WO2011137758A1

WO2011137758A1 - Novel ketolide derivatives, preparation methods and pharmaceutical compositions thereof

Info

Publication number: WO2011137758A1
Application number: PCT/CN2011/073762
Authority: WO
Inventors: 梁建华; 安堃
Original assignee: 北京理工大学
Priority date: 2010-05-07
Filing date: 2011-05-06
Publication date: 2011-11-10
Also published as: CN102234302A; CN102234302B

Abstract

Provided are ketolide derivatives of general formula (I) or (II), or pharmaceutically acceptable salts or esters thereof formed with inorganic acids or organic acids. In the formula, Ar represents aromatic heterocyclic alkyl or substituted aromatic heterocyclic alkyl; and X is hydrogen or fluorine. Preparation methods of the compounds of general formula (I) or (II), pharmaceutical compositions containing the same and their uses as anti-infectious drugs are also provided.

Description

Novel ketone lactone derivative, preparation method and pharmaceutical composition thereof

The invention belongs to the field of chemical synthesis and pharmacy, and relates to a novel ketone lactone (9-0-arylpropynyl ketolide derivative) and a preparation method thereof, and the use of the compound as an anti-infective drug and a corresponding drug combination. Background technique

The fourteen-membered macrolide antibiotic-erythromycin has been widely used in clinical practice for more than 50 years, especially for those who are allergic to penicillin. The second generation of erythromycin, such as clarithromycin, azithromycin, roxithromycin, etc., overcomes the problem of erythromycin resistance to acid. Currently, clinically isolated strains of respiratory tract bacteria are increasingly showing resistance, such as Streptococcus pneumoniae, S. pneumoniae, S. aureus, and S. pyogenes. Wait. A survey conducted by the previous world from 1997 to 1999 (Hoban, DJ et al., Clin. Infect. Dis. 2001, 32, S81-S93.) showed: 1601 strains of pneumonia isolated clinically in 34 hospitals in the United States. Among the cocci, 29.5% of the strains were resistant to penicillin, 19.3% to erythromycin, and 13.2% to tetracycline. Therefore, the task of developing novel antibiotics with novel structures and resistance to drug-resistant bacteria is imminent.

Compared with erythromycin, clarithromycin and azithromycin, the third-generation erythromycin derivative-ketolide has activity against multi-type resistant bacteria (Agouridas, C. et al., J. Med. Chem. 1998, 41: 4080-4100). Its structure-activity relationship indicates that the introduction of 3-carbonyl avoids the resistance-induced resistance of 3-carragedan in the original macrolide, and also proves that 3-clad sugar is not a necessary group. However, the introduction of 3-carbonyl alone could not increase the activity of resistant bacteria. The newly introduced aromatic side chain on the macrocycle produced a new binding target for the resistant bacteria, thus obtaining anti-resistant bacteria activity. Therefore, 3-carbonyl and aromatic side chains constitute important structural features of ketolactone antibiotics.

The binding position of the aromatic side chain on the ketolide and its side chain length directly affect the strength of its anti-resistant bacteria. For example, the aromatic side chain of Telithromycin is attached to 11,12-amino phthalate and has a length of 4 atoms (Denis A. et al., / oor. Med. Chem. Lett. 1999, 9'. 3075- 3080. ); The aromatic side chain of Cethromycin is attached to 6-0H and has a length of 3 atoms (Or YS et al, J. Med. Chem. 2000, 43: 1045-1049). In the derivative of erythromycin, after conversion of 9-carbonyl to oxime hydroxyl group, 9-decanoic acid formed by linking with various sulfhydryl groups or aromatic hydrocarbon groups is an important modification direction (Gasc JC et al., J. Antibiot. 1991, 44: 313-330; Kawashima Y. et al., Chem. Pharm. Bull. 1994, 42: 1088-1095; Kato H. et al., WO00/61593; Pandey, D. et al., Bioorg. Med. Chem. 2004, 12, 3807-3813. ) ₀ Recently, the introduction of oxime ether has also been applied to the search for ketolides with antibiotic resistance (Agouridas, C. et al., J. Med. Chem. 1998, 41: 4080-4100; Chen SX Et al., J. Antibiot. 2001, 54: 506-509; Ma Z. et al., US2002/0019355; Searle XB, WO03/090761; Akritopoulou-Zanze I. et al., Bioorg. Med. Chem. Lett. 2004, 14: 3809 —3813; Nomura T. et al, Bioorg. Med. Chem. 2005, 13: 6615-6628; Nomura T. et al, Bioorg. Med. Chem. 2006, 14: 3697-3711; Nam, G. et al, Bioorg. Med Chem. Lett. 2010, 20: 2671-2674), however, the activity of anti-resistant bacteria of the currently disclosed 9-nonyl ether ketone lactone is still less than ideal.

In short, a technical problem that needs to be solved urgently by those skilled in the art is: How to provide a novel 9-oxime ether ketone lactone derivative, which can better adapt to industrial production, and has a comparative effect on respiratory diseases such as Streptococcus pneumoniae. Good anti-allergic and anti-resistant bacteria activity. Summary of the invention

The technical problem to be solved by the present invention is to provide a novel ketolide compound (9-arylpropynyl ketolide derivative) and a synthesis method thereof, and the use of the compound as an anti-infective drug and a corresponding drug combination Things. The compound and the preparation method thereof can be better adapted to industrial production, and the compound has good anti-sensitive bacteria and anti-resistant bacteria activity against respiratory diseases and the like. In order to solve the above problems, the present invention discloses a compound having the following formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof formed with an inorganic or organic acid:

I π

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is hydrogen or fluorine. Preferably, the Ar is a nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group; or Ar is a substituted nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group.

Preferably, the Ar is imidazolyl, pyridyl, pyrimidinyl, benzopyrazinyl, benzoxazinyl, quinolinyl, isoquinolyl, imidazolylphenyl, thienylphenyl, fluorenyl Or thiophenyl; or, Ar is substituted imidazolyl, substituted pyridyl, substituted pyrimidinyl, substituted benzopyrazinyl, substituted benzoxazinyl, substituted quinolyl, substituted isoquinolyl, substituted imidazolylphenyl And a substituted thienylphenyl group, a substituted indenyl group, a substituted thienyl group.

Preferably, the Ar is 2-pyridyl, 3-pyridyl, 5-pyrimidinyl, 3-quino-p-linyl, 4-iso-p-quinolinyl, 4-p-quino-p-linyl, 5-iso-quinionyl " ¹林基, 5-^1^林基, 6-^1^林基, 4-(1-imisyl)phenyl, 4-(2-thienyl)phenyl, 5-nonyl, 2 -Thienyl, 2-[5-(2-pyridyl)]thienyl, or 2-(5-benzoyl)thienyl.

Preferably, the inorganic acid is selected from the group consisting of hydrochloric acid, acid, hydrobromic acid or phosphoric acid; the organic acid is selected from the group consisting of acetic acid, malonic acid, sulfonic acid, succinic acid, p-benzoic acid, citric acid, maleic acid. , fumaric acid or stearic acid.

According to another aspect of the present invention, there is also disclosed a method of preparing the compound of claim 1, comprising:

(1) A compound having the following formula (III):

Wherein the R group corresponds to an acetyl group, a benzoyl group or a trimethylsilyl group; the protecting reagent is used to achieve an R protecting group;

(2) selectively replacing the acetyl group on the 9-fluorenyl hydroxyl group of the compound of the step (1) in a THF single solvent, a DMF single solvent or a THF/DMS0 mixed solvent under the action of a propargylating agent and a strong base. a benzoyl or trimethylsilyl group; then oxidizing 3-0H to a 3-carbonyl group with an oxidizing reagent to give a compound of the formula (IV);

Alternatively, in the THF single solvent, DMF single solvent or THF/DMS0 mixed solvent, the acetyl group on the 9-fluorenyl hydroxyl group of the compound of the step (1) is selectively substituted by the combination of a propargylating agent and a strong base. a benzoyl or trimethylsilyl group; then, a ring closure reagent is used to ring 11, 12-0H, and then an oxidizing reagent is used to oxidize 3-0H to a 3-carbonyl group to obtain a formula (V).

Wherein the R group corresponds to an acetyl group, a benzoyl group or a trimethylsilyl group; (3) Substituting a heteroaromatic hydrocarbon (for example, a halo (for example, a brominated or iodo) heteroaromatic hydrocarbon) with a 9-fluorene hydroxyl group in the acetonitrile, THF or DMF solvent, catalyzed by a palladium salt and a copper salt. The propargyl group acts to form a heteroaromatic side chain, and the 2-0-R protecting group is removed to obtain a compound having the following formula (I) or (II);

Alternatively, in the acetonitrile, THF or DMF solvent, catalyzed by a palladium salt and a copper salt, substituted heteroaromatic hydrocarbons (for example, halo (for example, brominated or iodo) heteroaromatic hydrocarbons) and propargylpropane on 9-fluorene hydroxyl groups. The base acts to form a heteroaromatic side chain; further introduces a fluorine atom at the 2-position and removes 2 -0-R

I II

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is hydrogen or fluorine. 0- The ratio of the ratio of the ratio of the strong base to the compound of the step (1) is 1. 0- 4. 0.

Preferably, the protective reagent is selected from the group consisting of acetic anhydride, benzoic anhydride, tridecylchlorosilane or hexamethylenedisilylamine; the propargylating agent is selected from the group consisting of propargyl bromide or propargyl iodide; The strong base is selected from potassium t-butoxide, potassium hydroxide, sodium hydride, or hexamethyldisilazide; the ring-closing agent is selected from the group consisting of triphosgene, phosgene, or trichlorodecyl chlorodecanoate; The oxidizing agent is selected from the group consisting of N-chlorosuccinimide/disulfonium sulfide, or an oxidizing combination reagent containing disulfoxide; the palladium salt is selected from dichlorobis(triphenylphosphine)palladium, or tetra( Triphenylphosphine)palladium; the copper salt is selected from cuprous iodide or cuprous bromide. According to another aspect of the present invention, there is also disclosed a pharmaceutical composition for antibacterial treatment comprising an antibacterially effective amount of a compound having the following general formula (I) or (II), or a medicament thereof

I Π

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is hydrogen or fluorine. According to another aspect of the present invention, the present invention also provides a compound of the above formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof for use in the preparation of a medicament for the treatment of antibacterial microbial infections. Applications.

According to another aspect of the present invention, the present invention also claims the use of a compound of the formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof as described above as an antibacterial microbial infection drug.

According to another aspect of the invention, the invention also claims a method of treating a bacterial microbial infection, the method comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I) or (II) as hereinbefore described Or a pharmaceutically acceptable salt or ester thereof.

The term "aromatic heterocycloalkyl" as used herein denotes a heteroaryl group which includes a monocyclic heteroaryl group such as a 5-membered or 6-membered heteroaryl group such as furyl, pyrrolyl, thienyl, imidazole. , triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.; and fused bicyclic ring a heteroaryl group such as a fused bicyclic heteroaryl group having a 5- or 6-membered ring, such as a benzofuranyl group, an isobenzofuranyl group, an anthracenyl group, an isodecyl group, a benzo[b]thienyl group, Benzo[c]thienyl, benzimidazolyl, fluorenyl, carbazolyl, Benzooxazolyl, benzisoxazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, benzopyrazinyl (quinaclinyl), benzoxazinyl (噌淋基) and so on. The "aromatic heterocyclic hydrocarbon group" also includes an aryl group substituted with a heteroaryl group such as an imidazolylphenyl group, a thienylphenyl group or the like.

The term "aryl" as used herein means an aromatic carbocyclic group having one single ring or two or more fused rings. The aryl group preferably has 5 - 18, 5 - 14, 5 - 10, 5 - 8, 5 - 6 or 6 carbon atoms. Typical examples of the "aryl group" include, but are not limited to, a phenyl group, a naphthyl group, an anthryl group, and the like. The "aryl group" is most preferably a phenyl group.

The term "heteroaryl" as used herein denotes an aryl group, as defined herein, wherein one or two or more carbon atoms are one or two or more heteroatoms independently selected from 0, S or N. Alternative. The heteroaryl group is preferably 5 - 18 members, 5 - 14 members, 5 - 10 members, 5 - 8 members, 5 - 6 members or 5 members or 6-membered heteroaryl groups. Typical examples of the "heteroaryl" include, but are not limited to, furyl, pyrrolyl, p-septyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazole A pyridyl group (e.g., 3-pyridyl), pyrazinyl, pyrimidinyl (e.g., 5-pyrimidinyl), pyridazinyl, triazinyl, benzofuranyl, isobenzofuranyl, fluorenyl (e.g. 5-indenyl), isodecyl, benzo[b]thienyl, benzo[c]thienyl, benzimidazolyl, fluorenyl, carbazolyl, benzoxazolyl, benzoisomeric Azolyl, benzothiazolyl, quinolyl (eg 3-quinolyl, 4-quinolyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl), isoquinolyl (eg eg 4-iso-p-quino-l-based, 5-iso-quino-p-linyl, 6-iso-quino-p-l-yl), quinazolyl, benzopyrazine. Chinyl (p-quinone) or benzoxazinyl (phosphonium) and so on. The "heteroaryl group" is preferably a sulfur atom-containing heteroaryl group or a nitrogen atom-containing heteroaryl group, more preferably a thienyl group, a pyridyl group, a pyrimidinyl group, a benzopyrazinyl group, a benzoxazinyl group, a quinolyl group. , isoquinolyl or fluorenyl; most preferred is thienyl, pyridyl, p-quino-l-based or iso-p-quinolinyl.

The term "substituted heteroaryl" as used herein means that "heteroaryl" as defined herein is substituted by one or two or more substituents independently selected from the group consisting of aryl (eg phenyl), heteroaryl (e.g., furyl, pyrrolyl, p ^p plug points, imidazolyl, triazolyl, tetrazolyl, pyrazolyl group ¹ ^, ¹ ^ pyrimidinyl group, pyrazolyl group ¹³ Qin, da ^p group Qin, Qin three ^13-yl , quinolinyl, isoquinolinyl, p-quinazolyl, fluorenyl), 5- or 6-membered cycloalkyl, 5- or 6-membered heterocycloalkyl, C1-C4 alkyl, C2- C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, nitro, cyano, hydroxy, flavonoid, amino, carboxy, sulfonic acid and aldehyde groups. The term "C1-C4 sulfhydryl" as used herein refers to a saturated straight or branched chain hydrocarbon radical having from 1 to 4 carbon atoms.

The term "C2-C4 alkenyl" as used herein means an ethylenically unsaturated straight or branched hydrocarbon group containing at least one carbon-carbon double bond (_C=C_) having 2 to 4 carbon atoms.

The term "C2-C4 alkynyl" as used herein, refers to an acetylenically unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond (_C≡C-) having from 2 to 4 carbon atoms.

The term "C1-C4 alkoxy" as used herein refers to the group -ORa, wherein Ra is C1-C4 alkyl as defined herein.

The term "5- or 6-membered cycloalkyl" as used herein means a saturated cyclic hydrocarbon group having 5 or 6 carbon atoms.

The term "5- or 6-membered heterocycloalkyl" as used herein, is intended to mean a 5- or 6-membered cycloalkyl group, as defined herein, containing one or more heteroatoms independently selected from N, 0 and S. .

The term "halogen" as used herein means fluoro, chloro, bromo or iodo. Compared with the prior art, the present invention has the following advantages:

The compound of the formula (I) or (II) of the present invention has a novel structure, and an aroheterocyclic hydrocarbon group is bonded to the 9-fluorenylhydroxy group of the ketolide via a propargyl side chain, and is synthesized into a tube, which is suitable for industrial production.

The aromatic side chain of ketolide acts as an important pharmacophore for anti-resistant bacteria, and its attachment position on the ketolide and its side chain length and structure directly affect the activity of its anti-resistant bacteria. After repeated experiments and theoretical studies, the propargyl-linked aroheterocycloalkyl group has been selected as the aromatic side chain of the ketone lactone, and the activity of the anti-sensitive bacteria and the anti-resistant bacteria can be obtained.

After testing, the compound of the formula (I) or (II) of the invention has outstanding antibacterial activity against common clinical sensitive bacteria and resistant bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus epidermidis, Haemophilus influenzae, etc., can be used alone or as one of the active ingredients in combination with other drugs in various dosage forms or routes of administration for the treatment of infections such as bacteria.

In summary, the introduction of propargyl group in 9-indole and its further aromatic derivatization greatly enhance the antibacterial activity of ketolide, and the aromatic side chain is easy to synthesize and easy to industrialize. detailed description The present invention will be further described in detail with reference to the drawings and specific embodiments.

The present invention provides a compound having the following structural formula (I) or (Π),

I Π

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is a hydrogen atom or a fluorine atom.

Preferably, Ar may be 2-pyridyl, 3-pyridyl, 5-pyrimidinyl, 3-quinolinyl, 4-quinolinyl, 4-isoquinolinyl, 5-quinolinyl, 5- Isoquinolyl, 6-quinolyl, 6-isoquinolyl, 8-quinolinyl, 4-(1-imidazolyl)phenyl, 4-(2-thienyl)phenyl, 5-nonyl, 2-Thienyl, 3-thienyl, 2-[5-(2-pyridyl)]thienyl, or 2-(5-benzoyl)thienyl, and the like. In practical applications, Ar may also further substitute the derivatized group on the basis of the above groups.

The compound of the present invention having the above formula (I) or (?) may form a salt or ester with various pharmaceutically acceptable inorganic or organic acids. Preferably, the inorganic acid may be selected from hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid; the organic acid may be selected from the group consisting of acetic acid, malonic acid, sulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, and rich Horse acid, stearic acid. However, the invention is not limited to the above examples. The preparation method of the compound having the above formula (I) or (II) will be described below by way of example.

The preparation process of the invention is as follows:

1. Starting from the commercially available raw material - erythromycin oxime, 9-肟 hydroxy etherification protection, Z-OH and silicon sulfonation protection, 6-0H selective thiolation to obtain intermediate compounds of clarithromycin synthesis process 1, ^2/ , ⁴ "_6> - bis(trimethylsilyl) _ ⁶ _^ thioerythromycin A 9-0- (1-isopropoxycyclohexyl) hydrazine;

2, then hydrolyzed to obtain the key compound 2: 3-OH-6-nonyl erythromycin oxime;

3. Further, under the action of acetic anhydride, the 2,-OH and 9-hydrazine hydroxyl groups are acetylated to give compound 3: Z-O-acetyl_3_hydroxy-6_6>-mercaptoerythromycin Α9-6» - Acetylhydrazine. The above three steps of the process have been mentioned in the open literature and will not be described in detail herein. For similar processes, see Liang Jianhua et al., Organic Chemistry, 2005, 438-441; Zhou Baige et al., Fine Chemicals, 2005, 314-316; Li Shubin et al., Fine Chemicals, 2007, 678-680.

It is to be noted that only one example of the preparation process for obtaining the compound 3, or the compound 3 obtained directly from the supplier is given above; a core improvement of the present invention is to obtain the novel type required for the invention from the compound 3. Process for ketolide (9-arylpropynyl ketone lactone derivative).

For example, in the process of obtaining compound 3, compound 1 is 2, 4" -6>-bis(trimethylsilylsulfonyl)-6-fluorenylerythromycin A 9-0-( 1-isopropoxy Cyclohexyl) hydrazine can be replaced by 2, 4" - bis(trimethylsilyl) _6_^ thioerythromycin A9_^ (1-ethoxycyclohexyl) fluorene.

In fact, in the present invention, Compound 1 can also be replaced by 2, 4" _ 6> - bis (trimethylsilyl) _6_ fluorenylerythromycin A 9 - (1-decyloxy_1 - fluorenyl B Compound 1 can also be replaced by ^2/ , ⁴ " -OH (trimethylsilyl) - ⁶ -^-based erythromycin A 9-0- (1-ethoxyl-yl) Ethyl) hydrazine, or 2 4"_6> - bis (trimethylsilyl fluorenyl) _6_ fluorenyl erythromycin A 9-0- (di-tert-butyl fluorenyl silicon) hydrazine.

Of course, since the foregoing transformations can be implemented by those skilled in the art based on the prior art, they are not described herein again. And since these changes of compound 1 do not change the reaction history, the key compound 2 can still be obtained by hydrolysis under acidic conditions, and therefore, the influence on subsequent steps 2 and 3 is small.

Meanwhile, it should be noted that, in the process step of obtaining the compound 3, the reagent as the step 3 protecting reagent (the reagent for realizing the protecting group) can also be replaced. For example, acetic anhydride can be replaced with benzoic anhydride, or a silicon sulfonating reagent such as trimethyl chlorosilane, hexamethylene disilazane or the like to obtain an analog of compound 3, that is, the acetyl group on compound 3 is replaced with benzene. Decanoyl, tridecylsilyl, this analog can be used in the subsequent reaction without changing the reaction history.

4. In a mixed solvent of THF (tetrahydrofuran), DMF (N,-dimercaptoamide) or THF/DMS0 (dithiosulfoxide), 1. 0 - 4. 0 equivalent (amount ratio of the substance) The propargyl bromide and 1. 0 - 4. 0 equivalent of potassium t-butoxide can selectively replace the acetyl group on the 9-fluorenyl hydroxyl group of the compound 3 to obtain the compound 4: 2'- 0-acetyl-3- Hydroxy-6-methylerythromycin A 9 propargyl.

5. Further, in the dichlorosilane solvent, the 11, 12-0H ring is closed with 3 phosgene, and the 3-0H is oxidized to the 3-carbonyl group by the Corey-Kim oxidation (Cory-Gold Oxidation) reagent to obtain the key compound. 5: 2'-O-Acetyl-3- 6-methylerythromycin A 9-^propargyl 肟- 11, 12-cyclic carbonate.

6. Finally, in a solvent of acetonitrile, THF (tetrahydrofuran) or DMF (dimercaptophthalamide), catalyzed by a palladium salt such as dichlorobis(triphenylphosphine)palladium and a copper salt (such as cuprous iodide), The substituted heteroaromatic hydrocarbon (for example, a heteroaromatic hydrocarbon) interacts with the propargyl group on the 9-fluorene hydroxyl group to form a heteroaromatic side chain, and is removed in the decyl alcohol to give the target compound 6: 3-^^- 6-^methyl-red-receptor A 9-ίΜ3-heteroaryl- 2-propanyl]肟- 11, 12-cyclic carbonate;

Alternatively, in a solvent of acetonitrile, THF (tetrahydrofuran) or DMF (dimercaptophthalamide), substituted with a palladium salt such as dichlorobis(triphenylphosphine)palladium and a copper salt (such as cuprous iodide) The aromatic hydrocarbon interacts with the propargyl group on the 9-fluorenyl hydroxyl group to form a heteroaromatic side chain, further in the THF (tetrahydrofuran) or DMF (dimercaptophthalamide) solvent, sodium hydride and hydrazine-fluorobenzoimide A fluorine atom is introduced at the lower 2-position, and 2 _Ac is removed from the decyl alcohol to obtain a target compound 6 which is fluorinated at the 2-position.

Fluorination at the 2-position of the ketolide can increase the antibacterial activity. Since the technical process of fluorination at the 2-position of ketolide is relatively mature, it will not be described herein. For example, see, Deni s, A. et al, Drug. Future. 2001, 26, 975; Phan, LT, et al, Org. Le t t. 2000, 2, 2951; Sear le XB, WO03/09076 L It should be noted that if the 11,12-0H carbonation reaction is not carried out in the course of the reaction (such as "the use of triphos to turn off the 11, 12-0H ring" in process step 5), the final formula is (I Compound; If the 11,12-0H carbonation reaction is carried out, the compound of the formula (II) is finally obtained. Existing studies have shown that: 11, 12-carbonation can further enhance antibacterial activity than the parental 11, 12-0H uncarbonated (T. Nomura, et al, Bioorg. Med. Chem. 2005, 1 3: 6054- 6063), that is, in the case of the same substituent group, the compound of the formula (I) of the present invention has an antimicrobial activity slightly smaller than that of the compound of the formula (II).

In addition, some of the synthetic steps can be reversed, such as 11, 12-0H carbonated, then selective propargylation; or 3-0H oxidation followed by 11,12-0H carbonate; or take off first -0~ c , and then coupled with a heteroaromatic hydrocarbon to form a heteroaromatic side chain, and so on. Changes in the order of these operations do not affect the synthesis of the target compound. Those skilled in the art can carry out some feasible step sequence switching based on the preparation principle, and cannot exceed the protection scope of the present invention.

Among them, some reagents can also be replaced, for example,

The propargyl bromide as a propargylating agent can be replaced with propargyl iodide or the like;

Potassium tert-butoxide as a strong base can be replaced by potassium hydroxide, sodium hydride, hexamethyldisilazide potassium or the like; as a ring-closing reagent, triphosgene can be replaced by phosgene, trichlorodecyl chloroantimonate or the like; The Corey-Kim Oxidation Reagent (N-chlorosuccinimide/diterpene ether) as an oxidizing agent can be replaced with various oxidizing combination reagents containing disulfoxide, such as disulfoxide/oxalyl chloride, diterpene Sulfone/acetic anhydride, disulfoxide/trifluoroacetic anhydride, disulfoxide/dicyclohexylcarbodiimide, or disulfoxide/phosphorus pentoxide;

A fluorinating reagent for the fluorination of the keto lactone at the 2-position, N-fluorophenyl amide, can be replaced with a commercial reagent Se l ec t i f luorTM;

The palladium salt dichlorobis(triphenylphosphine)palladium may be replaced by tetrakis(triphenylphosphine)palladium; the copper salt cuprous iodide may be replaced with cuprous bromide.

The above changes in these reagents do not affect the synthesis of the target compound of formula (I) or (II). The following is a structural example of a specific example of the above preparation process, the single

Reagents and conditions: (a) HC1, EtOH. (b) Ac ₂ 0, CH ₂ C1 ₂ . (c) KO tu, propargyl bromide, THF. (d) bis(trichloroindenyl) carbonate, Pyridine, CH ₂ C1 ₂ . (e) Me ₂ S, N-chlorosuccinimide, Et ₃ N, CH ₂ C1 ₂ . (f) ArBr, (PPh ₃ ) ₂ PdCl ₂ , Cul, Et ₃ N , CH ₃ CN. (g) MeOH.

Example 1 (Production of Compound 1) 3-hydroxy-6-^methylerythromycin

13.2 g of compound 1 was dissolved in 40 ml of ethanol, 5 ml of 36% concentrated HC1 was diluted into 50 ml of water and then added dropwise to the reaction solution, and the reaction was carried out at 40 ° C for 1 '!, when the reaction was completed, concentrated aqueous ammonia was added to adjust the pH. When the value is around 9, a white precipitate precipitates and the white precipitate is filtered. This precipitate was recrystallized from ethanol and water to give 3-0H clarithromycin oxime (5.42 g, yield 71%). MS (M+H ⁺ ) m/z: 605.5.

Example 1 (Production of Compound 3)

V - 0-ethylhydroxy-6- (9-methylerythromycin A 9- (9-B

Add 5.42 g ( 8.96 mmol) of 3-hydroxy clarithromycin hydrazine to 50 ml of dichloromethane, and add 2.6 ml (24.88 mmol) of acetic anhydride dropwise. The reaction is '■! washed with saturated sodium bicarbonate solution, water, saturated aqueous sodium chloride by filtration, the solvent was removed to give the compound as a white foam 5.60 g (8.13 mmol, 90.7% yield) under reduced pressure ₀

Example 3 (Production of Compound 4)

-O-ethyl 3-hydroxy-6-methylerythromycin A 9-propargyl

Dissolve 1.00 g (1.5 mmol) of 2 _ 6>-acetyl-3-hydroxy-6- 6>-mercaptoerythromycin A 9-6>-acetyl hydrazine in 15 ml of THF solution, add potassium t-butoxide 489 mg (4.36 mmol) and propargyl bromide 0.52 ml (5.8 匪ol) were reacted one by one. Then, 20 ml of ethyl acetate and 20 ml of water were added, and the mixture was allowed to stand for separation. The upper layer was washed with saturated brine and filtered. The solvent was evaporated to dryness under reduced vacuo.

HRMS (ESI) (M+H) ⁺ m/z 685.42599, calcd for C ₃ 5H ₆₁ N ₂ 0 _n 685.42699. 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ: 0.83 (t, 3H, 15—CH ₃ ), 0.90 (d, 7=7.3 Hz, 3H, 8-CH3), 0.97 (d, 7=7.0 Hz, 4-CH ₃ ), 1.15-1.24 (m, 13H, H-4'ax, 10-CH ₃ , I2-CH3, 2 ^/ -CH ₃ , 5 — CH ₃ ), 1.30 (s, 3H, 6-CH ₃ ), 1.31—1.49 (m, 3H, H-7, H-14ax) , 1.71-1.75 (m , 1H, H-4'eq), 1.94-1.96 (m, 1H, H-14eq), 2.06 (s, 3H, 2'-0-kc), 2.06-2.11 (m, 1H, H-4), 2.26 (s, 6H, -N (CH ₃ ) ₂ ) , 2.49 (t, J=l.1 Hz, 1H, CH ₂ -C≡CH), 2.57-2.73 (m, 3H, H-10, H-2, H-3, 2.98 (s, 3H, 6-0CH ₃ ), 3.33 (s, 1H, 12- OH), 3.41 (d, 7=10.5 Hz, 1H, H-3), 3.47-3.51 (m, 1H, H-5, 3.58-3.62 (m, 1H, H -8), 3.71 (d, 7=1.7 Hz, 1H, H-5), 3.81 (s, 1H, H-ll), 4.48 (s, 1H, 11-OH), 4.57 (s, 2H, CH ₂ -C≡CH), 4.62 (d, 7=7.6 Hz, 1H, H-10, 4.76 (dd, 7=7.7 and 10.2 Hz, 1H, H-2, 5.25 (dd, 7=1.6 and 11.0 Hz, 1H , H-13). ¹³ C NMR (100 MHz, CDCI3) δ: 7.6, 10.2, 15.0, 15.2, 16.1, 18.2, 19.1, 20.9, 21.2, 21.3, 26.2, 30.8, 32.9, 35.8, 36.8, 40.4, 44.0 , 49.9, 60.7, 62.9, 68.4, 70.2, 71.2, 73.8, 74.2, 77.2, 78.0, 79.7, 80.3, 99.5, 169.8, 170.8, 174.6. Example 4 (generating compound 4)

2 -0-ethyl 3-hydroxy-6-methylerythromycin A 9-propargyl

Dissolve 0.500 g (0.73 mmol) of 2 - 6>-acetyl-3-hydroxy-6-6-oxime erythromycin A 9_6>-acetyl hydrazine in 15 ml THF/DMSO solution, add potassium t-butoxide 106 mg (0.95 匪ol) and propargyl bromide 0.13 ml (1.46 匪ol) were reacted one by one. Then, 10 ml of ethyl acetate and 10 ml of water were added, and the layers were allowed to stand. The upper layer was washed with saturated brine. The solvent was evaporated under reduced pressure to give 0.461 g (yield: Example 5 (First Step of Generating Compound 5)

2 - O-B-hydroxy-6-^methylerythromycin human 9-^ propargyl^"-11, 12-cyclic carbonate 1.06 g (1.55 mmol) 2 _ 6> acetyl _ 3 hydroxy - 6_^曱-erythromycin A9_^ propargyl hydrazine is dissolved in 50 ml of dichlorosilane, 1.5 ml ( 18.6 mmol) of pyridine is added, and stirred at -5 ° C for 10 minutes, and the dropwise addition is dissolved in 30 ml. 0.9 g (3.1 匪ol) triphosgene of chlorodecane, completed in 30 minutes. After -17 °C reaction for 17 hours, slowly add 70 ml of saturated brine to complete the reaction. The layer was allowed to stand, and the lower organic phase was saturated with hydrogen carbonate. The mixture was washed with EtOAc (EtOAc m.) 2 -0-ethyl^-3-^^-6-^methylerythromycin human 9-^ alkyne-propane-11, 12-ring carbonate Add 20 ml of dichlorosilane to a 100 ml three-necked flask, stir Add 0.212 g -chlorosuccinimide (NCS) (1.6 匪ol), keep the system at - 15 °C, slowly add 0.14 ml Me ₂ S (DMS) (1.9 mmol) to the white flocculent precipitate and continue to stir. For half an hour, 0.70 g (0.99 匪ol -O-acetyl_3_hydroxy-6-mercaptoerythromycin A9_i?" propargyl-11,12-cyclocarbonate 10 ml of dichlorodecane will be dissolved. The mixture was added dropwise to the system, and the addition was completed in half an hour. The reaction was carried out at -15 ° C for 1.5 hours. TLC showed the reaction was completed, and triethylamine (0.3 ml) was added dropwise to terminate the reaction. The system was clarified and stirred at -5 ° C for one hour. The reaction mixture was washed with aq. An example of another process for obtaining compound 5 is given.

Example 7 (Production of Compound 4)

2 -0-ethyl 3-hydroxy-6-methylerythromycin A 9-propargyl

0.50 g (0.73 匪ol ) 2 ^/ -acetyl-3-hydroxy-6-6>-mercaptoerythromycin octa-9-6-acetyl hydrazine was dissolved in 15 ml of DMF solution, and potassium tert-butoxide 0.120 was added. g (1.10 mmol) was stirred for 10 min, and additional potassium tert-butoxide 81 mg (0.73 mmol) propargyl bromide and 0.07 ml (0.80 mmol) ₀ was added 15 ml of ethyl acetate and 10ml water, standing layer, an upper layer The mixture was washed with saturated brine and evaporated to dryness. Example 8 (First Step of Generating Compound 5)

2 -6>-B 3- 6- ^methylerythromycin A

Add 40 ml of dichloromethane to a 250 ml three-necked flask, add 0.483 g of chlorosuccinimide (3.6 mmol) with stirring, keep the system at -15 °C, and slowly add 0.3 ml of dithizone (4.29 匪). Ol) A white flocculent precipitate appears. Stirring for an additional half an hour will dissolve 1.61 g (2.26 匪ol) of Z-O-acetyl-3-hydroxy-6- fluorenylerythromycin A 9-^propargyl hydrazine. 15 ml of dichloromethane was added dropwise to the system, and the addition was completed in half an hour. The reaction was carried out at -15 ° C for 1.5 hours. The reaction was completed by TLC. The reaction was terminated by dropwise addition of triethylamine 0.6 ml. The system became clear, _5 ° Stir for one hour at C. The reaction solution was washed with saturated sodium bicarbonate, water and brine, filtered and evaporated. The solvent yielded 1.344 g of solid ( 1.97 匪ol, yield 87.2%). _c . Example 9 (Step 2 of Compound 5)

2 - 0-B 3- - 6- ^methyl erythromycin A 9- propargyl propane 11, 12-cyclic carbonate 1.34 g ( 1.97 匪ol ) 2 _ 6> acetyl-3-carbonyl - 6_^ The thioerythromycin A 9-0-propargyl hydrazine was dissolved in 50 ml of dichlorosilane, and 1.9 ml ( 23.62 匪ol ) of pyridine was added, and the mixture was stirred at -5 ° C for 10 minutes, and the dropwise addition was dissolved in 30 ml. 1.17 g (3.94 匪ol) of triphosane was added to the phosgene in 30 minutes. After _5 ° C reaction, the reaction was terminated by slowly dropwise adding 70 ml of saturated salt water after 17 hours. The organic layer was separated and washed with saturated sodium hydrogen carbonate, water and brine, and evaporated.

In the above Examples 7, 8, and 9, in the process of producing the compound 5, a 3-carbonyl group was obtained, and 11, 12-ring carbonate was further obtained. In Examples 5 and 6, 11, 12-ring carbonate was obtained first, and a 3-carbonyl group was obtained. Example 10 (Production of 5-pyrimidinyl group 6)

3- - 6- ^methylerythromycin A 9- ίΜ3- (5-pyrimidin-2-propanol) 肟- 11, 12-ring carbon will be 0.700 g (0.988 mmol) of compound 5, 19 mg (0.099 匪ol Cuprous, 35 mg (0.049 mmol) of bistriphenylphosphine palladium dichloride, 0.471 mg (2.964 mmol) of 5-bromopyrimidine, 0.21 ml (1.482 mmol) of triethylamine, added to a pressure of 12 ml of acetonitrile In the bottle, the system was stirred under a nitrogen atmosphere at 80 ° C for 3 hours, and 15 ml of ethyl acetate and 15 ml of water were added to the system, and the mixture was allowed to stand for stratification. After column chromatography (200-300 mesh silica gel column, mobile phase: methylene chloride: ethanol: ammonia = 15: 0.4: 0.1), 175 mg (0.222 mmol, yield 22.5%) of the pure product. This compound was dissolved in 25 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound. The crude product was purified by silica gel column (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2) to give the product pure product 24 mg (0.032 mmol, yield 14.4%).

HRMS (ESI) (M+H) ⁺ m/z 745.40115, calcd for 745.40184. 3⁄4 NMR

(400 MHz, CDC1 ₃ ) δ: 0.89 (t, 3H, 15-CH ₃ ) , 1.01 (d, 7=6.9 Hz, 3H, 8-CH3), 1.22-1.30 (m, 10H, 4—CH ₃ , 10—CH ₃ , 5 - CH ₃ , H-4ax) , 1.36 (d, 7=6.8 Hz, 3H, 2-CH ₃ ), 1.43 (s, 3H, 6- CH ₃ ), 1.55 (s, 3H, 12-CH ₃ ),

1.55-1.63 (m, 1H, H-14ax) , 1.66-1.72 (m, 2H, H-7, H-4eq), 1.88-1.92 (m, 1H, H-14 eq), 2.28 (s, 6H, -N (CH ₃ ) ₂ ) , 2.43-2.55 (m, 2H, H-3', H-10)

2.71 (s, 3H, 6-OCH3), 2.98-3.05 (m, 1H, H-4), 3.19 (dd, 7=7.2 and 7.3 Hz, 1H, H-2, 3.51-3.56 (m, 1H, H -5 , 3.64 (br, 1H, H-8) , 3.82 (q, 7=6.7 Hz, 1H, H-2), 4.19 (d, 7=8.4 Hz, 1H, H-5), 4.29 (d, 7=7.3 Hz, 1H, H-1, 4.79 (s, 1H, H-ll), 4.92, 4.86 (d, 7=16.0 Hz, 2H, CH ₂ C≡C-Ar), 5.05 (dd, J= 2.6 and 10.2 Hz, 1H, H-13), [8.75 (s, 2H), 9.13 (s, 1H), pyr imidyl] . Example 11 (Formation of 4-isoquinolinyl compound 6)

6-^methylerythromycin A 9- Μ 3 - (4-isoquinolinyl)-2-propynyl] 肟-11, 12-cyclocarbonate

0.700 g (0.988 匪ol) compound 5, 19 mg (0.099 mmol) cuprous iodide, 35 mg (0.049 mmol) bistriphenylphosphine palladium dichloride, 411 mg (1.976 mmol) 4 -bromoiso-p-quine Porphyrin,

0.21 ml (1.482 mmol) of triethylamine was added to a pressure bottle containing 12 ml of acetonitrile. The system was stirred under nitrogen for 3 hours at 80 ° C. 15 ml of ethyl acetate and 15 ml of water were added to the system. Let stand layering. After column chromatography (200-300 mesh silica gel column, mobile phase: dichloromethane: ethanol: ammonia = 15: 0.4: 0.1), a pure product of 72 mg (0.086 mmol, yield: 8.70%) was obtained. This compound was dissolved in 25 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound. The crude product was purified by silica gel column (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2) to give the product pure product 23 mg (0.029 mmol, yield 33.7%).

HRMS (ESI) (M+H) ⁺ m/z 794.42221, calcd for Ο^ 794.42224. 3⁄4 NMR (400 MHz, CDCI3) δ: 0.89 (t, 3H, 15-CH ₃ ) , 1.02 (d, 7=6.8 Hz, 3H, 8-CH3) , 1.21-1.33 (m, 12H, 4-CH ₃ , 10-CH ₃ , 5 - CH ₃ , 2-CH ₃ ) , 1.46 (s, 3H, 6-CH3) , 1.57 (s, 3H, 12-CH ₃ ), 1.64-1.75 (m, 3H, H-7, H-4eq),

1.89-1.93 (m, 1H, H-14eq), 2.26 (s, 6H, -N (CH ₃ ) ₂ ) , 2.40-2.47 (m, 1H, H-3, 2.63 (br, 1H, H-10) , 2.69 (s, 3H, 6-0CH ₃ ) , 3.01-3.05 (m, 1H, H-4), 3.18 (dd, 7=7.3 and 10.2 Hz, 1H, H-2, 3.46-3.55 (m, 2H , H-2, H-5, 3.78 (br, 1H, H-8), 4.17 (d, 7=8.5 Hz, 1H, H-5), 4.28 (d, 7=7.3 Hz, 1H, H-1, 4.82 (s, 1H, H-ll), 4.97-5.06 (m, 3H, CH ₂ - C≡C- Ar, H-13), [7.64 (t, 1H), 7.79 (t, 1H), 7.97 (d, 1H) , 8.30 (d, 1H), 8.65 (s, 1H), 9.17 (s, 1H), isoquinolyl]. ¹³ C NMR (100 MHz, CDC1 ₃ ) δ: 10.4, 13.2, 14.3, 15.5, 15.8, 18.9, 19.8 , 21.2, 22.5, 26.5, 28.2, 38.4, 40.2, 46.1, 47.8, 49.7, 51.1, 62.0, 65.9, 69.5, 70.4, 76.4, 77.2, 78.5, 79.4, 80.9, 82.7, 84.7, 93.2, 103.9, 115.5, 125.2 , 127.7, 127.9, 131.2, 135.8, 146.5, 152.1, 154.4, 165.9, 169.0, 203.9. Example 12 (Production of 3-^-based compound 6)

3- - 6- ^methylerythromycin A 9- ίΜ3- (3-yl)- 2-propanyl]-- 11, 12-ring carbon will be 0.633 g (0.892 mmol) of compound 5, 17 mg (0.089 匪ol Cuprous iodide, 31 mg (0.045 mmol) of bistriphenylphosphine palladium dichloride, 0.24 ml (1.784 mmol) of 3-bromo ^p- quinoline,

0.19 ml (1.338 mmol) of triethylamine was added to a pressure bottle containing 12 ml of acetonitrile. The system was stirred under nitrogen for 3 hours at 80 ° C. 15 ml of ethyl acetate and 15 ml of water were added to the system. Let stand layering. After column chromatography (200-300 mesh silica gel column, mobile phase: methylene chloride: ethanol: aqueous ammonia = 15: 0.4: 0.1), a pure product of 99 mg (0.118 mmol, yield: 13.3%) was obtained. This compound was dissolved in 25 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound. The crude product was purified by silica gel column (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2) to obtain pure product 33 mg (0.042 mmol, yield 35.6%) ₀

HRMS (ESI) (M+H) ⁺ m/z 794.42311, calcd for 794.42224. 3⁄4 NMR

(400 MHz, CDC1 ₃ ) δ: 0.89 (t, 3H, 15-CH ₃ ), 1.08 (d, 3H, 8- CH ₃ ),

1.22-1.34 (m, 13H, 4—CH ₃ , 10—CH ₃ , 5' -CE 2-CH ₃ , H-4ax) , 1.46 (s, 3H, 6-CH3) , 1.57 (s, 3H, I2 -CH3), 1.66-1.74 (m, 2H, H-7, H-4eq), 1.89-1.93 (m, 1H, H-14eq), 2.27 (s, 6H, -N (CH ₃ ) ₂ ) , 2.44 -2.57 (m, 2H, H-3', H-10) _:

2.73 (s, 3H, 6-OCH3), 3.00-3.06 (m, 1H, H-4), 3.20 (dd, 1H, H-2,

3.51-3.55 (m, 2H, H-2, H-5, 3.79-3.84 (m, 1H, H-8), 4.19 (d, 7=8.4 Hz, 1H, H-5), 4.29 (d, 7 =7.3 Hz, 1H, H-1, 4.80 (s, 1H, H-ll), 4.96, 4.90 (d, 7=15.8 Hz, 2H, CH ₂ C≡C—Ar), 5.05 (dd, J=2.6 and 10.0 Hz, 1H, H-13), [7.53 (t, 1H), 7.72 (t, 1H), 7.78 (d, 1H), 8.07 (d, 1H), 8.24 (d, 1H), 8.88 (d, 1H), quinolyl]. Example 13 (Formation of 6-based compound 6)

3- - 6- ^methylerythromycin A 9- ίΗ3- (6-yl)- 2-propanyl]-- 11, 12-ring carbon will be 0.946 g ( 1.335 mmol ) ^ complex 5, 25 mg ( 0.134 mmol) iodine cuprous, 47 mg (0.067 mmol) of bistriphenylphosphine palladium dichloride, 0.36 ml (2.67 mmol) of 6-涣^p- p-lin,

0.30 ml (1.338 mmol) of triethylamine was added to a pressure flask containing 15 ml of acetonitrile. The system was stirred under nitrogen for 3 hours at 80 ° C. 15 ml of ethyl acetate and 15 ml of water were added to the system. , standing layered. After column chromatography (200-300 mesh silica gel column, mobile phase: chloroform: ethanol: ammonia = 15: 0.4: 0.1), 155 mg (0.185 mmol, yield 13.9%) of the pure product was obtained. This compound was dissolved in 25 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound. The crude product was purified by silica gel column (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2) to obtain pure product 29 mg (0.035 mmol, yield 18.8 %) ₀

HRMS (ESI) (M+H) ⁺ m/z 794.42082, calcd for 794.42224. 3⁄4 NMR

(400 MHz, CDC1 ₃ ) δ: 0.89 (t, 3H, 15-CH ₃ ), 1.02 (d, 7=6.8Hz, 3H, 8-CH ₃ ) _:

1.22-1. 32 (m, 4-CH ₃ , 10-CH ₃ , 5 - CH ₃ , 2-CH ₃ ) , 1.46 (s, 3H, 6- CH ₃ ), 1.57 (s, 3H, I2-CH3 ), 1.67-1.73 (m, 2H, H-7, H-4eq), 1.88-1.94 (m, 1H, H-14eq), 2.29 (s, 6H, -N (CH ₃ ) ₂ ) , 2.45-2.58 (m, 2H, , H-10), 2.73 (s, 3H, 6-OCH3), 2.99-3.07 (m, 1H, H-4), 3.21 (dd, 1H, H-2, 3.49-3.55 (m , 1H, H-5, 3.77 (br, 1H, H-8) , 4.18 (d, 7=8.5 Hz, 1H, H-5), 4.29 (d, J=l.3Hz, 1H, H-10, 4.81 (s, 1H, H-ll), 4.95, 4.89 (d, 7=15.8 Hz, 2H, CH ₂ C≡C—Ar), 5.04 (dd, J=2.5 Hz and 10.0 Hz, 1H, H-13 ), [7.41 (q, 1H), 7.69 (dd, 1H), 7.93 (s, 1H), 8.02 (d, 1H), 8.11 (d, 1H), 8.90 (dd, 1H), quinolyl]. 14 (Formation of 2-pyridyl compound 6) 0. 700 g (0. 988 mmol ) ^ conjugate 5 , 19 mg (0. 099 mmol) ^ cuprous, 35 mg (0. 05 mmol) bistriphenylphosphine palladium dichloride, 0. 29 Ml (2. 96 mmol) 2 -Bromopyridinium, 0. 21 ml (1. 48 mmo l) triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, and the system was reacted under nitrogen at 80 ° C. At the end of the hour, 10 ml of ethyl acetate and 10 ml of water were added to the system, and the layers were allowed to stand. The organic layer was washed with water and saturated brine. After the solvent was evaporated under reduced pressure and purified by silica gel column (mobile phase dichloro Yue alkoxy: ethanol: aqueous ammonia = 15: 0.4: 0.1) to give compound 110 m _go This compound was dissolved in 10ml alcohol Yue, 65 The acetyl group was removed by refluxing at ° C for 3 hours to obtain a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified by silica gel column to afford compound 69 mg (0. 093 mmol). The total yield was 9. 4 .

HRMS(ESI) (M+H)+ m/z: 744.40835, calcd for CggHsgNgOn 744.40659; 3⁄4丽R (400 MHz, CDC1 ₃ ) δ: 8. 52 (d, 1 H) , 7. 61 (td, 1 H) , 7. 39 (d, 1 H) , 7. 19 (dd, 1 H) , 2. 68 (s, 3 H) , 2. 26 (s, 6 H) ; ¹ C NMR (100 MHz, CDC1 ₃ ) δ: 204.0, 169.2, 165.8, 154.5, 150.0, 143.1, 136.2, 132.1, 127.4, 123.0, 103.8, 85.8, 85.2, 84.8, 82.8, 79.6, 78.5, 76.4, 70.4, 69.5, 66.0, 61.9, 51.2 , 49.8, 48.0, 40.3, 38.4, 28.5, 26.5, 22.5, 21.2, 19.9, 18.9, 16.0, 15.5, 14.4, 13.3, 10.5. Example 15 (Product 6 which produces 2-thienyl)

0. 700 g (0. 988 mmol ) ^ conjugate 5 , 19 mg (0. 099 mmol) ^ cuprous, 35 mg (0. 05 mmol) bistriphenylphosphine palladium dichloride, 0. 28 Ml (2. 96 匪ol) 2-bromo p-cetin, 0. 21 ml (1. 48 mmo l) triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, under nitrogen protection at 80 ° The reaction of C was completed in three hours, and 10 ml of ethyl acetate and 10 ml of water were added to the system, and the mixture was allowed to stand for stratification. The organic layer was washed with water and saturated brine. Purification (Yue-dichloro mobile phase hexane: ethanol: aqueous ammonia = 15: 0.4: 0.1) After the solvent was evaporated under reduced pressure and purified by silica gel column to give compound 117 m _go This compound was dissolved in 10ml alcohol Yue, 65 The acetyl group was removed by refluxing at ° C for 3 hours to obtain a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product is purified by silica gel column to give pure title compound 71 mg (0. 095 mmol) ₀ 9.6 overall yield.

HRMS(ESI) (M+H)+ m/z: 749.36901, calcd for C ₃₈ H ₅₇ N ₂ O _n S 749.36776; 3⁄4 NMR (400 MHz, CDC1 ₃ ) δ: 7. 22 (d, 1 H) , 7. 18 (d, 1 H) , 6. 94 (dd, 1 H) , 2. 71 (s, 3 H) , 2. 37 (s, 6 H) ; ¹ C NMR (75 MHz, CDC1 ₃ ) δ: 204.2, 169.2, 165.9, 154.5 133.4, 132.4, 131.9, 127.3, 127.0, 103.7, 89.9, 84.9, 82.8,

79.6, 79.3, 78.6, 70.4, 69.3, 66.3, 62.3, 51.3, 49.9, 48.0, 40.4, 38.6, 31.0, 29.1,

26.7, 22.7, 21.2, 19.9, 19.0, 16.0, 15.6, 14.5, 13.4, 10.5. Example 16 (Formation of 3-pyridyl compound 6)

1. 000 g ( 1. 412 mmol ) ^ conjugate 5 , 27 mg (0. 14 mmol) ^ cuprous ruthenium, 50 mg (0. 07 mmol) bistriphenylphosphine dichloride, 0. 41 Ml (4. 20 mmol) 3-bromopyridinium, 0. 29 ml (2. 12 mmo l) triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, and the system is reacted under nitrogen at 80 ° C. At the end of the hour, 10 ml of ethyl acetate and 10 ml of water were added to the system, and the layers were allowed to stand. The organic layer was washed with water and saturated brine. After the solvent was evaporated under reduced pressure and purified by silica gel column (mobile phase dichloro Yue alkoxy: ethanol: aqueous ammonia = 15: 0.4: 0.1) to give compound 112 m _go This compound was dissolved in 10ml alcohol Yue, 65 The acetyl group was removed by refluxing at ° C for 3 hours to obtain a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). 7%。 The crude product was purified by silica gel column to give a pure product 50 mg (0. 067 mmol), a total yield of 4.7%.

HRMS(ESI) (M+H)+ m/z 744.40750, calcd for CggHsgNgOn 744.40659; 丽R (400 MHz, CDC1 ₃ ) δ: 8. 65 (s, 1 H) , 8. 53 (s, 1 H) , 7. 71 (d, 1 H) , 7. 23-7. 26 (m, 1 H) , 2. 72 (s, 3 H) , 2. 30 (d, 6 H) ; ¹ C NMR (75 MHz, CDC1 ₃ ) δ: 204.1, 169.2, 165.9, 154.5, 152.5, 148.8, 138.8, 103.8, 89.3, 84.9,

82.8, 79.5, 78.6, 77.4, 76.6, 70.4, 69.4, 66.2, 62.0, 51.3, 49.8, 47.9, 40.4, 38.5, 28.8, 26.6, 22.6, 21.3, 19.9, 19.0, 15.9, 15.6, 14.4, 13.4, 10.5. Example 17 (Product 6 which produces 5-isoquinolyl)

0. 700 g (0. 988 mmol ) ^ composition 5, 19 mg (0. 099 mmol) ^ cuprous, 35 mg (0. 05 mmol) bistriphenylphosphine palladium dichloride, 0. 514 g (2. 47 mmol) 5_bromoisoquinoline, 0. 21 ml (1. 48 匪ol) triethylamine, added to a pressure bottle containing 10 ml of acetonitrile under nitrogen protection at 80 ° C After the reaction was completed for three hours, 10 ml of ethyl acetate and 10 ml of water were added to the system, and the mixture was allowed to stand for stratification. The organic layer was washed with water and saturated brine. Purification (Yue-dichloro mobile phase hexane: ethanol: aqueous ammonia = 15: 0.4: 0.1) After the solvent was evaporated under reduced pressure and purified by silica gel column to give Compound 111 m _go This compound was dissolved in 10ml alcohol Yue, 65 Reducing acetylation under reflux at °C for 3 hours Base product crude (mobile phase is petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified by a silica gel column to give a pure product of 30 mg (0. 037 匪ol) ₀ .

HRMS(ESI) (M+H) ⁺ m/z: 794.42208, calcd for

794.42224; 3⁄4丽R (400 MHz, CDC 1 ₃ ) δ: 9. 25 (s, 1 H) , 8. 60 (s, 1 H) , 8. 12 (d, 1 H) , 7. 94 (d , 1 H) , 7. 83 (d, 1 H) , 7. 55 (t, 1 H) , 2. 69 (s, 3 H) , 2. 33 (s, 6 H); ¹³ C NMR (100 MHz, CDC1 ₃ ) 5:204.1, 169.1, 166.0, 154.6, 152.7, 144.1,

136.3, 134.4, 128.2, 126.8, 120.0, 119.0, 103.7, 92.0, 84.8, 82.9, 82.5, 79.5, 78.5, 76.5, 70.3, 69.3, 66.2, 62.2, 51.2, 49.8, 47.9, 40.4, 38.5, 28.9, 26.6, 22.6, 21.2, 19.9, 19.0, 16.0, 15.7, 14.4, 13.4, 10.5. Example 18 (Product 6 to give 2-[5-(2-pyridine)]thienyl)

0. 700 g (0. 988 mmol ) ^ conjugate 5, 19 mg (0. 099 mmol) ^ cuprous, 35 mg (0. 05 mmol) bistriphenylphosphine dichloride, 0. 505 g (2. 10 mmol) 2-(5-bromo-2-thienyl)pyridine, 0. 21 ml (1. 48 匪ol) triethylamine, added to a pressure flask containing 10 ml of acetonitrile, system under nitrogen Under the protection, the reaction was completed at 80 ° C for three hours, and 10 ml of ethyl acetate and 10 ml of water were added to the system, and the mixture was allowed to stand for stratification. The organic layer was washed with water and saturated brine. The solvent was evaporated to dryness under reduced pressure and purified using silica gel column (mobile phase: methylene chloride: ethanol: ammonia = 15: 0. 4: 0. 1 ) Compound 59 mg. This compound was dissolved in 10 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified by silica gel column to afford compound 27 mg (0. 033 mmol) ₀ total yield 3. 3 % ₀ HRMS (ESI) (M+H) ⁺ m/z: 826.39418, calcd for

826.39431; 3⁄4 NMR (600 MHz, CDC1 ₃ ) δ: 8. 54 (d, 1 H) , 7. 65-7. 69 (m, 1 H) , 7. 61 (d, 1 H) , 7. 41 (d, 1 H) , 7. 14-7. 18 (m, 2 H) , 2. 73 (s, 3 H) , 2. 39 (s, 6 H); ¹³ C NMR (100 MHz, CDC1 ₃ δ: 203.8, 168.6, 165.7, 154.2, 151.6, 149.4,

136.4, 133.2, 132.8, 124.2, 123.9, 122.0, 118.6, 69.9, 68.9, 65.9, 62.0, 50.9, 49.5, 47.6, 40.0, 20.9, 15.2, 14.1, 10.2. Example 19 (Production of 5-nonyl group) 6)

0. 600 g (0. 847 mmol) ^ compound 5, 16 mg (0. 085 mmol) iodine ^ 匕 cuprous, 30 mg (0.04 mmol) of bistriphenylphosphine palladium dichloride, 0.415 g (2.12 匪ol) of 5-bromoindole, 0.18 ml (1.27 mmol) of triethylamine, added to a pressure bottle containing 10 ml of acetonitrile. The system was reacted under nitrogen for three hours at 80 ° C. 10 ml of ethyl acetate and 10 ml of water were added to the system, and the layers were allowed to stand. The organic layer was washed with water and saturated brine. The solvent was evaporated to dryness under reduced pressure, and purified using silica gel column (mobile phase: methylene chloride: ethanol: ammonia = 15: 0.4: 0.1). This compound was dissolved in 10 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified by silica gel column to afford compound 21 (0.027 mmol). The total yield is 3.2.

HRMS(ESI) (M+H)+ m/z: 782.42287, calcd for C HsoNgOn 782.42224; ^! H NMR (600 MHz, CDC1 ₃ ) δ: [8.33 (s, 1 H), 7.75 (s, 1 H) , 7.31 (d, J=8.4 Hz, 1 H), 7.25 (d, 1 H), 7.22 (d, 1H), 6.51 (s, 1 H), indole], 5.03 (dd, J=1.2 Hz, 3.0 Hz, 1 H, H-13), 4.92, 4.87 (d, J=16.0 Hz, 2 H, CH ₂ -C≡C-Ar), 4.78 (br, 1 H, H-11), 4.30 (d, J=7.2 Hz, 1 H, Η-Γ), 4.15 (d, J=3.0 Hz, 1 H, H-5), 3.52-3.84 (m 3 H, H-8, H-5', H-2 ), 3.26 (dd, J=4.2 Hz, 9.6 Hz, 1 H, H-2'), 3.03-3.06 (m, 1 H, H-4), 2.73 (s, 3 H, 6-OCH ₃ ), 2.49-2.61 (m, 2 H, H-3', H-10), 2.35 (s, 6 H, -N (CH ₃ ) ₂ ), 1.55-1.93 (m, 3 H, H-14eq, H- 7, H-4eq), 1.59 (s, 3 H, 12-CH ₃ ), 1.42 (s _: 3 H, 6-CH ₃ ), 1.33 (d, J=6.8 Hz, 3 H, 2-CH ₃ ) , 1.24-1.36 (m, 10 H, 4-CH ₃ , 10-CH ₃ , 5'-CH ₃ , H-4ax), 1.02 (d, J=4.2 Hz, 3 H, 8-CH ₃ ), 0.89 (t, J = 7.2 Hz, 3 H _: 15-CH ₃ ). Example 20 (Formation of 4-quinolyl compound 6)

0.600 g (0.847 mmol) ^ conjugate 5, 16 mg (0.085 mmol) iodine cuprous, 30 mg (0.04 mmol) bistriphenylphosphine dibromide 4 bar, 0.400 g (2.12 mmol) 4 - light p Kui Lin, 0.18 ml (1.27 mmol) of triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, the system was treated under nitrogen for three hours at 80 ° C, and 10 ml of ethyl acetate was added to the system. And 10 ml of water, standing still. The organic layer was washed with water and saturated brine. By silica gel column after the solvent was evaporated under reduced pressure and purification (mobile phase dichloro Yue alkoxy: ethanol: aqueous ammonia = 15: 0.4: 0.1) to give compound 106 m _go This compound was dissolved in 10ml alcohol Yue, at 65 ° C to reflux The acetyl group was removed in 3 hours to give a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified by silica gel column. The pure product was obtained as 33 mg (0.042 mmol). Total yield 4.9% ₀

HRMS(ESI) (M+H)+ m/z 794.42359, calcd for

794.42224; 丽R (600 MHz, CDC1 ₃ ) δ: 8.85 (d, 1 H) , 8.30 (d, 1 H) , 8.09 (d, 1 H) , 7.73 (t, 1 H), 7.61 (t, 1 H), 7.46 (d, 1 H), 2.71 (s, 3 H), 2.28 (s, 6 H); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ: 204.1, 169.2, 166.3, 154.5, 149.8, 148.2 , 130.0, 129.9, 129.5, 128.0, 127.4, 126.2, 123.9, 103.9, 95.5, 84.8, 82.9, 81.8,

79.5, 78.6, 70.4, 69.5, 66.2, 62.1, 51.3, 49.9, 47.9, 40.4, 38.5, 29.8, 28.7, 26.7,

22.6, 21.3, 20.0, 19.0, 15.9, 15.7, 14.4, 13.4, 10.5. Example 21 (Production of 2-[5-benzoquinone]thienyl group 6 )

0.600 g (0.847 mmol) ^ conjugate 5, 16 mg (0.085 mmol) iodine cuprous, 30 mg (0.04 mmol) bistriphenylphosphine dichloride, 0.452 g (1.694 mmol) 2-bromo -(5-Benzenzyl)thiophene, 0.18 ml (1.27 mmol) of triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, and the system was reacted under nitrogen for three hours at 80 ° C in the system. 10 ml of ethyl acetate and 10 ml of water were added and the layers were allowed to stand. The organic layer was washed with water and saturated brine. The solvent was evaporated to dryness under reduced pressure and purified using silica gel column (mobile phase: methylene chloride: ethanol: ammonia = 15: 0.4: 0.1) This compound was dissolved in 10 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product is purified by silica gel column to give pure title compound 46 mg (0.054 mmol) ₀ 6.4% overall yield. HRMS(ESI) (M+H)+ m/z 853.39585, calcd for C ₄₅ H ₆₁ N ₂ 0 ₁₂ S 853.39397; 3⁄4 NMR (600 MHz, CDC1 ₃ ) δ: [7.83—7.85 (m, 2 H) , 7.56—7.61 (m, 1 H) , 7.49-7.51 (m, 3 H) , 7.19 (d, 1 H) ] , 5.04 (dd, 1 H) , 4.92 (d, 1 H) , 4.87 (d, 1 H), 4.80 (s, 1 H) , 4.30 (d, 1 H) , 4.19 (d, 1 H) , 3.82 (q, 1 H), 3.65 (br, 1 H) , 3.53-3.56 (m, 1 H) , 3.21 (dd, 1 H) , 3.03-3.05 (m, 1 H), 2.72 (s, 1 H) , 2.47-2.54 (m, 2 H) , 2.29 (s, 6 H) , 1.89—1.93 (m, 1 H), 1.68-1.72 (m, 2 H) , 1.56 (s, 3 H) , 1.43 (s, 3 H) , 1.36 (d, 3 H), 1.24-1.35 (m, 10 H) , 1.02 (d, 3 H) , 0.89 (t, 3 H). Example 22 (Form of compound of formula (I) where X = H and Ar = ⁴ _isoquinolyl) 0.700 g (1.025 mmol) of 2 - O-acetyl-3-hydroxycarbonyl_6_0-fluorenylerythromycin A 9-0-propargyl hydrazine, 19 mg (0.099 mmol) ^ cuprous ruthenium, 35 mg (0.05 Methyl) bistriphenylphosphine palladium dichloride, 0.640 g (3.075 匪ol) 4-bromoisoquine, 0.21 ml (1.48 mmol) triethylamine, added to a pressure bottle containing 10 ml of acetonitrile, the system was protected with nitrogen Next, the reaction was completed at 80 ° C for three hours, and 10 ml of ethyl acetate and 10 ml of water were added to the system, and the layers were allowed to stand. The organic layer was washed with water and saturated brine. The solvent was evaporated to dryness under reduced pressure, and purified using silica gel column (mobile phase: methylene chloride: ethanol: ammonia = 15: 0.4: 0.1). This compound was dissolved in 10 ml of decyl alcohol, and refluxed at 65 ° C for 3 hours to remove the acetyl group to obtain a crude compound (mobile phase: petroleum ether: acetone: triethylamine = 5: 5: 0.2). The crude product was purified on a silica gel column to yield purified product 34 mg (0.044 mmol). Total yield 4.3% ₀

'Η NMR (600 MHz, CDC1 ₃ ) δ: 2.36 (s, 6 H, -N (CH ₃ ) ₂ ) , 2.80 (s, 3 H, 6-0CH ₃ ) , 3.14 (dd, 1 H, H- 2, 3.24-3.29 (m, 1 H, H-4), 3.33 (s, 1 H, 12-OH), 3.99 (s, 1 H, 11-H), 4.32 (d, 1 H, HI, 4.81 (s, 1 H, 11- OH), 4.98, 4.94 (d, 2 H, CH ₂ - C≡C- Ar), 5.21 (dd, 1 H, H-13), [7.64 (t, 1 H) , 7.80 (t, 1 H), 7.98 (d, 1 H) , 8.23 (d, 1 H) , 8.67 (s, 1 H), 9.19 (s, 1 H), isoquinolyl].

Example 23

Activity determination of pharmaceutical compositions

The present invention can also provide a pharmaceutical composition for antibacterial treatment, which composition can include an antibacterial effective amount of a compound having the above formula, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

The antibacterial therapeutic effect of the above pharmaceutical composition of the 9-nonyl ether ketone lactone derivative was measured.

According to the criteria recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010), some target compounds were tested by broth dilution method for sensitive Streptococcus pneumoniae ATCC49619, erm+mef-resistant Streptococcus pneumoniae PU-11, mef-type resistant pneumonia In vitro antibacterial activity (MIC) of Streptococcus pneumoniae PU-09, erm-resistant Streptococcus pneumoniae PU-27. See the results Table 1

Table 1 MIC value (g/mL) of 9-(aryl)propynyl oxime ketone lactone derivative clarithromycin azithromycin Example 10 Example 11 Example 12 Example 13 ATCC49619 0.032 0.064 < 0.016 < 0.016 < 0.016 < 0.016

PU-11 128 256 128 16 32 16

PU-09 4 8 0.125 0.032 0.064 0.125

PU-27 16 32 0.5 0.032 0.064 0.064 Further, the standard compound of Example 13 and the reference substance (9_^" aromatic propyl ketone were determined by the broth dilution method, recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010). In vitro antibacterial activity of lactone derivatives against sensitive Streptococcus pneumoniae ATCC49619, erm+mef-resistant Streptococcus pneumoniae PU-11, mef-resistant Streptococcus pneumoniae PU-09, erm-type resistant Streptococcus pneumoniae PU-27 (MIC) The results of the measurements are shown in Table 2.

Table 2 Comparison of antibacterial activity of 9-(aryl)propynyl oxime ketone lactone derivatives and 9- aryl propyl ketone ether ketone lactone derivatives (MIC value: μ g/mL)

Example 13 Reference

ATCC49619 0.016 0.016

PU-11 16 32

PU-09 0.125 0.25

PU-27 0.064 1 wherein, the reference substance is: 3_carbonyl-6-mercaptoerythromycin 9_[3_(6_quinoline)_2_propenyl]fluorene-11, 12-cyclic carbonate.

As can be seen from Tables 1 and 2, the target compounds showed more prominent anti-sensitive and anti-resistant bacteria activities than the current clinical main drugs, clarithromycin and azithromycin. The target compound of Example 13 is 3-carbonyl-6-oxime-based erythromycin A 9_6 3_(6-quinolinyl) 2 -propynyl]fluorene-11, 12-cyclocarbonate and analog (reference) 3 The carbonyl group _6_^ thioerythromycin A 9-^ (3-(6-quinolinyl)-2-propenyl) oxime-11, 12-cyclic carbonate, the antibacterial activity is further improved.

We compared the antibacterial activity with the analog 9-^ aryl allyl ketone lactone and found that the compound of the present invention has higher antibacterial activity, and the target compound of Example 13 in Table 2 and The difference between the reference product and the "allyl" and the "propargyl group" indicates that the side chain structure of the propargyl group of the present invention has a better antibacterial effect.

For the compounds of the general formula (I) and (II) of the present invention, the existing studies show that: 11 , π-carbonation can further enhance the antibacterial activity than the parent 11 , 12-0H uncarbonated (T. No leg Ra _: et al, Bioorg. Med. Chem. 2005, 1 3: 6054-6063), it can be deduced that, in the case of the same substituent group, the compound of the formula (I) of the present invention has less antibacterial activity than the formula (II) ) compound of.

It is to be noted that the compounds of the formulae (I) and (II) of the present invention can be used in various drugs for the treatment of microbial infections such as bacteria, including chlamydia or mycoplasma infection and the like.

A novel ketolide (9-arylpropynyl ketolide derivative) provided by the present invention, a synthetic preparation method thereof, and the use of the compound as an anti-infective drug and a corresponding pharmaceutical composition, DETAILED DESCRIPTION OF THE INVENTION The principles and embodiments of the present invention have been described herein with reference to specific examples. The foregoing description of the embodiments is merely to aid in understanding the method of the present invention and its core concepts. The present invention is not limited by the scope of the present invention.

Claims

The invention is directed to a compound having the following general formula (I) or (II) or its inorganic acid or organic

I Π

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; and X is hydrogen or fluorine.

The compound of claim 1 or a pharmaceutically acceptable salt or ester thereof formed with an inorganic or organic acid, characterized in that

The Ar is a nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group; or Ar is a substituted nitrogen-containing, sulfur-containing or oxygen-containing aromatic heterocycloalkyl group.

3. A compound of claim 1 or a pharmaceutically acceptable salt or ester thereof formed with an inorganic or organic acid, characterized in that

The Ar is imidazolyl, pyridyl, pyrimidinyl, benzopyrazinyl, benzoxazinyl, quinolyl, isoquinolyl, imidazolylphenyl, thienylphenyl, decyl, thienyl ;

Alternatively, Ar is a substituted imidazolyl group, a substituted pyridyl group, a substituted pyrimidinyl group, a substituted benzopyrazinyl group, a substituted benzoxazinyl group, a substituted quinolyl group, a substituted isoquinolyl group, a substituted imidazolylphenyl group, a substituted thienyl group. Phenyl, substituted indenyl, substituted thienyl.

4. A compound according to claim 2 or a medicament formed thereof with an inorganic or organic acid The Ar is 2-pyridyl, 3-pyridyl, 5-pyrimidinyl, 3-quino-p-linyl, 4-isoquino-p-linyl, 4-quinolinyl, 5-isoquinolinyl, 5-quinoline Lolinyl, 6-quinolyl, 4-(1-imidazolyl)phenyl, 4-(2-thienyl)phenyl, 5-nonyl, 2-thienyl, 2-[5-(2-pyridyl) ]Thienyl, 2-(5-benzoyl)thienyl.

The inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid;

The organic acid is selected from the group consisting of acetic acid, malonic acid, sulfonic acid, succinic acid, p-toluic acid, citric acid, maleic acid, fumaric acid or stearic acid.

6. A process for the preparation of a compound of the formula (I) or (II) according to claim 1, characterized in that it comprises the steps of:

(1) A compound having the following formula ( m ):

III

Alternatively, in the THF single solvent, DMF single solvent or THF/DMS0 mixed solvent, the acetyl group on the 9-fluorenyl hydroxyl group of the compound of the step (1) is selectively substituted by the combination of a propargylating agent and a strong base. Benzoyl or trimethylsilyl; then use a ring closure reagent 11, 12-OH ring closure, and then oxidize 3-0H to 3-carbonyl with an oxidizing reagent to obtain the general formula (V)

IV

Wherein the R group corresponds to an acetyl group, a benzoyl group or a trimethylsilyl group;

(3), in the acetonitrile, THF or DMF solvent, catalyzed by a palladium salt and a copper salt, the substituted heteroaromatic hydrocarbon and the propargyl group on the 9-fluorene hydroxyl group form a heteroaromatic side chain, and take off 2 -0- a R protecting group to give a compound having the following formula (I) or (II);

Alternatively, in the acetonitrile, THF or DMF solvent, the palladium salt and the copper salt catalyze the substitution of the heteroaromatic hydrocarbon with the propargyl group on the 9-fluorene hydroxyl group to form a heteroaromatic side chain; further introducing a fluorine atom at the 2-position, And removing the -0-R protecting group to obtain a formula (I) or (II)

I II

Wherein Ar represents an aromatic heterocyclic hydrocarbon group or a substituted aromatic heterocyclic hydrocarbon group; X is hydrogen or fluorine

7. The method of claim 6 wherein:

0-4. 0。 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. .

8. The method of claim 6 wherein:

The protective reagent is selected from the group consisting of acetic anhydride, benzoic anhydride, trimethylsilyl silane or hexamethylene disilazane;

The propargylating agent is selected from the group consisting of propargyl bromide or propargyl iodide;

The strong base is selected from potassium t-butoxide, potassium hydroxide, sodium hydride, or hexamethyldisilazide; the ring-closing agent is selected from the group consisting of triphosgene, phosgene, or trichlorodecyl chloroformate;

The oxidizing agent is selected from the group consisting of N-chlorosuccinimide/disulfonium sulfide, or an oxidizing combination reagent containing sulfoxide;

The palladium salt is selected from the group consisting of dichlorobis(triphenylphosphine)palladium or tetrakis(triphenylphosphine)palladium; the copper salt is selected from cuprous iodide or cuprous bromide.

A pharmaceutical composition for antibacterial treatment, which comprises an antibacterially effective amount of a compound having the following general formula (I) or (II), or a pharmaceutically acceptable salt thereof or

A compound of the formula (I) or (II) according to claim 1 or a medicament thereof

The use of a compound of the formula (I) or (II) or a pharmaceutically acceptable salt or ester thereof according to claim 1 as an antibacterial microorganism infectious agent.

12. A method of treating a bacterial microbial infection, the method comprising administering to a patient a therapeutically effective compound of at least one compound of formula (I) or (II) according to claim 1 or