WO2017177828A1 - Novel oxazolidinone-fluoroquinolone derivative and uses - Google Patents

Abstract

The present invention relates to a novel oxazolidinone-fluoroquinolone derivative and uses, and relates to the field of chemical drugs. The present invention also relates to a compound represented by formula (I), a pharmaceutically acceptable optical raceme, a stereoisomer, a salt, a solvate, a hydrate or a prodrug thereof, and applications of a pharmaceutical composition thereof in prevention or treatment of infections (such as a bacterial infection). They are effective antimicrobial agents and can effectively resist against multiple pathogens on human bodies and animals, and the pathogens comprise but are not limited to gram-positive bacteria, gram-negative bacteria, anaerobic microorganisms and acidotolerant microorganisms.

Description

Novel oxazolidinone-fluoroquinolone derivatives and uses thereof

Related application

The present application claims priority to Chinese Application No. 201610220830.4, filed on Apr. 12,,,,,,,,,

Technical field

The present invention relates to the use of a novel class of oxazolidinone-fluoroquinolone derivatives and pharmaceutical compositions thereof for preventing or treating infections, such as bacterial infections. The compounds of the present invention are effective antimicrobial agents which are effective against a variety of human and animal pathogens, including Gram-positive bacteria, Gram-negative bacteria, Anaerobic microorganisms and acid-resistant microorganisms.

Background technique

With the wide application of antibiotics, the sensitivity of bacteria to existing antibiotics is reduced or even disappeared, resulting in drug-resistant bacteria. The most resistant bacteria to humans are methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In medical institutions, the resistance of these bacteria makes the currently used antibiotics useless, seriously threatening the lives of patients and becoming a high-risk medical problem.

In addition to the problem of drug-resistant bacteria, the abuse of antibiotics can lead to an imbalance of intestinal flora, leading to the occurrence of antibiotic-associated diarrhea (AAD), especially pseudomembranous colitis (PMC). At present, the incidence of antibiotic-associated diarrhea has reached 1.8-6.9% in foreign countries, while the domestic level is higher, reaching 6.7-9.3%, which is becoming a serious medical problem.

Clostridium difficile is the most important infectious agent in antibiotic-associated diarrhea. The diarrhea caused by it is collectively called C. difficile-associated diarrhea (CDAD), which accounts for 20-30% of antibiotic-associated diarrhea. 90% of pseudomembranous colitis.

The compound disclosed in the present invention not only exhibits high inhibitory activity against common pathogenic bacteria, but also has unexpected inhibition on super-resistant bacteria resistant to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Activity, and more importantly, this compound also has a high inhibitory effect on C. difficile, which is of great significance for patients with CDAD, especially patients with MRSA or VRE in the hospital, providing a very effective treatment. .

Summary of the invention

The invention relates to a compound of formula I or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof:

In formula I:

n: 0, 1, 2, 3;

C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C _1-8 alkyl;

X is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ -, -CH(R ₄ )-;

Y is NR ₅ , -CH ₂ -, -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

R ₁ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ , C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ , C _1-8 alkyl;

R ₇ is H, C _1-8 alkyl;

R ₈ is H, C _1-8 alkyl;

R ₉ is H, C _1-8 alkyl;

R ₁₀ is H, C _1-8 alkyl;

In formula II:

n: 0, 1, 2, 3;

A is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ -, -CH(R ₄ )-;

B is O, S, SO, SO ₂ , NR ₅ , -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C _1-8 alkyl;

Z is N, CR ₁₁ ;

R ₂ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ , C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ , C _1-8 alkyl;

R ₇ is H, C _1-8 alkyl;

R ₈ is H, C _1-8 alkyl;

R ₉ is H, C _1-8 alkyl;

R ₁₀ is H, C _1-8 alkyl;

R ₁₁ is H, C _1-8 alkyl.

The compounds of formula I may contain one or more stereosymmetric centers or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of the formula I can therefore be present in the form of a mixture of stereoisomers or preferably in the form of pure stereoisomers. Stereoisomeric mixtures can be isolated in a manner known in the art.

The number of carbon atoms in the hydrocarbon moiety referred to herein is named by a prefix containing the smallest number and the largest number of carbon atoms. For example, an alkyl group prefixed with _{Cab exhibits} an alkyl group having from a to b carbon atoms. . For example, C _1-8 represents an alkyl group having 1-8 carbon atoms.

The term "alkyl", whether used alone or in combination, refers to a saturated straight or branched alkyl group containing from 1 to 10 carbon atoms and preferably from 1 to 8 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl Base, n-hexyl and iso-hexyl. Any alkyl group as defined herein may be substituted with one or more substituents, for example ₂ substituents F, Cl, Br, I, NH 2, OH, SH or NO.

"Pharmaceutically acceptable" as used in the present invention means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which constitute a pharmaceutical dosage form. And is physiologically compatible.

The "salt" and "pharmaceutically acceptable salt" refer to a compound of the formula I or II or a stereoisomer thereof, or an organic or inorganic salt thereof. These salts may be obtained directly in the final isolation and purification of the compound, or by reacting a compound represented by I or II or a stereoisomer thereof, or a prodrug thereof, respectively, using a suitable organic or inorganic acid or base. The salt is then isolated. Commonly used salts include, for example, hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, besylate, palmitate, hard acid, monthly silicate , borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, Gluconate, lactobionate, dodecyl sulfonate and other similar salts. These salts may also include salts formed by reaction with alkali or alkaline earth metals, such as lithium, sodium, potassium, magnesium or calcium salts, or ammonium salts, or organic base salts such as methylamine, dimethylamine, trimethylamine, triethylamine. a salt of ethylenediamine, ethanolamine, meglumine, tris-(2-hydroxyethyl)amine, choline hydroxide, piperidine, morpholine, lysine or arginine. Further examples are found in the references of this patent, Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

A salt of the compound of the formula I or II can be obtained by suitably mixing a solution of the compound of the formula I or II with a desired acid or base. These salts may form a precipitate in the solution, may be collected by filtration, or may be recovered after evaporation of the solvent.

The compound of formula I or II may exist in unsolvated as well as solvated forms of a pharmaceutically acceptable solvent such as water, ethanol, and the like, and it is contemplated that the invention encompasses all solvated and unsolvated forms.

"Prodrug" means a compound that is a prodrug that releases the active drug in vivo by a chemical or physiological process (eg, by placement at physiological pH or by enzymatic action) after administration to the subject. For a discussion of the synthesis and use of prodrugs, see the article by T. Higuchi and W. Stella: "Prodrugs as Novel Delivery Systems," vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The contents of both articles are incorporated herein by reference. "Prodrugs" may also include metabolic precursors of the compounds of the invention, which may not be active when administered to a subject, but may be converted in vivo to a compound of the invention. Prodrugs can also be naturally occurring or chemically synthesized compounds.

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

In formula I:

n:1;

C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C _1-8 alkyl;

X is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ -, -CH(R ₄ )-;

Y is NR ₅ , -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

R ₁ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ , C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ , C _1-8 alkyl;

R ₇ is H, C _1-8 alkyl;

R ₈ is H, C _1-8 alkyl;

R ₉ is H, C _1-8 alkyl;

R ₁₀ is H, C _1-8 alkyl;

In formula II:

n:1;

A is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ -, -CH(R ₄ )-;

B is O, S, SO, SO ₂ , NR ₅ , -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C _1-8 alkyl;

Z is N, CH;

R ₂ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ , C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ , C _1-8 alkyl;

R ₇ is H, C _1-8 alkyl;

R ₈ is H, C _1-8 alkyl;

R ₉ is H, C _1-8 alkyl;

R ₁₀ is H, C _1-8 alkyl.

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

In formula I:

n:1;

C is a phenyl group substituted by one or more fluorine atoms;

X is O, S, NR ₃ , -CH(R ₄ )-;

Y is NR ₅ , -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

R ₁ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, C _1-8 alkyl;

In formula II:

n:1;

A is S, NR ₃ , -CH(R ₄ )CH ₂ -, -CH(R ₄ )-;

B is S, NR ₅ , -CH(R ₆ )CH ₂ -, -CH(R ₆ )-;

C is a phenyl group substituted by one or more fluorine atoms;

Z is N, CH;

R ₂ is H or NH ₂ ;

R ₃ is H, C _1-8 alkyl;

R ₄ is H, C _1-8 alkyl;

R ₅ is H, C _1-8 alkyl;

R ₆ is H, C _1-8 alkyl.

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

In formula I:

n:1;

C is a phenyl group substituted by a fluorine atom;

X is O, S, NH, -CH ₂ -;

Y is NCH ₃ , -CH(CH ₃ )-;

R ₁ is H or NH ₂ ;

In formula II:

n:1;

A is S;

B is -CH(CH ₃ )-;

C is a phenyl group substituted by a fluorine atom;

Z is CH;

R ₂ is H or NH ₂ .

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

In formula I:

n:1;

C is a phenyl group substituted by a fluorine atom;

X is O, S, NH, -CH ₂ -;

Y is NCH ₃ , -CH(CH ₃ )-;

R ₁ is H;

In formula II:

n:1;

A is S;

B is -CH(CH ₃ )-;

C is a phenyl group substituted by a fluorine atom;

Z is CH;

R ₂ is H;

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij] Quinoline-6-carboxylic acid

8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5, 4-ij]quinoline-6-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid

(S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid

(R)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid

(R)-8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij] Quinoline-6-carboxylic acid

(S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3, 4-ij]quinoline-6-carboxylic acid

(R)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij] Quinoline-6-carboxylic acid

9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]thiadine[2,3,4-ij]quinoline-6-carboxylic acid

8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij]quinoline-6- carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6 -carboxylic acid

(S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de] quin Porphyrin-6-carboxylic acid

9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6-carboxylic acid

8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6-carboxylic acid

(R)-8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de] quin Porphyrin-6-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid

(R)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid

(S)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid

(R)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid

6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-Hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid

5-amino-6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) Methyl)-4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3 -formic acid

3-fluoro-2-(4-((2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-hydroxy-piperidin-1-yl)-8-methyl-5-oxo-5,8-dihydro-[1,3]thiaza[3,2-a][1,8]naphthalene Pyridine-6-carboxylic acid

4-amino-3-fluoro-2-(4-((2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxy-piperidin-1-yl)-8-methyl-5-oxo-5,8-dihydro-[1,3]thiazepine [3,2-a][1 , 8] naphthyridine-6-carboxylic acid

(S)-8-(4-((2,3-difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid

(S)-8-(4-((2,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid

(S)-8-(4-((2,6-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid

(S)-8-(4-((3,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid

(S)-8-(4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid

(S)-8-(4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid

(S)-8-(4-((4,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 -ij]quinoline-2-carboxylic acid

(S)-8-(4-((3,4-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) )oxy)methyl)-4-hydroxypiperidone Pyridin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2-carboxylic acid

(S)-9-fluoro-8-(4-((2,3,5-trifluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)) -pyridin-3-yl)oxy)methyl)-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2 , 1-ij]quinoline-2-carboxylic acid

(S)-9-fluoro-8-(4-((3,4,6-trifluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)) -pyridin-2-yl)oxy)methyl)-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2 , 1-ij]quinoline-2-carboxylic acid

(S)-8-(4-((2,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 -ij]quinoline-2-carboxylic acid

(S)-8-(4-((3,6-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 -ij]quinoline-2-carboxylic acid

(S)-8-(4-((2,4-difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 -ij]quinoline-2-carboxylic acid

(S)-8-(4-((4,6-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 -ij]quinoline-2-carboxylic acid

7-(4-((2,3-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid

7-(4-((2,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid

7-(4-((3,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid

7-(4-((2,6-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid

6-fluoro-7-(4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)) 4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylate acid

6-fluoro-7-(4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)) 4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylate acid

7-(4-((4,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

7-(4-((3,4-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

7-(4-((2,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

7-(4-((3,6-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

7-(4-((4,6-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

7-(4-((2,4-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

6-fluoro-7-(4-((3,4,6-trifluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridine-2- Ethyl)oxy)methyl)-4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine [3,2-a] Quinoline-3-carboxylic acid

6-fluoro-7-(4-((2,4,5-trifluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridine-2- Ethyl)oxy)methyl)-4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine [3,2-a] Quinoline-3-carboxylic acid

5-amino-7-(4-((2,5-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

5-amino-7-(4-((2,6-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

5-amino-7-(4-((3,5-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid

5-amino-6-fluoro-7-(4-hydroxy-4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidine-3) -yl)-phenoxy)methyl)piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quina Porphyrin-3-carboxylic acid

5-amino-6-fluoro-7-(4-hydroxy-4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidine-3) -yl)-phenoxy)methyl)piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quina Porphyrin-3-carboxylic acid

One embodiment of the invention comprises a group of compounds of formula I, the compounds of which are structurally characterized by:

9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij] Quinoline-6-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid

(S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid

6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-Hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid

One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:

(S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid

6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-Hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid

The invention further comprises a compound of formula I or II, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for the treatment and prevention of human or animal diseases Aspect of the application.

"Treatment" when referring to a disease means treating the disease in a patient or animal, or although the animal or patient is affected by the disease, some or all of the symptoms of the disease are alleviated or eliminated.

By "preventing" a reference to a disease means that the patient or animal does not develop the disease, or that although the animal or patient is affected by the disease, some or all of the symptoms of the disease are alleviated or absent.

"Animals" include canines, felines, equines, bovidae, pigs, etc., such as dogs, cats, horses, cows, pigs, and the like.

The invention further comprises a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for use in the treatment and prevention of bacterial infections Application in human or animal diseases.

The present invention also includes a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for treating and preventing brain and heart The use of human or animal diseases caused by bacterial infections in the respiratory tract, skin, lungs, gastrointestinal tract, eyes, ears, breast, and urinary tract.

The present invention also includes a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for treating and preventing skin, gastrointestinal Use of human or animal diseases caused by bacterial infections in the tract, breast, and urinary tract.

The invention further comprises a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for the treatment and prevention of gastrointestinal sites The application of bacterial infections to human or animal diseases.

The invention further comprises an infectious bacterium preferably comprising a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for prevention and treatment But not limited to: Staphylococcus, Streptococcus, Enterococcus, Polymorpha spp., Clostridium spp., Clostridium difficile, Clostridium perfringens, Mycobacterium tuberculosis, Mycobacterium tuberculosis or tuberculosis Mycobacteria.

The invention further comprises an infectious bacterium preferably comprising a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for prevention and treatment However, it is not limited to: Staphylococcus, Streptococcus, Enterococcus, Polymorpha spp., Clostridium spp., Clostridium difficile, Clostridium perfringens.

The present invention includes a pharmaceutical composition comprising an effective amount of a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug thereof , and one or more pharmaceutically acceptable excipients.

Routes of administration of the pharmaceutical compositions encompassed by the invention: oral, parenteral or topical.

abbreviation:

The following abbreviations are used throughout the specification and examples:

CFU: colony forming unit

DCM: dichloromethane

DMSO: dimethyl sulfoxide

EA: ethyl acetate

Eq.: equivalent

MeOH: methanol

MIC: minimum inhibitory concentration

MRSA: methicillin-resistant Staphylococcus aureus

PE: petroleum ether

pH: hydrogen ion concentration index

TEA: Triethylamine

THF: tetrahydrofuran

VRE: vancomycin-resistant enterococci

Compounds of formula I can be obtained by:

Route 1:

According to Route 1, an inert polar solvent is selected to dissolve the compound S1 and S2 (or S4), then an inorganic base or an organic base is added, and the mixture is heated to 100-120 ° C for nucleophilic substitution reaction, and after overnight reaction, by thin layer chromatography or After high performance liquid chromatography-mass spectrometry was used to determine that most of the reactants had been converted to the product S3 or S5, the reaction was stopped, neutralized to pH = 6 using a mineral acid solution, and the solid was precipitated. After filtration, the solid was collected and subjected to column chromatography. The final product S3 is obtained after recrystallization. The solvent should be stable under the reaction conditions and not participate in the reaction, and should be able to completely dissolve S1 and S2 (or S4), preferably the solvent is DMSO.

If R ₁₂ is a hydrogen atom, S3 or S5 is the final product I or II.

If R ₁₂ is an ethyl group, it is necessary to dissolve S3 or S5 in a mixed solvent of a polar solvent of methanol and tetrahydrofuran, add an alkali-free lithium hydroxide, and carry out a hydrolysis reaction under heating. When all the esters are hydrolyzed to an acid, the reaction is stopped. Adding mineral acid solution to neutralize to pH=6, precipitate solid, filter, collect solid, after column chromatography or recrystallization, to obtain final product I or II

Path 2:

In some embodiments, the nucleophilic substitution yield of S1 and S2 is not high, so the reaction of S2 with boron triacetate to form S6 can improve the yield (S6 preparation method such as Chem. Pharm. Bull. (1996), 44(4), 642-645)). S1 and S6 are dissolved in DMF (N,N-dimethylformamide), heated to 50 ° C for 12 hours, the reaction solution is cooled to room temperature, poured into ice water, solid is precipitated, filtered, and the obtained solid is added to hydrogen. Sodium oxide was stirred in a mixed solution of water and acetonitrile until clarification, dilute hydrochloric acid was added dropwise to pH = 1, a solid was precipitated, and the solid was collected, and purified by column chromatography to give the final compound I.

DRAWINGS

Figure 1 is a chemical structural formula for the synthesis of Compound I.

2 is a chemical structural formula of the synthesized compound II.

Figure 3 is a schematic diagram of a synthetic compound of Formula I.

Figure 4 is a schematic diagram of a synthetic compound of Formula II.

Figure 5 is another path diagram of the synthetic compound Formula I.

Detailed ways

The specific embodiments of the present invention are set forth in the following examples, which are intended to illustrate the invention in detail and not to limit the scope thereof.

Table 1. Structure and naming of Examples 1-4

Examples 1-4 were synthesized from Route 1, and the specific experimental details are as follows:

Example 1: 9-Fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl -4-hydroxy-piperidine -1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij]quinoline-6- carboxylic acid

(R)-3-[3-Fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-5-hydroxymethyl-oxazolidin-2-one and 9- Fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4]quinoline-6-carboxylic acid (1 eq.) It was added to DMSO in turn, and then TEA (5 eq.) was added, and the reaction system was reacted at 120 ° C for 20 hours. The solution was cooled to room temperature and the pH was adjusted to pH <6 with 50% sulfuric acid, filtered, and the filtrate was concentrated, and then recrystallized from PE: EA = 2:1 to give the desired product as pale white solid ( 516 g, 30%).

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 15.11 (s, 1H), 8.76 (s, 1H), 7.66-7.53 (m, 2H), 7.21. (dd, J = 14.4, 5.2 Hz, 2H ), 5.32 (s, 2H), 5.22 (s, 1H), 4.82 (s, 1H), 4.71-4.66 (m, 1H), 4.05 (t, J = 8.8 Hz, 1H), 3.88 (s, 2H) , 3.83-3.77(m,1H), 3.67(d,J=12.8Hz,1H),3.57-3.50(m,3H),3.23(s,2H),3.02(s,3H),1.88(t,J =11.0 Hz, 2H), 1.65 (d, J = 12.8 Hz, 2H).

ESI-MS (m/z): 602.9 [M+H]+.

Example 2: (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxymethyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4 -ij]quinoline-6-carboxylic acid

(R)-3-[3-Fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-5-hydroxymethyl-oxazole according to the method described in Example 1. Alkan-2-one and (S)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij]- Reaction of quinoline-6-carboxylic acid (1 eq.) gave a white solid (m.

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 15.26 (s, 1H), 8.96 (s, 1H), 7.58 (d, J = 12.4 Hz, 2H), 7.27-7.18 (m, 2H), 5.22 (t, J = 5.6 Hz, 1H), 4.97 - 4.86 (m, 1H), 4.79 (s, 1H), 4.72-4.65 (m, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.39 (s, 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.88 (s, 2H), 3.80 (dd, J = 8.8, 6.4 Hz, 1H), 3.72-3.62 (m, 1H), 3.58- 3.46 (m, 3H), 3.24 (d, J = 11.6 Hz, 2H), 1.96-1.79 (m, 2H), 1.64 (d, J = 12.8 Hz, 2H), 1.45 (d, J = 6.8 Hz, 3H) ).

ESI-MS (m/z): 602.0 [M+H] ⁺ .

Example 3: (S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidine-3- -Phenoxymethyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2 ,3,4-ij]quinoline-6-carboxylic acid

(R)-3-[3-Fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-5-hydroxymethyl-oxazole according to the method described in Example 1. Alkan-2-one (1.1 eq.) and 3.2 (500 mg, 1.69 mmol, 1 eq.) were added to DMSO in turn, then TEA (1.09 g, 8.45 mmol, 5 eq.) was added and the reaction was reacted at 120 ° C for 20 hours. . The solution was cooled to room temperature and the pH was adjusted to pH <6 with 50% sulphuric acid. The filtrate was concentrated, filtered, and brine (100 mL). The organic phase was concentrated and purified with EtOAc EtOAc EtOAc EtOAc

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 15.09 (s, 1H), 8.68 (s, 1H), 7.59 (d, J = 14.4 Hz, 1H), 7.29-7.12 (m, 2H), 6.91(s,2H), 5.23(s,1H),4.82-4.61(m,3H), 4.38(d,J=11.2Hz,1H), 4.16-3.99(m,2H),3.87(s,2H) , 3.83-3.76 (m, 1H), 3.67 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 14.4 Hz, 1H), 3.50-3.42 (m, 2H), 3.24 (s, 2H), 1.93-1.75 (m, 2H), 1.63 (d, J = 12.0 Hz, 2H), 1.38 (d, J = 6.4 Hz, 3H).

ESI-MS (m/z): 617.0 [M+H] ⁺ .

Example 4: 6-Fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl) 4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3- Formic acid

Step 1: 6-Fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl) -4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid Ethyl ester

Ethyl 6,7-difluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylate (1.2 g, 3.86 mmol, 1 eq.) and (R)-3-[3-fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-5-hydroxymethyl-oxazolidine- 2-ketone (1.44 g, 4.24 mmol, 1.1 eq.) and TEA (1.97 g, 19.29 mmol, 5 eq.) were sequentially added to DMSO (20 mL), stirred and heated to 100 ° C for 20 hours, and the reaction solution was cooled to room temperature. After adjusting the pH <6 with 50% sulphuric acid, a large amount of solid was precipitated, and the obtained solid was purified by silica gel column chromatography (DCM: MeOH = 20:1) to afford white solid (1.

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 10.28 (s, 1H), 7.68 (d, J = 13.6 Hz, 1H), 7.58 (d, J = 14.4 Hz, 1H), 7.22 (d, J = 5.2 Hz, 2H), 6.85 (d, J = 7.2 Hz, 1H), 6.19 (q, J = 6.4 Hz, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.88 (s, 1H) , 4.73-4.66 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.05 (t, J = 8.8 Hz, 1H), 3.89 (s, 2H), 3.84-3.77 (m, 1H), 3.70-3.62 (m, 1H), 3.55 (dd, J = 10.8, 6.4 Hz, 1H), 3.42 (d, J = 10.4 Hz, 2H), 3.20 (dd, J = 24.4, 12.4 Hz, 2H), 3.05 (dd, J = 14.4, 6.8 Hz, 4H), 2.04 (d, J = 6.4 Hz, 3H), 1.89 (t, J = 10.6 Hz, 2H), 1.70 (d, J = 12.4 Hz, 2H), 1.26 (d, J = 7.2 Hz, 3H).

Step 2: 6-Fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl) -4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid

The white solid obtained in step 1 (1.58 g, 2.5 mmol, 1 eq.) was dissolved in a mixture of methanol (20mL) and THF (20mL). The mixture was stirred at room temperature for 2 hours. After adjusting the pH <6 with 50% sulfuric acid, the solid product was obtained by filtration. The crude solid was isolated with EtOAc EtOAc EtOAc (EtOAc:

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 14.70 (s, 1H), 7.79 (d, J = 13.6 Hz, 1H), 7.58 (d, J = 14.4 Hz, 1H), 7.27-7. m, 2H), 6.96 (d, J = 6.4 Hz, 1H), 6.40 (s, 1H), 5.23 (t, J = 5.6 Hz, 1H), 4.90 (s, 1H), 4.68 (dd, J = 8.8 , 5.4 Hz, 1H), 4.04 (t, J = 8.8 Hz, 1H), 3.90 (s, 2H), 3.82-3.75 (m, 1H), 3.71-3.62 (m, 1H), 3.57-3.50 (m, 3H), 3.29-3.23 (m, 2H), 2.11 (d, J = 5.6 Hz, 3H), 1.90 (t, J = 10.8 Hz, 2H), 1.71 (d, J = 12.8 Hz, 2H).

ESI-MS (m/z): 604.1 [M+H] ⁺ .

Table 2. Structure and naming of Example 5

Example 5 was synthesized by Route 2, and the specific experimental details are as follows:

Example 5: (S)-9-fluoro-8-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxymethyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline -2-carboxylic acid

(S)-8,9-Difluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2-carboxylic acid diacetic acid Boron complex (2.5 g, 5.5 mmol), (R)-3-[3-fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-5-hydroxymethyl- Oxazolidine-2-one (3.18 g, 9.35 mmol) and TEA (1.89 g, 18.7 mmol) were mixed with DMF (30 mL) and stirred at 50 ° C for 12 hours. The reaction solution was cooled to room temperature and poured into ice water (300 mL) The solid was filtered. After roughly drying, the obtained product was added to a mixed solution of a 3.5% (w/w) aqueous sodium hydroxide solution (25 mL) and acetonitrile (10 mL). The mixture was stirred at normal temperature until it became a clear solution. Concentrated hydrochloric acid was added to this solution until pH = 1 and filtered to give a solid.

¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 8.97 (s, 1H), 7.88 (d, J = 12.8 Hz, 1H), 7.59 (d, J = 12.0 Hz, 1H), 7.28 - 7.21. m, 2H), 5.22 (s, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 4.69 (s, 1H), 4.05 (t, J = 9.2 Hz, 1H), 3.91 (s, 2H) ), 3.82-3.78 (m, 1H), 3.67 (d, J = 12.8 Hz, 2H), 3.55 (d, J = 10.4 Hz, 1H), 3.18 - 2.91 (m, 5H), 2.17 - 2.05 (m, 2H), 2.00-1.94 (m, 1H), 1.88-1.75 (m, 1H), 1.68 (t, J = 13.6 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H).

ESI-MS (m/z): 600.2 [M+H] ⁺ .

The minimum inhibitory concentrations of Examples 1-5 and the efficacy of the mouse C. difficile infection model:

The minimum inhibitory concentration (MIC) test of the examples was performed using a standard broth double dilution method. The antibacterial drug has a concentration range of 256-0.002 mg/L. The final concentration of the test solution was about 5 x 10 ⁵ CFU/ml. The high dose (10 mg) of Example 3 was administered for 5 consecutive days to substantially eliminate the C. difficile in the intestine of the mice, and showed good protection against the mice infected with Clostridium difficile during the treatment period. The rate is 100%, and the efficacy in vivo is better than oxazolamide. The strains tested included:

1) 6 standard quality control strains:

Staphylococcus aureus ATCC29213,

Streptococcus pneumoniae ATCC49619,

Enterococcus faecalis ATCC29212,

Escherichia coli ATCC25922,

Haemophilus influenzae ATCC49247.

2) 3 clinical isolates:

Methicillin-resistant Staphylococcus aureus (MRSA),

Levofloxacin resistant to a strain of Streptococcus agalactiae,

One strain of vancomycin-resistant Enterococcus faecium.

Experimental results: The MICs of the disclosed examples against the standard strains and the resistant strains are far superior to the current clinically used super antibiotic linezolid, and the MICs of all the examples are close to or better than the oxazolamide. (cadazolid), wherein Examples 4 and 5 have a 4-fold inhibitory activity against Levofloxacin-resistant Streptococcus agalactiae, which is 4-fold higher than that of indoxazol, and Example 5 except for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus The inhibitory activity is comparable to that of indazolamide, and the inhibitory activity against other test bacteria is better than that of indazolamide, especially for common S. aureus, which is 30 times more potent than indoxazolamide.

Table 3. Minimum inhibitory concentration (mg/L) of Examples 1-5

Claims (17)

1. a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof, wherein:

   

   In formula I:

   n: 0, 1, 2 or 3;

   C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from F, Cl, Br or C _1-8 alkyl;

   X is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ - or -CH(R ₄ )-;

   Y is NR ₅ , -CH ₂ -, -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   R ₁ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ or C _1-8 alkyl;

   R ₇ is H or C _1-8 alkyl;

   R ₈ is H or C _1-8 alkyl;

   R ₉ is H or C _1-8 alkyl;

   R ₁₀ is H or C _1-8 alkyl;

   In formula II:

   n: 0, 1, 2 or 3;

   A is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ - or -CH(R ₄ )-;

   B is O, S, SO, SO ₂ , NR ₅ , -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from F, Cl, Br or C _1-8 alkyl;

   Z is N, or CR ₁₁ ;

   R ₂ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ or C _1-8 alkyl;

   R ₇ is H or C _1-8 alkyl;

   R ₈ is H or C _1-8 alkyl;

   R ₉ is H or C _1-8 alkyl;

   R ₁₀ is H or C _1-8 alkyl;

   R ₁₁ is H or a C _1-8 alkyl group.
2. A compound of formula I or II according to claim 1 or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof, characterized by:

   In formula I:

   n:1;

   C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br and C _1-8 alkyl;

   X is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ - or -CH(R ₄ )-;

   Y is NR ₅ , -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   R ₁ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ or C _1-8 alkyl;

   R ₇ is H or C _1-8 alkyl;

   R ₈ is H or C _1-8 alkyl;

   R ₉ is H or C _1-8 alkyl;

   R ₁₀ is H or C _1-8 alkyl;

   In formula II:

   n:1;

   A is O, S, SO, SO ₂ , NR ₃ , -CH(R ₄ )CH ₂ - or -CH(R ₄ )-;

   B is O, S, SO, SO ₂ , NR ₅ , -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br and C _1-8 alkyl;

   Z is N or CH;

   R ₂ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H, F, Cl, Br, OR ₇ , S R ₇ , NR ₇ R ₈ or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H, F, Cl, Br, OR ₉ , S R ₉ , NR ₉ R ₁₀ or C _1-8 alkyl;

   R ₇ is H or C _1-8 alkyl;

   R ₈ is H or C _1-8 alkyl;

   R ₉ is H or C _1-8 alkyl;

   R ₁₀ is H or a C _1-8 alkyl group.
3. A compound of formula I or II according to claim 2, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof, characterized by:

   In formula I:

   n:1;

   C is a phenyl group substituted by one or more fluorine atoms;

   X is O, S, NR ₃ or -CH(R ₄ )-;

   Y is NR ₅ , -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   R ₁ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H or C _1-8 alkyl;

   In formula II:

   n:1;

   A is S, NR ₃ , -CH(R ₄ )CH ₂ - or -CH(R ₄ )-;

   B is S, NR ₅ , -CH(R ₆ )CH ₂ - or -CH(R ₆ )-;

   C is a phenyl group substituted by one or more fluorine atoms;

   Z is N or CH;

   R ₂ is H or NH ₂ ;

   R ₃ is H or C _1-8 alkyl;

   R ₄ is H or C _1-8 alkyl;

   R ₅ is H or C _1-8 alkyl;

   R ₆ is H or a C _1-8 alkyl group.
4. A compound of formula I or II according to claim 3, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvent thereof a compound, hydrate or prodrug characterized by:

   In formula I:

   n:1;

   C is a phenyl group substituted by a fluorine atom;

   X is O, S, NH or -CH2-;

   Y is NCH3 or -CH(CH3)-;

   R1 is H or NH2;

   In formula II:

   n:1;

   A is S;

   B is -CH(CH3)-;

   C is a phenyl group substituted by a fluorine atom;

   Z is CH;

   R2 is H or NH2.
5. A compound of formula I or II according to claim 4, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof, which is characterized by:

   In formula I:

   n:1;

   C is a phenyl group substituted by a fluorine atom;

   X is O, S, NH or -CH2-;

   Y is NCH3, -CH(CH3)-;

   R1 is H;

   In formula II:

   n:1;

   A is S;

   B is -CH(CH3)-;

   C is a phenyl group substituted by a fluorine atom;

   Z is CH;

   R2 is H.
6. A compound according to claims 1-5, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof, characterized in that the compound is selected from the group consisting of:

   9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij] Quinoline-6-carboxylic acid;

   8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5, 4-ij]quinoline-6-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid;

   (S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid;

   (R)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid;

   (R)-8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij] Quinoline-6-carboxylic acid;

   (S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3, 4-ij]quinoline-6-carboxylic acid;

   (R)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij] Quinoline-6-carboxylic acid;

   9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]thiadine[2,3,4-ij]quinoline-6-carboxylic acid;

   8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]thiazide [2,3,4-ij]quinoline-6- carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6 -carboxylic acid;

   (S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de] quin Porphyrin-6-carboxylic acid;

   9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6-carboxylic acid;

   8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)- 4-hydroxy-piperidin-1-yl)-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de]quinoxaline-6-carboxylic acid;

   (R)-8-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-1,2,3,7-tetrahydropyridine [1,2,3-de] quin Porphyrin-6-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid;

   (R)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid;

   (S)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- carboxylic acid;

   (R)-10-amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid;

   6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid;

   5-amino-6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) Methyl)-4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3 -formic acid;

   3-fluoro-2-(4-((2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-hydroxy-piperidin-1-yl)-8-methyl-5-oxo-5,8-dihydro-[1,3]thiaza[3,2-a][1,8]naphthalene Pyridine-6-carboxylic acid;

   4-amino-3-fluoro-2-(4-((2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxy-piperidin-1-yl)-8-methyl-5-oxo-5,8-dihydro-[1,3]thiazepine [3,2-a][1 , 8] naphthyridine-6-carboxylic acid;

   (S)-8-(4-((2,3-difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid;

   (S)-8-(4-((2,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid;

   (S)-8-(4-((2,6-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid;

   (S)-8-(4-((3,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)methyl) )-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline- 2-carboxylic acid;

   (S)-8-(4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid;

   (S)-8-(4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-phenoxy)) Methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quina Porphyrin-2-carboxylic acid;

   (S)-8-(4-((4,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   (S)-8-(4-((3,4-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   (S)-9-fluoro-8-(4-((2,3,5-trifluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)) -pyridin-3-yl)oxy)methyl)-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2 , 1-ij]quinoline-2-carboxylic acid;

   (S)-9-fluoro-8-(4-((3,4,6-trifluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)) -pyridin-2-yl)oxy)methyl)-4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2 , 1-ij]quinoline-2-carboxylic acid;

   (S)-8-(4-((2,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   (S)-8-(4-((3,6-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   (S)-8-(4-((2,4-difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-3-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   (S)-8-(4-((4,6-difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-pyridin-2-yl) Oxy)methyl)-4-hydroxypiperidin-1-yl)-9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1 - ij] quinoline-2-carboxylic acid;

   7-(4-((2,3-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid;

   7-(4-((2,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid;

   7-(4-((3,5-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid;

   7-(4-((2,6-Difluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxyl Piperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiaza[3,2-a]quinoline-3-carboxylic acid;

   6-fluoro-7-(4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)) 4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylate acid;

   6-fluoro-7-(4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)phenoxy)) 4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylate acid;

   7-(4-((4,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   7-(4-((3,4-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   7-(4-((2,5-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   7-(4-((3,6-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   7-(4-((4,6-Difluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   7-(4-((2,4-Difluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridin-3-yl)oxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   6-fluoro-7-(4-((3,4,6-trifluoro-5-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridine-2- Ethyl)oxy)methyl)-4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine [3,2-a] Quinoline-3-carboxylic acid;

   6-fluoro-7-(4-((2,4,5-trifluoro-6-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)pyridine-2- Ethyl)oxy)methyl)-4-hydroxypiperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine [3,2-a] Quinoline-3-carboxylic acid;

   5-amino-7-(4-((2,5-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   5-amino-7-(4-((2,6-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   5-amino-7-(4-((3,5-difluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)) 4-hydroxypiperidin-1-yl)-6-fluoro-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline 3-carboxylic acid;

   5-amino-6-fluoro-7-(4-hydroxy-4-((2,3,5-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidine-3) -yl)-phenoxy)methyl)piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quina Porphyrin-3-carboxylic acid; and

   5-amino-6-fluoro-7-(4-hydroxy-4-((2,3,6-trifluoro-4-((R)-5-hydroxymethyl-2-oxooxazolidine-3) -yl)-phenoxy)methyl)piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quina Porphyrin-3-carboxylic acid.
7. A compound according to claim 6 or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, characterized in that said compound is selected from the group consisting of:

   9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxoxazol-3-yl)-phenoxy)methyl)-4 -hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij] Quinoline-6-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3,4-ij] Quinoline-6-carboxylic acid;

   (S)-8-Amino-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-benzene Oxy)methyl)-4-hydroxy-piperidin-1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazine [2,3, 4-ij]quinoline-6-carboxylic acid;

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- Carboxylic acid; and

   6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-Hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid.
8. A compound according to claim 7 or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, characterized in that said compound is selected from the group consisting of:

   (S)-9-fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy) A 4-hydroxy-piperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2- Carboxylic acid; and

   6-fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxy)methyl)- 4-Hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid.
9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for use in the treatment or prevention of a human or animal disease application.
10. A compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for use in the treatment and prevention of a bacterial infection caused by a human or Application in animal diseases.
11. A compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for treating and preventing brain, heart, and respiratory tract Use of human or animal diseases caused by bacterial infections in the skin, lungs, gastrointestinal tract, eyes, ears, breast or urinary tract.
12. A compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for treating and preventing skin, gastrointestinal tract, Application of human or animal diseases caused by bacterial infection of the breast or urinary tract.
13. A compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for the treatment and prevention of bacterial infections in the gastrointestinal tract The resulting use of human or animal diseases.
14. The bacteria according to claims 9-13 are preferably, but not limited to, staphylococcus, streptococcus, enterococci, polymorphic spp., Clostridium spp., Clostridium difficile, Clostridium perfringens, tuberculosis Mycobacteria, Mycobacterium tuberculosis and Mycobacterium tuberculosis.
15. The bacterium according to claim 14 is preferably, but not limited to, Staphylococcus, Streptococcus, Enterococcus, Polymorpha spp., Clostridium spp., Clostridium difficile, and Clostridium perfringens.
16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-8, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate or prodrug thereof , and one or more pharmaceutically acceptable excipients.
17. The route of administration of the pharmaceutical composition of claim 16 includes oral, parenteral or topical administration.

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