Quinolone aminothiadiazoles, processes for their preparation and medical use

Abstract

The application relates to quinolone aminothiadiazole compounds, a preparation method and medical applications thereof, and belongs to the technical field of chemical synthesis. The quinolone aminothiadiazole compounds are shown in a general formula I. The compounds have good inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and / or antifungal drugs, have no obvious drug resistance, and can provide more efficient and safe candidate drugs for clinical anti-infection treatment.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to quinolone aminothiadiazole compounds, their preparation methods, and pharmaceutical applications. Background Technology

[0002] Thiadiazoles are an important class of five-membered aromatic heterocycles. Due to their multi-heteroatomic aromatic structure and π-electron richness, they can interact with various non-covalent bonds with biomolecules such as DNA, enzymes, and receptors, thus exhibiting unique biological activities. They are widely used in the construction of various drug molecules, especially in the development of antimicrobial drugs. Among them, 2-amino-1,3,4-thiadiazole (diclofenac) was developed and marketed in the 1970s for the control of plant diseases caused by Xanthomonas. In addition, 2-amino-1,3,4-thiadiazole, as a pharmaceutical intermediate, is widely used in drug development in other pharmaceutical fields. For example, the main skeleton of the clinically used diuretic acetazolamide is 2-amino-1,3,4-thiadiazole, and 2-amino-1,3,4-thiadiazole derivatives are also serine protease inhibitors used clinically to treat mental illnesses. Therefore, aminothiadiazoles have extremely high development value in the pharmaceutical field.

[0003] Quinolones are a class of synthetic broad-spectrum antibacterial drugs that have made significant contributions to protecting human health. Since the first generation of quinolones (nalidixic acid) was marketed in 1962, four generations of quinolones have been developed and applied clinically. However, with the widespread and even abused use of these drugs in clinical practice, bacterial resistance to quinolones has increased significantly. Therefore, structural modification of the core quinolone skeleton of these drugs to develop new structural antibacterial drugs has become an important approach to solving the resistance problem. The N-1, C-3, and C-7 positions are the main modification sites, and current research focuses on introducing other aliphatic nitrogen-containing heterocycles at the C-7 position or further modifying existing aliphatic nitrogen-containing heterocycles. This study differs from traditional modification methods by linking azole heterocycles to non-aliphatic nitrogen heterocyclic fragments such as methylene or thioether bonds at the C-7 position of quinolones. Simultaneously, different substituents are introduced at the N-1 position to adjust physicochemical properties, constructing novel quinolone aminothiadiazole compounds. These compounds are expected to exert multi-target antibacterial effects through various non-covalent interactions with biomolecules or structures, thereby yielding highly efficient, low-toxicity, and broad-spectrum antibacterial compounds capable of overcoming drug resistance. Summary of the Invention

[0004] In view of this, one objective of the present invention is to provide quinolone aminothiadiazole compounds and their pharmaceutically acceptable salts; a second objective is to provide a method for preparing quinolone aminothiadiazole compounds and their pharmaceutically acceptable salts; and a third objective is to provide the application of quinolone aminothiadiazole compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and / or antifungal drugs, providing highly effective, low-toxicity, and broad-spectrum new drug candidate molecules for clinical anti-infective treatment, helping to solve the global public health problem of microbial infection, and contributing to the fight against microbial diseases.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] 1. Quinolone aminothiadiazole compounds, with structures shown in general formula I:

[0007]

[0008] In the formula,

[0009] n is an integer between 0 and 18, R 1 The radicals are hydrogen, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxyl, ester, carboxyl, amide, phenyl, substituted phenyl, or heteroaryl. 2 It is hydrogen;

[0010] (CH2) n R 1 ,R 2 for

[0011] R 3 For hydrogen, R 4 It can be hydrogen, alkyl, phenyl, acetyl, chloroacetyl, or dichloroacetyl;

[0012] R 3 ,R 4 for

[0013] X is a methylene or thioether bond.

[0014] Preferred values: n is any one of 1, 3, 7, or 11, R 1 R is any one of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl. 2 It is hydrogen;

[0015] (CH2) n R 1 ,R 2 for

[0016] R 3 For hydrogen, R 4It is any one of hydrogen, acetyl, chloroacetyl, or dichloroacetyl;

[0017] R 3 ,R 4 for

[0018] X is a methylene or thioether bond.

[0019] Preferably, it is any one of the following compounds:

[0020]

[0021]

[0022] Preferably, the pharmaceutically acceptable salt is a hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate, or acetate.

[0023] 2. The method for preparing the quinolone aminothiadiazole compound is as follows:

[0024] a. Preparation of quinolone aminothiadiazole compounds represented by general formulas I-1, I-2 and I-3: The intermediates represented by general formulas II and III are reacted with aminothiourea in trifluoroacetic acid to obtain quinolone aminothiadiazole compounds represented by general formulas I-1, I-2 and I-3.

[0025]

[0026] in:

[0027] n is 1, 3, 7 or 11;

[0028] R 1 It can be alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl.

[0029] b. Preparation of quinolone aminothiadiazole compounds shown in I-4-1, I-4-2 and I-4-3: Compound I-3, triethylamine and acetyl chloride, chloroacetyl chloride or dichloroacetyl chloride are reacted in dichloromethane to obtain quinolone aminothiadiazole compounds shown in I-4-1, I-4-2 and I-4-3.

[0030] c. Preparation of quinolone aminothiadiazole compounds represented by general formula I-5: Compound I-3 is reacted with N,N-dimethylformamide dimethyl acetal in ethanol to obtain quinolone aminothiadiazole compounds represented by general formula I-5.

[0031] Preferably,

[0032] In step a, the molar ratio of intermediate II or III to aminothiourea is 1:5 to 8, and the reaction is specifically carried out using trifluoroacetic acid as a solvent at 70 to 80°C for 4 to 8 hours.

[0033] In step b, the molar ratio of compound I-3, triethylamine, and acetyl chloride, chloroacetyl chloride, or dichloroacetyl chloride is 1:1 to 2:2 to 5, and the reaction is specifically carried out using dichloromethane as a solvent for 8 to 12 hours at room temperature.

[0034] In step c, the molar ratio of compound I-3-1 to N,N-dimethylformamide dimethyl acetal is 1:2 to 5, and the reaction is specifically carried out using ethanol as a solvent at 70 to 90°C for 2 to 3 hours.

[0035] 3. The use of the quinolone aminothiadiazole compounds and their pharmaceutically acceptable salts in the preparation of antibacterial and / or antifungal drugs.

[0036] Preferably, the bacteria are methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC(B)26001, Staphylococcus aureus CMCC(B)26003, Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, and Pseudomonas aeruginosa ATCC. 9027, any one or more of Pseudomonas aeruginosa CMCC(B)10104 or Acinetobacter baumannii; the fungus is any one or more of Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019.

[0037] 4. Preparations containing the aforementioned quinolone aminothiadiazole compounds.

[0038] Preferably, the preparation is one of the following: tablets, capsules, granules, injections, powder for injection, eye drops, liniments, suppositories, ointments, or aerosols.

[0039] The beneficial effects of this invention are as follows: This invention provides quinolone aminothiadiazole compounds, their preparation methods, and applications. Utilizing the principle of drug design and synthesis, this invention introduces aminothiadiazoles at the C-7 position of quinolones, designing and synthesizing a series of quinolone aminothiadiazole compounds. These compounds, after in vitro antimicrobial activity testing, were found to be effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC(B)26001, Staphylococcus aureus CMCC(B)26003) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC). The bacteria exhibit inhibitory activity against *Pseudomonas aeruginosa* (25922, *Pseudomonas aeruginosa* ATCC 27853, *Pseudomonas aeruginosa* ATCC 15442, *Pseudomonas aeruginosa* ATCC9027, *Pseudomonas aeruginosa* CMCC(B)10104, and *Acinetobacter baumannii*) and fungi (*Candida albicans*, *Candida albicans* ATCC90023, *Candida tropicalis*, *Aspergillus fumigatus*, or *Candida parapsilosis* ATCC 22019). These bacteria can be used to prepare antibacterial and / or antifungal drugs without significant drug resistance. This provides highly effective, low-toxicity, and broad-spectrum new drug candidates for clinical anti-infective therapy, contributing to solving the global public health problem of microbial infection and the fight against microbial diseases.

[0040] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Detailed Implementation

[0041] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content described in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0042] Example 1: Preparation of intermediates II and III:

[0043]

[0044]

[0045] References "[1] Sunduru, N.; Gupta, L.; Chauhan, K.; Mishra, NN; Shukla, PK; Chauhan, PMSSynthesis and antibacterial evaluation of novel 8-fluoronorfloxacin derivatives as potential probes for methicillin and vancomycin-resistant Staphylococcus aureus.Eur.J.Med.Chem.2011,46,1232-1244.[2]Valery,NC;Nataliya,NM;Fedor,VA;Svetlana,KK;Emiliya,VN;Marina,AE;Mikhail,IK;Marionella,AKSynthesis and antimycobacterial evaluation of new(2-oxo-2H-chromen-3-yl)substituted fluoroquinolones.J.Fluorine Chem.2018,208,15-23. The method described was modified in this embodiment (potassium carbonate was replaced with sodium carbonate in the reaction with ethyl cyanoacetate as described in reference [2], and the solvent N,N-dimethylformamide was replaced with dimethyl sulfoxide) to prepare intermediates II and III.

[0046] Example 2, Preparation of compound I-1-1:

[0047]

[0048] Intermediate II-1-1 (100 mg, 0.36 mmol) and aminothiourea (199 mg, 2.19 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 97 mg of yellow solid compound I-1-1, yield: 76.4%, melting point: 158.9-160.3 °C. 1HNMR (600MHz, 25℃, DMSO-d6) δ15.02(s,1H,COOH),9.07(s,1H,quinolone-2-H),8.24(d,J=5.8Hz,1H,quinolone-8-H),8.02(d,J= 9.4Hz,1H,quinolone-5-H),7.14(s,2H,NH2),4.60(q,J=7.1Hz,2H,CH2CH3),4.46(s,2H,CH2),1.43(t,J=7.0Hz,3H,CH2CH3)ppm.

[0049] Example 3, Preparation of compound I-1-2:

[0050]

[0051] Intermediate II-1-2 (200 mg, 0.73 mmol) and aminothiourea (399 mg, 4.38 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 202 mg of yellow solid compound I-1-2, yield: 73.6%, melting point: 250.1-252.3 °C. 1 HNMR(600MHz,25℃,DMSO-d6)δ15.00(s,1H,COOH),9.05(s,1H,quinolone-2-H),8.18( d,J=5.8Hz,1H,quinolone-8-H),8.03(d,J=9.4Hz,1H,quinolone-5-H),7.14(s,2H,N H2),4.55(t,J=7.4Hz,2H,CH2(CH2)2CH3),4.47(s,2H,CH2),1.80–1.75(m,2H,CH2CH2 CH2CH3), 1.35 (q, J=7.5Hz, 2H, (CH2)2CH2CH3), 0.92 (t, J=7.4Hz, 3H, (CH2)3CH3)ppm.

[0052] Example 4, Preparation of compound I-1-3:

[0053]

[0054] Intermediate II-1-3 (200 mg, 0.56 mmol) and aminothiourea (253 mg, 2.77 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 97 mg of yellow solid compound I-1-3, yield: 40.2%, melting point: 234.3-235.9 °C. 1 HNMR (400MHz, 25℃, DMSO-d6) δ15.00(s,1H,COOH),9.06(s,1H,quinolone-2-H),8.20(d,J=5.9Hz,1H,quinolone-8-H),8.03(d,J=9.5Hz,1H,quinolone-5-H),7.13(s,2H, NH2),4.54(t,J=7.3Hz,2H,CH2(CH2)6CH3),4.47(s,2H,CH2),1.79(m,2H,CH2CH2(CH2 )5CH3),1.33–1.20(m,10H,(CH2)2(CH2)5CH3),0.84(t,J=6.6Hz,3H,(CH2)7CH3)ppm.

[0055] Example 5, Preparation of compound I-1-4:

[0056]

[0057] Intermediate II-1-4 (200 mg, 0.48 mmol) and aminothiourea (224 mg, 2.46 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 96 mg of yellow solid compound I-1-4, yield: 40.7%, melting point: 153.2-154.8 °C. 1 HNMR(400MHz,25℃,DMSO-d6)δ15.00(s,1H,COOH),9.06(s,1H,quinolone-2-H),8.20(d,J=5.9Hz,1H,qu inolone-8-H),8.03(d,J=9.6Hz,1H,quinolone-5-H),7.16(s,2H,NH2),4.54(t,J=7.1Hz,2H,CH2(CH2) 10CH3),4.47(s,2H,CH2),1.78(t,J=7.4Hz,2H,CH2CH2(CH2)9CH3),1.21(s,18H,(CH2)2(CH2)9CH3),0.84(t,J=6.7Hz,3H,(CH2) 11 CH3)ppm.

[0058] Example 6, Preparation of compound I-1-5:

[0059]

[0060] Intermediate II-1-5 (100 mg, 0.35 mmol) and aminothiourea (191 mg, 2.10 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 90 mg of yellow solid compound I-1-5, yield: 71.5%, melting point: 253.6-254.3 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.94(s,1H,COOH),9.08(s,1H,quinolone-2-H),8.08(d,J=3.6Hz,1H,quinolone-8-H),8.04(d,J=9.5Hz,1H,q uinolone-5-H),7.11(s,2H,NH2),6.07(m,1H,CH=CH2),5.29(d,J=10.4Hz,1H,CH=CH2),5.25–5.21(m,3H,CH=CH2&NCH2),4.43(s,2H,CH2)ppm.

[0061] Example 7, Preparation of compound I-1-6:

[0062]

[0063] Intermediate II-1-6 (100 mg, 0.35 mmol) and aminothiourea (192 mg, 2.10 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 26 mg of yellow solid compound I-1-6, yield: 21.1%, melting point: 216.9-218.1 °C. 1HNMR (600MHz, 25℃, DMSO-d6) δ14.87(s,1H,COOH),9.14(s,1H,quinolone-2-H),8.07(d,J=9.3Hz,1H,quinolone-5-H),7. 94(d,J=5.7Hz,1H,quinolone-8-H),7.09(s,2H,NH2),6.30(m,1H,CH),5.37(d,J=6.0Hz,2H,NCH2),4.37(s,2H,CH2)ppm.

[0064] Example 8, Preparation of compound I-1-7:

[0065]

[0066] Intermediate II-1-7 (200 mg, 0.64 mmol) and aminothiourea (348 mg, 3.82 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 142 mg of yellow solid compound I-1-7, yield: 60.2%, melting point: 228.1-230.8 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.96(s,1H,COOH),9.05(s,1H,quinolone-2-H),8.04(d,J=9.4Hz,1H,quinolone-5-H),7.87(d,J=5.9Hz,1H,quinolone-8-H) ,7.16(s,2H,NH2),5.29(d,J=6.5Hz,1H,CH=C(CH3)2),5.14(d,J=6.7Hz,2H,NC H2), 4.44(s,2H,CH2), 1.82(s,3H,CH=C(CH3)2), 1.72(s,3H,CH=C(CH3)2)ppm.

[0067] Example 9, Preparation of compound I-1-8:

[0068]

[0069] Intermediate II-1-8 (200 mg, 0.67 mmol) and aminothiourea (364 mg, 4.00 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 169 mg of yellow solid compound I-1-8, yield: 67.9%, melting point: 261.2-263.3 °C.1 HNMR (600MHz, 25℃, DMSO-d6) δ15.01(s,1H,COOH),9.09(s,1H,quinolone-2-H),8.35(d,J=5.7Hz,1H,quinolone-8-H),8.04(d,J=9.4Hz,1H,quinolone-5-H),7. 12(s,2H,NH2),4.49–4.43(m,4H,NCH2&CH2),1.42–1.36(m,1H,cyclopropyl-CH),0.61–0.58(m,2H,cyclopropyl-CH2),0.54–0.51(m,2H,cyclopropyl-CH2)ppm.

[0070] Example 10, Preparation of compound I-1-9:

[0071]

[0072] Intermediate II-1-9 (100 mg, 0.29 mmol) and aminothiourea (160 mg, 1.75 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 49 mg of yellow solid compound I-1-9, yield: 40.3%, melting point: 280.3-283.0 °C. 1 HNMR (400MHz, 25℃, DMSO-d6) δ15.01(s,1H,COOH),8.97(s,1H,quinolone-2-H),8.15(d,J=6. 0Hz,1H,quinolone-8-H),8.04(d,J=9.6Hz,1H,quinolone-5-H),7.14(s,2H,NH2),4.47(s,2 H,CH2),4.40(d,J=7.4Hz,2H,NCH2),1.81(s,1H,cyclohexyl-CH),1.73–1.57(m,4H,cyclohe xyl-CH2), 1.51 (d, J = 10.6 Hz, 2H, cyclohexyl-CH2), 1.13–1.05 (m, 4H, cyclohexyl-CH2) ppm.

[0073] Example 11, Preparation of compound I-1-10:

[0074]

[0075] Intermediate II-1-10 (200 mg, 0.59 mmol) and aminothiourea (342 mg, 3.56 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 185 mg of yellow solid compound I-1-10, yield: 75.8%, melting point: 293.0-295.2 °C. 1 H NMR (400MHz, 25℃, DMSO-d6) δ14.95(s,1H,COOH),9.27(s,1H,quinolone-2-H),8.44(d,J=4.7 Hz,1H,pyridinyl-6-H),8.03(d,J=9.5Hz,1H,quinolone-5-H),7.93(d,J=5.9Hz,1H,quinolo ne-8-H),7.83(t,J=7.7Hz,1H,pyridinyl-4-H),7.52(d,J=7.8Hz,1H,pyridinyl-3-H),7.31 (t,J=11.8Hz,1H,pyridinyl-5-H),7.13(s,2H,NH2),5.93(s,2H,NCH2),4.32(s,2H,CH2)ppm.

[0076] Example 12, Preparation of compound I-2-1:

[0077]

[0078] Intermediate II-2-1 (100 mg, 0.30 mmol) and aminothiourea (163 mg, 1.78 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 90 mg of yellow solid compound I-2-1, yield: 73.6%, melting point: 264.2-265.5 °C. 1HNMR (600MHz, 25℃, DMSO-d6) δ14.92(s,1H,COOH),9.30(s,1H,quinolone-2-H),8.04(d,J=9.5Hz,1H,quinolone-5-H),8.00(d,J=5.8Hz,1H,quinolone-8-H),7.36(t ,J=7.5Hz,2H,phenyl-3,5-2H),7.30(t,J=7.3Hz,1H,phenyl-4-H),7.27(d,J=7.6 Hz,2H,phenyl-2,6-2H),7.22(s,2H,NH2),5.82(s,2H,NCH2),4.35(s,2H,CH2)ppm.

[0079] Example 13, Preparation of compound I-2-2:

[0080]

[0081] Intermediate II-2-2 (250 mg, 0.71 mmol) and aminothiourea (386 mg, 4.23 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 219 mg of yellow solid compound I-2-2, yield: 72.5%, melting point: 295.3-295.8 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.84(s,1H,COOH),9.24(s,1H,quinolone-2-H),8.05(d,J=9.5Hz,1H,quinolone-5-H),7.94(d,J=5.8Hz,1H,quinolo ne-8-H),7.41–7.37(m,1H,phenyl-3-H),7.27–7.23(m,1H,phenyl-6-H),7.17(m,4H,NH2&phenyl-4,5-2H),5.88(s,2H,NCH2),4.36(s,2H,CH2)ppm.

[0082] Example 14, Preparation of compound I-2-3:

[0083]

[0084] Intermediate II-2-3 (100 mg, 0.28 mmol) and aminothiourea (154 mg, 1.69 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 73 mg of yellow solid compound I-2-3, yield: 60.7%, melting point: 296.5-298.4 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.91(s,1H,COOH),9.29(s,1H,quinolone-2-H),8.04(d,J=9.4Hz,1H,quinolone-5-H),7.96(d,J=5.7Hz,1H,quinolone-8 -H),7.43–7.38(m,1H,phenyl-5-H),7.23–7.11(m,4H,phenyl-4,6-2H&NH2),7.09(d,J=7.7Hz,1H,phenyl-2-H),5.84(s,2H,NCH2),4.35(s,2H,CH2)ppm.

[0085] Example 15, Preparation of compound I-2-4:

[0086]

[0087] Intermediate II-2-4 (200 mg, 0.56 mmol) and aminothiourea (309 mg, 3.39 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 197 mg of yellow solid compound I-2-4, yield: 81.5%, melting point: >300 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.91(s,1H,COOH),9.31(s,1H,quinolone-2-H),8.04(d,J=9.4Hz,1H,quinolone-5-H),8.00(d,J=5.8Hz ,1H,quinolone-8-H),7.36(t,J=6.9Hz,2H,phenyl-2,6-2H),7.19(m,4H,phenyl-3,5-2H&NH2),5.80(s,2H,NCH2),4.36(s,2H,CH2)ppm.

[0088] Example 16, Preparation of compound I-2-5:

[0089]

[0090] Intermediate II-2-5 (200 mg, 0.54 mmol) and aminothiourea (295 mg, 3.24 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 159 mg of yellow solid compound I-2-5, yield: 66.3%, melting point: 292.6-293.3 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.89(s,1H,COOH),9.31(s,1H,quinolone-2-H),8.04(d,J=9.4Hz,1H,quinolone-5-H),7.98(d,J=5.8Hz,1H,quinol one-8-H),7.41(d,J=8.3Hz,2H,phenyl-2,6-2H),7.32(d,J=8.2Hz,2H,phenyl-3,5-2H),7.19(s,2H,NH2),5.81(s,2H,NCH2),4.35(s,2H,CH2)ppm.

[0091] Example 17, Preparation of compound I-2-6:

[0092]

[0093] Intermediate II-2-6 (100 mg, 0.25 mmol) and aminothiourea (135 mg, 1.48 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 33 mg of white solid compound I-2-6, yield: 27.7%, melting point: >300 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.89(s,1H,COOH),9.35(s,1H,quinolone-2-H),8.05(d,J=9.4Hz,1H,quinolone-5-H),7.97(d,J=5.7Hz,1H,quinol one-8-H),7.71(d,J=8.0Hz,2H,phenyl-2,6-2H),7.49(d,J=8.1Hz,2H,phenyl-3,5-2H),7.14(s,2H,NH2),5.94(s,2H,NCH2),4.34(s,2H,CH2)ppm.

[0094] Example 18, Preparation of compound I-2-7:

[0095]

[0096] Intermediate II-2-7 (200 mg, 0.55 mmol) and aminothiourea (299 mg, 3.28 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 166 mg of yellow solid compound I-2-7, yield: 69.0%, melting point: 287.4-287.8 °C. 1 HNMR (400MHz, 25℃, DMSO-d6) δ14.93(s,1H,COOH),9.26(s,1H,quinolone-2-H),8.10(d,J=5.9Hz,1H,quinolone-8-H),8.03(d,J=9.5Hz,1H,quinolone-5-H) ,7.27(d,J=8.7Hz,2H,phenyl-2,6-2H),7.19(s,2H,NH2),6.91(d,J=8.7Hz,2H ,phenyl-3,5-2H),5.71(s,2H,NCH2),4.38(s,2H,CH2),3.73(s,3H,OCH3)ppm.

[0097] Example 19, Preparation of compound I-2-8:

[0098]

[0099] Intermediate II-2-8 (100 mg, 0.27 mmol) and aminothiourea (147 mg, 1.61 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 91 mg of yellow solid compound I-2-8, yield: 75.9%, melting point: 276.3-278.2 °C. 1 HNMR(600MHz,25℃,DMSO-d6)δ14.84(s,1H,COOH),9.24(s,1H,quinolone-2-H),8.05(s,1H,quinolone-5-H),7.93(d,J=5.7Hz,1H, quinolone-8-H),7.30(m,2H,phenyl-3,6-2H),7.23(s,2H,NH2),7.03(m,1H,phenyl-5-H),5.85(s,2H,NCH2),4.37(s,2H,CH2)ppm.

[0100] Example 20, Preparation of compound I-2-9:

[0101]

[0102] Intermediate II-2-9 (200 mg, 0.54 mmol) and aminothiourea (294 mg, 3.22 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 177 mg of yellow solid compound I-2-9, yield: 73.8%, melting point: 291.1-292.2 °C. 1 HNMR(400MHz,25℃,DMSO-d6)δ14.85(s,1H,COOH),9.23(s,1H,quinolone-2-H),8.06( d,J=9.5Hz,1H,quinolone-5-H),7.87(d,J=5.8Hz,1H,quinolone-8-H),7.33(td,J=9 .4,4.5Hz,1H,phenyl-3-H),7.23(td,J=8.7,8.3,4.4Hz,1H,phenyl-4-H),7.15–7.11 (m,2H,NH2),7.11–7.07(m,1H,phenyl-6-H),5.87(s,2H,NCH2),4.36(s,2H,CH2)ppm.

[0103] Example 21, Preparation of compound I-2-10:

[0104]

[0105] Intermediate II-2-10 (100 mg, 0.27 mmol) and aminothiourea (147 mg, 1.61 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 97 mg of yellow solid compound I-2-10, yield: 80.5%, melting point: 265.5-266.4 °C. 1H NMR (600MHz, 25℃, DMSO-d6) δ14.73(s,1H,COOH),9.24(s,1H,quinolone-2-H),8.05(d,J=9.0Hz,1H,quinolone-5-H),7.75(d,J=5.7Hz ,1H,quinolone-8-H),7.51–7.46(m,1H,phenyl-4-H),7.18–7.13(m,4H,NH2&phenyl-3,5-2H),5.90(s,2H,NCH2),4.36(s,2H,CH2)ppm.

[0106] Example 22, Preparation of compound I-3:

[0107]

[0108] Intermediate III (1.500 g, 4.96 mmol) and aminothiourea (2.710 g, 29.78 mmol) were reacted in trifluoroacetic acid (5 mL) at 80 °C with stirring for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution, and the solid was obtained by filtration. Recrystallization gave 93 mg of yellow solid compound I-3, yield: 74.7%, melting point: 299.6-302.4 °C. 1 HNMR (600MHz, 25℃, DMSO-d6) δ14.99(s,1H,COOH),9.07(s,1H,quinolone-2-H),7.65(d,J=9.3Hz,1H,quinolone-5-H),7.11(s,2H,NH2),5. 03–4.97(m,1H,NCH),4.69(d,J=11.6Hz,1H,OCH2),4.47(d,J=11.6Hz,1H,OCH2),4.32(d,J=4.3Hz,2H,CH2),1.47(d,J=6.7Hz,3H,CH3)ppm.

[0109] Example 23, Preparation of compound I-4-1:

[0110]

[0111] Compound I-3 (100 mg, 0.27 mmol) and triethylamine (27 mg, 0.27 mmol) were dissolved in dichloromethane (5 mL) at room temperature with stirring. Acetyl chloride (63 mg, 0.80 mmol) was added dropwise under ice bath conditions, and the mixture was slowly brought back to room temperature with stirring. After the reaction was complete, most of the dichloromethane was removed by rotary evaporation. Saturated brine (10 mL) was added and stirred for 15 minutes. The mixture was then filtered to give 92 mg of a yellow solid, compound I-4-1, with a yield of 82.8% and a melting point of >300 °C. 1 H NMR (600MHz, 25℃, DMSO-d6) δ14.96(s,1H,COOH),12.44(s,1H,NH),9.06(s,1H,quinolone-2-H),7.67(d,J=9.3Hz,1H,quinolone-5-H),5.00(q,J=7.1,6.7 Hz,1H,NCH),4.68(d,J=11.6,2.0Hz,1H,OCH2),4.50(d,J=5.9Hz,2H,CH2),4. 47(d,J=9.8Hz,1H,OCH2),2.15(s,3H,COCH3),1.47(d,J=6.8Hz,3H,CH3)ppm.

[0112] Example 24, Preparation of compound I-4-2:

[0113]

[0114] Compound I-3 (150 mg, 0.40 mmol) and triethylamine (61 mg, 0.60 mmol) were dissolved in dichloromethane (5 mL) at room temperature with stirring. Chloroacetyl chloride (135 mg, 1.20 mmol) was added dropwise under ice bath, and the mixture was slowly brought back to room temperature with stirring. After the reaction was complete, most of the dichloromethane was removed by rotary evaporation. Saturated brine (10 mL) was added and stirred for 15 minutes. The mixture was then filtered to give 147 mg of a yellow solid, compound I-4-2, with a yield of 81.5% and a melting point of 291.4–293.1 °C. 1H NMR (600MHz, 25℃, DMSO-d6) δ12.89(s,1H,COOH),9.07(s,1H,quinolone-2-H),7.68(d,J=9.4Hz,1H,quinolone-5-H),5.75(s,1H,NH),5.02–4.98(m ,1H,NCH),4.69(d,J=10.6Hz,1H,OCH2),4.54(d,J=5.9Hz,2H,CH2Cl),4.47(d,J=10.7Hz,1H,OCH2),4.42(s,2H,CH2),1.47(d,J=6.8Hz,3H,CH3)ppm.

[0115] Example 25, Preparation of compound I-4-3:

[0116]

[0117] Compound I-3 (100 mg, 0.27 mmol) and triethylamine (40 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL) at room temperature with stirring. Dichloroacetyl chloride (117 mg, 0.80 mmol) was then added dropwise under ice bath conditions, and the mixture was slowly brought back to room temperature with stirring. After the reaction was complete, most of the dichloromethane was removed by rotary evaporation. Saturated brine (10 mL) was added and stirred for 15 minutes. The mixture was then filtered to obtain 71 mg of a yellow solid, compound I-4-3, with a yield of 54.8% and a melting point of 248.4–250.2 °C. 1 H NMR (600MHz, 25℃, CF3COOH+DMSO-d6) δ9.06(s,1H,quinolone-2-H),7.68(d,J=9.2Hz,1H,quinolone-5-H),6.66(s,1H,CHCl2),5. 03–4.95(m,1H,NCH),4.67(d,J=11.6Hz,1H,OCH2),4.54(s,2H,CH2),4.47(d,J=11.6Hz,1H,OCH2),1.47(d,J=6.8Hz,3H,CH3)ppm.

[0118] Example 26, Preparation of compound I-5:

[0119]

[0120] Compound I-3 (100 mg, 0.27 mmol) and compound N,N-dimethylformamide dimethyl acetal (95 mg, 0.80 mmol) were reacted in ethanol (5 mL) at 80 °C for 2.5 h. After the reaction was completed, the solid precipitated upon cooling and was filtered to give 59 mg of yellow solid compound I-5, yield: 51.5%, melting point: 185.4-186.6 °C. 1 H NMR(600MHz,25℃,DMSO-d6)δ14.66(s,1H,COOH),9.05(s,1H,quinolone-2-H),8.14(s,1H,N=CH),7.70–7.60(d,1H,quinolone-5-H),4.99(s,1H,NC H),4.67(d,J=11.4Hz,1H,OCH2),4.45(d,J=12.8Hz,1H,OCH2),4.41(s,2H,CH2),3.09(s,3H,N(CH3)2),2.95(s,3H,N(CH3)2),1.46(s,3H,CH3)ppm.

[0121] Example 27: In vitro antimicrobial activity of quinolone aminothiadiazole compounds

[0122] The quinolone aminothiadiazole compounds prepared in Examples 2–26 were tested for their effectiveness against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC(B)26001, Staphylococcus aureus CMCC(B)26003) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853 ... The minimum inhibitory concentrations (MICs) of *Pseudomonas aeruginosa* (ATCC 9027, CMCC(B)10104, Acinetobacter baumannii) and fungi (*Candida albicans*, *Candida albicans* (ATCC 90023), *Candida tropicalis*, *Aspergillus fumigatus*, or *Candida parapsilosis* (ATCC 22019)) were determined by dissolving the test compound in a small amount of dimethyl sulfoxide and then diluting it to 512 μg / mL with culture medium. The mixture was incubated at 37°C for 24 hours. After thoroughly mixing the culture plate on a shaker, the MICs were measured at a wavelength of 600 nm and read visually. The results are shown in Tables 1-3.

[0123] Table 1. In vitro anti-Gram-positive bacteria activity (MIC, μg / mL) of quinolone aminothiadiazole compounds prepared in Examples 2-26

[0124]

[0125]

[0126] As can be seen from Table 1, some of the quinolone aminothiadiazole compounds I-1 to 2 prepared in this invention showed certain inhibitory effects on the tested Gram-positive bacteria. Among them, compound I-3, which has quinolone cyclization at the C-1 and C-8 positions, showed a broader spectrum of inhibitory activity. At the same time, some benzyl-substituted compounds also showed good inhibitory activity, and some compounds showed better activity than the clinical drugs norfloxacin and ciprofloxacin.

[0127] Table 2. In vitro anti-Gram-negative bacterial activity (MIC, μg / mL) of the quinolone aminothiadiazole compounds prepared in Examples 2-26

[0128]

[0129]

[0130] As can be seen from Table 2, some of the quinolone aminothiadiazole compounds I-1 to 2 prepared in this invention showed certain inhibitory effects on the tested Gram-negative bacteria. Compound I-3, which has quinolone cyclization at the C-1 and C-8 positions, and some compounds with hydrocarbon substituents showed good inhibitory activity. Some compounds showed activity against Gram-negative bacteria that was superior to the reference drug.

[0131] Table 3. In vitro antifungal activity (MIC, μg / mL) of the quinolone aminothiadiazole compounds prepared in Examples 2-26

[0132]

[0133]

[0134] As shown in Table 3, some of the quinolone aminothiadiazole compounds I-4 prepared in this invention exhibited certain inhibitory effects on the tested fungi. Compound I-4-2 showed good inhibitory activity against all five tested fungi, with the MIC value of compound I-4-2 reaching 1 μg / mL against Candida albicans, and its inhibitory activity being twice that of fluconazole.

[0135] Example 28: Pharmaceutical Uses of Quinolone Aminothiadiazole Compounds

[0136] Based on the above antimicrobial activity test results, the quinolone aminothiadiazole compounds of the present invention exhibit good antibacterial and antifungal activity and can be formulated into antibacterial and antifungal drugs for clinical use. These drugs can be single-component formulations, such as those composed of a single-structure quinolone aminothiadiazole compound and pharmaceutically acceptable excipients; or they can be compound formulations, such as those composed of a single-structure quinolone aminothiadiazole compound with existing antibacterial and antifungal active ingredients (e.g., norfloxacin or fluconazole) and pharmaceutically acceptable excipients, or composed of several quinolone aminothiadiazole compounds with different structures and pharmaceutically acceptable excipients. The formulation types include, but are not limited to, tablets, capsules, powders, granules, drop pills, injections, powder for injection, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches, and various sustained-release, controlled-release, and nano-formulations.

[0137] In summary, this invention provides quinolone aminothiadiazole compounds. This invention retains the classic benzopyridinolone acid structure of quinolones, but differs from traditional quinolone C-7 modification methods. It modifies the quinolone C-7 position by introducing an aromatic heterocyclic aminothiadiazole via a methylene or thioether group. This utilizes the various non-covalent interactions between the aminothiadiazole and biomolecules such as DNA to enhance antimicrobial activity. Simultaneously, different substituents such as alkyl, alkenyl, alkynyl, aryl, or heterocyclic groups are introduced at the N-1 position to regulate physicochemical properties and thus influence antimicrobial activity. A series of novel quinolone aminothiadiazole compounds were designed and synthesized. In vitro antimicrobial activity tests showed that these compounds are effective against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 2592 ... 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC(B)26001, Staphylococcus aureus CMCC(B)26003), Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Escherichia coli ATCC 25922, Pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027, Pseudomonas aeruginosa CMCC(B)10104, Acinetobacter baumannii) and fungi (Candida albicans, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 12600, Candida albicans ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 90023, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 90023, Candida tropicalis, Candida ...20023, Candida parapsilosis 20023, Candida tropicalis, Candida fumigatus or Candida parapsilosis 2 22019) has certain inhibitory activity and can be used to prepare antibacterial and antifungal drugs, providing new candidate drug molecules that are highly effective, low in toxicity, and broad-spectrum for clinical anti-infective treatment. This will help solve the global public health problem of microbial infection and contribute to the fight against microbial diseases.

[0138] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. Quinolone aminothiadiazoles and their usable salts, characterized in that, The quinolone aminothiadiazoles are selected from I-1-1 to I-1-10, I-2-1 to I-2-10, I-3, I-4-1 to I-4-3 or I-5:

2. The quinolone aminothiadiazole compound and pharmaceutically acceptable salt thereof according to claim 1, wherein The pharmaceutically acceptable salt is hydrochloride, bromide, iodide, sulfate, nitrate, trifluoroacetate or acetate.

3. Process for the preparation of a quinolone aminothiadiazole compound according to any one of claims 1 to 2, characterized in that, The method is as follows: a. Preparation of quinolone aminothiadiazoles of general formula I-1, I-2 and I-3: the intermediate of general formula II and III reacts with aminothiourea in trifluoroacetic acid to obtain quinolone aminothiadiazoles of general formula I-1, I-2 and I-3; wherein: n is 1, 3, 7 or 11; R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or heteroaryl; b. Preparation of quinolone aminothiadiazoles of I-4-1, I-4-2 and I-4-3: compound I-3, triethylamine and acetyl chloride, chloroacetyl chloride or dichloroacetyl chloride react in dichloromethane to obtain quinolone aminothiadiazoles of I-4-1, I-4-2 and I-4-3; c. Preparation of quinolone aminothiadiazoles of general formula I-5: compound I-3 and N,N-dimethylformamide dimethyl acetal react in ethanol to obtain quinolone aminothiadiazoles of general formula I-5.

4. The method of claim 3, wherein, In step a, the mass ratio of general formula II or III to aminothiourea is 1:5-8, and the reaction is specifically carried out in trifluoroacetic acid at 70-80℃ for 4-8 hours; In step b, the mass ratio of compound I-3, triethylamine and acetyl chloride, chloroacetyl chloride or dichloroacetyl chloride is 1:1-2:2-5, and the reaction is specifically carried out in dichloromethane at room temperature for 8-12 hours; In step c, the mass ratio of compound I-3 to N,N-dimethylformamide dimethyl acetal is 1:2-5, and the reaction is specifically carried out in ethanol at 70-90℃ for 2-3 hours.

5. Use of the quinolone aminothiadiazoles of any one of claims 1-2 in the preparation of an antibacterial or antifungal drug.

6. The use according to claim 5, wherein the compound is ###0002### The bacteria are selected from Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa or Acinetobacter baumannii; and the fungi are selected from Candida albicans, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019.

7. Use according to claim 6, characterized in that, The Staphylococcus aureus is methicillin-resistant Staphylococcus aureus N315, methicillin-resistant Staphylococcus aureus ATCC 43300, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Staphylococcus aureus ATCC 12600, Staphylococcus aureus ATCC 6538, Staphylococcus aureus CMCC(B)26001 or Staphylococcus aureus CMCC(B)26003, the Escherichia coli is Escherichia coli ATCC 25922, the Pseudomonas aeruginosa is Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa ATCC 15442, Pseudomonas aeruginosa ATCC 9027 or Pseudomonas aeruginosa CMCC(B)10104; and the Candida albicans is Candida albicans ATCC 90023.

8. A preparation comprising the quinolone aminothiadiazole compound according to any one of claims 1 to 2.

9. The formulation of claim 8, wherein, The preparation is one of a tablet, a capsule, a granule, an injection, a powder injection, an eye drop, a liniment, a suppository, an ointment or an aerosol.

Images