] Term "C" 6-20 "Aryl" should preferably be understood to represent a monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring), or tricyclic hydrocarbon ring having 6 to 20 carbon atoms and possessing monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms.6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0068] The term "5-20-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzofused.

[0069] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0070] The compounds described herein may exist as solvates (such as hydrates), wherein the compounds contain a polar solvent, particularly water, methanol, or ethanol, as a structural element of the compound's lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0071] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0072] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms).

[0073] The term "quinolone" as used herein refers to benzopyridone or hydroxyquinoline, such as quinoline-4(1H)-one or 4-hydroxyquinoline. In particular, in this paper, quinolones have the following skeletal structure due to the presence of a carboxyl group at the 3-position:

[0074]

[0075] In this configuration, the N-1 position can be substituted with an alkyl, cycloalkyl, or aryl group, or with a haloalkyl, halocycloalkyl, or haloaryl group, such as methyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, or 2,4-difluorophenyl. The 6-position can be substituted with a halogen, such as chlorine or fluorine. The 7-position can be substituted with a halogen, alkyne, alkane, amino group, or heterocyclic alkyl group, such as iodine, bromine, piperazine, or tetrahydropyrrole. The 5-, 6-, and 8-positions can be substituted independently with alkyl, halogen, amino, or alkoxy groups, such as methyl, chlorine, fluorine, or methoxy groups. Additionally, the 8-position substituent can form a ring with the 1-position substituent. As an example, in this case, the heterocycle formed between the 8- and 1-positions in levofloxacin, for instance, the quinolone in this invention, can include a 7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine ring.

[0076] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form an acid addition salt; if these compounds have an acidic center, they can form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form an inner salt. In this invention, various pharmaceutically acceptable acids can form salts on the nitrogen atom of the dimethylamino group of 5-O-glycosamine. The acid can be an inorganic acid or an organic acid; 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.

[0077] As used herein, the term "excipient" refers to any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delayers of pharmaceutically active substances, which are well known in the art. The use of any conventional media or reagents in a pharmaceutical composition may be considered, except for any conventional media or reagents incompatible with the compound. Complementary compounds may also be added to the composition.

[0078] The term "prodrug compound" as used herein can refer to a compound that, although administered in a structure not disclosed, is metabolized or converted in the human body and exerts a pharmacological effect as a pharmacodynamic component. In this invention, the prodrug compound may be an esterified quinolone, such as a methyl ester, ethyl ester, isopropyl ester, or other (cyclo)alkyl ester containing heteroatoms, etc., in vivo hydrolysis of the ester group releases the active 3-carboxyl group. Conventional methods for the preparation of prodrugs are described in *Design of Prodrugs* (H. Bundgaad, Elsevier, 1985). Detailed Implementation

[0079] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0080] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0081] Regarding the synthetic method of the target compound, a stepwise introduction method can be used in this paper, that is, first constructing a side chain containing an alkyne, then introducing a quinolone through a Sonogashira coupling reaction, and finally removing the protecting group to obtain the target compound; or first introducing an amino alcohol of different lengths, then sulfonating it, reacting it with a quinolone reagent containing an amino group, and finally removing the protecting group to obtain the compound of this invention. The synthetic route is briefly described as follows:

[0082] Preparation of intermediate compounds:

[0083] Preparation Example 1: Intermediate compounds 1 and 2

[0084] Intermediate compound 1 and compound 2 are known compounds. The synthesis method of compound 1 can be found in European Journal of Medicinal Chemistry 59(2013)54-63, and the synthesis method of compound 2 can be found in Chinese Invention Patent Application No. 202210114328.0;

[0085]

[0086] Preparation Example 2: Preparation of intermediate compound 3-5

[0087]

[0088] Reaction conditions and reagents: a. Benzoic anhydride, DMAP (4-dimethylaminopyridine), triethylamine, THF, room temperature; b. CDI (carbonyl diimidazole), NaHMDS, THF / DMF = 1.5 / 1, room temperature; c. Ammonia, THF / DMF = 1.5 / 1, potassium tert-butoxide, room temperature; d. 2M HCl solution, ethanol, 45℃.

[0089] Synthesis of Compound 3

[0090]

[0091] 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. The reaction was monitored by TLC. After approximately 48 h of complete reaction, N,N-dimethylethylenediamine (5.84 mL, 53.480 mmol) was added dropwise under ice bath. After reacting for half an hour, the reaction solution was concentrated by rotary evaporation. Then, 200 mL of dichloromethane was added to the system, and the organic phase was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and saturated brine, respectively. After the organic phase was dried by rotary evaporation, anhydrous ethanol was added, and recrystallization yielded 22.440 g (23.469 mmol, 87.77%) of white crystals of compound 3.

[0092] Synthesis of Compound 4

[0093]

[0094] Compound 3 (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). 2 mol / L NaHMDS solution (8.37 mL, 16.733 mmol) was slowly added dropwise while stirring. After the addition was complete, the mixture was stirred at room temperature for approximately 2 hours. After the reaction was complete, 100 mL of ethyl acetate was added, followed by washing with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic phase was then evaporated to dryness to give 10.660 g (10.327 mmol, 98.75%) of compound 4 as a white solid.

[0095] Synthesis of Compound 5

[0096]

[0097] Compound 4 (10.660 g, 10.327 mmol) was dispersed in a mixed solution of THF / DMF (42 mL / 15 mL) under ice bath conditions, and 20 mL of concentrated ammonia was added. The mixture was stirred under ice bath conditions for 48 h, then transferred to room temperature for 48 h. After the reaction was complete, 100 mL of ethyl acetate was added, followed by washing with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic phase was evaporated to dryness, and 60 mL of THF and potassium tert-butoxide (1.158 g, 10.327 mmol) were added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 100 mL of ethyl acetate was added, followed by washing with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic phase was evaporated to dryness. The residue was recrystallized from ethanol to give a white solid.

[0098] The white solid was dispersed in 40 mL of ethanol, and 40 mL of 2 M hydrochloric acid solution was slowly added dropwise at 45 °C. The reaction was monitored by TLC. After the reaction was complete, 20 mL of water was added, and the aqueous layer was washed with methyl tert-butyl ether. The layers were separated, and the aqueous layer was adjusted to pH 9 with ammonia and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, respectively, and the organic phase was evaporated to dryness to give 3.080 g (4.284 mmol, 41.48%) of compound 5 as a white solid. HRMS (ESI) (M+H) + m / z 719.4114, calculated value: C 38 H 59 N2O 11 719.4223. 1H NMR(CDCl3,400MHz)δ:8.11-8.03(m,2H,2H-Bz),7.60-7.52(m,1H,2H-Bz),7.48-7.42(m,2H,2H-Bz),5.77(s,1H,11-NH),5.16(dd,J=2.3Hz,10.9Hz,1H,H-13),5.04(dd,J=7.6Hz,10.5Hz,1H,H-2′),4.76(d,J=7.6Hz,1H,H-1′),3.73(d,J=2.6Hz,1H,H-5),3.71(s,1H,H-11),3.61-3.51(m,1H,H-5′),3.46(dd,J=6.6Hz,10.6Hz,1H,H-3),2.95-2.89(m,1H,H-3′),2.97(s,3H,6-O-CH3),2.79(q,J=6.5Hz,1H,H-10),2.64-2.54(m,1H,H-2),2.52-2.42(m,1H,H-8),2.28(s,6H,-N(CH3)2),2.18(d,J=6.5Hz,1H,3-OH),1.94-1.83(m,2H,H-4,H-14eq),1.94-1.81(m,1H,H-4′a),1.66-1.55(m,1H,H-7a),1.52-1.37(m,3H,H-7b,H-14eq,H-4′a),1.32(s,3H,12-CH3),1.31-1.24(m,6H,6-CH3,5′-CH3),1.22(d,J=6.8Hz,3H,2-CH3),1.09(d,J=6.6Hz,3H,10-CH3),1.05(d,J=7.1Hz,3H,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.71(d,J=7.4Hz,3H,4-CH3). 13 C NMR(CDCl3,100MHz)δ:217.87,175.24,165.40,158.54,132.73,130.65,129.79,128.26,99.79,83.95,80.83,77.96,77.65,75.53,72.11,68.99,63.27,58.18,49.52,45.34,44.08,40.82,38.76,37.18,35.84,32.00,22.08,21.15,19.27,18.13,15.34,13.82,13.28,10.22,7.81.

[0099] Preparation Example 3: Preparation of intermediate compounds 13-25

[0100]

[0101] Reaction conditions and reagents: a. CDI, DMAP, dichloromethane, room temperature; b. Amino alcohols of different carbon atom lengths (2-aminoethanol, 3-aminopropanol, 4-aminobutanol, etc.), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DMF, room temperature; c. Alkyne hydrochlorides of different carbon atom lengths (6-heptyne-1-amine hydrochloride, 7-octyne-1-amine hydrochloride, 8-nonyne). d. Diamines of different carbon atom lengths (1,2-ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, etc.), DMF, room temperature; e. Formic acid, NaNO2, alkynols of different carbon atom lengths (2-propyn-1-ol, 3-butyn-1-ol, 4-pentyn-1-ol, etc.), -15℃.

[0102] Preparation Example 3.1: General Synthetic Method for Compounds 6-8

[0103] In a round-bottom flask, add the starting materials (compound 1, or 2, or 5, 1 eq), DMAP (2 eq), and CDI (3 eq), then add anhydrous dichloromethane and react at room temperature for 12 h. After the reaction is complete, add more dichloromethane and wash successively with saturated ammonium chloride, saturated sodium bicarbonate solution, water, and saturated brine. Dry the organic phase by rotary evaporation to obtain compounds 6-8.

[0104] Synthesis of Compound 6

[0105]

[0106] Using compound 1 (2.207 g, 3.213 mmol) as the starting material, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10:0.05:0.05) according to the general synthetic method of this preparation example, yielding 1.384 g (1.775 mmol, 55.24%) of compound 6, a pale yellow, fluffy solid.

[0107] Synthesis of Compound 7

[0108]

[0109] Using compound 2 (5.500 g, 8.36 mmol) as the starting material, and following the general synthetic method of this preparation example, 5.650 g (7.52 mmol, 90.0%) of compound 7, a pale yellow, fluffy solid, was obtained. HRMS(ESI)(M+H) +m / z 752.3957, Calculated value: C 37 H 58 N3O 13 752.3964. 1 ¹H NMR (CDCl₃, 500 MHz) δ: 8.22 (s, 1H, H-imidazole), 7.50 (s, 1H, H-imidazole), 7.17 (s, 1H, H-imidazole), 5.20 (d, J = 11.1 Hz, 1H, H⁻³), 5.17 (dd, J = 10.9, 2.5 Hz, 1H, H⁻¹³), 4.70 (s, 1H, H⁻¹¹), 4.62 (dd, J = 10.6, 7.5 Hz, 1H, H⁻²′), 3.38 (d, J = 7.5 Hz, 1H, H⁻¹′), 4.21 (d, J = 3.4 Hz, 1H, H⁻⁵), 3.10–3.09 (m, 4H, H⁻², 6-O-CH₃), 2.95 (q, J = 6.8 Hz, 1H, H⁻¹⁰), 2.6 4-2.50(m,2H,H-8,H-5′),2.25-2.14(m,8H,H-3′,H-4,N(CH3)2),2.07(s,3H,CH 3CO),1.97-1.86(m,1H,H-14eq),1.65-1.57(m,1H,H-14ax),1.57-1.45(m,6H,H- 7a,H-7b,H-4′a,12-CH3),1.27(s,3H,6-CH3),1.24-1.18(m,6H,2-CH3,4-CH3),1 .17-1.08(m,10H,H-4′b,5′-CH3,8-CH3,10-CH3),0.89(t,J=7.4Hz,3H,15-CH3).

[0110] Synthesis of Compound 8

[0111]

[0112] According to the general synthesis method of this preparation example, using compound 5 (3.080 g, 4.284 mmol) as the starting material, 3.415 g (4.201 mmol, 98.06%) of compound 8 white solid was obtained.

[0113] Preparation Example 3.2: General Synthetic Method for Compounds 9-12

[0114] Compounds 6 or 8 (1 eq) were dissolved in DMF, and diamines of different carbon lengths (5 eq) were added dropwise at room temperature. The reaction was carried out at room temperature for 6 h. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was purified by dry column chromatography to obtain compounds 9-12.

[0115] Synthesis of Compound 9

[0116]

[0117] Using compound 6 (2.500 g, 3.205 mmol) and ethylenediamine (1.08 mL, 16.025 mmol) as starting materials, the product was purified using the general synthetic method of this preparation example. The product was purified with 100-200 mesh silica gel and dichloromethane / ethanol / ammonia water = 10 / 0.8 / 0.1 developing solvent to give compound 9 as a white, fluffy solid, 1.918 g (2.481 mmol, 77.40%).

[0118] Synthesis of Compound 10

[0119]

[0120] Using compound 6 (2.485 g, 3.186 mmol) and propylenediamine (1.24 mL, 15.930 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.9 / 0.1 eluent) to give compound 10 as a white, fluffy solid, 1.227 g (1.559 mmol, 48.93%).

[0121] Synthesis of Compound 11

[0122]

[0123] Using compound 8 (4.253 g, 4.985 mmol) and propylenediamine (2.07 mL, 24.927 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.9 / 0.1) to obtain compound 11 2.576 g (3.604 mmol, 72.30%).

[0124] Synthesis of Compound 12

[0125]

[0126] Using compound 8 (2.000 g, 2.632 mmol) and butanediamine (1.33 mL, 13.159 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.9 / 0.1) to obtain compound 12 1.175 g (1.644 mmol, 62.46%).

[0127] Preparation Example 3.3: General Synthetic Methods for Compounds 13 and 14

[0128] Compounds 6 or 8 (1 eq) were dissolved in DMF, and alcoholamines of different carbon lengths (3 eq) and DBU (1 eq) were added dropwise at room temperature. The reaction was carried out at room temperature for 6 h. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was purified by dry column chromatography to obtain compounds 13-14.

[0129] Synthesis of Compound 13

[0130]

[0131] Using compound 6 (1.000 g, 1.282 mmol), DBU (0.57 mL, 3.846 mmol), and 2-aminoethanol (0.23 mL, 3.846 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.3 / 0.1) to give compound 13 as a white, fluffy solid, 0.472 g (0.611 mmol, 47.66%).

[0132] Synthesis of Compound 14

[0133]

[0134] Using compound 8 (0.500 g, 0.615 mmol) as a starting material, 3-aminopropanol (0.094 mL, 1.230 mmol) was added and reacted according to the general synthetic method of this preparation example. The product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.7 / 0.1) to give compound 14 0.282 g (0.371 mmol, 60.32%). HRMS(ESI)(M+H) + m / z 820.4589, Calculated value: C 42 H 66 N3O 13 820.4590. 1HNMR(CDCl3,400MHz)δ:8.09-8.02(m,2H,2H-Bz),7.61-7.55(m,1H,2H-Bz),7.49-7.43(m,2H,2H-Bz), 5.80(s,1H,11-NH),5.35(t,J=6.0Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.3Hz,11.0Hz,1H,H-13),4.99( dd, J=7.5Hz, 10.5Hz, 1H, H-2′), 4.88 (d, J=11.0Hz, 1H, H-3), 4.30 (d, J=7.5Hz, 1H, H-1′), 3.80 (d, J=3. 1Hz,1H,H-5),3.78-3.72(m,2H,-CH2-OH),3.70(s,1H,H-11),3.60-3.50(m,1H,3-O-CO-NH-CH2),3.47- 3.38(m,1H,H-5′),3.33-3.24(m,1H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2.90-2.70(m,3H,H-3′,H -10,H-2),2.52-2.43(m,1H,H-8),2.28(s,6H,-N(CH3)2),1.99-1.69(m,5H,H-4,H-14eq,H-4′a,-CH2-) ,1.58-1.36(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.29-1.23(m,6H,6-CH3,5′-CH3) ,1.15-1.03(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.73(d,J=7.5Hz,3H,4-CH3).

[0135] Preparation Example 3.4: General Synthetic Methods for Compounds 15-20

[0136] Compounds 6-8 (1 eq) were dissolved in DMF, and acetylene hydrochloride (2 eq) and DBU (3 eq) of different carbon atom lengths were added dropwise at room temperature. The reaction was carried out at room temperature for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, ethyl acetate was added, and the organic layer was washed three times with water and once with saturated brine. The organic phase was purified by dry column chromatography to obtain compounds 15-20.

[0137] Synthesis of Compound 15

[0138]

[0139] Using compound 6 (2.463 g, 3.158 mmol), DBU (1.70 mL, 11.369 mmol), and 6-heptyne-1-amine hydrochloride (0.560 g, 3.790 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / petroleum ether / ethanol / ammonia = 6:4:0.05:0.05) according to the general synthetic method of this preparation example. 1.304 g (1.583 mmol, 50.13%) of compound 15 was obtained as a pale yellow, fluffy solid.

[0140] Synthesis of Compound 16

[0141]

[0142] Using compound 6 (0.500 g, 0.641 mmol), DBU (0.344 mL, 2.308 mmol), and 7-octyne-1-amine hydrochloride (0.124 g, 0.769 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / petroleum ether / ethanol / ammonia = 6:4:0.05:0.05) according to the general synthetic method of this preparation example. 0.421 g (0.502 mmol, 86.18%) of compound 16 was obtained as a pale yellow, fluffy solid.

[0143] Synthesis of Compound 17

[0144]

[0145] Using compound 7 (2.000 g, 2.66 mmol) and 6-heptyne-1-amine hydrochloride (0.471 g, 3.19 mmol) as starting materials, the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / petroleum ether / ethanol / ammonia = 6:4:0.05:0.05) and evaporated to dryness to give compound 17 as a white, fluffy solid, 1.200 g (1.51 mmol, 56.4%).

[0146] Synthesis of Compound 18

[0147]

[0148] Using compound 8 (0.600 g, 0.748 mmol) and 6-heptyne-1-amine hydrochloride (0.166 g, 1.122 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.1 / 0.05) to give compound 18 as a white fluffy solid, 0.308 g (0.360 mmol, 48.09%).

[0149] Synthesis of Compound 19

[0150]

[0151] Using compound 8 (1.200 g, 1.470 mmol) and 7-octyne-1-amine hydrochloride (0.475 g, 2.941 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.1 / 0.05) to give compound 19 as a white, fluffy solid, 0.399 g (0.458 mmol, 31.16%). HRMS(ESI)(M+H) + m / z 870.5114, calculated value: C 47 H 72 N3O 12 870.5111. 1H NMR(CDCl3,400MHz)δ:8.08-8.00(m,2H,2H-Bz),7.62-7.55(m,1H,2H-Bz),7.50-7.43(m,2H,2H-Bz),5. 76(s,1H,11-NH),5.18(dd,J=2.3Hz,10.9Hz,1H,H-13),4.98(dd,J=7.4Hz,10.4Hz,1H,H-2′),4.91-4.84 (m,2H,H-3,3-O-CO-NH-CH2),4.29(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.2Hz,1H,H-5),3.70(m,1H,H-11), 3.46-3.29(m,2H,H-5′,3-O-CO-NH-CH2),3.19-3.09(m,1H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2.86 -2.69(m,3H,H-3,H-10,H-2),2.52-2.43(m,1H,H-8),2.28(s,6H,-N(CH3)2),2.23-2.16(m,2H,-CH2-C≡ CH),1.95(t,J=2.6Hz,1H,-CH2-C≡CH),1.93-1.79(m,2H,H-4,H-14eq),1.79-1.73(m,1H,H-4′a),1.63-1 .34(m,12H,H-7a,H-7b,H-14eq,H-4′a,4(-CH2-)),1.32(s,3H,12-CH3),1.29-1.23(m,6H,6-CH3,5′-CH3 ),1.15-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0152] Synthesis of Compound 20

[0153]

[0154] Using compound 8 (0.605 g, 0.750 mmol) and 8-nonyne-1-amine hydrochloride (0.159 g, 0.900 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified by column chromatography (100-200 mesh silica gel, petroleum ether / dichloromethane / ethanol / ammonia = 4 / 6 / 0.1 / 0.05) to give compound 20 as a white fluffy solid, 0.341 g (0.350 mmol, 50.00%).

[0155] Preparation Example 3.5: General Synthetic Method for Compounds 21-25

[0156] Compounds 9-12 (1 eq) were added to alkynyl alcohol (20-100 eq) as solvent, the system was transferred to -20°C, and formic acid (4.5 eq) was added dropwise. Then, sodium nitrite (6 eq) was added in portions while stirring, and the reaction was carried out overnight. The temperature was then slowly increased to room temperature and reacted for 12 h. After the reaction was monitored by TLC until complete, 20 mL of dichloromethane and 20 mL of distilled water were added to the system. The organic phase was washed with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic layer was evaporated to dryness and purified by column chromatography to obtain compounds 21-25.

[0157] Synthesis of Compound 21

[0158]

[0159] Using compound 9 (0.897 g, 1.161 mmol) and 3-butyn-1-ol (8.79 mL, 116.1 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified with 100-200 mesh silica gel and petroleum ether / dichloromethane / ethanol / ammonia water = 3 / 7 / 0.1 / 0.1 as developing solvent to give compound 21 as 0.398 g (0.482 mmol, 41.51%) of white fluffy solid.

[0160] Synthesis of Compound 22

[0161]

[0162] Using compound 9 (1.500 g, 1.941 mmol) and 4-pentyn-1-ol (5.42 mL, 58.23 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified with 100-200 mesh silica gel and petroleum ether / dichloromethane / ethanol / ammonia water = 3 / 7 / 0.2 / 0.1 developing solvent to give compound 22 as 0.347 g (0.428 mmol, 22.05%) of white fluffy solid.

[0163] Synthesis of Compound 23

[0164]

[0165] Using compound 10 (1.227 g, 1.559 mmol) and 3-butyn-1-ol (11.80 mL, 155.9 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified with 100-200 mesh silica gel, using petroleum ether / dichloromethane / ethanol / ammonia water = 4 / 6 / 0.1 / 0.1 as developing solvent to give compound 23 as 0.469 g (0.586 mmol, 37.59%), a white, fluffy solid. HRMS(ESI)(M+H) + m / z 798.4725, calculated value: C 40 H 68 N3O 13 798.4747. 1H NMR (CDCl3, 400MHz) δ: 5.48 (t, J = 5.8Hz, 1H, 3-O-CO-NH-CH2), 5.17 (dd, J = 2.6Hz, 10.7Hz, 1H, H-13), 4.92-4.8 2(m,2H,H-3,H-11),4.05(d,J=7.2Hz,1H,H-1′),3.82(s,3H,9-O-CH3),3.77(d,J=3.2Hz,1H,H-5),3.74-3.66 (m,1H,H-8),3.61-3.52(m,4H,3-O-CO-NH-CH2-CH2,-O-CH2-CH2-C≡CH),3.49-3.35(m,2H,H-5′,3-O-CO-NH-C H2),3.27-3.17(m,2H,H-2′,3-O-CO-NH-CH2),3.02(s,3H,6-O-CH3),2.90-2.81(m,1H,H-2),2.64-2.53(m,2H, H-3′),2.52-2.43(m,3H,CH2-C≡CH,H-10),2.38(s,6H,-N(CH3)2),2.12-2.03(m,2H,C≡CH,H-4),1.96-1.74(m ,3H,H-14eq,3-O-CO-NH-CH2-CH2-CH2),1.74-1.67(m,1H,H-4′a),1.62-1.51(m,1H,H-14ax),1.49(s,3H,12- CH3),1.42-1.33(m,1H,H-4′b),1.32(s,3H,6-CH3),1.29-1.17(m,8H,H-7a,H-7b,5′-CH3,10-CH3),1.14(d,J =6.7Hz,3H,2-CH3),1.06(d,J=7.5Hz,3H,4-CH3),0.93(d,J=7.0Hz,3H,8-CH3),0.86(t,J=7.3Hz,3H,15-CH3).

[0166] Synthesis of Compound 24

[0167]

[0168] Using compound 11 (2.576 g, 3.604 mmol) and 3-butyn-1-ol (13.60 mL, 180.200 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified with 100-200 mesh silica gel, using petroleum ether / dichloromethane / ethanol / ammonia water = 4 / 6 / 0.1 / 0.1 as developing solvent to give compound 24 as 0.456 g (0.522 mmol, 14.49%), a white, fluffy solid. HRMS(ESI)(M+H) + m / z 872.4890, Calculated value: C 46 H 70 N3O 13 872.4903. 1 H NMR(CDCl3,400MHz)δ:8.10-8.02(m,2H,2H-Bz),7.62-7.55(m,1H,2H-Bz),7.51-7.43(m,2H,2H-Bz),5.77(s ,1H,11-NH),5.45(t,J=5.7Hz,1H,3-O-CO-NH-CH2),5.18(dd,J=2.2Hz,10.9Hz,1H,H-13),5.00(dd,J=7.3Hz ,10.5Hz,1H,H-2′),4.89(d,J=11.0Hz,1H,H-3),4.30(d,J=7.5Hz,1H,H-1′),3.83(d,J=3.3Hz,1H,H-5),3.7 0(m,1H,H-11),3.66-3.55(m,4H,-CH2-O-CH2-),),3.51-3.39(m,2H,H-5′,3-O-CO-NH-CH2),3.37-3.28(m,1 H,3-O-CO-NH-CH2),2.96(s,3H,6-O-CH3),2.89-2.70(m,3H,H-3,H-10,H-2),2.55-2.41(m,3H,-CH2-C≡CH,H -8),2.27(s,6H,-N(CH3)2),2.05(t,J=2.6Hz,1H,-CH2-C≡CH),1.98-1.81(m,2H,H-4,H-14eq),1.79-1.70(m ,1H,H-4′a),1.60-1.36(m,4H,H-7a,H-7b,H-14eq,H-4′a),1.31(s,3H,12-CH3),1.28-1.23(m,6H,6-CH3,5′ -CH3),1.16-1.03(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.5Hz,3H,4-CH3).

[0169] Synthesis of Compound 25

[0170]

[0171] Using compound 12 (1.175 g, 1.644 mmol) and 3-butyn-1-ol (6.22 mL, 82.177 mmol) as starting materials, the reaction was carried out according to the general synthetic method of this preparation example. The product was purified by column chromatography (100-200 mesh silica gel, petroleum ether / dichloromethane / ethanol / ammonia = 4 / 6 / 0.1 / 0.1 eluent) to give compound 25 as 0.320 g (0.361 mmol, 21.96%) of white, fluffy solid. HRMS (ESI) (M+H) + m / z 886.5061, Calculated value: C 47 H 72 N3O 13 886.5060. 1H NMR(CDCl3,400MHz)δ:8.10-7.98(m,2H,2H-Bz),7.62-7.55(m,1H,2H-Bz),7.51-7.42(m,2H,2H-Bz),5.76(s,1H ,11-NH),5.18(dd,J=2.4Hz,10.9Hz,1H,H-13),5.15-5.08(m,1H,3-O-CO-NH-CH2),4.98(dd,J=7.5Hz,10.4Hz,1 H,H-2′),4.88(d,J=10.8Hz,1H,H-3),4.29(d,J=7.1Hz,1H,H-1′),3.83(d,J=3.2Hz,1H,H-5),3.70(m,1H,H-11) ,3.60-3.48(m,4H,-CH2-O-CH2-),),3.47-3.36(m,2H,H-5′,3-O-CO-NH-CH2),3.22-3.12(m,1H,3-O-CO-NH-CH2) ,2.96(s,3H,6-O-CH3),2.85-2.69(m,3H,H-3,H-10,H-2),2.52-2.43(m,1H,-CH2-C≡CH),2.38-2.31(m,1H,H-8) ,2.27(s,6H,-N(CH3)2),2.00(t,J=2.7Hz,1H,-CH2-C≡CH),1.97-1.82(m,2H,H-4,H-14eq),1.79-1.63(m,3H,H- 4′a,-CH2-),1.58-1.37(m,6H,H-7a,H-7b,H-14eq,H-4′a,-CH2-),1.31(s,3H,12-CH3),1.29-1.23(m,6H,6-CH3 ,5′-CH3),1.15-1.04(m,9H,2-CH3,10-CH3,8-CH3),0.81(t,J=7.4Hz,3H,15-CH3),0.74(d,J=7.6Hz,3H,4-CH3).

[0172] Example 1: Preparation of target compound 26x-36x

[0173]

[0174] Where x is the number corresponding to the Ar group selected in the target compound. For example, when Ar in target compound 26x is selected from the a group, the number of the target compound is recorded as 26a.

[0175] General synthetic methods for compounds 26x-36x

[0176] A mixture of iodoquinolone derivative (1.2 eq), cuprous iodide (0.1 eq), 5 mL triethylamine, and 5 mL acetonitrile was stirred at room temperature for 20 min. Then, 0.05 eq of bis(triphenylphosphine)palladium dichloride and compound 15-25 (1 eq) were added to the system. The system was sonicated while purging with argon gas to replace the air. The mixture was then sealed and transferred to 40 °C for 12 h. After the reaction was complete, 30 mL of ethyl acetate was added to the reaction system, followed by washing with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution to remove the organic phase. Methanol was then added and refluxed at 65 °C for 2-12 h to remove the protecting group R. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated to dryness, and purified by column chromatography to obtain compound 26x-36x.

[0177] The quinolone derivatives used in the synthesis are shown below.

[0178]

[0179] Synthesis of compound 26a

[0180]

[0181] According to the general synthetic method of this embodiment, compound 15 (0.300 g, 0.364 mmol) and compound aI (0.155 g, 0.437 mmol) were reacted as starting materials. Column chromatography conditions were 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.8 / 0.5, yielding compound 26a 24.8 mg (0.246 mmol, 6.75%). HRMS (ESI) (M+H) + m / z 1009.5381, Calculated value: C 53 H 77 N4O 15 1009.5380. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, 2″-quinolone), 8.40 (d, J = 8.3Hz, 1H, 5″-quinolone), 8.06 (d, J = 1.4Hz, 1H, 8″-quinolone), 7.54 (dd, J = 1.4Hz, 8.3Hz, 1H, 6″-quinolone), 5.16 (dd, J = 2.5Hz, 10.8Hz, 1H, H⁻¹³), 5.07 (br, 1H, 3-O-CO-NH-CH₂), 4.91–4.79 (m, 2H, H⁻³). ,H-11), 4.03(d,J=7.3Hz,1H,H-1′), 3.82(s,3H,9-O-CH3), 3.73(d,J=3.0Hz,1H,H-5), 3.72-3.64(m,1H,H-8), 3.63-3.56(m,1H,1H-cyclopropyl), 3.44-3.31(m,2H,H-5′,3-O-CO-NH-CH2), 3.21(dd,J=7.2Hz,10.1Hz,1H,H-2′), 3.15-3.05(m,1H,3-O- CO-NH-CH2), 3.01(s,3H,6-O-CH3), 2.87-2.76(m,1H,H-2), 2.56-2.43(m,4H,H-3′,H-10,-CH2-C≡C-quinolone), 2.33(s,6H,-N(CH3)2), 2.12-2.02(m,1H,H-4), 1.95-1.83(m,1H,H-14eq), 1.75-1.50(m,8H,3(-CH2-),H-4′a,H-14ax), 1.49(s,3H,1 2-CH3), 1.46-1.35(m,3H,2H-cyclopropyl,H-4′b), 1.32(s,3H,6-CH3), 1.30-1.17(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.12(d,J=6.8Hz,3H,2-CH3), 1.06(d,J=7.4Hz,3H,4-CH3), 0.93(d,J=7.0Hz,3H,8-CH3), 0.84(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:178.19,174.04,166.74,164.55,156.48,154.66,148.48,141.07,130.03,129. 40,126.88,124.86,119.83,109.02,103.21,95.50,85.02,83.19,81.28,79.99,78.34,78.21,77.24, 75.52,70.47,69.37,66.07,61.42,49.82,43.35,40.94,40.35,37.34,35.95,35.37,32.73,29.78,28.92,28.04,26.08,25.60,22.22,21.17,19.54,19.32,18.86,15.60,14.87,13.01,10.17,8.92,8.36.

[0182] Synthesis of compound 27a

[0183]

[0184] According to the general synthesis method of this embodiment, compound 16 (0.421 g, 0.502 mmol) and compound aI (0.214 g, 0.602 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, to obtain compound 27a 63.0 mg (0.0616 mmol, 12.26%), melting point: 158.1-159.6 °C. HRMS (ESI) (M+H) + m / z 1023.5521, Calculated value: C 54 H 79 N4O 15 1023.5536. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, 2″-quinolone), 8.40 (d, J = 8.4Hz, 1H, 5″-quinolone), 8.06 (d, J = 1.4Hz, 1H, 8″-quinolone), 7.54 (dd, J = 1.4Hz, 8.4Hz, 1H, 6″-quinolone), 5.16 (dd, J = 2.5Hz, 10.8Hz, 1H, H-13), 4.96 (t, J = 5.8Hz, 1H, 3-O-CO-NH-CH₂), 4.90-4.82 (m, 2H, H-3, H -11), 4.10(d, J = 7.3 Hz, 1H, H-1′), 3.82(s, 3H, 9-O-CH3), 3.74(d, J = 3.1 Hz, 1H, H-5), 3.72-3.65(m, 1H, H-8), 3.59(tt, J = 4.0 Hz, 7.2 Hz, 1H, 1H-cyclopropyl), 3.42-3.29(m, 2H, H-5′, 3-O-CO-NH-CH2), 3.18(dd, J = 7.3 Hz, 10.1 Hz, 1H, H-2′), 3.13-3.04(m, 1H, 3-O-C O-NH-CH2), 3.02(s,3H,6-O-CH3), 2.89-2.80(m,1H,H-2), 2.54-2.44(m,3H,H-10,-CH2-C≡C-quinolone), 2.42-2.34(m,1H,H-3′), 2.27(s,6H,-N(CH3)2), 2.12-2.04(m,1H,H-4), 1.96-1.84(m,1H,H-14eq), 1.73-1.50(m,8H,3(-CH2-),H-4′a,H-14ax), 1.49( s,3H,12-CH3), 1.47-1.36(m,5H,2H-cyclopropyl,H-4′b,CH2), 1.32(s,3H,6-CH3), 1.27-1.18(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.14(d,J=6.8Hz,3H,2-CH3), 1.07(d,J=7.5Hz,3H,4-CH3), 0.93(d,J=7.0Hz,3H,8-CH3), 0.86(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:178.19,174.06,166.76,164.57,156.42,154.68,148.48,141.06,130.11,129. 42,126.87,124.82,119.80,108.99,103.33,95.79,85.03,83.21,81.21,79.85,78.34,78.20,75.49, 70.45,69.49,66.09,61.42,49.82,43.35,41.07,40.37,37.32,35.96,35.36,32.71,30.10,28.64,28.58,28.33,26.32,25.60,22.22,21.21,19.54,19.34,18.86,15.60,14.89,13.02,10.19,8.91,8.35.

[0185] Synthesis of compound 28a

[0186]

[0187] According to the general synthetic method of this embodiment, compound 17 (0.275 g, 0.340 mmol) and compound aI (0.135 g, 0.370 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, to obtain compound 28a 0.160 g (0.163 mmol, 41.8%). HRMS(ESI)(M+H) + m / z 980.5125, Calculated value: C 52 H 74 N3O 15 980.5114.mp 137.9-139.7℃. 1¹H NMR (CDCl₃, 400MHz) δ: 8.79 (s, 1H, H-quinolone), 8.34 (d, J = 8.3Hz, 1H, H-quinolone), 8.00 (s, 1H, H-quinolone), 7.47 (d, J = 8.3Hz, 1H, H-quinolone), 5.45 (s, 1H, CONH), 5.06 (dd, J = 10.8, 2.4Hz, 1H, H-13), 4.82 (d, J = 11.0Hz, 1H, H-3), 4.66 ( s, 1H, H-11), 4.01 (d, J = 7.0 Hz, 1H, H-1′), 3.66 (d, J = 2.7 Hz, 1H, H-5), 3.60-3.49 (m, 1H, H-cyclopropyl), 3.40-3.26 (m, 2H, -CH2-NHCO, H-5′), 3.23-3.15 (m, 1H, H-2′), 3.06-2.98 (m, 1H, -CH2-NHCO), 2.93 (s, 3H, 6-O-CH3), 2.88 (q ,J=6.8Hz,H-10),2.80-2.67(m,2H,H-10,H-3′),2.60-2.49(m,1H,H-8),2.47-2.33(m,8H,N(CH3)2,-CH2-C≡ C-),2.04-1.93(m,1H,H-4),1.86-1.77(m,1H,H-14eq),1.73-1.44(m,10H,H-7a,H-4′a,H-7b,-C≡CCH2-CH2-C H2-CH2-CH2NCO,H-14ax), 1.42(s,3H,12-CH3), 1.40-1.34(m,2H,H-cyclopropyl), 1.21(s,3H,6-CH3), 1.20-1.08(m,10H,8-CH3,H-4′b,2-CH3,10-CH3), 1.07-0.98(m,8H,2H-cyclopropyl,5′-CH3,4-CH3), 0.77(t,J=7.3Hz,3H,15-CH3). 13 C NMR(CDCl3,100MHz)δ:212.0,178.2,174.2,166.8,156.5,154.0,148.5,1 41.1,130.1,129.4,126.9,124.9,119.9,109.0,84.9,82.4,80.8,80.0,78 .1,77.9,77.2,75.4,70.4,49.8,45.2,43.4,40.9,38.8,37.5,35.8,35.4, 29.7,28.0,26.0,22.0,21.1,19.5,19.4,18.4,14.9,13.0,10.1,9.1,8.4.

[0188] Synthesis of compound 29a

[0189]

[0190] According to the general preparation method of this embodiment, compound 18 (0.360 g, 0.47 mmol) and compound aI (0.217 g, 0.57 mmol) were reacted as starting materials to synthesize compound 29a 30.5 mg (0.031 mmol, 6.63%). HPLC: t = 10.50 min, 96.55%. HRMS (ESI) (M+H) + m / z 979.5274, Calculated value: C 52 H 75 N4O 14 979.5274.mp 137.0-139.5℃. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, H-quinolone), 8.41 (d, J = 8.3Hz, 1H, H-quinolone), 8.07 (s, 1H, H-quinolone), 7.54 (d, J = 8.3Hz, 1H, H-quinolone), 5.80 (s, 1H, ¹¹-CONH), 5.46 (s, 1H, ³-CONH), 5.22 (dd, J = 10.9, 2.3Hz, 1H, H⁻¹³), 4.91 (d, J = 11.0Hz, 1H, H⁻³) ), 4.06 (d, J = 7.1 Hz, 1H, H-1′), 3.76 (s, 1H, H-11), 3.74 (d, J = 2.7 Hz, 1H, H-5), 3.65-3.55 (m, 1H, H-cyclopropyl), 3.46-3.33 (m, 2H, -CH2-NHCO, H-5′), 3.26-3.19 (m, 1H, H-2′), 3.11-3.02 (m, 1H, -CH2-NHCO), 2.97 (s, 3H, 6-O-CH3), 2.90 (q, J = 6.8 Hz,H-10),2.84-2.76(m,1H,H-2),2.73-2.62(m,1H,H-3′),2.50(t,J=6.7Hz,-CH2-C≡CH),2.42(s,7H,N(CH3)2,H-8) ,2.16-2.02(m,1H,H-4),1.97-1.86(m,1H,H-14eq),1.84-1.75(m,1H,H-7a),1.74-1.64(m,3H,H-4′a,-CH2-CH2NCO) ,1.64-1.49(m,6H,H-7b,-C≡CCH2-CH2-CH2-,H-14ax),1.49-1.37(m,5H,12-CH3,2H-cyclopropyl),1.27(s,3H,6-CH3),1.30-1.26(m,8H,2H-cyclopropyl,5′-CH3,10-CH3),1.18-1.06(m,10H,H-4′b,2-CH3,4-CH3,8-CH3),0.83(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.6,178.2,174.4,166.7,158.4,156.5,148.5,141.1,130 .0,129.4,126.9,124.9,119.8,109.0,103.2,95.5,83.9,82.5,80.0,78.3,77.8,77 .2,75.8,70.5,69.1,65.7,58.2,49.8,45.3,43.4,40.9,39.9,39.1,37.3,35.7,35.4,29.8,28.0,26.1,22.0,21.2,19.5,19.3,18.3,15.0,13.9,13.3,10.2,9.1,8.4.

[0191] Synthesis of compound 30a

[0192]

[0193] According to the general preparation method of this embodiment, compound 30a was synthesized by reacting compound 19 (0.700 g, 0.87 mmol) and compound aI (0.399 g, 1.04 mmol) as raw materials. The yield was 35.5 mg (0.036 mmol, 4.11%). HPLC: t = 10.66 min, 94.88%. HRMS (ESI) (M+H) + m / z 993.5415, Calculated value: C 53 H 77 N4O 14 993.5431.mp 126.3-128.4℃. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, H-quinolone), 8.41 (d, J = 8.3Hz, 1H, H-quinolone), 8.06 (d, J = 1.3Hz, 1H, H-quinolone), 7.55 (dd, J = 8.3, 1.3Hz, 1H, H-quinolone), 5.80 (s, 1H, ¹¹-CONH), 5.47 (t, J = 6.0Hz, 1H, ³-CONH), 5.23 (dd, J = 10.9, 2.3Hz, 1H, H⁻¹³), 4.91 (d, J = 11.0Hz). ,1H,H-3), 4.06(d,J=7.3Hz,1H,H-1′), 3.77(s,1H,H-11), 3.74(d,J=2.7Hz,1H,H-5), 3.63-3.55(m,1H,H-cyclopropyl), 3.44-3.30(m,2H,-CH2-NHCO,H-5′), 3.27-3.19(m,1H,H-2′), 3.09-2.99(m,1H,-CH2-NHCO), 2.79(s,3H,6-O-CH3), 2.93-2.80(m,1H,H-10, H-2),2.77-2.68(m,1H,H-3′),2.49(t,J=7.1Hz,3H,H-8,-CH2-C≡C-),2.43(s,6H,N(CH3)2),2.11-2.03(m,1H,H-4),1.97-1. 87(m,1H,H-14eq),1.84-1.75(m,1H,H-7a),1.74-1.62(m,3H,H-4′a,-CH2-CH2NHCO),1.62-1.47(m,6H,H-7b,-C≡CCH2-CH2-C H2-CH2-,H-14ax), 1.47-1.36(m,7H,-C≡CCH2CH2CH2-CH2-,H-14ax,12-CH3,2H-cyclopropyl), 1.27(s,3H,6-CH3), 1.25-1.19(m,6H,5′-CH3,10-CH3), 1.18-1.11(m,9H,H-4′b,2-CH3,8-CH3,2H-cyclopropyl), 1.09(d,J=7.1Hz,3H,4-CH3), 0.84(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.6,178.2,174.4,166.8,158.4,156.5,148.5,141.1,130.1, 129.4,126.9,124.8,119.8,109.0,103.2,95.8,83.9,82.5,79.9,78.2,77.8,77.2,75 .8,70.5,69.1,65.6,58.2,49.8,45.3,43.4,41.0,39.9,39.1,37.3,35.8,35.4,30.1,29.2,28.7,28.3,26.3,22.0,21.1,19.5,19.3,18.3,15.0,13.9,13.3,10.3,9.1,8.4.

[0194] Synthesis of compound 30b

[0195]

[0196] According to the general synthetic method of this embodiment, compound 19 (0.200 g, 0.229 mmol) and compound bI (0.102 g, 0.275 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 30b 37.7 mg (0.0384 mmol, 16.77%). HRMS (ESI) (M+H) + m / z 981.5443, Calculated value: C 52 H 77 N4O 14 981.5431. 1¹H NMR (CD₃OD, 400MHz) δ: 8.87 (s, 1H, 2″-quinolone), 8.34 (d, J = 8.3Hz, 1H, 5″-quinolone), 7.80 (s, 1H, 8″-quinolone), 7.43 (s, 1H, 6″-quinolone), 5.15 (dd, J = 2.5Hz, 10.7Hz, 1H, H⁻¹³), 4.87 (d, J = 11.1Hz, 1H, H⁻³), 4.45 (br, 2H, NCH₂) CH3),4.14(d,J=7.2Hz,1H,H-1′),3.84(d,J=3.1Hz,1H,H-5),3.80(s,1H,H-11),3.84-3.36(m,1H,H-5′ ),3.29-3.20(m,2H,H-2′,3-O-CO-NH-CH2),3.11-3.01(m,2H,H-10,3-O-CO-NH-CH2),2.97(s,3H,6-O-CH 3),2.92-2.81(m,1H,H-2),2.79-2.66(m,1H,H-3′),2.55-2.47(m,3H,-CH2-C≡C-,H-8),2.41(s,6H,-N( CH3)2),2.16-2.05(m,1H,H-4),1.90-1.73(m,3H,H-14ax,H-7a,H-4′a),1.69-1.48(m,9H,3(-CH2-),H-7 b,H-14eq,NCH2CH3),1.46(s,3H,12-CH3),1.32-1.26(m,3H,-CH2-,H-4′b),1.24(s,3H,6-CH3),1.18(d ,J=6.0Hz,3H,5′-CH3),1.16-1.08(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.84(t,J=7.3Hz,3H,15-CH3). 13 CNMR(CD3OD,100MHz)δ:217.95,174.81,159.42,157.39,101.70,84.50,79. 48,78.80,77.88,77.44,75.49,70.68,68.67,64.57,58.06,48.93,45.34,4 3.24, 40.49, 39.51, 38.68, 37.41, 35.68, 30.89, 29.44, 28.30, 28.11, 26.02, 21.80, 20.00, 18.69, 18.43, 17.17, 13.98, 13.60, 12.92, 12.22, 9.42, 8.07.

[0197] Synthesis of compound 30c

[0198]

[0199] According to the general synthetic method of this embodiment, compound 19 (0.361 g, 0.414 mmol) and compound cI (0.177 g, 0.497 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 30c 43.2 mg (0.0447 mmol, 10.79%). HRMS (ESI) (M+H) + m / z 967.5287, Calculated value: C 51 H 75 N4O 14 967.5274. 1¹H NMR (CD₃OD, 400MHz) δ: 8.82 (s, 1H, 2″-quinolone), 8.32 (d, J = 8.4Hz, 1H, 5″-quinolone), 7.72 (s, 1H, 8″-quinolone), 7.42 (s, 1H, 6″-quinolone), 5.16 (dd, J = 2.4Hz, 10.7Hz, 1H, H⁻¹³), 4.87 (d, J = 11.1Hz, 1H, H⁻³), 4.13 (d, J = 7.3H⁺). z,1H,H-1′),3.99(s,3H,N-CH3),3.84(d,J=3.1Hz,1H,H-5),3.79(m,1H,H-11),3.46-3.35(m,1H,H-5′ ),3.28-3.20(m,2H,H-2′,3-O-CO-NH-CH2),3.10-3.00(m,2H,H-10,3-O-CO-NH-CH2),2.97(s,3H,6-O- CH3),2.92-2.83(m,1H,H-2),3.77-3.67(m,1H,H-3′),2.57-2.47(m,3H,H-8,-CH2-C≡C-),2.40(s,6H, -N(CH3)2),2.14-2.06(m,1H,H-4),1.91-1.71(m,3H,H-14ax,H-7a,H-4′a),1.70-1.49(m,8H,3(-CH2- ),H-7b,H-14eq),1.46(s,3H,12-CH3),1.44-1.27(m,3H,-CH2-,H-4′b),1.25(s,3H,6-CH3),1.17(d,J =6.1Hz,3H,5′-CH3),1.15-1.07(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.84(t,J=7.4Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.96,174.81,159.41,157.39,101.73,84.49,79.4 8,78.81,77.89,77.45,75.49,70.72,68.70,64.54,58.06,48.92,45.34,43 .24,40.93,40.49,39.53,38.68,37.41,35.68,30.89,29.42,28.28,28.12,26.01,21.80,20.01,18.68,18.43,17.17,13.99,12.92,12.22,9.42,8.07.

[0200] Compound 30d Synthesis

[0201]

[0202] According to the general synthesis method of this embodiment, compound 19 (0.217 g, 0.249 mmol) and compound dI (0.0941 g, 0.299 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 30d 31.4 mg (0.0329 mmol, 13.23%). Melting point: 162.9-166.0 °C. HRMS (ESI) (M+H) + m / z 953.5132, Calculated value: C 50 H 73 N4O 14 953.5118. 1¹H NMR (CDCl₃, 400MHz) δ: 8.92 (s, 1H, 2″-quinolone), 8.26 (d, J = 8.4Hz, 1H, 5″-quinolone), 7.70 (s, 1H, 8″-quinolone), 7.42 (d, J = 8.4Hz, 1H, 6″-quinolone), 5.88 (s, 1H, 11-NH), 5.54 (s, 1H, 3-O-CO-NH-CH₂), 5.20 (dd, J = 2.4Hz, 10.9Hz, 1... H,H-13),4.89(d,J=11.0Hz,1H,H-3),4.09(d,J=7.2Hz,1H,H-1′),3.79(d,J=2.8Hz,1H,H-5),3.76(s,1H ,H-11),3.48-3.37(m,1H,H-5′),3.36-3.24(m,2H,H-2′,3-O-CO-NH-CH2),3.19-3.04(m,2H,NH,3-O-CO-N H-CH2),2.97(s,3H,6-O-CH3),2.89(q,J=6.5Hz,1H,H-10),2.81-2.63(m,2H,H-2,H-3′),2.54-2.46(m,3 H,H-8,-CH2-C≡C-),2.38(s,6H,-N(CH3)2),2.09-2.00(m,1H,H-4),1.94-1.81(m,1H,H-14eq),1.80-1.67 (m,2H,H-14eq,H-7a),1.67-1.42(m,10H,H-7b,H-4′a,4(-CH2-)),1.40(s,3H,12-CH3),1.31-1.18(m,7H ,6-CH3,H-4′b,5′-CH3),1.18-1.02(m,12H,2-CH3,10-CH3,8-CH3,4-CH3),0.82(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.61,174.49,158.57,156.52,129.31,128.79,125.45,123 .45,108.69,102.74,84.05,81.39,78.18,77.85,77.23,75.77,70.68,69.20,65.73, 58.20,49.81,45.30,43.41,41.05,40.13,39.11,37.29,35.73,29.93,29.69,28.95,28.32,27.92,26.19,22.03,21.13,19.30,18.24,15.02,13.87,13.27,10.23,9.09.

[0203] Synthesis of compound 30e

[0204]

[0205] According to the general synthetic method of this embodiment, compound 19 (0.181 g, 0.208 mmol) and compound eI (0.0899 g, 0.249 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 1.1 / 0.5, yielding compound 30e 62.1 mg (0.0622 mmol, 29.9%). HRMS(ESI)(M+H) + m / z 999.5339, Calculated value: C 52 H 76 FN4O 14 999.5337. 1¹H NMR (CD₃OD, 400MHz) δ: 8.87 (s, 1H, 2″-quinolone), 8.35 (d, J = 8.2Hz, 1H, 5″-quinolone), 7.84 (s, 1H, 8″-quinolone), 7.41 (s, 1H, 6″-quinolone), 5.16 (dd, J = 2.4Hz, 10.7Hz, 1H, H⁻¹³), 4.87–4.63 (m, 5H, H⁻³, NCH₂C) H2),4.17(d,J=7.2Hz,1H,H-1′),3.85(d,J=3.1Hz,1H,H-5),3.79(s,1H,H-11),3.53-3.40(m,1 H,H-5′),3.30-3.20(m,2H,H-2′,3-O-CO-NH-CH2),3.15-3.02(m,2H,H-10,3-O-CO-NH-CH2),2. 99(s,3H,6-O-CH3),2.93-2.78(m,2H,H-2,H-3′),2.61-2.40(m,9H,H-8,-N(CH3)2),2.16-2.0 7(m,1H,H-4),1.93-1.76(m,3H,H-14ax,H-7a,H-4′a),1.70-1.50(m,8H,3(-CH2-),H-7b,H-14e q),1.48(s,3H,12-CH3),1.46-1.29(m,3H,-CH2-,H-4′b),1.26(s,3H,6-CH3),1.19(d,J=6.0Hz ,3H,5′-CH3),1.17-1.06(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.85(t,J=7.4Hz,3H,15-CH3).

[0206] Synthesis of compound 30f

[0207]

[0208] According to the general synthetic method of this embodiment, compound 19 (0.199 g, 0.228 mmol) and compound fI (0.0974 g, 0.342 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / ethanol / ammonia = 10 / 0.2 / 0.1, yielding compound 30f 78.2 mg (0.0786 mmol, 34.46%). HRMS (ESI) (M+H) + m / z 995.5598, Calculated value: C 53 H 79 N4O 14 995.5587. 1¹H NMR (CD₃OD, 400MHz) δ: 8.68 (s, 1H, 2″-quinolone), 8.30 (d, J = 8.4Hz, 1H, 5″-quinolone), 7.69 (d, J = 1.4Hz, 1H, 8″-quinolone), 7.45 (dd, J = 1.4Hz, 8.4Hz, 1H, 6″-quinolone), 5.17 (dd, J = 2.5Hz, 10.7Hz, 1H, H⁻¹³), 4.87 (d, J = 11.0Hz, 1H, H⁻³), 4.32 ( q,J=7.1Hz,2H,OCH2CH3),4.10(d,J=7.3Hz,1H,H-1′),3.95(s,3H,N-CH3),3.85(d,J=3.2Hz,1H,H-5),3.80(m, 1H,H-11),3.44-3.36(m,1H,H-5′),3.28-3.19(m,2H,H-2′,3-O-CO-NH-CH2),3.12-2.99(m,2H,H-10,3-O-CO-NH -CH2),2.97(s,3H,6-O-CH3),2.92-2.84(m,1H,H-2),2.62-2.45(m,4H,H-3′,H-8,-CH2-C≡C-),2.31(s,6H,-N( CH3)2),2.14-2.06(m,1H,H-4),1.91-1.78(m,2H,H-14ax,H-7a),1.73-1.49(m,8H,3(-CH2-),H-7b,H-14eq,H-4 ′a),1.46(s,3H,12-CH3),1.45-1.40(m,3H,-CH2-,H-4′b),1.37(q,J=7.1Hz,2H,OCH2CH3),1.25(s,3H,6-CH3), 1.18(d,J=6.1Hz,3H,5′-CH3),1.16-1.09(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.84(t,J=7.4Hz,3H,15-CH3). 13C NMR(CD3OD,100MHz)δ:217.98,174.82,164.67,159.43,157.39,150.68,140.09,129.12,128.06,12 6.88,126.46,119.33,109.92,101.91,94.17,84.50,79.52,78.82,77.91,77.50,75.48,70.93,68. 81,64.41,60.20,58.07,48.90,45.34,43.27,40.61,40.51,39.58,38.69,37.41,35.70,30.85,29.41,28.28,28.13,26.02,21.80,20.05,18.66,18.43,17.15,13.98,13.31,12.91,12.22,9.40,8.08.

[0209] Synthesis of compound 31c

[0210]

[0211] According to the general synthetic method of this embodiment, compound 20 (0.341 g, 0.350 mmol) and compound cI (0.151 g, 0.421 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 31c 52.2 mg (0.0532 mmol, 15.20%). HRMS (ESI) (M+H) + m / z 981.5438, Calculated value: C 52 H 77 N4O 14 981.5431. 1¹H NMR (CD₃OD, 400MHz) δ: 8.79 (s, 1H, 2″-quinolone), 8.29 (d, J = 8.4Hz, 1H, 5″-quinolone), 7.71 (s, 1H, 8″-quinolone), 7.43 (s, 1H, 6″-quinolone), 5.15 (dd, J = 2.5Hz, 10.7Hz, 1H, H⁻¹³), 4.86 (d, J = 11.3Hz, 1H, H⁻³), 4.13 (d, J = 7.2... Hz,1H,H-1′),3.99(s,3H,N-CH3),3.83(d,J=3.1Hz,1H,H-5),3.78(m,1H,H-11),3.47-3.38(m,1H,H-5 ′),3.29-3.20(m,2H,H-2′,3-O-CO-NH-CH2),3.10-2.99(m,2H,H-10,3-O-CO-NH-CH2),2.98(s,3H,6-O -CH3),2.90-2.80(m,1H,H-8),3.79-3.69(m,1H,H-3′),2.54-2.45(m,2H,-CH2-C≡C-),2.42(s,6H,-N( CH3)2),2.13-2.04(m,1H,H-4),1.90-1.72(m,3H,H-14ax,H-7a,H-4′a),1.70-1.47(m,8H,3(-CH2-),H -7b,H-14eq),1.45(s,3H,12-CH3),1.42-1.27(m,5H,2(-CH2-),H-4′b),1.24(s,3H,6-CH3),1.18(d,J =6.1Hz,3H,5′-CH3),1.15-1.07(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.83(t,J=7.4Hz,3H,15-CH3). 13 C NMR(CD3OD,100MHz)δ:217.96,174.79,159.39,157.37,101.69,84.48,79.40 ,78.80,77.88,77.42,75.47,70.72,68.68,64.54,58.06,48.95,45.34,43.22 ,40.99,40.50,39.54,38.69,37.41,35.67,30.93,29.52,28.57,28.50,28.10,26.38,21.80,20.02,18.75,18.44,17.19,14.01,12.94,12.24,9.44,8.09.

[0212] Synthesis of compound 32a

[0213]

[0214] According to the general synthetic method of this embodiment, compound 21 (0.398 g, 0.482 mmol) and compound aI (0.205 g, 0.578 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.8 / 0.5, yielding compound 32a 52.5 mg (0.0519 mmol, 10.77%). Melting point: 161.5-163.7 °C. HRMS (ESI) (M+H) + m / z 1011.5182, Calculated value: C 52 H 75 N4O 16 1011.5173. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, 2″-quinolone), 8.41 (d, J = 8.3Hz, 1H, 5″-quinolone), 8.08 (s, 1H, 8″-quinolone), 7.56 (dd, J = 1.4Hz, 8.3Hz, 1H, 6″-quinolone), 5.30 (br, 1H, 3-O-CO-NH-CH₂), 5.15 (dd, J = 2.5Hz, 10.8Hz, 1H, H-13), 4.90–4.79 (m, 2H, H-3, H-11), 4.01 (d, J =7.2Hz, 1H, H-1′), 3.82(s, 3H, 9-O-CH3), 3.77-3.66(m, 4H, H-5, H-8, 3-O-CO-NH-CH2-CH2), 3.65-3.53(m, 4H, CH2-CH2-O-CH2-CH2-C≡C-quinolone, 1H-cyclopropyl), 3.43-3.33(m, 1H, H-5′), 3.32-3.23(m, 1H, 3-O-CO-NH-CH2), 3.18(dd, J = 7.2Hz, 10.2Hz, 1H, H-2′), 3.01(s,3H,6-O-CH3), 2.78(t,J=6.7Hz,2H,CH2-C≡C-quinolone), 2.76-2.68(m,1H,H-2), 2.52-2.37(m,2H,H-3′,H-10), 2.29(s,6H,-N(CH3)2), 2.10-2.00(m,1H,H-4), 1.96-1.84(m,1H,H-14eq), 1.69-1.62(m,1H,H-4′a), 1.61-1.51(m,1H,H-14ax), 1.4 8(s,3H,12-CH3), 1.46-1.35(m,3H,2H-cyclopropyl,H-4′b), 1.32(s,3H,6-CH3), 1.30-1.16(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.11(d,J=6.8Hz,3H,2-CH3), 0.99(d,J=7.5Hz,3H,4-CH3), 0.93(d,J=7.0Hz,3H,8-CH3), 0.85(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:178.15,173.98,166.65,164.58,156.48,154.66,148.53,141.05,129.53, 129.37,126.95,125.07,120.03,109.07,103.25,92.10,85.03,83.18,81.11,80.69,78.42,78.35 ,77.24,75.55,70.46,68.80,66.05,61.40,49.81,43.30,40.89,40.35,37.32,35.94,35.36,32.74,28.70,25.61,22.20,21.17,20.95,19.30,18.86,15.59,14.87,12.98,10.17,8.83,8.38,8.33.

[0215] Synthesis of compound 33a

[0216]

[0217] According to the general synthetic method of this embodiment, compound 22 (0.347 g, 0.428 mmol) and compound aI (0.182 g, 0.514 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.8 / 0.5, to obtain compound 33a 22.7 mg (0.0221 mmol, 5.17%). Melting point: 148.0-148.2 °C. HRMS (ESI) (M+H) + m / z 1025.5347, Calculated value: C 53 H 77 N4O 16 1025.5329. 1¹H NMR (CDCl₃, 400MHz) δ: 8.79 (s, 1H, 2″-quinolone), 8.34 (d, J = 8.3Hz, 1H, 5″-quinolone), 7.99 (s, 1H, 8″-quinolone), 7.47 (dd, J = 8.3Hz, 1H, 6″-quinolone), 5.29 (br, 1H, 3-O-CO-NH-CH₂), 5.09 (dd, J = 2.5Hz, 10.6Hz, 1H, H-13), 4.85–4.70 (m, 2H, H-3, H-11), 3.98 (br ,1H,H-1′),3.74(s,3H,9-O-CH3),3.69-3.58(m,2H,H-5,H-8),3.65-3.53(m,6H,3-O-CO-NH-CH2-CH2-O-CH2-CH2-CH2-C≡C-quinolone,1H-cyclopropyl),3.39-3.26(m,1H,H-5′),3.23-3.10(m,2H,H-2′,3-O-CO-NH-CH2),2.94(s,3H,6-O-CH3),2.83-2.70(m ,1H,H-2),2.52(t,J=7.1Hz,2H,CH2-C≡C-quinolone),2.46-2.34(m,2H,H-3′,H-10),2.29(s,6H,-N(CH3)2),2.06-1.94(m,1H,H-4),1.91-1.76(m,1H,H-14eq,CH2-CH2-C≡C-quinolone),1.67-1.55(m,1H,H-4′a),1.54-1.44(m,1H,H-14ax),1.41(s,3H, 12-CH3), 1.40-1.28(m,3H,2H-cyclopropyl,H-4′b), 1.25(s,3H,6-CH3), 1.21-1.11(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.07(d,J=6.8Hz,3H,2-CH3), 0.99(d,J=7.4Hz,3H,4-CH3), 0.86(d,J=7.0Hz,3H,8-CH3), 0.78(t,J=7.4Hz,3H,15-CH3). 13CNMR(CDCl3,100MHz)δ:178.18,174.05,166.72,164.55,156.57,154.67,148.51,141.07 ,129.89,129.37,126.93,124.92,119.86,109.04,85.03,83.20,80.03,78.33,77.25,75. 52,70.44,69.57,65.92,61.43,49.84,43.32,40.98,40.23,37.31,35.97,35.36,32.72,28.50,25.60,22.22,21.17,19.32,18.87,16.43,15.61,14.89,13.01,10.19,8.93,8.36.

[0218] Synthesis of compound 34a

[0219]

[0220] According to the general synthetic method of this embodiment, compound 23 (0.468 g, 0.586 mmol) and compound aI (0.250 g, 0.703 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 34a 43.7 mg (0.0426 mmol, 7.27%). Melting point: 144.6-145.2 °C. HRMS (ESI) (M+H) + m / z 1025.5295, Calculated value: C 53 H 77 N4O 16 1025.5329. 1¹H NMR (CDCl₃, 400MHz) δ: 8.86 (s, 1H, 2″-quinolone), 8.42 (d, J = 8.3Hz, 1H, 5″-quinolone), 8.08 (s, 1H, 8″-quinolone), 7.56 (dd, J = 1.1Hz, 8.3Hz, 1H, 6″-quinolone), 5.36 (br, 1H, 3-O-CO-NH-CH₂), 5.16 (dd, J = 2.3Hz, 10.7Hz, 1H, H-13), 4.89–4.80 (m, 2H, H-3, H-11), 4.03 (d, J = 7.2 Hz, 1H, H-1′), 3.82 (s, 3H, 9-O-CH3), 3.75-3.65 (m, 4H, H-5, H-8, 3-O-CO-NH-CH2-CH2), 3.65-3.55 (m, 3H, -O-CH2-CH2-C≡C-quinolone, 1H-cyclopropyl), 3.49-3.33 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.28-3.16 (m, 2H, H-2′, 3-O-CO-NH-CH2), 3.01 (s, 3H, 6-O-CH2-CH2-C≡C-quinolone, 1H-cyclopropyl), -O-CH3), 2.84-2.72(m,3H,H-2,CH2-C≡C-quinolone), 2.60-2.42(m,2H,H-3′,H-10), 2.35(s,6H,-N(CH3)2), 2.12-2.00(m,1H,H-4), 1.96-1.78(m,3H,H-14eq,3-O-CO-NH-CH2-CH2-CH2), 1.71-1.63(m,1H,H-4′a), 1.61-1.50(m,1H,H-14ax), 1.48(s,3 (H,12-CH3), 1.46-1.34(m,3H,2H-cyclopropyl,H-4′b), 1.32(s,3H,6-CH3), 1.30-1.16(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.11(d,J=6.6Hz,3H,2-CH3), 1.05(d,J=7.5Hz,3H,4-CH3), 0.93(d,J=7.1Hz,3H,8-CH3), 0.85(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:178.18,174.03,166.67,164.53,156.47,154.65,148.52,141.06,129.65,129. 39,126.97,125.06,119.98,109.09,103.24,92.29,85.01,83.19,81.51,80.57,78.35,78.21,77.23, 75.54,70.47,69.27,69.08,68.83,65.94,61.42,49.80,43.40,40.18,38.99,37.36,35.97,35.36,32.75,29.97,28.97,25.59,22.24,21.14,21.01,19.31,18.85,15.59,14.90,13.00,10.18,8.92,8.36.

[0221] Synthesis of compound 35a

[0222]

[0223] According to the general synthetic method of this embodiment, compound 24 (0.170 g, 0.195 mmol) and compound aI (0.0831 g, 0.234 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 35a 25.6 mg (0.0257 mmol, 13.19%). HRMS (ESI) (M+H) + m / z 995.5229, Calculated value: C 52 H 74 N4O 15 995.5223. 1¹H NMR (CD₃OD, 400MHz) δ: 8.86 (s, 1H, 2″-quinolone), 8.32 (d, J = 8.2Hz, 1H, 5″-quinolone), 7.18 (s, 1H, 8″-quinolone), 7.50 (s, 1H, 6″-quinolone), 5.16 (dd, J = 2.5Hz, 10.7Hz, 1H, H⁻¹³), 4.85 (d, J = 11.2Hz, 1H, H⁻³), 4.12 (d, J = 7.2Hz, 1H, H⁻¹′), 3.84 ( d, J = 3.1 Hz, 1H, H-5), 3.78 (s, 1H, H-11), 3.76-3.65 (m, 3H, 1H-cyclopropyl, -CH2-O-CH2-), 3.63-3.55 (m, 2H, -CH2-O-CH2-), 3.46-3.38 (m, 1H, H-5′), 3.37-3.32 (m, 1H, 3-O-CO-NH-CH2), 3.26 (dd, J = 7.3 Hz, 10.3 Hz, 1H, H-2′), 3.21-3.13 (m,1H,3-O-CO-NH-CH2),3.07(q,J=6.6Hz,1H,H-10),2.97(s,3H,6-O-CH3),2.86-2.70(m,4H,H-2,H-3′,-CH2-C ≡C-),2.55-2.47(m,1H,H-8),2.45(s,6H,-N(CH3)2),2.14-2.03(m,1H,H-4),1.90-1.72(m,5H,H-14ax,H-7a,H-4 ′a,-CH2-), 1.66-1.51(m,2H,H-7b,H-14eq), 1.46(s,3H,12-CH3), 1.42-1.34(m,2H,2H-cyclopropyl), 1.31-1.15(m,9H,H-4′b,6-CH3,5′-CH3,2H-cyclopropyl), 1.15-1.04(m,12H,2-CH3,4-CH3,10-CH3,8-CH3), 0.83(t,J=7.3Hz,3H,15-CH3). 13C NMR(CD3OD,100MHz)δ:17.93,174.78,159.41,157.30,101.65,84.48,78.77,77.88,77.49,75.51,70.53,68.67,68.53,68.18,58.05,48.94 ,45.33,43.22,39.44,38.68,38.05,37.41,35.68,30.75,29.58,21.8 0,20.26,19.96,18.43,17.16,14.00,12.91,12.22,9.41,8.06,7.19.

[0224] Synthesis of compound 35b

[0225]

[0226] According to the general synthetic method of this embodiment, compound 24 (0.250 g, 0.286 mmol) and compound cI (0.128 g, 0.334 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 35c 46.4 mg (0.0472 mmol, 16.5%). HRMS (ESI) (M+H) + m / z 983.5234, Calculated value: C 51 H 75 N4O 15 983.5223. 1¹H NMR (CD₃OD, 400MHz) δ: 8.87 (s, 1H, 2″-quinolone), 8.35 (d, J = 8.3Hz, 1H, 5″-quinolone), 7.83 (s, 1H, 8″-quinolone), 7.44 (s, 1H, 6″-quinolone), 5.15 (dd, J = 2.5Hz, 10.7Hz, 1H, H⁻¹³), 4.85 (d, J = 11.4Hz, 1H, H⁻³), 4.45 (br, 2H, NCH₂CH₃), 4.12 (d, J = 7.2Hz, 1H, H⁻¹³). 1′),3.83(d,J=3.1Hz,1H,H-5),3.75(m,1H,H-11),3.67(t,J=6.5Hz,2H,-CH2-O-CH2-),3.64-3.54(m,2H,-CH2-O-CH2- ),3.46-3.38(m,1H,H-5′),3.38-3.33(m,2H,3-O-CO-NH-CH2),3.26(dd,J=7.3Hz,10.2Hz,1H,H-2′),3.22-3.10(m,1H, 3-O-CO-NH-CH2),3.07(q,J=6.5Hz,1H,H-10),2.97(s,3H,6-O-CH3),2.87-2.71(m,4H,H-2,H-3′,-CH2-C≡C-),2.52-2 .45(m,1H,H-8),2.42(s,6H,-N(CH3)2),2.14-2.03(m,1H,H-4),1.91-1.71(m,5H,H-14ax,H-7a,H-4′a,-CH2-),1.68-1 .55(m,2H,H-7b,H-14eq),1.49(t,J=7.2Hz,3H,NCH2CH3),1.45(s,3H,12-CH3),1.32-1.26(m,1H,H-4′b),1.24(s,3H,6 -CH3),1.16(d,J=6.2Hz,3H,5′-CH3),1.14-1.04(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.83(t,J=7.3Hz,3H,15-CH3). 13C NMR(CD3OD,100MHz)δ:217.95,174.77,159.41,157.30,101.68,84.48,79 .96,78.77,77.88,77.50,75.49,70.64,68.69,68.54,68.17,64.60,58.05 ,48.94,45.33,43.22,39.52,38.68,38.02,37.41,35.67,30.84,29.58,2 1.79,20.25,19.99,18.43,17.18,14.02,13.63,12.92,12.23,9.42,8.07.

[0227] Synthesis of compound 35c

[0228]

[0229] According to the general synthetic method of this embodiment, compound 24 (0.200 g, 0.229 mmol) and compound cI (0.0905 g, 0.275 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 35c 16.1 mg (0.0166 mmol, 7.25%). Melting point: 157.9-158.8 °C. HRMS (ESI) (M+H) + m / z 969.5081, Calculated value: C 50 H 73 N4O 15 969.5067. 1¹H NMR (CDCl₃, 400MHz) δ: 8.76 (s, 1H, 2″-quinolone), 8.44 (d, J = 8.2Hz, 1H, 5″-quinolone), 7.63 (s, 1H, 8″-quinolone), 7.56 (d, J = 8.2Hz, 1H, 6″-quinolone), 5.80 (s, 1H, 11-NH), 5.34 (s, 1H, 3-O-CO-NH-CH₂), 5.22 (dd, J = 2.3Hz, 10.9Hz) ,1H,H-13),4.89(d,J=11.1Hz,1H,H-3),4.10-3.96(m,4H,H-1′,N-CH3),3.80-3.73(m,2H,H-5,H-11),3. 71-3.56(m,4H,-CH2-O-CH2-),3.48-3.33(m,2H,H-5′,3-O-CO-NH-CH2),3.28-3.14(m,2H,H-2′,3-O-CO- NH-CH2),2.97(s,3H,6-O-CH3),2.89(q,J=6.4Hz,1H,H-10),2.81-2.71(m,3H,H-2,-CH2-C≡C-),2.56-2 .42(m,2H,H-8,H-3′),2.31(s,6H,-N(CH3)2),2.08-1.99(m,1H,H-4),1.95-1.88(m,1H,H-14eq),1.88-1 .72(m,1H,H-7a,-CH2-),1.67-1.50(m,3H,H-7b,H-14eq,H-4′a),1.42(s,3H,12-CH3),1.32-1.18(m,7H, 6-CH3,H-4′b,5′-CH3),1.16-1.05(m,12H,2-CH3,10-CH3,4-CH3,8-CH3),0.83(t,J=7.4Hz,3H,15-CH3). 13CNMR(CDCl3,100MHz)δ:217.62,178.07,174.37,166.78,158.42,156.44,149.54,140 .16,129.89,129.35,127.06,125.28,119.32,109.12,92.59,83.89,80.34,77.87,75. 80,70.51,69.39,69.09,68.78,58.14,49.81,45.30,43.38,40.26,39.13,37.29,35.78,29.90,29.69,22.03,21.17,20.98,19.29,18.28,15.02,13.86,13.27,10.24,9.02.

[0230] Compound 35d Synthesis

[0231]

[0232] According to the general synthetic method of this embodiment, compound 24 (0.200 g, 0.229 mmol) and compound dI (0.0866 g, 0.275 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 35d 26.3 mg (0.0275 mmol, 12.02%). Melting point: 163.7-164.9 °C. HRMS (ESI) (M+H) + m / z 955.4890, Calculated value: C 49 H 71 N4O 15 955.4910. 1¹H NMR (CDCl₃, 400MHz) δ: 8.84 (s, 1H, 2″-quinolone), 8.28 (d, J = 8.4Hz, 1H, 5″-quinolone), 7.70 (s, 1H, 8″-quinolone), 7.44 (d, J = 8.4Hz, 1H, 6″-quinolone), 5.85 (s, 1H, 11-NH), 5.82 (s, 1H, 3-O-CO-NH-CH₂), 5.20 (dd, J = 2.3Hz, 10.8Hz, 1H, H⁻¹) 3),4.89(d,J=11.0Hz,1H,H-3),4.11(d,J=7.1Hz,1H,H-1′),3.83(d,J=2.6Hz,1H,H-5),3.75(s,1H,H-11),3 .71-3.59(m,4H,-CH2-O-CH2-),3.51-3.38(m,2H,H-5′,3-O-CO-NH-CH2),3.37-3.25(m,2H,H-2′,3-O-CO-NH- CH2),2.96(s,3H,6-O-CH3),2.87(q,J=6.5Hz,1H,H-10),2.80-2.66(m,4H,H-2,-CH2-C≡C-,H-3′),2.54-2.4 6(m,2H,H-8),2.42(s,6H,-N(CH3)2),2.08-1.98(m,1H,H-4),1.94-1.80(m,3H,H-14eq,-CH2-),1.79-1.67(m ,2H,H-7a,H-4′a),1.57-1.46(m,2H,H-7b,H-14eq),1.39(s,3H,12-CH3),1.33-1.18(m,7H,6-CH3,H-4′b,5′ -CH3),1.15-1.05(m,9H,2-CH3,10-CH3,8-CH3),0.99(t,J=7.3Hz,3H,4-CH3),0.82(t,J=7.3Hz,3H,15-CH3). 13C NMR(CDCl3,100MHz)δ:217.59,177.50,174.43,168.97,158.54,156.56,145.85,128.90,1 25.60,123.90,123.04,108.71,102.51,92.14,84.04,81.04,80.24,78.15,77.83,77.24,7 5.78,70.71,69.40,69.17,68.70,65.65,58.19,49.77,45.27,43.34,40.06,39.57,39.07,37.28,35.71,29.51,28.92,22.02,21.09,19.28,18.21,15.04,13.84,13.26,10.22,9.08.

[0233] Synthesis of compound 36c

[0234]

[0235] According to the general synthetic method of this embodiment, compound 25 (0.421 g, 0.502 mmol) and compound cI (0.214 g, 0.602 mmol) were reacted as starting materials. The column chromatography conditions were: 100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 0.9 / 0.5, yielding compound 36c 51.2 mg (0.0521 mmol, 10.37%). HRMS (ESI) (M+H) + m / z 983.5243, Calculated value: C 51 H 75 N4O 15 983.5223. 1¹H NMR (CD₃OD, 400MHz) δ: 8.82 (s, 1H, 2″-quinolone), 8.32 (d, J = 8.2Hz, 1H, 5″-quinolone), 7.72 (s, 1H, 8″-quinolone), 7.40 (s, 1H, 6″-quinolone), 5.15 (dd, J = 2.4Hz, 10.7Hz, 1H, H⁻¹³), 4.85 (d, J = 11.4Hz, 1H, H⁻³), 4.13 (d, J = 7.3Hz, 1H, H⁻¹′), 3.9 9(s,3H,N-CH3),3.83(d,J=3.1Hz,1H,H-5),3.78(m,1H,H-11),3.66(t,J=6.5Hz,2H,-CH2-O-CH2-),3.58-3.51 (m,2H,-CH2-O-CH2-),3.46-3.37(m,1H,H-5′),3.29-3.22(m,2H,H-2′,3-O-CO-NH-CH2),3.10-3.01(m,2H,H-1 0,3-O-CO-NH-CH2),2.97(s,3H,6-O-CH3),2.89-2.78(m,2H,H-2,H-3′),2.74(t,J=6.4Hz,2H,-CH2-C≡C-),2.5 1-2.45(m,1H,H-8),2.43(s,6H,-N(CH3)2),2.13-2.05(m,1H,H-4),1.90-1.74(m,3H,H-14ax,H-7a,H-4′a),1. 70-1.52(m,6H,2(-CH2-),H-7b,H-14eq),1.45(s,3H,12-CH3),1.32-1.26(m,1H,H-4′b),1.24(s,3H,6-CH3),1 .17(d,J=6.1Hz,3H,5′-CH3),1.15-1.05(m,12H,2-CH3,4-CH3,10-CH3,8-CH3),0.82(t,J=7.4Hz,3H,15-CH3). 13C NMR(CD3OD,100MHz)δ:217.96,174.78,159.40,157.34,101.69,84.49,79.9 2,78.83,77.88,77.46,75.48,70.66,70.20,68.69,68.44,64.58,58.06,48 .93,45.34,43.23,40.95,40.37,39.54,38.68,37.41,35.66,30.87,26.68,26.37,21.79,20.25,20.00,18.43,17.19,14.00,12.93,12.23,9.43,8.09.

[0236] Example 2 Preparation of target compounds 41a and 42a

[0237]

[0238] Synthesis of Compound 38

[0239]

[0240] Phthalimide (5.000 g, 34.933 mmol), 3-butyn-1-ol (2.64 mL, 36.680 mmol), and triphenylphosphine (10.079 g, 38.426 mmol) were dissolved in 50 mL of toluene. DIAD (7.57 mL, 38.426 mmol) was added dropwise with stirring in an ice bath. After the addition was complete, the mixture was transferred to room temperature for reaction. The reaction was monitored by TLC and completed in approximately 1-2 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1, 100-200 mesh silica gel).

[0241] The product from the previous step was dissolved in 50 mL of anhydrous ethanol, and hydrazine hydrate (4.24 mL, 69.866 mmol) was added dropwise. The temperature was raised to 80 °C, and the reaction was monitored by TLC. The reaction was completed in about 1.5-2 h. After the reaction was complete, the mixture was filtered, and concentrated hydrochloric acid was added dropwise to the filtrate under ice bath. A solid was formed. After the precipitation was complete, the mixture was filtered again, and the filtrate was collected and evaporated to dryness to obtain an oily crude product. The oily liquid was recrystallized from ethyl acetate or petroleum ether to give 2.801 g (26.532 mmol, 72.33%) of compound 38, a white 3-butynedi-1-amine hydrochloride.

[0242] Synthesis of Compound 39

[0243]

[0244] 3-Butynylamine hydrochloride (0.211 g, 2.000 mmol) and triethylamine (0.56 mL, 4.000 mmol) were added to 20 mL of THF and stirred until the solution was clear. Then, BOC anhydride (0.436 g, 2.000 mmol) was added. The mixture was stirred at room temperature for about 4 h, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was evaporated to dryness. 20 mL of dichloromethane and 20 mL of distilled water were added to the residue. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and saturated brine, respectively. The organic phase was evaporated to dryness to obtain compound 39 as a colorless oily liquid.

[0245] Synthesis of Compound 40

[0246]

[0247] A mixture of compound aI (0.500 g, 1.408 mmol), cuprous iodide (0.0179 g, 0.0939 mmol), 5 mL of triethylamine, and 5 mL of acetonitrile was stirred at room temperature for 20 min. Then, bis(triphenylphosphine) palladium dichloride (0.0328 g, 0.0468 mmol) and the compound obtained in the previous step were added to the system. After venting, the mixture was sealed and transferred to 50 °C for 1 h. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography (100-200 mesh silica gel, dichloromethane / methanol = 10 / 0.3) to give 0.330 g (0.832 mmol, 59.09%) of a pale yellow solid compound.

[0248] The solid was dissolved in a mixture of 2 mL ethanol and 3 mL dichloromethane, and 2 mL concentrated hydrochloric acid was added dropwise at room temperature. The mixture was stirred at room temperature for about 2-3 hours. After the reaction was complete, the reaction solution was evaporated to dryness and recrystallized from ethyl acetate. The filter cake was dried overnight in a forced-air drying oven at 60 °C. 0.220 g (0.661 mmol, 79.44%) of compound 40 was obtained as a pale yellow powder. HRMS(ESI)(M+H) + m / z 297.1234, calculated value: C 17 H 17 N2O3 297.1234. 1¹H NMR (DMSO-d₆, 400MHz) δ: 8.73 (s, 1H, 2-quinolone), 8.34 (d, J = 1.3Hz, 1H, 8-quinolone), 8.30 (d, J = 8.3Hz, 1H, 5-quinolone), 7.71 (d, J = 1.3Hz, 8.3Hz, 1H, 6-quinolone), 3.83 (tt, J = 4.0Hz, 7.3Hz, 1H, 1H-cyclopropyl), 3.14–3.03 (m, 2H, NH₂-CH₂), 2.93 (t, J = 7.0Hz, 2H, CH₂-C≡C-quinolone), 1.38–1.30 (m, 2H, 2H-cyclopropyl), 1.21–1.14 (m, 2H, 2H-cyclopropyl).

[0249] General synthetic methods for compounds 41a and 42a

[0250]

[0251] Compound 13 or 14 (1 eq) was dissolved in 20 mL of dichloromethane, and triethylamine (2 eq) was added. Methanesulfonyl chloride (1.5 eq) was then added dropwise at room temperature, and the mixture was stirred for approximately 10–20 min. The reaction was monitored by TLC. After the reaction was complete, the mixture was washed twice with water and once with saturated brine. The sulfonated derivatives of the 3-terminal hydroxyl group of compound 13 or 14 were purified by dry column chromatography using an organic phase separator.

[0252] The obtained derivative (2 eq), compound 40 (1.5 eq), and triethylamine (2 eq) were dispersed in anhydrous acetonitrile and stirred at 75°C for 72 h. After the reaction was complete, the reaction mixture was evaporated to dryness, 50 mL of dichloromethane was added, and the mixture was washed three times with water and once with saturated brine. The organic phase was evaporated to dryness and purified by column chromatography.

[0253] Synthesis of compound 41a

[0254]

[0255] According to the general synthesis method of this embodiment, compound 13 (0.472 g, 0.611 mmol) was used as the starting material. The product was purified with 100-200 mesh silica gel and dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 as the developing solvent to obtain 0.350 g (0.435 mmol, 71.19%) of white, fluffy solid compound 13 methanesulfonyl derivative.

[0256] Compound 40 (0.0819 g, 0.246 mmol) was reacted with a methanesulfonated derivative of compound 13 (0.496 g, 0.616 mmol), and the product was purified by column chromatography (100-200 mesh silica gel, dichloromethane / methanol / ammonia = 10 / 1 / 0.5 eluent) to give compound 41a as a white, fluffy solid, 9.0 mg (0.00890 mmol, 3.62%). HRMS (ESI) (M+H) + m / z 1010.5351, Calculated value: C 52 H 76 N5O 15 1010.5332. 1¹H NMR (CDCl₃, 400MHz) δ: 8.84 (s, 1H, 2″-quinolone), 8.39 (d, J = 8.3Hz, 1H, 5″-quinolone), 8.07 (s, 1H, 8″-quinolone), 7.54 (d, J = 8.3Hz, 1H, 6″-quinolone), 5.45 (br, 1H, 3-O-CO-NH-CH₂), 5.16 (dd, J = 2.5Hz, 10.8Hz, 1H, H⁻¹³), 4.91–4.81 (m, 2H, H⁻³, H⁻¹¹), 4.03 (d, J = 7.2Hz, 1H, H⁻¹′) ), 3.82(s,3H,9-O-CH3), 3.75(d,J=3.0Hz,1H,H-5), 3.73-3.64(m,1H,H-8), 3.63-3.54(m,1H,1H-cyclopropyl), 3.54-3.44(m,1H,3-O-CO-NH-CH2), 3.42-3.31(m,1H,H-5′), 3.25-3.12(m,2H,3-O-CO-NH-CH2,H-2′), 3.01(s,3H,6-O-CH3), 2.99-2.91(m,2H,CH2-CH2-C≡ C-quinolone group), 2.91-2.84(m,2H,CH2-CH2-NH), 2.84-2.75(m,1H,H-2), 2.71(t,J=6.5Hz,2H,CH2-C≡C-quinolone group), 2.54-2.41(m,2H,H-3′,H-10), 2.31(s,6H,-N(CH3)2), 2.12-2.01(m,1H,H-4), 1.97-1.83(m,1H,H-14eq), 1.69-1.61(m,1H,H-4′a), 1.61-1.51(m,1H,H-14) ax), 1.48(s,3H,12-CH3), 1.46-1.34(m,3H,2H-cyclopropyl,H-4′b), 1.32(s,3H,6-CH3), 1.30-1.15(m,10H,2H-cyclopropyl,H-7a,H-7b,5′-CH3,10-CH3), 1.12(d,J=6.7Hz,3H,2-CH3), 1.04(d,J=7.4Hz,3H,4-CH3), 0.93(d,J=7.0Hz,3H,8-CH3), 0.84(t,J=7.3Hz,3H,15-CH3). 13CNMR(CDCl3,100MHz)δ:178.03,174.02,166.84,164.51,156.59,154.67,148.54,140 .99,129.46,129.32,126.92,125.11,119.99,103.26,93.07,85.00,83.20,81.24,80 .92,78.38,78.34,75.55,70.48,61.44,49.81,43.38,40.38,37.32,35.97,35.30,32.73,25.60,22.21,21.20,19.33,18.86,15.61,14.95,13.02,10.19,8.90,8.38,8.35.

[0257] Synthesis of compound 42a

[0258]

[0259] According to the general synthesis method of this embodiment, compound 14 (0.490 g, 0.645 mmol) was used as the starting material. The product was purified with 100-200 mesh silica gel and dichloromethane / ethanol / ammonia water = 10 / 0.1 / 0.1 as the developing solvent to obtain 0.277 g (0.308 mmol, 47.75%) of white, fluffy solid compound 14 methanesulfonyl derivative.

[0260] Compound 40 (0.137 g, 0.463 mmol) was reacted with a methanesulfonated derivative of compound 14 (0.277 g, 0.308 mmol). The product was purified with 100-200 mesh silica gel using dichloromethane / methanol / ammonia (10 / 1 / 0.5) as the developing solvent to give compound 42a as a white, fluffy solid, 9.6 mg (0.00966 mmol, 3.14%). Melting point: 148.6-149.5 °C. HRMS (ESI) (M+H) + m / z 994.5401, Calculated value: C 52 H 76 N5O 14 994.5399. 1¹H NMR (CDCl₃, 400MHz) δ: 8.85 (s, 1H, 2″-quinolone), 8.41 (d, J = 8.3Hz, 1H, 5″-quinolone), 8.07 (s, 1H, 8″-quinolone), 7.55 (d, J = 8.3Hz, 1H, 6″-quinolone), 5.80 (s, 1H, 11-NH), 5.52 (s, 1H, 3-O-CO-NH-CH₂), 5.22 (dd, J = 2.3Hz, 10.9Hz, 1H, H-13). 4.90 (d, J = 11.1 Hz, 1H, H-3), 4.04 (d, J = 7.0 Hz, 1H, H-1′), 3.83-3.74 (m, 1H, H-5, H-11), 3.63-3.54 (m, 1H, 1H-cyclopropyl), 3.50-3.31 (m, 2H, H-5′, 3-O-CO-NH-CH2), 3.23-3.12 (m, 2H, H-2′, 3-O-CO-NH-CH2), 2.97 (s, 3H, 6-O-CH3), 2 .96-2.84(m,4H,H-10,H-2,-CH2-N-),2.85-2.76(m,2H,-N-CH2-),2.75-2.63(m,2H,-CH2-C≡C-),2.56-2.39( m,2H,H-8,H-3′),2.28(s,6H,-N(CH3)2),2.09-2.02(m,1H,H-4),1.97-1.85(m,1H,H-14eq),1.82-1.70(m,3H, H-7a,-CH2-), 1.67-1.49(m,3H,H-7b,H-14eq,H-4′a), 1.47-1.38(s,5H,12-CH3,2H-cyclopropyl), 1.31-1.17(m,9H,6-CH3,H-4′b,5′-CH3,2H-cyclopropyl), 1.20-1.06(m,12H,2-CH3,10-CH3,4-CH3,8-CH3), 0.87(t,J=7.4Hz,3H,15-CH3). 13C NMR(CDCl3,176MHz)δ:217.68,174.40,158.45,156.57,148.54,141.00,129.49,129.3 6,126.94,125.07,120.00,103.13,83.90,81.60,80.84,77.86,75.79,70.53,69.45,5 8.13,49.82,45.31,43.39,40.35,39.13,37.29,35.79,35.31,29.70,29.37,22.70,22.03,21.19,19.31,18.29,15.06,14.13,13.89,13.29,11.10,10.26,9.28,9.06,8.36.

[0261] Test Example In Vitro Antibacterial Activity Experiment

[0262] According to the standards recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010), the in vitro antibacterial activity of some target compounds against susceptible Streptococcus pneumoniae ATCC49619, Streptococcus pneumoniae PU09 (mef-resistant), Streptococcus pneumoniae 07P390 (constitutive erm-resistant), Streptococcus pneumoniae 05O173 (mef+ constitutive erm-resistant), Streptococcus pyogenes 12-206 (constitutive ermA-resistant), Staphylococcus aureus ATCC29213, Staphylococcus aureus PU32, 19K266, 19F300 (induced ermA-resistant), Staphylococcus aureus 15B196, 19D052, 19B133, 19E131 (constitutive erm-resistant), catarrhal molar 13L332, and Haemophilus influenzae ATCC49247 was determined using the broth dilution method. Each bacterial strain was plate-transferred and purified before testing, and fresh bacterial cells were used for the experiment. A standard strain was used as a quality control for susceptibility testing in each experiment; antibiotic-free bacterial suspensions were used as growth controls for the test strains. The minimum inhibitory concentration (MIC) was determined using the broth two-fold dilution method. The antibiotic concentration range was 256–0.008 μg / mL, and the final concentration of the test bacterial suspension was approximately 5 × 10⁻⁶ μg / mL. 5 CFU / ml.

[0263] The measurement results are shown in the table below:

[0264] Table 1: Antibacterial activity of compound 26a (MIC, μg / mL)

[0265]

[0266]

[0267] Existing technical literature, *Current Topics in Medicinal Chemistry*, 2021, 21, 2455-2473, summarizes the structure-activity relationships of known macrolide-quinolone hybrids. It finds that changing a 6-substituted quinolone to a 7-substituted quinolone decreases activity, while reducing the terminal alkyne linker of the side chain increases activity. However, in the representative compounds of this invention, the 7-substituted quinolone exhibits significant advantages over its 6-substituted counterpart, and the alkyne-linked 7-quinolone also generally shows advantages over its alkane-linked counterpart.

[0268] Under the same testing conditions, the antibacterial activity of the representative compound of the present invention and commercially available structurally similar drugs, namely clarithromycin and telithromycin, was tested in batches, and the results are shown in Tables 2 to 5 below.

[0269] Table 2: Antibacterial activity (MIC, μg / mL) of compounds 27a-30a, 32a-34a, and 41a

[0270]

[0271]

[0272] Table 3: Antibacterial activity (MIC, μg / mL) of compounds 30a, 30d, 35c, 35d, and 42a

[0273]

[0274] (Note: Compound D corresponds to compound 14n in Eur J Med Chem, 125(2017)210-224)

[0275]

[0276] The results show that the representative compound of the present invention has better structure and antibacterial advantages than similar compounds disclosed in the literature.

[0277] Table 4: Antibacterial activity (MIC, μg / mL) of compounds 30b, 30c, 31c, 35a, 35b, 35c, and 36c

[0278]

[0279] Table 5: Antibacterial activity of compounds 30c and 35c (MIC, μg / mL)

[0280]

[0281] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: （I） in, A represents O or N-OCH3; B represents O or NH; X represents CH2, NH, or O; Y represents H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 2-fluoroethyl, cyclopropyl, or fluorocyclopropyl; Z represents H; R represents H; m is selected from 2, 3, or 4; n is selected from 1, 2, or 3.

2. The following compounds or their pharmaceutically acceptable salts: (IA), 。 3. A method for preparing the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Compound I-1 deprotecting group R 0 The compound shown in formula (I) was obtained; Among them, R 0 The components are selected from methyl, triphenylmethyl, acetyl, neopentanoyl, benzoyl, or benzyl; A, B, X, Y, Z, R, m, and n independently have the definitions described in claim 1 or 2.

4. Compounds: ； in, A, B, R, R 0 X, X', Y, Z, m, and n each have the definition as described in any one of claims 1-3.

5. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

6. Use of at least one of the compounds of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of an antimicrobial drug; The pathogenic microorganisms are selected from Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, or Moraxella catarrhalis.

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