A quinolone bacterial degrading agent, and a preparation method and application thereof

Abstract

The application provides a quinolone bacterial degradation agent and a preparation method and application thereof, the quinolone bacterial degradation agent is a compound shown in formula I or formula II or a pharmaceutically acceptable salt thereof, and the compound shown in formula I or formula II or the pharmaceutically acceptable salt thereof is a solvate, an enantiomer, a diastereoisomer or a mixture of the compound in any proportion thereof.The quinolone bacterial degradation agent can induce target protein degradation, reduce the drug resistance pressure caused by only relying on target inhibition, and can be used for preparing an antibacterial infection drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a quinolone bacterial degrader targeting DNA gyrase, its preparation method, and its application. Background Technology

[0002] Quinolone antibiotics are a class of broad-spectrum antibiotics that primarily work by inhibiting bacterial DNA gyrase and topoisomerase IV. They are widely used clinically for infections caused by Gram-negative bacteria and some Gram-positive bacteria. These drugs exert their antibacterial effects by interfering with bacterial DNA replication, transcription, and repair processes. They are characterized by good oral absorption and wide tissue distribution, and have therefore long been an important choice for treating various infectious diseases.

[0003] With the long-term use of quinolone drugs, bacterial resistance has become an increasingly prominent problem. Resistance mechanisms include decreased affinity between the drug and target protein due to mutations in target genes, plasmid-mediated production of protective proteins, enhanced efflux pumps, and decreased membrane permeability. Current improvement strategies primarily focus on structural modifications to the quinolone core or side chains to increase affinity for target proteins or improve pharmacokinetic properties. However, the mechanisms of action of these strategies are mainly reversible inhibition, primarily manifesting as temporary suppression of target protein activity, making sustained removal of the target protein difficult. Furthermore, in the context of multifactorial resistance, efficacy attenuation or cross-resistance risks often occur. Summary of the Invention

[0004] In order to overcome the shortcomings of the prior art, the present invention aims to provide a quinolone bacterial degrading agent, its preparation method and application, which can induce the degradation of target proteins, reduce the drug resistance pressure caused by relying solely on transient inhibition of the target, and can be used to prepare antibacterial infection drugs.

[0005] To achieve the above objectives, the present invention employs the following technical solution: This invention discloses a quinolone bacterial degrading agent, which is a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer or mixture thereof in any proportion thereof, including racemic mixtures; The structural formula of the compound of formula I or formula II is:

[0006] Where n = 1~6, the quinolone compounds are one of the following compounds:

[0007] In Formula I or Formula II, X represents the piperazine ring or -NH₂ ring in the quinolone compound obtained by removing an H atom to form -NH₃ or... .

[0008] Preferably, n=2~4 in the compound of formula II, more preferably n=2.

[0009] Preferably, the representative compounds of the quinolone bacterial degrading agent are selected from the following compounds:

[0010]

[0011] This invention also discloses a method for preparing the above-mentioned quinolone bacterial degrading agent, comprising the following steps: (1) Using N-benzyloxycarbonyl-L-arginine as a raw material, its carboxyl group was protected to obtain compound I; the guanidinyl group of compound I was phosphorylated with bis(trichloroethyl)phosphoryl chloride to obtain compound II; under acidic conditions, Pd / C catalysis and hydrogen deprotection were used to obtain compound III; finally, the α-amino group on compound III was protected with Fmoc to obtain compound IV.

[0012] Among them, compound I is Compound II is Compound III is Compound IV is .

[0013] (2) Using quinolone compounds as raw materials, an amide condensation reaction is carried out with PEG Linker to obtain intermediate 1 (e.g., compounds a1~a21). Then, the terminal tert-butyloxycarbonyl group is removed to obtain intermediate 2 (e.g., compounds b1~b21). Intermediate 2 (e.g., compounds b1~b21) or the terminal amino group of the quinolone compound undergoes an amide condensation reaction with compound IV to obtain intermediate 3 (e.g., compounds c1~c28). Subsequently, the Fmoc group on intermediate 3 (e.g., compounds c1~c28) is removed to obtain intermediate 4 (e.g., compounds d1~d28). Subsequently, the arginine α-amino group on intermediate 4 (e.g., compounds d1~d28) reacts with an anhydride to generate an amide bond, to obtain intermediate 5 (e.g., compounds e1~e28). Finally, under alkaline conditions and a hydrogen atmosphere, deprotection is carried out by Pd / C catalytic hydrogenolysis to obtain quinolone bacterial degrading agents (e.g., compounds 1~28).

[0014] Among them, PEG Linker is ; Compounds a1~a3 are n=2,4,6; Compounds a4~a6 are n=2,4,6; Compounds a7~a9 are n=2,4,6; Compounds a10~a12 are n=2,4,6; Compounds a13~a15 are n=2,4,6; Compounds a16~a18 are n=2,4,6; Compounds a19~a21 are n=2,4,6; Compounds b1~b3 are n=2,4,6; Compounds b4~b6 are n=2,4,6; Compounds b7~b9 are n=2,4,6; Compounds b10~b12 are n=2,4,6; Compounds b13~b15 are n=2,4,6; Compounds b16~b18 are n=2,4,6; Compounds b19~b21 are n=2,4,6; Compound c1 is ; Compounds c2~c4 are n=2,4,6; Compound C5 is ; Compounds c6~c8 are n=2,4,6; Compound C9 is ; Compounds with c10~c12 are n=2,4,6; Compound C13 is ; Compounds c14~c16 are n=2,4,6; Compound C17 is ; Compounds with c18~c20 are n=2,4,6; Compound C21 is ; Compounds c22~c24 are n=2,4,6; Compound C25 is ; Compounds with c26~c28 are n=2,4,6; Compound d1 is ; Compounds d2~d4 are n=2,4,6; Compound d5 is ; Compounds d6~d8 are n=2,4,6; Compound d9 is ; Compounds d10~d12 are n=2,4,6; Compound d13 is ; Compounds d14~d16 are n=2,4,6; Compound d17 is ; Compounds d18~d20 are n=2,4,6; Compound d21 is ; Compounds d22~d24 are n=2,4,6; Compound d25 is ; Compounds d26~d28 are n=2,4,6; Compound e1 is ; Compounds e2~e4 are n=2,4,6; Compound e5 is ; Compounds e6~e8 are n=2,4,6; Compound e9 is ; Compounds e10~e12 are n=2,4,6; Compound e13 is ; Compounds e14~e16 are n=2,4,6; Compound e17 is ; Compounds e18~e20 are n=2,4,6; Compound e21 is ; Compounds e22~e24 are n=2,4,6; Compound e25 is ; Compounds e26~e28 are n=2,4,6; Compound 1 is ; Compounds 2-4 are n=2,4,6; Compound 5 is ; Compounds 6-8 are n=2,4,6; Compound 9 is ; Compounds 10-12 are n=2,4,6; Compound 13 is ; Compounds 14-16 are n=2,4,6; Compound 17 is ; Compounds 18-20 are n=2,4,6; Compound 21 is ; Compounds 22-24 are n=2,4,6; Compound 25 is ; Compounds 26-28 are n=2,4,6.

[0015] In step (1), the molar ratio of compound I to bis(trichloroethyl)phosphoryl chloride is 1:(1~2); in step (2), the molar ratio of quinolone compound to PEG Linker is 1:(1~2), and the molar ratio of intermediate 2 or quinolone compound to compound IV is 1:(1~2).

[0016] In step (2), the condensing agent used in the synthesis of intermediate 1 is HATU reagent.

[0017] The present invention also provides the application of the quinolone bacterial degrading agent in the preparation of antibacterial drugs.

[0018] The quinolone-based bacterial degrading agent has the function of degrading bacterial target proteins (such as DNA gyrase), and completely eliminates bacteria through the degradation mechanism.

[0019] Preferably, the bacteria are Gram-positive or Gram-negative bacteria, or the bacteria are drug-resistant strains of Gram-positive or Gram-negative bacteria.

[0020] Preferably, the drug-resistant strains of the Gram-positive bacteria are ATCC 43300, MDRSA-171 or VREfs-80, and the drug-resistant strains of the Gram-negative bacteria are MDRPA-264, CR-EC-361 or MDRAB-183.

[0021] The quinolone bacterial degrading agent can be used alone or in combination with other quinolone bacterial degrading agents, or mixed with pharmaceutically acceptable excipients and diluents to form oral tablets, capsules, granules, syrups, premixes or microcapsules, or to form liniments or injections for non-oral administration.

[0022] Compared with the prior art, the present invention has the following beneficial effects: Existing quinolone antibiotics primarily inhibit bacterial growth by suppressing DNA gyrase / topoisomerase IV activity, a reversible mechanism that fails to fundamentally address bacterial resistance. To combat bacterial resistance, this invention proposes an event-driven target degradation strategy. Through molecular design, it induces the clearance of key target proteins by the bacterial protein quality control system, resulting in a more sustained inhibitory effect. Specifically, a quinolone targeting fragment with DNA gyrase-binding activity is coupled to a degradation tag, phosphorylated arginine (pArg), recognized by the bacterial ClpCP protease system. This introduces a novel mechanism of action that maintains targeting while inducing target protein degradation and weakening its function, thereby inhibiting key life processes such as bacterial DNA replication and repair. This achieves a more sustained intervention on the key target, reducing the likelihood of rapid bacterial resurgence after drug withdrawal. This invention, through a dual-function mechanism, can, to some extent, reduce the resistance pressure resulting from relying solely on transient target inhibition, potentially improving the performance of quinolone-resistant strains. By introducing PEG linkers, the spatial conformation, flexibility, and polarity of molecules can be regulated within a certain range, thereby achieving a better balance between target binding, effective intracellular exposure, and degradation efficiency, and improving the overall performance of the compounds. The compounds of this invention can be used as candidate antibacterial molecules for monotherapy or in combination with other antibacterial drugs or other degrading agents, thereby expanding the treatment strategies and drug combination space for complex infections (including drug-resistant infections). Attached Figure Description

[0023] Figure 1 The minimum inhibitory concentration of compound 6 against ATCC 25923; Figure 2 The minimum inhibitory concentration of compound 6 against ATCC 43300; Figure 3 The minimum inhibitory concentration of compound 6 against multidrug-resistant Acinetobacter baumannii 183; Figure 4 The effect of compound 6 on the expression level of DNA gyrase GyrA protein in MRSA ATCC 43300. Detailed Implementation

[0024] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0025] The present invention will now be described in further detail with reference to the accompanying drawings: The present invention provides a quinolone bacterial degrading agent, which is a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, and a solvent compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer or a mixture thereof in any proportion thereof, including racemic mixtures; The structural formula of the compound of formula I or formula II is:

[0026] Where n = 1~6, the quinolone compounds are one of the following compounds: ; In Formula I or Formula II, X represents the piperazine ring or -NH₂ ring in the quinolone compound obtained by removing an H atom to form -NH₃ or... .

[0027] The preparation method of the quinolone bacterial degrading agent provided in this embodiment of the invention is as follows: (1) Using N-benzyloxycarbonyl-L-arginine as a starting material, its carboxyl group was protected to obtain compound I; the guanidinyl group of compound I was phosphorylated with bis(trichloroethyl)phosphoryl chloride to obtain compound II; under acidic conditions, Pd / C catalysis and hydrogenolysis protection were used to obtain compound III; finally, the α-amino group of compound III was protected with Fmoc to obtain compound IV. The reaction formula is as follows:

[0028] (2) Using the seven quinolone compounds shown as raw materials, amide condensation reactions were carried out with PEG Linkers of different lengths to obtain the corresponding compounds a1~a21. Then, the Boc protecting group was removed using trifluoroacetic acid (TFA) to obtain the corresponding compounds b1~b21. The reaction formula for norfloxacin is as follows:

[0029] Then, compounds b1-b21 or quinolone compounds undergo an amide condensation reaction with compound IV to obtain the corresponding compounds c1-c28. Compounds c1-c28 are then de-Fmoc groups in DMF using 20% ​​piperidine to obtain compounds d1-d28, as shown in the following reaction formula:

[0030] Then, compounds d1-d28 were acylated with acetic anhydride to give the corresponding compounds e1-e28. e1-e28 were then dissolved in ammonium carbonate buffer, anhydrous ethanol and palladium on carbon catalyst were added, and a deprotection reaction was carried out under a hydrogen atmosphere to give the target compounds 1-28, as shown in the following reaction formula:

[0031] 1. Specific examples of synthesizing compounds 1-28 Example 1 Compound 1: 7-(4-( N 2 -acetyl- N w Preparation of phosphono-L-arginine-1-piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1) Preparation of compound IV

[0032] Step 1: Synthesis of Compound I N-Benzyloxycarbonyl-L-arginine (18.50 g, 60 mmol) was placed in a reactor and dissolved in 120 mL of NMP. Benzyl bromide (8.55 mL, 72 mmol) was added, and the mixture was stirred at room temperature for 5 h, monitored by TLC. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent. The resulting solid residue was washed with saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected. The product was purified by column chromatography (dichloromethane:methanol = 20:1) and dried to give compound I 17.47 g, with a yield of 73.08%.

[0033] Step 2: Synthesis of Compound II Compound I (12.00 g, 30 mmol) and bis(trichloroethyl)phosphoryl chloride (13.65 g, 36 mmol) were placed in a reactor and dissolved in 150 mL of acetonitrile. Triethylamine (6.25 mL, 45 mmol) was slowly added to the reactor at room temperature, and the reaction was stirred for 7 hours under TLC monitoring. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetonitrile. The product was purified by column chromatography (dichloromethane:methanol = 10:1) and dried to give 17.28 g of compound II, with a yield of 77.73%.

[0034] Step 3: Synthesis of Compound III The obtained compound II (17.05 g, 23 mmol) was placed in a reactor, and TFA (80 mL), acetic acid (60 mL), and 2.00 g of Pd / C (10 wt% Pd) were added. Hydrogen gas was then introduced, and the mixture was stirred overnight at room temperature. The extent of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered to remove Pd / C. The filtered reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 8:1). After drying, 8.82 g of compound III was obtained, with a yield of 74.18%.

[0035] Step 4: Synthesis of Compound IV Compound III (5.17 g, 10 mmol), triethylamine (1.67 mL, 12 mmol), and Fmoc-Osu (4.05 g, 12 mmol) were placed in a reactor and dissolved in 80 mL of acetonitrile. The mixture was stirred at room temperature for 5 hours and monitored by TLC. After the reaction was complete, the resulting reaction solution was concentrated under reduced pressure to remove acetonitrile. The product was purified by column chromatography (dichloromethane:methanol = 10:1) and dried to give compound IV 5.39 g, with a yield of 72.92%.

[0036] (2) Synthesis of compounds c1 and d1

[0037] Step 1: Synthesis of compound c1 Compound IV (3.70 g, 5 mmol) was dissolved in 30 mL of DMF in a reactor. The condensing agent HATU (1.90 g, 5 mmol) and N,N-diisopropylethylamine (DIEA) (1.31 mL, 7.5 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Norfloxacin (1.33 g, 4.17 mmol) was then added, and the reaction was stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected. The organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1). After drying, compound c13.21 g was obtained, with a yield of 73.98%.

[0038] Step 2: Synthesis of compound d1 Compound c1 (1.95 g, 2.00 mmol) was placed in a reactor and dissolved in 20 mL of DMF. 10 mL of a 20 wt% piperidine solution was added to the reactor, and the reaction was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected. The organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 8:1). After drying, compound d1 was obtained as 1.19 g, with a yield of 72.71%.

[0039] (3) Synthesis of compound e1 and compound 1

[0040] Step 1: Synthesis of compound e1 Compound d1 (163.65 mg, 0.20 mmol) was placed in a reactor and dissolved in 10 mL of NMP. Acetic anhydride (22.69 μL, 0.24 mmol) and DIEA (52.25 μL, 0.3 mmol) were added to the reactor, and the reaction was stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the acetic anhydride was quenched by slowly adding the reaction solution to ice water. The pH was then adjusted to weakly alkaline with saturated sodium bicarbonate solution. The reaction solution was then concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1). After drying, compound e1 was obtained, 129.87 mg, with a yield of 75.48%.

[0041] Step 2: Synthesis of Compound 1 Compound e1 (100 mg, 0.12 mmol) was placed in a reactor and dissolved in 5 mL of ammonium carbonate buffer. 5 mL of anhydrous ethanol and 300 mg of Pd / C were added to the reactor. The reaction mixture was vigorously stirred for 4 hours under a hydrogen atmosphere, and the reaction was monitored by TLC. After the reaction was complete, Pd / C was removed by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 1:1). The purified compound was dried to give 156.58 mg of the compound, with a yield of 78.91%.

[0042] The proton NMR and carbon NMR spectra of compound 1 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.33 (s, 1H), 9.15 (s, 1H), 8.38 (s,1H), 6.97 (s, 2H), 6.54 (d, J = 0.8 Hz, 1H), 5.24 (s, 2H), 4.95 (d, J = 0.7 Hz,2H), 4.12 (s, 1H), 3.73 (s, 1H), 3.00 (s, 2H), 2.86 – 2.73 (m, 10H), 2.24 (s,1H), 1.84 (s, 3H), 1.41 (d, J = 12.4 Hz, 1H), 1.23 (d, J = 12.5 Hz, 1H), 1.14 (s, 1H), 0.96 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.13, 175.02, 173.55, 170.44, 165.38,153.77, 149.92, 142.63, 141.58, 123.67, 115.21, 113.47, 108.36, 55.48, 53.62,51.79, 49.11, 47.28, 45.67, 42.19, 31.44, 26.83, 23.59, 15.72. Example 2 Compound 2: ( S Preparation of 7-(4-(3-((2-(2-acetamido-5-(3-phosphonoguanidinyl)pentamido)ethyl)-(ethyl)peroxy)propionyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1) Preparation of compound IV The preparation method is the same as in Example 1. (2) Synthesis of compounds a2 and b2

[0043] Step 1: Synthesis of compound a2 N-tert-butoxycarbonyl-diethylene glycol-carboxylic acid (332.78 mg, 1.2 mmol) was placed in a reactor and dissolved in 5 mL of LDM. The condensing agents HATU (456.29 mg, 1.2 mmol) and DIEA (261.27 μL, 1.5 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Norfloxacin (319.34 mg, 1 mmol) was then added, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was extracted with ethyl acetate, and the organic phase was collected and purified by column chromatography (dichloromethane:methanol = 10:1). The purified phase was dried to give compound a2379.59 mg, with a yield of 65.60%.

[0044] Step 2: Synthesis of compound b2 Compound a2 (289.32 mg, 0.50 mmol) was placed in a reactor and dissolved in a mixed solvent of 3 mL DCM and 2 mL TFA. The reaction was stirred at room temperature and monitored by TLC. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 8:1), and dried to give compound b2 182.56 mg, with a yield of 76.30%.

[0045] (3) Synthesis of compounds c2 and d2 The preparation method is the same as in Example 1.

[0046] (4) Synthesis of compound e2 and compound 2 The preparation method was the same as in Example 1, and the yield of compound 2 was 57.21%.

[0047] The proton NMR and carbon NMR spectra of compound 2 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.65 (s, 1H), 9.36 (s, 1H), 8.58 (s,1H), 7.78 (s, 2H), 7.37 (s, 1H), 6.96 (s, 1H), 5.34 (s, 1H), 4.93 (d, J= 0.7Hz, 2H), 4.83 (s, 2H), 4.68 (s, 1H), 3.86 – 3.75 (m, 3H), 3.68 – 3.56 (m,6H), 3.38 – 3.29 (m, 10H), 2.57 (s, 1H), 2.45 (s, 2H), 2.41 (d, J = 12.5 Hz, 1H), 2.38 (d, J = 12.5 Hz, 2H), 1.86 (s, 3H), 1.71 – 1.67 (m, 2H), 1.42 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.65, 176.02, 175.11, 173.44, 169.33,165.21, 153.68, 149.41, 144.52, 141.63, 123.58, 115.37, 113.26, 108.74,73.91, 72.34, 71.12, 68.54, 59.73, 56.84, 55.39, 54.12, 51.44, 49.33, 44.52,41.67, 38.55, 31.44, 28.73, 25.62, 15.82. Example 3 Compound 3: ( S )-7-(4-(6-acetamido-18-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,18λ 3 Preparation of (-tetraoxa-2,8-diazaeicosano-21-acyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only requiring the replacement of the corresponding raw materials. The yield of compound 3 was 25.23%.

[0048] The proton NMR and carbon NMR spectra of compound 3 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.34 (s, 1H), 9.68 (s, 1H), 8.86 (s,1H), 7.37 (s, 1H), 7.28 (s, 1H), 6.69 (s, 1H), 4.93 (d, J= 0.7 Hz, 1H), 4.69(s, 2H), 3.93 – 3.84 (m, 2H), 3.74 (d, J = 4.8 Hz, 1H), 3.67 (d, J = 4.6 Hz, 5H), 3.61 – 3.52 (m, 14H), 3.35 (d, J = 12.4 Hz, 1H), 3.32 – 3.23 (m, 8H), 2.68 (s,1H), 2.40 (s, 2H), 2.34 (d, J = 12.5 Hz, 1H), 2.31 (d, J = 12.5 Hz, 2H), 1.92 (s, 3H), 1.45 (d, J = 3.8 Hz, 2H), 1.39 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.72, 176.08, 174.39, 173.11, 171.67,167.84, 160.92, 153.74, 149.63, 144.52, 141.36, 123.47, 115.43, 113.74,108.66, 73.42, 72.19, 71.38, 70.57, 69.74, 68.92, 66.81, 59.74, 56.48, 54.63,53.12, 51.44, 49.57, 44.38, 41.52, 38.66, 31.47, 28.71, 25.46, 15.62. Example 4 Compound 4: ( S )-7-(4-(6-acetamido-24-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20,23,24λ 3 Preparation of (-hexaoxa-2,8-diazaheptadecane-27-acyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 4 was 10.76%.

[0049] The proton NMR and carbon NMR spectra of compound 4 are as follows: 1H NMR (400 MHz, DMSO- d6 ) δ 13.67 (s, 1H), 9.69 (s, 1H), 8.12 (s,1H), 7.50 (s, 1H), 7.28 (s, 1H), 6.51 (s, 1H), 5.81 (s, 2H), 4.48 (d, J = 0.7Hz, 2H), 4.20 (s, 1H), 3.72 – 3.66 (m, 3H), 3.59 (d, J = 4.6 Hz, 5H), 3.57 –3.51 (m, 20H), 3.47 – 3.44 (m, 2H), 3.38 – 3.30 (m, 8H), 2.69 (s, 1H), 2.58(s, 2H), 2.40 (d, J = 12.5 Hz, 1H), 2.36 (d, J = 12.5 Hz, 2H), 1.92 (s, 3H), 1.70(d, J = 3.8 Hz, 2H), 1.39 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.44, 176.12, 174.66, 171.91, 167.38,160.83, 153.72, 149.35, 144.53, 141.47, 123.61, 115.37, 109.84, 108.41,73.44, 72.97, 72.41, 72.05, 71.66, 71.28, 70.91, 70.37, 69.94, 69.51, 68.73,67.58, 59.74, 56.17, 54.64, 53.46, 51.27, 49.13, 44.55, 41.39, 38.44, 31.46, 28.62, 25.45, 15.21. Example 5 Compound 5: 7-(4-( N 2 -acetyl- N w Preparation of (-phosphonyl-L-arginine)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 5 was 16.55%.

[0050] The proton NMR and carbon NMR spectra of compound 5 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.32 (s, 1H), 9.33 (s, 1H), 8.83 (s,1H), 7.76 (s, 1H), 6.84 (s, 1H), 6.51 (s, 1H), 5.70 (s, 2H), 4.77 (s, 1H), 4.26 (s, 1H), 3.89 (s, 2H), 3.65 (s, 2H), 3.53 (s, 2H), 3.29 – 3.22 (m, 4H), 3.01 (d, J = 10.0 Hz, 1H), 1.94 (d, J = 12.4 Hz, 1H), 1.87 (s, 3H), 1.81 (d, J =12.5 Hz, 2H), 1.67 (s, 2H), 1.57 (d, J = 4.9 Hz, 2H), 1.34 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.12, 175.63, 172.84, 171.47, 166.39,160.91, 153.88, 149.32, 146.41, 136.44, 115.27, 114.96, 109.72, 107.56,55.63, 54.32, 53.61, 48.74, 44.52, 37.31, 31.74, 28.66, 25.39, 9.84, 7.58. Example 6 Compound 6: ( S Preparation of 7-(4-(3-((2-(2-acetamido-5-(3-phosphonoguanidinyl)pentamido)ethyl)-(ethyl)peroxy)propionyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 6 was 21.18%.

[0051] The proton NMR and carbon NMR spectra of compound 6 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 13.91 (s, 1H), 9.67 (s, 1H), 8.74 (s,1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 5.81 (s, 1H), 4.79 (s, 2H), 4.42 (s, 1H), 4.20 (s, 1H), 3.89 (s, 1H), 3.72 – 3.65 (m, 2H), 3.62 (s, 3H), 3.60 (d, J = 1.5 Hz, 2H), 3.58 – 3.52 (m, 4H), 3.35 (d, J = 12.4 Hz, 2H), 3.32 –3.29 (m, 2H), 3.24 (s, 4H), 3.14 (s, 1H), 3.04 (d, J = 12.5 Hz, 2H), 2.94 (d, J =12.5 Hz, 1H), 2.10 (s, 3H), 1.95 (s, 2H), 1.92 (d, J = 3.8 Hz, 2H), 1.59 (d, J =4.9 Hz, 2H), 1.16 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.03, 176.22, 175.44, 174.52, 167.82,160.91, 153.88, 149.41, 147.32, 136.44, 115.26, 114.92, 109.74, 107.83,73.41, 72.63, 71.47, 68.72, 59.84, 56.17, 54.66, 49.73, 48.62, 44.39, 41.53,38.44, 32.58, 31.47, 28.66, 25.38, 9.74, 7.53. Example 7 Compound 7: ( S)-7-(4-(6-acetamido-18-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,18λ 3 Preparation of (-tetraoxa-2,8-diazaeicosano-21-acyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 7 was 17.83%.

[0052] The proton NMR and carbon NMR spectra of compound 7 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.94 (s, 1H), 9.69 (s, 1H), 8.78 (s,1H), 7.54 (s, 1H), 7.28 (s, 1H), 6.99 (s, 1H), 6.51 (s, 1H), 5.81 (s, 2H), 4.20 (s, 1H), 3.89 (s, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 3.71– 3.59 (m, 11H), 3.57 – 3.52 (m, 2H), 3.42 (s, 2H), 3.35 (d, J = 12.4 Hz, 2H), 3.32 – 3.25 (m,2H), 3.10 (s, 4H), 2.76 (s, 1H), 2.62 (s, 2H), 2.33 (d, J = 12.5 Hz, 1H), 2.12(d, J = 12.5 Hz, 2H), 1.97 (s, 3H), 1.68 (d, J = 3.8 Hz, 2H), 1.24 (d, J = 4.9 Hz, 2H), 1.12 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 178.04, 176.37, 175.12, 174.39, 171.84,167.73, 160.83, 153.74, 149.36, 143.77, 141.52, 115.28, 114.96, 109.74,107.63, 73.42, 72.56, 72.04, 71.63, 71.14, 70.52, 69.91, 68.44, 59.72, 56.18,54.67, 49.71, 48.39, 44.36, 42.48, 38.55, 31.47, 28.68, 25.37, 9.82, 7.57. Example 8 Compound 8: ( S )-7-(4-(6-acetamido-24-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20,23,24λ 3 Preparation of (-hexaoxa-2,8-diazaheptadecane-27-acyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) The preparation method is the same as in Example 2, only requiring the replacement of the corresponding raw materials. The yield of compound 8 was 17.54%.

[0053] The proton NMR and carbon NMR spectra of compound 8 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 13.87 (s, 1H), 8.34 (s, 1H), 7.94 (s,1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 5.77 (s, 1H), 4.26 (s, 2H), 3.93 (s, 1H), 3.68 (s, 1H), 3.64 (d, J = 15.9 Hz, 6H), 3.62 – 3.48 (m, 22H), 3.39 (d, J = 12.4 Hz, 2H), 3.36 – 3.29 (m, 2H), 3.11 (s, 4H), 2.67 (s, 1H), 2.42 (s, 2H), 2.35 (d, J = 12.5 Hz, 1H), 2.27 (d, J= 12.5 Hz, 2H), 1.96 (s, 3H), 1.75 – 1.64 (m, 2H), 1.34 (d, J = 4.9 Hz, 2H), 1.16 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.31, 176.57, 175.06, 174.48, 171.39,167.64, 153.12, 149.07, 143.26, 136.11, 115.03, 114.68, 109.22, 108.14,73.99, 73.36, 72.94, 72.28, 71.01, 70.86, 70.03, 69.83, 69.14, 68.72, 68.09,67.21, 59.34, 56.42, 54.18, 49.52, 48.03, 44.11, 41.03, 38.12, 32.18, 31.06, 28.41, 25.72, 9.63, 7.41. Example 9 Compound 9: 7-(( R )-3-(( S Preparation of 2-acetamido-5-(3-phosphonoguanidinyl)pentamido)azacycloheptane-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 9 was 13.77%.

[0054] The proton NMR and carbon NMR spectra of compound 9 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.18 (s, 1H), 8.49 (s, 1H), 7.77 (s,1H), 7.57 (s, 1H), 7.39 (s, 1H), 5.94 (s, 1H), 4.75 (s, 2H), 4.54 (s, 1H), 3.87 (s, 1H), 3.68 (s, 1H), 3.51 (s, 1H), 3.43 (s, 1H), 3.35 – 3.26 (m, 4H), 2.59 (d, J= 12.5 Hz, 1H), 2.40 (d, J = 12.5 Hz, 1H), 1.82 (s, 3H), 1.74 (s, 2H), 1.61 (dd, J = 12.3, 4.4 Hz, 6H), 1.43 (d, J = 15.6 Hz, 2H), 1.37 (d, J = 4.9 Hz, 2H), 1.24 (d, J = 5.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 179.42, 175.86, 167.21, 161.07, 150.68,147.01, 143.52, 140.63, 137.74, 129.11, 125.38, 115.24, 113.02, 63.91, 59.44,55.77, 53.04, 44.56, 38.09, 32.74, 31.82, 28.94, 28.16, 26.03, 25.87, 9.92,7.48. Example 10 Compound 10: 7-(( R )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14-dioxa-2,8-diazaheptadecane-17-amino)azacycloheptane-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 10 was 27.64%.

[0055] The 1H NMR and 1C NMR spectra of compound 10 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 13.50 (s, 1H), 8.71 (s, 1H), 7.86 (s,1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 4.84 (s, 2H), 4.76 (s, 1H), 4.05 (s, 1H), 3.94 – 3.81 (m, 2H), 3.78 (d,J = 12.1 Hz, 2H), 3.72 (d, J = 1.5 Hz, 2H), 3.61 – 3.54 (m, 4H), 3.46 (s, 1H), 3.37 – 3.28 (m,6H), 2.84 (d, J = 12.5 Hz, 1H), 2.65 (dd, J = 13.3, 12.4 Hz, 2H), 2.41 (s, 1H), 2.20 (d, J = 12.5 Hz, 2H), 2.11 (s, 3H), 2.01 (s, 2H), 1.80 (dd, J = 12.3, 4.4Hz, 4H), 1.65 (d, J = 1.3 Hz, 2H), 1.39 (d, J = 4.9 Hz, 2H), 1.27 (d, J = 5.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.44, 173.59, 173.56, 172.18, 171.24,166.53, 160.37, 145.70, 144.41, 138.83, 136.54, 128.65, 124.92, 116.18,109.27, 72.07, 71.22, 70.41, 68.05, 62.11, 58.93, 56.64, 54.22, 44.83, 41.34,38.03, 36.11, 32.18, 29.62, 26.98, 25.37, 24.09, 9.24, 7.11. Example 11 Compound 11: 7-(( R )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20-tetraoxa-2,8-diazatoritriane-23-amino)azacycloheptane-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 11 was 22.19%.

[0056] The 1H NMR and 1C NMR spectra of compound 11 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.48 (s, 1H), 8.65 (s, 1H), 7.96 (s,1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 4.77 (s, 2H), 4.20 (s, 1H), 4.06 (s, 1H), 3.76 – 3.70 (m, 2H), 3.64 (d, J = 12.1 Hz, 2H), 3.58 (m, 10H), 3.57 – 3.47 (m, 2H), 3.45 (s, 2H), 3.40 (s, 1H), 3.38 – 3.19(m, 6H), 2.41 (d, J = 12.4 Hz, 1H), 2.36 (dd, J = 13.3, 12.4 Hz, 2H), 2.33 (s,1H), 2.27 (d, J = 12.5 Hz, 2H), 1.92 (s, 3H), 1.88 (s, 2H), 1.71 – 1.61 (m,4H), 1.48 (d, J = 1.3 Hz, 2H), 1.25 (d, J = 4.9 Hz, 2H), 1.12 (d, J = 5.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.61, 176.50, 175.12, 171.95, 171.80,157.09, 148.90, 143.11, 141.88, 134.03, 123.05, 121.01, 114.95, 109.83,73.41, 72.61, 71.62, 70.88, 69.12, 69.05, 68.78, 66.22, 63.17, 56.02, 54.12,52.04, 44.57, 38.22, 36.05, 33.06, 32.49, 29.02, 26.95, 25.69, 25.42, 23.10, 9.90, 7.12. Example 12 Compound 12: 7-(( R )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20,23,26-hexaoxa-2,8-diazaeicosane-29-amino)azacycloheptane-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 12 was 19.53%.

[0057] The 1H NMR and 1C NMR spectra of compound 12 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.53 (s, 1H), 8.69 (s, 1H), 8.26 (s,1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 4.81 (s, 2H), 4.23 (s, 1H), 4.04 (s, 1H), 3.80 – 3.74 (m, 4H), 3.67 (d, J = 12.1 Hz, 2H), 3.62 (s, 2H), 3.61 (m, 16H), 3.59 (d, J = 12.3 Hz, 1H), 3.55 – 3.49 (m, 3H), 3.44 (s, 1H), 3.36 (d, J = 12.4 Hz, 1H), 3.34 – 3.28 (m, 3H), 3.26 (s, 1H), 3.23 (d, J = 12.3Hz, 1H), 2.40 (d, J = 12.5 Hz, 1H), 2.39 (dd, J = 13.3, 12.4 Hz, 2H), 2.30 (d, J =12.5 Hz, 2H), 1.95 (s, 3H), 1.89 (s, 2H), 1.75 – 1.65 (m, 4H), 1.51 (d, J = 1.3Hz, 2H), 1.28 (d, J = 4.9 Hz, 2H), 1.15 (d, J= 5.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.95, 176.34, 175.81, 173.99, 166.73,158.12, 148.91, 143.11, 141.88, 138.02, 122.41, 121.01, 113.65, 109.87,74.33, 73.15, 72.98, 72.80, 72.44, 71.66, 71.08, 70.25, 70.12, 69.95, 66.95,66.10, 62.44, 56.11, 54.03, 52.09, 44.88, 39.12, 36.02, 33.58, 32.77, 29.21, 27.04, 25.90, 23.12, 22.99, 9.95, 8.08. Example 13 Compound 13: ( S )-10-(1-(( S )-2-acetamido-5-(3-phosphonoguanidinyl)pentamido)cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H -[1,4]oxazinazino[2,3,4- ij Preparation of quinoline-6-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 13 was 15.87%.

[0058] The 1H NMR and 1C NMR spectra of compound 13 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.47 (s, 1H), 8.45 (s, 1H), 7.63 (d, J =7.3 Hz, 2H), 7.51 (s, 1H), 7.06 (s, 1H), 4.44 (s, 2H), 4.33 (s, 1H), 4.25 (d, J = 3.3 Hz, 2H), 3.97 – 3.91 (m, 2H), 3.32 (d, J = 12.5 Hz, 1H), 3.26 (d, J = 12.3Hz, 1H), 2.09 (d, J= 12.5 Hz, 1H), 1.92 (s, 3H), 1.89 (d, J = 4.9 Hz, 2H), 1.81(d, J = 4.9 Hz, 2H), 1.77 (s, 3H), 1.72 – 1.64 (m, 2H), 1.33 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.33, 176.41, 172.57, 166.72, 159.94,151.77, 149.52, 147.63, 132.81, 128.74, 123.12, 112.68, 109.71, 72.54, 67.92,59.77, 44.68, 31.84, 28.51, 25.34, 23.17, 20.82, 15.89, 13.74. Example 14 Compound 14: ( S )-10-(1-(3-((2-((S)-2-acetamido-5-(3-phosphonoguanidinyl)pentamido)ethyl)-(ethyl)peroxy)propamido)cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H -[1,4]oxazinazino[2,3,4- ij Preparation of quinoline-6-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 14 was 20.64%.

[0059] The 1H NMR and 1C NMR spectra of compound 14 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 16.99 (s, 1H), 10.99 (s, 1H), 10.23 (s,1H), 9.96 (s, 1H), 9.90 (s, 1H), 9.87 (s, 1H), 9.75 (s, 1H), 6.99 (s, 1H),6.98 (s, 1H), 6.87 (d, J= 6.9 Hz, 1H), 5.99 (s, 2H), 5.88 – 5.81 (m, 4H), 5.75– 5.69 (m, 4H), 5.64 – 5.53 (m, 5H), 5.08 (s, 1H), 4.98 (d, J = 12.5 Hz, 2H), 4.15 (d, J = 12.5 Hz, 1H), 4.09 (s, 3H), 3.97 (d, J = 4.9 Hz, 2H), 3.74 (d, J = 4.9Hz, 2H), 2.65 (s, 3H), 2.41 – 2.23 (m, 2H), 1.14 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.33, 176.57, 173.84, 171.90, 166.31,159.11, 151.09, 149.73, 146.85, 132.78, 128.15, 122.41, 111.68, 108.53,72.44, 71.62, 70.47, 70.14, 68.26, 65.83, 60.12, 44.68, 41.93, 39.52, 31.56,28.42, 25.37, 23.11, 20.87, 15.94, 13.77. Example 15 Compound 15: ( S )-10-(1-(( S )-6-acetamido-18-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,18λ 3 -tetraoxa-2,8-diazaeicosano-21-amino)cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4- ij Preparation of quinoline-6-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 15 was 19.31%.

[0060] The 1H NMR and 1C NMR spectra of compound 15 are as follows: 1 H NMR (400 MHz, DMSO- d6) δ 14.92 (s, 1H), 9.21 (s, 1H), 8.44 (s,1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.12 (s, 1H), 5.03 (s, 1H), 4.78 (s, 1H), 4.36 (d, J = 7.1 Hz, 1H), 3.98 (s, 2H), 3.82 – 3.69 (m, 16H), 3.55 – 3.39 (m, 5H), 2.93 (s, 1H), 2.65 (d, J = 12.7 Hz, 2H), 2.59 (d, J = 12.5Hz, 1H), 2.17 (s, 3H), 2.02 (d, J = 4.9 Hz, 2H), 1.88 (d, J = 5.2 Hz, 2H), 1.79(s, 3H), 1.72 – 1.58 (m, 2H), 1.41 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.11, 176.89, 175.46, 173.29, 166.33,159.18, 151.42, 149.37, 147.12, 132.79, 128.15, 122.54, 111.32, 108.73,73.01, 72.12, 71.28, 70.93, 70.55, 70.23, 69.81, 69.12, 68.74, 65.82, 61.01,44.87, 42.32, 39.45, 31.42, 28.11, 25.67, 24.83, 20.98, 15.62, 13.47. Example 16 Compound 16: ( S )-10-(1-(( S )-6-acetamido-24-ethyl-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20,23,24λ 3 -hexaoxa-2,8-diazaheptadecane-27-amino)cyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H -[1,4]oxazinazino[2,3,4- ijPreparation of quinoline-6-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 16 was 16.36%.

[0061] The proton NMR and carbon NMR spectra of compound 16 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.12 (s, 1H), 9.28 (s, 1H), 8.41 (s,1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.14 (s, 1H), 4.97 (s, 2H), 4.78 (s, 1H), 4.36 (d, J = 7.2 Hz, 1H), 3.91 (s, 1H), 3.78 (s, 4H), 3.73 – 3.56(m, 22H), 3.52 (s, 2H), 3.44 (d, J = 12.4 Hz, 1H), 3.39 – 3.29 (m, 1H), 3.27(d, J = 12.3 Hz, 2H), 2.73 (s, 1H), 2.17 (s, 3H), 2.05 (d, J = 5.0 Hz, 2H), 1.96(d, J = 4.8 Hz, 2H), 1.89 (s, 3H), 1.74 (d, J = 3.7 Hz, 2H), 1.43 (s, 2H) 13 C NMR (101 MHz, DMSO- d6 ) δ 178.21, 176.33, 175.12, 173.41, 171.29,156.14, 151.02, 149.62, 147.55, 132.88, 129.37, 124.56, 112.87, 109.76,73.88, 73.12, 72.95, 72.21, 71.84, 71.67, 71.21, 71.08, 70.96, 70.83, 70.26,70.03, 68.83, 65.42, 59.67, 44.32, 41.12, 38.55, 31.28, 28.14, 25.36, 23.81, 20.42, 15.98, 14.27. Example 17 Compound 17: 7-(( Z )-3-((( S Preparation of 2-acetamido-5-(3-phosphonoguanidinyl)pentamido)methyl)-4-(methoxyimino)pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthidine-3-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 17 was 22.44%.

[0062] The 1H NMR and 1C NMR spectra of compound 17 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.18 (s, 1H), 9.03 (s, 1H), 8.61 (s,1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 5.82 (s, 2H), 4.96 (s, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.28 (s, 3H), 4.07 (dd, J = 11.5, 9.6 Hz, 2H), 3.88 –3.75 (m, 2H), 3.49 – 3.36 (m, 2H), 3.33 – 3.24 (m, 2H), 2.97 (s, 1H), 2.61(d, J = 12.5 Hz, 1H), 2.43 (d, J = 12.5 Hz, 1H), 2.18 (s, 3H), 1.84 – 1.72 (m,2H), 1.48 (s, 2H), 1.33 (d, J = 4.9 Hz, 2H), 1.19 (d, J = 5.0 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 176.81, 175.29, 174.21, 169.92, 165.87,161.73, 155.32, 154.89, 152.14, 151.67, 121.88, 119.77, 112.56, 64.88, 60.82,59.93, 59.01, 49.71, 44.36, 40.28, 35.77, 31.89, 28.92, 25.31, 9.78, 7.69. Example 18 Compound 18: 7-(( Z )-3-(( S )-12-acetamido-6-ethyl-17-imino-3,11-dioxo-17-(phosphonoamino)-6λ 3 Preparation of 7-dioxa-2,10,16-triazaheptadecyl)-4-(methoxyimino)pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthidine-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 18 was 20.81%.

[0063] The 1H NMR and 1C NMR spectra of compound 18 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.32 (s, 1H), 9.04 (s, 1H), 8.67 (s,1H), 8.41 (s, 2H), 7.82 (s, 1H), 7.33 (s, 1H), 5.91 (s, 2H), 5.03 (s, 1H), 4.39 (d, J = 7.1 Hz, 1H), 4.27 (d, J = 9.6 Hz, 3H), 4.11 (dd, J = 11.6, 9.5 Hz,2H), 3.92 – 3.78 (m, 4H), 3.71 (d, J = 1.6 Hz, 2H), 3.64 (d, J = 12.2 Hz, 1H),3.63 – 3.53 (m, 3H), 3.48 (d, J = 12.5 Hz, 1H), 3.44 – 3.35 (m, 2H), 3.33 (d, J=7.7 Hz, 1H), 3.29 (d, J = 12.3 Hz, 1H), 3.23 (d, J = 12.5 Hz, 1H), 2.98 (s, 1H), 2.66 (d, J = 1.2 Hz, 1H), 2.41 (d, J = 12.4 Hz, 2H), 2.36 (d, J = 12.5 Hz, 1H), 2.18 (s, 3H), 1.82 (d, J = 3.8 Hz, 2H), 1.57 (s, 2H), 1.34 (d, J = 4.9 Hz, 2H), 1.21 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 179.18, 175.91, 173.86, 170.88, 168.91,164.92, 160.45, 155.88, 154.11, 151.37, 148.19, 122.87, 119.76, 112.87,71.51, 70.88, 69.92, 63.48, 59.97, 58.91, 57.76, 49.37, 44.28, 41.23, 38.17,37.12, 35.17, 31.26, 28.17, 25.43, 13.76, 9.14, 7.26. Example 19 Compound 19: 7-((Z)-3-((S)-18-acetamido-6-ethyl-23-imino-3,17-dioxo-23-(phosphonoamino)-6λ 3 Preparation of 7,10,13-tetraoxa-2,16,22-triazatridecyl)-4-(methoxyimino)pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthidine-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 19 was 17.26%.

[0064] The 1H NMR and 1C NMR spectra of compound 19 are as follows: 1 H NMR (400 MHz, DMSO- d6) δ 15.27 (s, 1H), 9.04 (s, 1H), 8.73 (s,1H), 8.46 (s, 2H), 7.89 (s, 1H), 7.71 (s, 1H), 5.12 (s, 2H), 4.44 (d, J = 7.1Hz, 1H), 4.31 (d, J = 9.6 Hz, 1H), 4.09 (dd, J = 11.6, 9.7 Hz, 3H), 3.91 – 3.79(m, 2H), 3.74 (d, J = 3.1 Hz, 10H), 3.69 – 3.57 (m, 2H), 3.52 (s, 2H), 3.48 (d, J = 12.5 Hz, 2H), 3.44 – 3.36 (m, 2H), 3.34 (d, J = 7.8 Hz, 2H), 3.29 (d, J = 12.4Hz, 2H), 3.23 (d, J = 12.6 Hz, 2H), 2.97 (s, 1H), 2.59 (d, J = 1.1 Hz, 1H), 2.41(d, J = 12.4 Hz, 2H), 2.36 (d, J = 12.6 Hz, 1H), 2.18 (s, 3H), 1.83 (d, J = 3.8 Hz,2H), 1.62 (s, 2H), 1.33 (d, J = 4.9 Hz, 2H), 1.21 (d, J = 5.0 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 179.21, 176.41, 173.12, 172.98, 171.63,168.42, 164.82, 160.92, 154.81, 152.08, 151.37, 150.88, 119.76, 112.87,73.92, 73.61, 73.28, 72.87, 71.72, 71.11, 70.88, 69.08, 63.42, 60.12, 59.98,58.87, 49.32, 44.27, 41.12, 38.28, 37.11, 35.28, 31.17, 28.43, 25.62, 9.08, 7.12. Example 20 Compound 20: 7-(( Z )-3-(( S )-24-acetamido-6-ethyl-29-imino-3,23-dioxo-29-(phosphonoamino)-6λ 3 Preparation of 7,10,13,16,19-hexaoxa-2,22,28-triazanonyl)-4-(methoxyimino)pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthidine-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 20 was 10.29%.

[0065] The proton NMR and carbon NMR spectra of compound 20 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.55 (s, 1H), 8.93 (s, 1H), 8.46 (s,1H), 8.21 (s, 2H), 7.75 (s, 1H), 7.50 (s, 1H), 5.18 (s, 2H), 4.85 (s, 1H), 4.28 (d, J = 7.2 Hz, 1H), 4.10 (d, J = 9.7 Hz, 4H), 3.90 (dd, J= 11.5, 9.6 Hz, 4H), 3.77 – 3.63 (m, 18H), 3.61 (s, 2H), 3.59 (s, 8H), 3.57 – 3.51 (m, 8H), 3.44 – 3.30 (m, 1H), 3.29 – 3.18 (m, 2H), 2.42 – 2.35 (m, 1H), 1.91 (s, 3H), 1.70 (d, J = 3.9 Hz, 2H), 1.42 (s, 2H), 1.14 (d, J = 4.8 Hz, 2H), 1.03 (d, J = 4.8Hz, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 176.32, 174.21, 173.87, 172.88, 166.93,164.72, 161.12, 159.92, 155.87, 153.88, 146.83, 124.33, 116.78, 112.98,73.98, 73.87, 73.22, 72.87, 72.54, 72.18, 71.88, 71.34, 70.96, 70.42, 70.18,68.94, 63.87, 60.82, 59.98, 58.47, 50.18, 44.23, 41.12, 38.28, 37.12, 35.21, 31.18, 28.14, 25.87, 9.02, 7.14. Example 21 Compound 21: ( S )-8-(4-(( N 2 -acetyl- N w -phosphono-L-arginyl-L-alanyl)oxy)piperidin-1-yl)-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1 H 5 H -pyrido[3,2,1- ij Preparation of quinoline-2-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 21 was 9.34%.

[0066] The proton NMR and carbon NMR spectra of compound 21 are as follows: 1H NMR (400 MHz, DMSO- d6 ) δ 14.63 (s, 1H), 8.72 (d, J = 14.7 Hz, 1H),8.48 (s, 2H), 7.79 (s, 1H), 7.65 (s, 1H), 5.53 (s, 1H), 5.05 (s, 2H), 4.92(s, 1H), 4.41 (s, 1H), 4.23 (s, 2H), 4.08 (s, 2H), 3.98 (s, 2H), 3.31 (s,1H), 3.28 – 3.24 (m, 2H), 2.91 (s, 1H), 2.67 (s, 1H), 2.23 (s, 2H), 2.11 –2.00 (m, 3H), 1.97 (s, 3H), 1.93 (d, J = 12.6 Hz, 1H), 1.85 (s, 2H), 1.76 –1.66 (m, 2H), 1.47 (s, 3H), 1.30 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 178.72, 175.11, 172.18, 170.92, 166.88,160.93, 147.32, 144.78, 141.87, 139.91, 118.89, 114.76, 111.92, 75.82, 64.91,54.68, 53.77, 51.24, 49.18, 44.21, 34.07, 32.14, 31.28, 29.92, 26.77, 25.44,22.38, 19.94, 17.42. Example 22 Compound 22: ( S )-8-(4-(((6 S 17 S )-6-acetamido-12-ethyl-1-imino-17-methyl-7,15-dioxo-1-(phosphonoamino)-11,12λ 3 -dioxa-2,8,16-triazaoctadecane-18-acyl)oxy)piperidin-1-yl)-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1 H 5 H -pyrido[3,2,1- ij Preparation of quinoline-2-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 22 was 10.98%.

[0067] The 1H NMR and 1C NMR spectra of compound 22 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.02 (s, 1H), 8.63 (s, 1H), 7.84 (s,1H), 7.71 (s, 1H), 7.57 (s, 2H), 7.36 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 5.85 (s, 1H), 4.93 (s, 1H), 4.36 (s, 1H), 4.27 (s, 1H), 4.12 (s, 1H), 3.99(s, 2H), 3.78 (d, J = 12.6 Hz, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.65 – 3.54 (m,7H), 3.42 (d, J = 12.5 Hz, 1H), 3.38 – 3.25 (m, 6H), 2.69 (s, 1H), 2.59 (d, J =12.6 Hz, 1H), 2.41 – 2.36 (m, 2H), 2.34 (d, J = 12.5 Hz, 1H), 2.26 (s, 1H), 2.09 (s, 2H), 1.99 (s, 3H), 1.86 (s, 2H), 1.78 (s, 1H), 1.74 – 1.66 (m, 2H), 1.45 (s, 3H), 1.31 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 179.21, 176.87, 175.82, 174.62, 173.97,171.12, 164.28, 155.92, 147.98, 144.62, 141.28, 139.42, 122.94, 118.82,114.77, 111.28, 75.38, 73.83, 73.17, 72.41, 68.97, 64.87, 56.17, 53.42,50.88, 49.97, 44.87, 41.92, 38.83, 34.88, 32.17, 31.44, 29.82, 28.14, 25.87, 22.41, 19.76. Example 23 Compound 23: ( S )-8-(4-(((6 S ,twenty three S )-6-acetamido-18-ethyl-1-imino-23-methyl-7,21-dioxo-1-(phosphonoamino)-11,14,17,18λ 3 -tetraoxa-2,8,22-triazatetracosane-24-acyl)oxy)piperidin-1-yl)-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1 H 5 H -pyrido[3,2,1- ij Preparation of quinoline-2-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 23 was 14.36%.

[0068] The 1H NMR and 1C NMR spectra of compound 23 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.05 (s, 1H), 8.63 (s, 1H), 7.83 (s,1H), 7.72 (s, 1H), 5.86 (s, 1H), 4.91 (s, 1H), 4.37 (s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 3.99 (s, 2H), 3.77 (d, J = 12.6 Hz, 1H), 3.69 (d, J= 12.4 Hz, 1H),3.65 – 3.52 (m, 16H), 3.46 (s, 2H), 3.42 – 3.24 (m, 7H), 2.91 (s, 1H), 2.68(s, 1H), 2.61 (d, J = 12.6 Hz, 1H), 2.40 – 2.37 (m, 3H), 2.34 (d, J = 12.5 Hz,1H), 2.27 (s, 1H), 2.09 (s, 2H), 1.99 (s, 3H), 1.86 (s, 2H), 1.75 – 1.65 (m,3H), 1.47 (s, 3H), 1.32 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 179.01, 176.21, 175.42, 174.66, 174.01,171.28, 164.32, 160.87, 155.78, 147.32, 144.78, 141.28, 122.88, 118.93,114.87, 111.92, 75.12, 74.18, 73.87, 73.11, 72.96, 72.83, 71.14, 68.97,64.87, 56.12, 53.88, 51.08, 50.12, 44.87, 41.87, 38.12, 34.88, 32.17, 31.44, 29.88, 28.14, 25.87, 22.41, 19.88, 17.92. Example 24 Compound 24: ( S )-8-(4-(((6 S 29 S )-6-acetamido-24-ethyl-1-imino-29-methyl-7,27-dioxo-1-(phosphonoamino)-11,14,17,20,23,24λ 3 -hexoxa-2,8,28-triazatriacontane-30-acyl)oxy)piperidin-1-yl)-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1 H 5 H -pyrido[3,2,1- ij Preparation of quinoline-2-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 24 was 12.19%.

[0069] The proton NMR and carbon NMR spectra of compound 24 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 15.01 (s, 1H), 8.63 (s, 1H), 7.85 (s,1H), 7.71 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 6.57 (s, 1H),5.85 (s, 1H), 4.91 (s, 1H), 4.36 (s, 1H), 4.28 (s, 1H), 4.10 (s, 1H), 3.99(s, 2H), 3.78 (d, J = 12.6 Hz, 1H), 3.70 (d, J = 12.5 Hz, 1H), 3.64 – 3.52 (m,16H), 3.45 (d, J = 12.5 Hz, 1H), 3.38 – 3.26 (m, 5H), 2.91 (s, 1H), 2.68 (s,1H), 2.59 (d, J = 12.6 Hz, 1H), 2.45 – 2.36 (m, 2H), 2.35 (d, J = 12.5 Hz, 1H),2.27 (s, 1H), 1.99 (s, 3H), 1.87 (s, 2H), 1.78 (s, 1H), 1.74 – 1.66 (m, 2H),1.47 (s, 3H), 1.32 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 179.08, 176.87, 175.88, 174.62, 174.03,171.88, 164.72, 155.92, 147.88, 144.62, 141.28, 139.62, 122.93, 118.88,114.77, 111.92, 75.18, 74.22, 73.92, 73.08, 72.97, 72.88, 71.12, 68.88,64.92, 56.12, 53.88, 51.28, 49.88, 44.87, 41.88, 38.19, 34.88, 32.17, 31.44, 29.87, 28.18, 25.87, 22.41, 19.88. Example 25 Compound 25: 7-((3) S 5 S )-3-(( S Preparation of 2-acetamido-5-(3-phosphonoguanidinyl)pentamido)-5-methylpiperidin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 1, only the corresponding raw materials need to be changed. The yield of compound 25 was 11.78%.

[0070] The 1H NMR and 1C NMR spectra of compound 25 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.85 (s, 1H), 8.76 (s, 1H), 7.57 (d, J =7.5 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.07 – 6.92 (m, 3H), 6.77 (s, 1H), 5.96 (s, 1H), 4.64 – 4.02 (m, 4H), 3.97 (s, 3H), 3.79 (s, 1H), 3.43 (s, 1H), 3.23 – 3.15 (m, 2H), 3.11 (s, 1H), 3.07 (s, 1H), 2.82 (d, J = 12.5 Hz, 1H), 2.16 (d, J= 12.5 Hz, 1H), 1.94 (s, 1H), 1.86 (s, 3H), 1.64 (s, 1H), 1.27 (s,1H), 1.24 (d, J = 5.1 Hz, 3H), 1.13 (d, J = 4.9 Hz, 3H), 0.79 (s, 3H). 13 C NMR (101 MHz, DMSO- d6 ) δ 176.27, 174.81, 173.23, 169.76, 158.85,154.66, 147.57, 145.29, 140.35, 133.91, 123.62, 122.07, 121.78, 113.89,62.17, 60.80, 59.06, 54.77, 49.98, 43.59, 42.62, 38.20, 30.54, 29.46, 26.31,23.83, 18.71, 11.60. Example 26 Compound 26: 7-((3) S 5 S )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14-dioxa-2,8-diazaheptadecane-17-amino)-5-methylpiperidin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 26 was 16.27%.

[0071] The 1H NMR and 1C NMR spectra of compound 26 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.59 (s, 1H), 8.63 (s, 1H), 8.37 (s,1H), 7.75 (d, J= 7.5 Hz, 1H), 7.35 (s, 2H), 7.13 (s, 1H), 7.08 (s, 1H), 7.00 –6.87 (m, 3H), 6.29 (s, 1H), 5.76 (s, 1H), 4.89 (s, 2H), 4.31 (s, 1H), 4.22(s, 1H), 3.86 (s, 2H), 3.69 (s, 1H), 3.67 – 3.57 (m, 2H), 3.53 (d, J = 12.4 Hz,1H), 3.44 – 3.40 (m, 7H), 3.35 (d, J = 12.4 Hz, 1H), 3.31 – 3.22 (m, 2H), 3.20(d, J = 12.3 Hz, 1H), 3.14 (s, 1H), 3.11 (s, 1H), 2.38 (d, J = 12.5 Hz, 1H), 2.29(dd, J = 13.3, 12.4 Hz, 2H), 2.17 (d, J = 12.5 Hz, 1H), 1.76 (d, J = 17.9 Hz, 3H),1.68 – 1.62 (m, 3H), 1.48 (s, 1H), 1.27 (d, J = 5.1 Hz, 2H), 1.04 (d, J = 4.9 Hz,2H), 0.91 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 176.75, 174.58, 174.37, 173.79, 169.70,164.71, 158.50, 147.91, 145.20, 139.48, 133.76, 123.69, 122.23, 121.71,113.46, 71.72, 71.48, 71.07, 66.31, 62.93, 60.82, 59.27, 54.35, 49.78, 42.96,42.52, 41.06, 38.89, 36.61, 30.10, 29.93, 26.33, 23.83, 18.71, 11.60. Example 27 Compound 27: 7-((3) S 5 S )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20-tetraoxa-2,8-diazatoritriane-23-amino)-5-methylpiperidin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 27 was 18.46%.

[0072] The 1H NMR and 1C NMR spectra of compound 27 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.85 (s, 1H), 8.96 (s, 1H), 8.41 (s,1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.25 (s, 2H), 7.16(s, 1H), 7.07 (s, 1H), 7.05 – 6.97 (m, 3H), 6.22 (s, 1H), 5.66 (s, 1H), 4.31(s, 1H), 4.24 (s, 1H), 3.75 (s, 2H), 3.71 (s, 1H), 3.63 – 3.60 (m, 2H), 3.55(d, J = 12.5 Hz, 1H), 3.51 (d, J = 3.0 Hz, 10H), 3.50 (d, J = 12.3 Hz, 1H), 3.43 –3.39 (m, 4H), 3.37 (d, J = 12.4 Hz, 1H), 3.29 – 3.24 (m, 2H), 3.20 (d, J = 12.3Hz, 1H), 3.13 (s, 1H), 3.07 (s, 1H), 2.64 (d, J = 12.5 Hz, 1H), 2.33 (dd, J =13.3, 12.4 Hz, 2H), 2.02 (d, J = 12.5 Hz, 1H), 1.85 (d, J= 17.9 Hz, 3H), 1.72 –1.53 (m, 3H), 1.40 (s, 1H), 1.36 (d, J = 5.1 Hz, 2H), 1.05 (d, J = 4.9 Hz, 2H), 0.76 (s, 2H). 13 C NMR (101 MHz, DMSO- d6 ) δ 176.24, 175.52, 174.47, 174.35, 173.44,169.76, 164.28, 158.53, 150.40, 147.28, 145.13, 139.53, 133.26, 123.14,122.05, 121.64, 113.37, 74.85, 74.40, 73.33, 72.37, 71.15, 66.69, 62.79,60.15, 59.37, 54.95, 49.98, 42.65, 42.57, 41.00, 38.85, 36.77, 30.25, 29.96, 26.71, 23.11, 18.34, 11.47. Example 28 Compound 28: 7-((3) S 5 S )-3-(( S Preparation of 6-acetamido-1-imino-7-oxo-1-(phosphonoamino)-11,14,17,20,23,26-hexaoxa-2,8-diazaeicosane-29-amino)-5-methylpiperidin-1-yl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid The preparation method is the same as in Example 2, only the corresponding raw materials need to be changed. The yield of compound 28 was 11.53%.

[0073] The 1H NMR and 1C NMR spectra of compound 28 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) δ 14.82 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.62 (s, 2H), 7.43 (s, 1H), 7.38(s, 1H), 7.09 – 6.87 (m, 3H), 6.27 (s, 1H), 5.56 (s, 1H), 4.75 (s, 1H), 4.38(s, 1H), 4.24 (s, 1H), 3.91 (s, 2H), 3.72 (s, 1H), 3.69 – 3.57 (m, 2H), 3.51(d, J = 12.4 Hz, 1H), 3.49 (s, 2H), 3.42 – 3.37 (m, 17H), 3.33 – 3.28 (m, 4H),3.26 (d, J = 12.4 Hz, 1H), 3.24 – 3.21 (m, 2H), 3.20 (d, J = 12.3 Hz, 1H), 3.18(s, 1H), 3.11 (s, 1H), 2.59 (d, J = 12.5 Hz, 1H), 2.42 (dd, J = 13.3, 12.4 Hz,2H), 2.36 (d, J = 12.5 Hz, 1H), 1.80 (d, J = 17.9 Hz, 3H), 1.77 – 1.65 (m, 3H),1.60 (s, 1H), 1.32 (d, J = 5.1 Hz, 2H), 1.04 (d, J = 4.9 Hz, 2H), 0.87 (s, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 176.59, 174.86, 174.73, 173.25, 170.67,169.71, 164.54, 147.72, 145.16, 139.74, 133.20, 130.58, 123.23, 122.09,121.48, 117.37, 113.85, 109.38, 104.24, 71.82, 71.70, 71.27, 71.19, 71.03,66.57, 62.77, 60.78, 59.22, 57.78, 54.61, 49.51, 48.35, 42.66, 42.47, 41.05, 38.81, 36.75, 30.34, 29.99, 26.27, 23.25, 18.83, 11.46. 2. In vitro antibacterial activity assay According to the clinical and laboratory standards institute (CLSI) methodology, using ciprofloxacin and vancomycin as positive controls, the minimum inhibitory concentration (MIC) of quinolone bacterial degrading agents was tested using the microbroth dilution method.

[0074] The experimental strains included Gram-positive bacteria: *Staphylococcus aureus* ATCC 25923, *Bacillus subtilis* ATCC 6633, *Staphylococcus epidermidis* ATCC 12228, methicillin-resistant *Staphylococcus aureus* ATCC 43300, multidrug-resistant *Staphylococcus aureus* 171, and vancomycin-resistant *Enterococcus faecalis* 80; and Gram-negative bacteria: *Acinetobacter baumannii* ATCC 19606, *Escherichia coli* ATCC 25922, *Pseudomonas aeruginosa* ATCC 27853, *Salmonella enterica* ATCC 14028, multidrug-resistant *Pseudomonas aeruginosa* 264, carbapenem-resistant *Escherichia coli* 361, and multidrug-resistant *Acinetobacter baumannii* 183. The above-mentioned standard control strains were purchased from ATCC, while the remaining strains were clinically isolated drug-resistant strains provided by the Institute of Antibiotics, Huashan Hospital, Fudan University, and were used after identification using standard methods.

[0075] The specific steps are as follows: (1) MHB medium: Prepare 1 L according to the label prescription, dispense into Erlenmeyer flasks, autoclave at 121℃ for 15 min, and set aside (MHB medium was purchased from Qingdao High-tech Industrial Park Haibo Biotechnology Co., Ltd.). (2) Sample solution preparation: Weigh the quinolone bacterial degradation agent to be tested, dissolve it in distilled water, and prepare a sample solution with a concentration of 5.12 mg / mL; weigh the positive control, dissolve it in distilled water, and prepare a sample solution with a concentration of 5.12 mg / mL; (3) Cultivation of experimental strains to the logarithmic growth phase: Under aseptic conditions, the experimental strains were inoculated into MHB medium and cultured overnight at 37°C with shaking (200 rpm). The next day, the overnight bacterial culture was transferred to fresh MHB medium at a volume ratio of 1:50 and cultured at 37°C to the logarithmic growth phase for later use; (4) Preparation of bacterial suspension: Under aseptic conditions, the experimental strain cultured to the logarithmic growth phase was corrected to a turbidity standard of 0.5 McFarland units using MHB medium, and then diluted 100 times to obtain a concentration of 1×10⁻⁶. 6 CFU / mL bacterial suspension, for later use; (5) MIC determination by micro-dilution method: Take a sterile 96-well plate, add 10 μL of the test compound, and perform serial dilution using the 2-fold dilution method. Simultaneously, set up a positive control with the drug and a growth control group without the drug. Next, add 190 μL of diluted bacterial solution to each well, so that the final bacterial concentration in each well is 5 × 10⁻⁶. 5 CFU / mL, incubated in a 37℃ constant temperature and humidity incubator for 20 h; (6) MIC endpoint interpretation: Add 20 μL of 0.01% azadirachtin solution to each well of the 96-well plate after incubation, and continue incubation in a constant temperature and humidity chamber at 37℃ for 1-2 h. When the growth control group without drug changes from blue to pink, the results can be observed and the MIC value of the compound can be determined.

[0076] Table 1. Minimum inhibitory concentration (μg / mL) of the test drug against standard control strains

[0077] Table 2. Minimum inhibitory concentrations (μg / mL) of the tested drugs against drug-resistant strains

[0078] As shown in Tables 1 and 2, the quinolone bacterial degrading agents compounds 1-28 of this invention exhibit varying degrees of antibacterial activity against both Gram-positive and Gram-negative bacteria tested, with MICs ranging from 0.06 to 128 μg / mL. The modification of the degrading agents with different quinolone heads significantly affected the antibacterial activity. Among them, compounds 5-8 containing ciprofloxacin heads showed superior overall activity, with compound 6 being particularly outstanding. The minimum inhibitory concentrations (MICs) of compound 6 against ATCC 25923, ATCC 43300, and multidrug-resistant Acinetobacter baumannii 183 are as follows: Figure 1 , Figure 2 , Figure 3 As shown, compound 6 had MICs of 0.25, 1, and 2 μg / mL against resistant Gram-positive bacteria MRSA ATCC43300, MDRSA-171, and VREfs-80, respectively, all superior to ciprofloxacin (4, 4, and 8 μg / mL, respectively) and vancomycin (4, 8, and 16 μg / mL, respectively). Among resistant Gram-negative bacteria, compound 6 had MICs of 0.5 and 1 μg / mL against MDRPA-264 and CR-EC-361, respectively, further lower than ciprofloxacin (both 4 μg / mL), while maintaining an effective inhibitory level of 2 μg / mL against MDRAB-183. Notably, compound 6 has a MIC of 2 μg / mL against non-drug-resistant Pseudomonas aeruginosa ATCC 27853, slightly higher than ciprofloxacin, but its activity against multidrug-resistant Pseudomonas aeruginosa MDRPA-264 is significantly improved (0.5 μg / mL vs. 4 μg / mL). This difference indicates that the degradation mechanism antibiotics of this invention can effectively combat bacterial resistance. In summary, the compounds of this invention show more significant advantages against drug-resistant Gram-positive bacteria, while also maintaining effective activity against a variety of drug-resistant Gram-negative bacteria, supporting their status as a candidate compound for combating drug-resistant bacteria.

[0079] Compounds 17-20 containing the gemifloxacin trigger also exhibited broad-spectrum antibacterial activity. Compound 18, in particular, showed MICs of 0.5, 2, and 4 μg / mL against MRSA ATCC 43300, MDRSA-171, and MDRAB-183, respectively, and maintained an activity of 1 μg / mL against Acinetobacter baumannii ATCC 19606, indicating that this gemifloxacin trigger possesses good antibacterial activity against drug-resistant Gram-positive bacteria and Acinetobacter spp. Furthermore, the PEG linker length and activity showed a relatively consistent trend. Compounds with PEG linkers exhibited enhanced antibacterial activity compared to those without, indicating that the introduction of PEG linkers can improve the antibacterial activity of compounds. However, the antibacterial activity decreased with increasing PEG linker length; that is, shorter PEG linkers generally showed better activity. n=2 exhibited the best or near-optimal MIC spectrum in most trigger series, while extending to n=4 or n=6 was often accompanied by a decrease in activity. This may be related to the increased molecular flexibility and polarity caused by the elongation of PEG Linker, which reduces effective intracellular exposure or weakens the conformational matching of the quinolone moiety with DNA gyrase, ultimately resulting in decreased antibacterial activity.

[0080] 3. Assessment of GyrA target protein degradation capacity To investigate the degradation ability of the test compound on the target protein DNA gyrase A subunit (GyrA) in the target strain, the expression changes of GyrA protein before and after administration of methicillin-resistant Staphylococcus aureus ATCC 43300 were detected by Western blotting (WB).

[0081] The specific steps are as follows: (1) Extraction and quantification of bacterial protein: The experimental strains in the logarithmic growth phase were exposed to MHB medium containing the test compounds (10, 30, 100 μg / mL) and incubated at 37℃ for 4 h; then the bacterial pellet was collected by centrifugation at 4℃ and 6000 rpm for 10 min and washed twice with pre-cooled PBS buffer; an appropriate amount of lysis buffer [50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1% Triton X-100] was added, and a protease inhibitor mixture (Protease Inhibitor Cocktail), 1 mM PMSF and lysostaphin (final concentration 100 μg / mL) were added in advance. After incubation at 37℃ for 30 min, the bacterial solution was observed to gradually become clear from turbid. Then MgCl2 and BeyoZonase nuclease were added to reduce the viscosity of the lysis buffer; after centrifugation at 4℃ and 6000 rpm for 15 min, the supernatant was collected as the total protein of the whole cells. The protein concentration in the supernatant was determined using the BCA protein quantification kit. Based on the quantification results, 5×SDS loading buffer was added and the volume was made up with lysis buffer to ensure that the total protein concentration of each group was consistent. The samples were then placed in a 95℃ metal bath for 10 min to denature and obtain denatured protein samples for later use.

[0082] (2) SDS-PAGE electrophoresis: Prepare a 10% SDS-PAGE gel, add 25 μL of denatured protein sample to each well, and set up a normal bacterial growth control group, a control drug treatment group treated with the DNA gyrase inhibitor ciprofloxacin (100 μg / mL), and a pre-stained protein marker as a molecular weight reference. Perform stacking gel electrophoresis at 80 V. After the sample enters the separating gel, adjust the voltage to 120 V until the bromophenol blue indicator reaches the bottom of the gel.

[0083] (3) Transfer and blocking: The protein on the gel was transferred to a pre-activated PVDF membrane using the wet transfer method (4℃, 300 mA constant current, transfer for 90 min); after the transfer, the membrane was immersed in TBST blocking solution containing 5% skim milk powder and blocked by shaking at room temperature for 2 h to eliminate non-specific binding.

[0084] (4) Antibody incubation: The membrane was placed in the primary antibody dilution buffer [Anti-GyrA Antibodies (Inspiralis), 1:1000 dilution] and incubated overnight at 4°C with shaking. The next day, the membrane was removed and washed three times with TBST buffer at room temperature with shaking for 10 min each time to remove free primary antibody. Then, HRP-labeled goat anti-mouse IgG secondary antibody (1:5000 dilution) was added and incubated at room temperature in the dark with shaking for 2 h. The washing steps were repeated to remove free secondary antibody. GAPDH was used as an internal control for the above incubation steps.

[0085] (5) Development and Data Analysis: ECL chemiluminescent substrate solution A and solution B were mixed in a 1:1 ratio and uniformly coated onto a PVDF membrane. Development and exposure were performed using a chemiluminescence imaging system. The grayscale values ​​of the protein bands were quantitatively analyzed using ImageJ image analysis software. The grayscale ratio of the target protein to the internal reference protein was used as the relative expression level of the target protein to evaluate the degradation ability of the test compound on GyrA protein.

[0086] Western blot results ( Figure 4 The results showed that in MRSA ATCC 43300, treatment with the traditional DNA gyrase inhibitor ciprofloxacin (100 μg / mL) did not significantly differ from the control group in GyrA protein abundance (P > 0.05), indicating that it mainly works by inhibiting enzyme activity rather than reducing target protein levels. In contrast, treatment with compound 6 significantly reduced GyrA protein levels, showing a clear concentration-dependent trend. Compared with the control group, compound 6 induced GyrA protein downregulation at 10 μg / mL, further reduced it at 30 μg / mL, and reached its lowest relative expression at 100 μg / mL, with statistically significant differences (P < 0.0001). These results indicate that compound 6 not only targets DNA gyrase but also triggers a decrease in target protein abundance in drug-resistant strains, demonstrating an "event-driven" degradation effect. The downregulation of the target protein is consistent with its low MIC activity against drug-resistant strains such as MRSA, supporting the antibacterial mechanism of compound 6, which is mainly based on "target degradation" rather than simple "target inhibition," and providing support for the effectiveness of the degradation agent strategy of this invention.

Claims

1. A quinolone bacterio-degrader, characterized by, It is a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, or a solvent compound, enantiomer, diastereomer or mixture thereof in any proportion of the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof; The structural formula of the compound of formula I or formula II is: Where n = 1~6, the quinolone compounds are one of the following compounds: ； X in Formula I or Formula II is -NH- or -N- obtained by removing one H from the piperazine ring or -NH2 in the quinolone compound .

2. The quinolone bacterial degradation agent according to claim 1, characterized by, n=2~4。 3. The quinolone bacterial degradation agent according to claim 2, characterized by n=2。 4. The quinolone bacterial degradation agent according to claim 1, characterized by, The quinolone compound is ciprofloxacin.

5. A quinolone-based bacterial degrading agent according to claim 1, characterized in that, Selected from the following compounds: 。 6. A method for preparing a quinolone bacterial degrading agent according to any one of claims 1 to 5, characterized in that, The following steps are included: (1) The carboxyl group of N-benzyloxycarbonyl-L-arginine was protected to obtain compound I; the guanidinyl group of compound I was phosphorylated with bis(trichloroethyl)phosphoryl chloride to obtain compound II; Compound II was protected by Pd / C catalysis and hydrogenolysis under acidic conditions to yield compound III; the α-amino group on compound III was protected by Fmoc to yield compound IV; Among them, compound I is Compound II is Compound III is Compound IV is ; (2) Using quinolone compounds as raw materials, an amide condensation reaction is carried out with PEG Linker to obtain intermediate 1. The terminal tert-butyloxycarbonyl group of intermediate 1 is removed to obtain intermediate 2. The terminal amino group of intermediate 2 undergoes an amide condensation reaction with compound IV, and then the Fmoc group is removed. The α-amino group on the arginine in the obtained compound is reacted with an acid anhydride to generate an amide bond. Then, under alkaline conditions and a hydrogen atmosphere, deprotection is carried out by Pd / C catalytic hydrogenolysis to obtain the quinolone bacterial degrading agent. Among them, PEG Linker is ; Alternatively, the terminal amino group of the quinolone compound undergoes an amide condensation reaction with compound IV, followed by the removal of the Fmoc group. Then, the α-amino group on the arginine in the resulting compound is reacted with an acid anhydride to generate an amide bond. Subsequently, under alkaline conditions and a hydrogen atmosphere, deprotection is carried out by Pd / C catalytic hydrogenolysis to obtain the quinolone bacterial degrading agent.

7. A method for preparing a quinolone bacterial degrading agent according to claim 6, characterized in that, In step (1), the molar ratio of compound I to bis(trichloroethyl)phosphoryl chloride is 1:(1~2); in step (2), the molar ratio of quinolone compound to PEGLinker is 1:(1~2), and the molar ratio of intermediate 2 or quinolone compound to compound IV is 1:(1~2).

8. The use of the quinolone bacterial degrading agent according to any one of claims 1 to 5 in the preparation of antibacterial drugs.

9. The application according to claim 8, characterized in that, The bacteria are Gram-positive or Gram-negative bacteria, or drug-resistant strains of Gram-positive or Gram-negative bacteria.

10. The application according to claim 9, characterized in that, The drug-resistant strains of the Gram-positive bacteria are ATCC43300, MDRSA-171 or VREfs-80, and the drug-resistant strains of the Gram-negative bacteria are MDRPA-264, CR-EC-361 or MDRAB-183.

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