JPH06509792A - Novel quinolone compound and method for producing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Background of the invention of a novel quinolone compound and its manufacturing method Industrial applications The present invention provides novel quinolone compounds with excellent antibacterial activity and their pharmaceutically approved compounds. This invention relates to acceptable salts and methods for their production.

Conventional technology norfloxacin (norf　oxacin), pefloxacin (pef　f　f) oxacin), ofloxacin (ojl (Ixacin), ciprofloxa Ciprofloxacin and Sparfloxacin (5parf) Previously developed quinolone antibacterial agents, such as It shows excellent antibacterial activity against Gram-positive bacteria, but relatively little against Gram-positive bacteria. Shows low activity.

Additionally, many of the bacteria-fighting strains of these drugs are more potent and superior. It has been clinically found that it is required to be an antibacterial agent.

Recently, considerable attempts have been made to overcome these problems and to develop better quinolone Bacterial agents are being manufactured.

Various types of diazanicyclic compounds have been used as substitutes at the 7-position of quinolone antibacterial agents. Some examples are listed below.

European Patent Application No. 215650Ax discloses a compound having the following structural formula: It is.

In the formula, R2 is a diazabicycloalkyl group having the following structural formula: To be elected.

(where n is 1, 2 or 3, m is 1 or 2, P is 0 or ISQ is hydrogen or (C, ~ C2) represents alkyl).

European Patent Application No. 266576Ax discloses a compound having the following structural formula: It is.

In the formula, R1 is a substituted or unsubstituted tertiary alkyl group, and Z is an N-heterocycle. The formula group is selected from the group consisting of the following structural formula.

(In the formula, R2 is hydrogen or an alkyl group, and n is an integer of 0 to 3).

However, the diazabicycloamine derivatives mentioned above have a higher antibacterial effect than conventionally developed agents. Does not exhibit particularly excellent properties in terms of activity.

Summary of the invention The purpose of the present invention is to introduce a novel amine substituent into the 7-position of the quinolone nucleus. , against both Durham-positive and -negative bacteria, than previously developed. The objective is to provide an excellent quinolone antibacterial agent that is more effective.

The present invention provides novel quinolone compounds represented by the following formula (1) and their pharmaceutically approved compounds. Regarding acceptable salts.

In the above formula R1 is hydrogen or a protecting group, R2 is hydrogen, amino, alkylamino having 1 to 4 carbon atoms, hydroxy Ci, alkoxy with 1 to 4 carbon atoms, mercapto, 1 to 4 carbon atoms alkylthio or halogen, R3 is alkyl having 1 to 4 carbon atoms, alkyl having 2 to 4 carbon atoms; rukenyl, cycloalkyl with 3 to 6 carbon atoms, haloalkyl, 2 to 4 hydroxyalkyl, methoxy, amino, 1-2 carbon atoms Alkylamino, dimethylamino or halogen atom or 1- phenyl optionally substituted with one or more alkyls having 3 carbon atoms; Z is an amine represented by the following formula.

(wherein R4 is hydrogen or alkyl having 1 to 4 carbon atoms, R6 and R7 are hydrogen or alkyl having 1 to 2 carbon atoms, which may be the same or different; basis).

X is N or C-R' (wherein R@ is hydrogen, hydroxy, methyl, cyano, - Forming a bridge with the following formula with methoxy, halogen or R3 It is something that can be done. ) The present invention provides a compound of formula (II) in the presence of a solvent and a base. A compound of the above formula (1) is produced by reacting with a compound of formula (I[I) A method is also provided.

In the formula, R', R2, R3, X and Z are as described above, and Y represents halogen.

Detailed description of the invention The novel quinolone compound of the present invention represented by the above formula (1) is characterized by Durham positive and Shows excellent antibacterial activity against both Ram-negative bacteria.

The compound of formula (1) of the present invention has the following formula: A novel 3. The Z group, which is a 6-diazabicyclo(3,1,0)hexane derivative, is It is characterized by its introduction at the 7-position.

The present invention further provides 15 to 300 3-quinolinecarboxylic acid derivative of formula (n) at a temperature of °C. -diazabicyclo(3,l.

0] A method for producing a compound of formula (1) by reacting with a hexane derivative It also relates to

In the formula, R', R2, R', Z and X are as described above, and Y represents halogen. More books The invention comprises one or more compounds of formula (1) or their pharmaceutical compositions as active ingredients. It also relates to pharmaceutical compositions containing acceptable salts.

In particular, the compound of formula (1) can furthermore be used to form a compound of formula (II) according to the following reaction mechanism: It can be easily produced by reacting with an amine of formula (I).

, ■, (III) (I) (In the formula, R1, R2, R3, ZSX and Y are as described above).

Compounds of formula (In) can be prepared by the reported methods or by e.g.

504-509 (1987), U.S. Patent No. 4,885,386, European Patent Publication No. 2 35762, Japanese Patent Publication No. 7203085, German Patent No. 2057440 It can be manufactured by the method according to No. 1, etc.

The novel amine compounds of formula (I) can be prepared in three ways according to the following reaction scheme: .

[To the mechanism]

2RM(2,H,So,, heat (IIJAa) (III-4b) (”-5) (■1.6) (III) During the ceremony, RS and R7 are as above, R is an amino reserve that can be removed by acid or base hydrolysis or catalytic hydrogenation. Mamoki, R' represents an alkyl or amino protecting group having 1 to 4 carbon atoms.

In the reaction sequence of Mechanism A, the maleimide compound of formula (III-3) has the formula Reaction of maleic anhydride compound (I-1) with benzylamine derivative (RNH2) The mixture of maleamic acid (m-2a+ll-2b) was diluted with acetic anhydride-acetic acid sodium chloride. By cyclizing with thorium, or maleic anhydride compound of formula (I-1) benzylamine derivative (RNH2) and bisbenzylammonium sulfate It can be obtained by reacting in situ with Alkyl azide (R'-N,) ( I-3) 1. By adding 3-dipolar cyclo, triazolinization A mixture of compound (I[-4a+III-4b) is obtained. Heat of the above mixture following Alternatively, a compound of formula (Illr-5) is obtained by photolysis reaction, which is pyrrolidine The ring and aziridine ring are fused together.

Reduction of (III-5) using lithium aluminum hydride provides formula (I[ -6) is obtained, which is deprotected by hydrolysis or hydrogenolysis ( deprotect) to provide a novel amine compound of formula (I).

[Machine 4*B] (In・l) (111,7) (nl-11) (In-9) (I old 0) ( ll-11a) (1■-11b) where, X' is a halogen such as chloro or bromo, R, R' and R5 are as described above. show.

In the reaction sequence of mechanism B, the compound of formula (I-8) (when R'=H, Available on the market, but when R6 = alkyl, reduction and halogen from (I-1) cyclization of the compound (prepared via Compound (I-9) is obtained.

The chlorohydrin obtained by reacting the 3-pyrroline derivative (I-9) with chlorine gas The intermediate is cyclized with a base to obtain an epoxide compound of formula (1-10). Amine (R 4-NH2) and (I[-10), the amino alcohol (I[-11 a+nl-11b) was obtained, which was then treated with diethyl azodicarbo ring using xylate (DEAD) and triphenylphosphine (Pt+sP) to obtain an aziridine compound of formula (I[l-6).

Finally, (I-6) is deprotected to obtain a novel amine compound of formula (I).

[Mechanism C]

(111,10) (1■-+2a) (III-12b) B■-13a) (III-13b) (1■-6a) (nl-14) (ma) (+11) During the ceremony, Ro is an amino protecting group X# is halogen, methanesulfonyloxy, P-)luene-sulfonyloxy , diethylphosphoryloxy, diethylthiophosphoryloxy, acetoxy, or is a radical removal such as alkoxy, R, R' and R5 are as described above.

In the reaction sequence of Mechanism C, a compound of formula (llll-1o) is reacted with sodium acetate. React with azido (NaN, ) to produce azide alcohol (III-12a + If [ -12b), which is then combined with a compound (II A mixture of I-13a and I-13b) is induced. By reduction of the above mixture , to obtain an aziridine compound of formula (m-6a).

The compound of formula (m-6a) can be directly deprotected or other protecting groups can be added to the aziridine ring. A novel amine compound of formula (III) by introducing and then selectively deprotecting get something

Therefore, the compound of formula (1) reacts with the compound of formula (II) with the amine of formula (III). It can be manufactured by reacting. Examples of suitable reaction solvents include tetrahydrofuran Ran, dimethyl sulfoxide, N, N-dimethylformamide, N, N-di Methylacetamide, N-methylpyrrolidone, acetonitrile, water, alcohol (e.g. methanol, ethanol, n-propertool or iso-propertool), Includes glycol monomethyl ether, pyridine or mixtures thereof.

This reaction can be carried out without the use of a solvent or if the solvent is a basic solvent. Adding some base to the reaction mixture can be helpful if the solvent (e.g. pyridine) is not available. preferable.

The base is reacted by reacting with the hydrohalide formed from the reaction mixture. Promote perfecting.

Alkali metal hydroxides, alkali metal carbonates, organic amines and amides especially triethylamine, 1,4-diazabicyclo(2,2,2)octane ( DABCO), 1,8-diazabicyclo(5,’4.O) unde -7-cene (DBU), 1,5-diazabicyclo(4,3,0)non-5-ene (DBN), or an excess of amine (In). Preferably used.

This reaction is carried out at a temperature of 15 to 300°C, preferably 60 to 120°C, or under reflux of the solvent. Perform at temperature.

This reaction can be carried out over several days, but preferably for 1 to 24 hours. Ru. Typically, higher reaction temperatures shorten reaction times.

The amine compound of formula (III) may be used to form an inorganic or organic salt during the reaction. It will be done. Some examples of inorganic or organic salts include hydrochloride, hydropromide, sulfur including phates, formates, acetates or oxylates. Furthermore, the formula (I[) Desired is 1 to 6 equivalents of the amine compound of formula (III) to the quinoline carboxylic acid of Or use it.

The compounds of general formula (I) of the present invention can be used in a wide range of Gram-positive or Gram-negative bacteria. The following biological tests have shown that it has effective antibacterial activity against a spectrum of It was.

Therefore, the compounds of the invention may be used to protect against susceptible bacteria, both in humans and animals. It is useful in the antibiotic treatment of Ria infections. Furthermore, this compound can be used on counter surfaces, etc. Can be used in scrubbing solutions for surface inhibition of bacterial growth such as Ru.

Susceptible microorganisms generally include Staphylococcus spp., Lactobacillus spp., Sarcina spp. Genus, Escherichia, Enterobacter.

Klebsiella, Pseudomonas, Acinetobacter, Proteus, Cyto Lobacter spp., Nisseria spp., Buckrus spp.

Bacteroides, Pbutococcus, and Clostridium.

Such as Salmonella, Shigella, Serratia, Haemophilus, Purcella including gram-negative and gram-negative, aerobic and anaerobic microorganisms and other microorganisms, These growths can be inhibited by the compounds of the invention.

The bioactivity spectrum of the compounds of the present invention is shown on Mueller-Hinton agar (Muel). Two fold agar dilution (Ler-Hinton) r-dilution) method. Japan Chemotherapy Society Standards recommended by Academic Therapy, 29(1), 76-79 (1981)) According to the method, each bacterium is planted in a dilute manner. Test microorganisms containing approximately 104 colony-forming units (106 cells/ml) were cultured overnight. To culture, this is plated on drug-containing agar and incubated at 37°C for 18 hours. This means that

MIC is defined as the lowest concentration of drug that inhibits visible bacterial growth. It will be done.

The MICs of the compounds of the present invention are shown in Table 1 in comparison with ciprofloxacin, and the test compounds Items are represented by example numbers.

test microorganisms 1. Streptococcus pyogenes 308A 2. Streptococcus pyogenes 77A 3 Fecal streptococcus MD86 4. Staphylococcus aureus SG511 5. Staphylococcus aureus 285 6. Staphylococcus aureus 503 7. Escherichia coli 055 8. Escherichia coli DCO 9. E. coli DC2 10. Escherichia coli TEM 11. Escherichia coli 1507E 12. Pseudomonas aeruginosa 9027 13. Pseudomonas aeruginosa 1592E 14. Pseudomonas aeruginosa 1771 15. Pseudomonas aeruginosa 1771M 16. Salmonella typhimurium 17, Klebsiella oxytoca 1082 E18, Klebsiella oxytoca (aerogenes) l　522　E19, found in human and animal feces 20 Henterobacter bacteria, 321 Henterobacter bacteria found in human and animal feces E Table 1 M[C (μg/ynl) values measured by agar dilution method Continuation of Table 1 Continuation of Table 1 Continuation of Table 1 Continuation of Table 1 Continuation of Table 1 Continuation of Table 1 Continuation of Table 1 Several pharmacokinetic parameters of the compounds of the invention were determined in mice.

Test compounds were administered to ICR mice weighing approximately 18 g at a dosage of 40 mg/kg. Oral and subcutaneous administration, 10.20°30.45,60,90,120 after administration Serum was collected after , 150, 180, and 240 minutes, and urine after 24 hours.

Pharmacokinetic parameters were determined using E. coli (E-col) as a standard living organism. 1) Determined by bioassay using 055, and the results are shown in Table 2.

Table 2 Pharmacokinetic parameters Po in mice: Historically SC9 subcutaneous Cmax: Time to maximum concentration in serum Tmax: To maximum concentration in serum Time TI/2: Serum half-life AUG: Area below the curve UR: Urinary recovery On the other hand, the compounds of formula (I) of the present invention are capable of forming pharmaceutically acceptable salts. , herein the term "pharmaceutically acceptable salts" refers to non-toxic acid addition salts, alkali metal salts, Refers to base salts formed with alkaline earth metals or organic amines.

These salts may be prepared in situ during the final isolation and purification of the compound of formula (I). or separately with a suitable organic or inorganic acid or base, respectively. It can be produced by reaction.

Typical acid addition salts in the present invention include hydrochloride, hydropromide, sulfur Phate, bisulfate, formate.

Acetate, oxalate, valerate, oleate, palmitate, stair Rate Laurate, borate, benzoate, lactate, phosphate, p -1-Luenesulfonate.

Methanesulfonate Citrate Maleate Fumarate, Succinate, Ta Contains lutelate and ascorbate, typical alkali metals and alkaline earths Metallic salts include sodium, potassium, calcium and magnesium salts. Ru.

Further examples of suitable organic amines include N,N-dibenzyl-ethylenediamine, Chloropropylene, choline, jetanolamine, ethylenediamine, N-methylene Contains luglucamine and proton.

The carboxyl protecting group included in the term protecting group in the present invention is, for example, 1 to 4 alkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms and containing reported protecting groups such as benzyl and benzyl groups, as well as amine protecting groups. is asol, alkoxycarbonyl, (substituted) sulfonyl.

Contains (substituted) hensyloxycarbonyl, (substituted) benzyl, etc. It will be done.

The term alkali includes, for example, methyl, ethyl, n-propyl.

Straight and branched carbons such as iso-propyl, n-butyl, t-butyl, etc. Contains a chain, and alkenyl is ethynyl.

Containing straight and branched carbon chains such as propenyl, iso-propenyl, etc. It is.

The term haloalkyl refers to one or more of the same or different halogen atoms. includes substituted alkyl groups; the term halogen refers to fluorine, chlorine, Contains bromine and iodine.

Some compounds of the invention exist in optically active forms: in particular racemic mixtures. , meso-isomers, dA-isomers, pure isomers, including diastereomeric mixtures, pure Isomers and mixtures thereof are contemplated by the present invention. Asymmetric carbon atoms are examples may be present on substituents such as alkyl groups or fused carbon atoms. However, these isomers as well as mixtures thereof are also included within the scope of the present invention. It is something.

Representative compounds of the present invention are shown below as compounds of formula (I).

(1) 1-cyclopropyl-6-fluoro-7-(6-methyl-3,6-dia zabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro-4-oxy So-3-quinolinecarboxylic acid and its salts.

(2) ■-dicyclopropyl-68-difluoro-7-(6-methyl-3,6 -diazabicyclo[:3.1.0)hexan-3-yl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and its salts.

(3) 5-amino-1-noclobropyru-6,8-difluoro-7-(6-methyl thyl-3,6-diabicyclo(3,1,0)hexan-3-yl)-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid and its salts.

(4) ■-dicyclopropyl-6-fluoro7-(6-methyl-3,6-dia zabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro-4-oxy So-1,8-naphthyridine-3-carboxylic acid and its salts.

(5) 6,8-difluoro-1-(2,4-difluorophenyl)-7-(6- Methyl-3,6-diazabicyclo(3,1°O]hexan-3-yl)-1,4 -dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.

(6) 1-cyclopropyl-8-chloro-6-fluoro-7-(6-methyl- 3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihyde Low-4-year-old xo-3-quinolinecarboxylic acid and salts thereof.

(7) 9-fluoro-2,3-dihydro-3-methyl 1O-(6-methy/L, -3,5-diazabicyclo(3,1,0)hexan-3-yl)-7-oxo -7H-pyrido(1,2,3-deu-1,4-benzoxazine-6-carvone Acids and their salts.

(8) l-cyclopropyl-6-fluoro-8-methoxy-7-(6-methy/ l,-3,5-diazabicyclo(3,l,0)hexan-3-yl)-1,4 -dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.

(9) l-cyclopropyl-6-fluoro-7-(1,6-cymethyl-3.6 -diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro-4 -Oxo-1,8-naphthyridine-3-carboxylic acid and salts thereof.

(10) l-cyclopropyl-6-fluoro-7-(1,6-cymethyl-3, 6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and its salts.

(II) 5-amino-1-cyclopropyl-6,8-difluoro-7-(1,6 -Simethyl-3,6-diazabicyclo(3,1゜0]hexadi-3-yl)-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(12) 9-Fluoro-2,3-dihydro-3-methyl-10-(1,6-dihydro-3-methyl-10-(1,6-dihydro-3-methyl) Methyl-3,6-diazabicyclo(3,1,0)hexan-3-yl)-7-o Xo-7H-pyrido(1,2゜3-de)-1,4-benzoxazine-6-cal Bonic acid and its salts.

(13)]-]Nclobroby-6-fluoro-8methoxy-7-(1,6- dimethyl-3,6-diazabicyclo(3,1゜0]hexan-3-yl)-1, 4-dihydro-4-year-old xo-3-quinolinecarboxylic acid and salts thereof.

(+4)]-]nclobropyru-6,8-difluoro7-(1゜6-dimethyl -3,6-diasabicyclo(3,1,0)hexan-3-yl)-1,4-dihy Dro-4-oxo-3-quinolinecarphonic acid and its salts.

(15) l-Fucloprovir-8-chloro-6-fluoro-7-(1,6-siloxane) Methyl-3,6-diazabicyclo[3,1,0)hexan-3-yl)-1,4 -dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.

(16) I-cyclopropyl-7-(3,6-diazabicyclo(3,1,O) hexan-3-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8 -Naphthyridine-3-carboxylic acid and its salts.

(17) l-silocpropyl-7-(3,6-diazabicyclo(3,1,0) hexan-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-x Norincarboxylic acid and its salts.

(18) 1-cyclopropyl-7-(3,6-diazabicyclo(3,1,0) hexan-3-yl)-6,8-difluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid and its salts.

(19) 1-cyclopropyl-8-chloro-7-(3,6-diazabicyclo( 3,1,0)hexan-3-yl)-6-fluoro-1,4-dihydro-4-o Xo-3-quinolinecarboxylic acid and its salts.

(20) 5-amino-1-cyclopropyl-7-(3,6-diazabicyclo( 3,1,0)hexan-3-yl)-6,8-difluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and its salts.

(21) 7-(3,6-diazabicyclo(3,1,0)hexan-3-yl )-6,8-difluoro-1=ethyl-1,4-dihydro-3-quinolinecarbo acid and its salts.

(22) 9-fluoro-2,3-dihydro-3-methyl-10-(3,6-di AzabicycloC3,1,O)hexan-3-yl)-7-oxo-7H-pyrido -(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid and its salts .

(23)]-cyclopropyl-6,8-difluoro-7-(l-methyl-3, 6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro- 4-year-old xo-3-quinolinecarboxylic acid and its salts.

(24) l-cyclopropyl-8-chloro-6-fluoro-7-(1-methyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihy Dro-4-oxo-3-quinolinecarboxylic acid and its salts.

(25) 5-amino-1-cyclopropyl-6,8-difluoro-7-(1- Methyl-3,6-diazabicyclo[:3. 1. 0]Hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(26) l-cyclopropyl-6-fluoro-7-(1-methyl-3,6-di Azabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro-4-o Xo-1,8-naphthyridine-3-carboxylic acid and its salts.

(27) 1-cyclopropyl-6-fluoro-7-(l-methyl-3,6-di Azabicyclo(3,1,0)hexan-3-yl)-1,4-dihydro-4-year-old Xo-3-quinolinecarboxylic acid and its salts.

(28) 9-fluoro-2,3-dihydro-3-methyl-10-(l-methyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-7-oxo- 7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carvone Acids and their salts.

(29) 6,8-difluoro-1-(2,4-difluorophenyl)-7-(3 ,6-diazabicycloC3,1,0)hexan-3-yl)-1,4-dihydro -4-oxo-3-quinolinecarboxylic acid and salts thereof.

(30) 6,8-difluoro-1-(2,4-difluorophenyl)-7-(1 -Methyl-3,6-diazabicyclo(3,1゜0]hexan-3-yl)-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(31) 6,8-difluoro-1-(2,4-difluorophenyl)-7-(1 ,6-dimethyl-3,6-diazabicyclo(3,1,0)hexan-3-yl) -1,4-dihydro-4-year-old xo-3-quinolinecarboxylic acid and salts thereof.

(32) l-cyclopropyl-6,8-difluoro-7-(1°5-dimethyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihy Dro-4-oxo-3-quinolinecarboxylic acid and its salts.

(33) l-cyclopropyl-8-chloro-6-fluoro-7-(1,5-di Methyl/l/-3,6-diazabicyclo(3,1,0)hexan-3-yl)-1 , 4-dihydro-4-oxo-3=quinolinecarboxylic acid and salts thereof.

(34) 5-amino-1-cyclopropyl-6,8-difluoro-7-(1, 5-dimethyl-3,6-diazabicyclo[3°1.0]hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(35) I-cyclopropyl-7-(1,5-dimethyl-3゜6-diazabisi chloro(3,1,0)hexan-3-yl)6-fluoro-1,4-dihydro-4 -Oxo-1,8-naphthyridine-3-carphonic acid and its salts.

(36)! -cyclopropyl-7-(1,5-dimethyl-3゜6-diazabisi Chlo(3,1,0)hexan-3-yl)-6-fluoro-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid and its salts.

(37) l-ethyl-7-(1,5-dimethyl-3,6-diazabicyclo(3 ,1,0)hexan-3-yl)-6,8-difluoro-1,4-dihydro-4 -Oxo-3-quinolinecarboxylic acid and salts thereof.

(38) 9-fluoro-2,3-dihydro-3-methyl-10-(1,5-di Methyl-3,6-diazabicyclo(3,1,0)hexan-3-yl)-7-o Xo-7H-pyrido(1,2°3-de)-1,4-benzosazine-6-carbo acid and its salts.

(39) 6,8-difluoro-1-(2,4-difluorophenyl')-7-( 1,5-dimethyl-3,6-diazabicyclo(3,1,0)hexan-3-yl )-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its salts.

(40) 1-cyclopropyl-6,8-difluoro-7-(1゜5.6-4ly Methyl-3,6-diazabicyclo[:3.1. O) hexane-3-yl)-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(41) 8-chloro-1-cyclopropyl-6-fluoro-7-(1,5,6 -1-tmethyl-3,6-diazabicyclo[3°10]hexan-3-yl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and salts thereof.

(42) 5-amino-1-fuclopropyl-6,8-difluoro-7-(1, 5,6-trimethyl-3,6-diazabicyclo[3,1,0)hexane-3-y )-1,4-dihydro-4-oxo-3-quinolinecarphonic acid and its salts.

(43) I-Fucloprovir-6-fur-7-(1,5゜6-drimethyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihy Thorough 4-oxo-1,8-naphthyridine-3-carboxylic acid and salts thereof.

(44) l-cyclopropyl-6-fluoro-7-(1,5°6-dolimethyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihy Dro-4-oxo-3-quinolinecarboxylic acid and its salts.

(45) 1-ethyl-6,8-difluoro-7-(1,5,6=trimethyl- 3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dihyde Rho-4-oxo-3-quinolinecarboxylic acid and its salts.

The compounds of the invention may be formed into compositions with pharmaceutically acceptable carriers. These include injections, solid or liquid forms for oral administration, rectal administration, ointments, etc. be.

Compositions of the invention for injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions; Including suspensions or emulsions.

Suitable non-aqueous carriers, diluents, materials or vehicles include propylene glycol. , polyethylene glycol, vegetable oils such as olive oil or sesame oil, and injectable organic ethers such as ethyl oleate.

Such compositions may be prepared, for example, by filtration through a bacteria-retaining filter; can be dissolved in sterile water or some other sterile injection medium immediately before use. Sterilization is achieved by incorporating a sterilizing agent in the form of a sterile solid composition.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and Contains grains and granules. In such solid dosage forms, the active compound may contain at least Also, an inert carrier such as sucrose, rough]-su, dicalcium phosphate can be used. Mix with sphate, etc. Such dosage forms include Furthermore, besides the inert solids, other substances, such as magnesium stearate, may also be used. Contains lubricants. In the case of capsules, tablets and tablets, the dosage form may additionally contain buffers. Contains agents.

Liquid administration for oral administration may include conventional inert diluents such as water. Pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing nothing. Besides such inert diluents, the compositions may also include lubricants, emulsifying and suspending agents, and sweetening agents. Contains flavoring agents, flavoring agents, and fragrances.

Compositions for rectal administration are preferably herbal medicines, which further include cocoa butter. - or active substances such as medicinal waxes, excipients. Pharmaceutically acceptable for ointment formulations metal salts of the compounds of formula (1) together with possible carriers. career is desirable are conventional water-dispersed hydrophilic or water-in-oil carriers, especially conventional semi-soft or Creamy water dispersion or water dispersion, water-in-oil emulsion, which is suitable for scalded surfaces. It can be applied to surfaces or diseased surfaces with any discomfort. appropriate composition , hydrophilic carriers or bases or ointments are mainly incorporated into the finely divided compound. Alternatively, it can be manufactured by uniformly mixing.

The actual dosage of the active ingredient in the compositions of the invention will vary depending on the desired method of dosing. The amount of active ingredient that is effective to achieve the desired properties may vary widely.

The dosage chosen will therefore depend on the nature of the active compound administered, the mode of administration desired, Depends on duration of treatment and other factors. Generally, about 0 per kilogram of body weight ．． Sunset doses of the compound of formula (1) containing from 5 to about 500 mg of active ingredient are effective and sensitizing. effective when administered orally to human patients suffering from infections caused by infectious microorganisms. Ru. If desired, the sunset dosage may be divided into several doses, e.g. 2 to 4 times per day. It may be divided into multiple doses.

The following examples are of the invention, but are not limited thereto.

Manufacture IN-benzyl maleamic acid 150 ml0) Methylene chloride, 9.8 g (0,1OM) (7) Anhydrous macerate Stir the solution in which leic acid is dissolved, and add 10.7 g (0.10 mol) of benzene to it. Zylamine was added dropwise for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 3 hours and filtered. washed with methylene chloride, and then dried to give 17.8 g (yield: 8796). N-benzylmaleamic acid was obtained as a white crystalline solid. Melting point: 135-13 6°C'H-NMR (CDCI, ) 64.2 (s, 2l-1), 6.0- 7.9 (m, 7H), 9.7 (s, IH).

13.0-16.0 (Broad, IH).

Production 2 N-benzylmaleimide 5g (24mM) of N-benzylmaleamic acid in 12me acetic anhydride and 1. A mixture containing 2 g of sodium acetate was stirred at 95-100 °C for 1.5 h. Ta. The reaction mixture was poured into 50 g of crushed water and stirred mechanically for 2 hours. .

The aqueous layer was decanted and 500 mρ of ether was added to the dark brown residue and an additional 20 mρ of ether was added to the dark brown residue. Stir for a minute. The undissolved dark brown solid was removed by filtration and the filtrate was dissolved in saturated sodium bicarbonate. solution, dried over magnesium sulfate and evaporated under vacuum.

The residue was recrystallized from methanol to give 2 g (yield: 4496) of N-benzyl male. The imide was obtained as a pale yellow crystalline solid.

Melting point: 67-68°C Production 3 2-methyl-2,3,4,7-titraazabicyclo(3,3,0)-o ct-3-ene-6,8-dione In a third lβ flask with a temperature of 81 and a dropping funnel and condenser, 8.46 g (0,13M) of sodium azide and 21g of NaHCO3-Na,Co, (1:1 molar ratio) in 480 mN H2O and heated in an oil bath. did. In another container, add 4g (21.4mM) of male to 100mE toluene. The imide was dissolved and cooled to -50 to -78 °C in a triice-acetone bath. Ta. These two containers are connected with a glass tube, and the generated methyl azide gas is transferred to N- Na0Hl-label is placed in the middle of the solution. connected.

Add 40% of 37.2+n('(0.4M) dimethyl sulfate to a basic solution. Dropwise at 75-85°C for minutes and removed from the reaction solution in a tri-ice-acetone bath. Ta.

The reaction mixture was left at room temperature overnight and evaporated under vacuum. Filter the residue and and dried under vacuum. 4.8 g of the target compound was obtained as a white crystalline solid. Ta.

Melting point +39°C 'TI-NN=IR(CDCI,) 63.4(s, 3H), 4.1(d, IH, J=12.0Hz), 4.6(s, 2H).

5.4 (d, IH, J=12.0Hz), 7.2 (s, 5H).

Chlo(3,1,0)hexane-2,4-dione [Production method 1 Photolysis reaction] 4.0 m in 1,4-dioxane of 300 m (!) in a 500 m quartz reactor. g (12,3mM) of 2-methyl-2,3,4,7-titraazahisoclo(3 ,3,0)-oct-3-ene-6,8-dione was added, and N2 gas was added. was bubbled through for 15 minutes.

The reaction solution was irradiated with a 254 nm UV lamp for 4 hours. Evaporate the solvent under vacuum The residue was recrystallized from isopropyl ether to give 2.2 g (yield: (3296) of The target compound was obtained as a pale yellow solid.

Melting point = 78-80℃ 'H-NMR (CDCI,) δ2.4 (s, 3H), 2.8 (s, 2H ), 4.5 (s, 2H), 7.3 (s, 5H).

[Production method 2: thermal decomposition reaction] in 300 mN xylene (one combination of or-l-, meta-1 and para-isomers). 13.7g (56.1mM) of 2-methyl-2,3,4°7-ti-diazabi mixture containing cyclo[3,3,0)oct-3-ene-6,8-dione for 7 hours. Heat to reflux.

The xylene is evaporated under vacuum and the residue is subjected to column chromatography (eluent - vinegar). Partially purified with ethyl acid: n-hexane = 1:3) and further purified with isopropyl ether The target compound was purified by recrystallizing it 3 to 4 times with tel. Obtained as a pale yellow solid.

The melting point and 'H-NMR data are the same as in Preparation 1.

Production 5 3-benzyl-6-methyl-3,6-diazabicyclo[3,1,O) Kisan 1.76g (46.3mM) of lithium in 50ml of dry tetrahydrofuran Stir the solution in which aluminum aluminum hydride is dissolved, and add 15 mj of dry 5g (23,1mM) 3-bentu-6-methyl-3 in tetrahydrofuran ,6-diazabicyclo[3,1゜0]hexane-2,4-dione. Dropped warm.

The reaction mixture was heated to reflux for 3 hours, cooled in a water bath and treated with 0.85 ml of water, 0.85 ml of water, 85 mN 1596-KOH solution and 2.5 ml water were added sequentially. Tet Bovine Dorofuran was evaporated under vacuum and the residue was purified using 100 mN chloroform. Extracted. The chloroform extract was washed with saturated thorium chloride solution and dried; Filtered and evaporated under vacuum to obtain 4.0 g of brownish residue.

The residue was purified by column chromatography (eluent: ethanol:ethyl acetate-1=4 ) to obtain the target compound as a yellow part.

'H-NMR (CDCI, ): δ2.0 (s, 2H), 2.2 (s, 3 H), 2.3 (dd, 2H), '3.1 (d, 2g, J=12.0H z).

3.6 (s, 2H), 7.3 (s, 5H).

1.0 g (5.3 mM) of 3-benzyl- in 100 ml of methanol 6-methyl-3,6-diazabicyclo(3,1,0)hexane, 0.32g ( A mixture of 5.3 mM) acetic acid and 1.0 g of 10% Pd-C catalyst for 1 hour at room temperature. (Hydrogenated under ioPsi H2 pressure.

The reaction mixture was filtered through a Celite pad and evaporated under vacuum to give 0.78 g. The target compound (yield: 9396) was obtained as a bluish brown semi-solid.

'H-NMR (CDCI, ): δ2.0 (s, 3H), 2.1 (s, 2 H), 2.3 (s, 3H), 2.8 (d, 2H, J≠P2.0Hz).

3.2 (d, 2H, J = 12.0Hz), 7.4 (s, IH), 8.2 (blow Do S, 2H).

Production 7 2-methyl-5-benzylmaleamic acid and 3-methyl-5-hensyl Mixture of maleamic acid (1:1a combination) +50mff (7) in methylene chloride +]1.2g (0.1M) (7) Anhydrous silicone Stir the solution in which tracon was dissolved, and add IO, 7 g (0.10 M) of benzyl amine. was added dropwise for 30 minutes at room temperature. The reaction mixture was stirred for 3 hours at room temperature and 50 ml of salt After washing with methylene chloride and drying, 17.6 g (yield 8096) of the target compound was obtained as white. Obtained as a colored crystalline solid.

Melting point, 103-105℃ 'H-NMR (DMSO-δ6): δ1.9 (s, 3H), 4.3 (d, 2H), 5.7 (s, l/2H), 6.1 (s, ∟^2H).

7.3 (s, 5H), 8-5 (1a-"s, 1/2H), 8.9 (10-dos, l/2H).

Production 8 l-hensyl-3-methylmaleimide 8 g ( 36.5mM) of 2- and 3-methyl-5-benzylmaleamic acid (1:1 mixture). In this case, a mixture containing the compound of Preparation 7) and 1.6 g of sodium acetate was heated at 1 hour for 1 hour. The mixture was stirred at 00 to +10°C. Pour the reaction mixture onto 60g crushed ice; Stir mechanically for 1 hour.

The aqueous layer was decanted and 500 ml of ether was added to the dark brownish residue and 1 Stirred for 0 minutes. The insoluble dark brown solid was removed by filtration and the filtrate was diluted with saturated bicarbonate. Washed with thorium solution, dried over magnesium sulphate and evaporated under vacuum.

The residue was subjected to column chromatography (eluent: ethyl acetate: n-hexane = l: 3) to obtain 2.9 g (yield: 4096) of the target compound as a yellow part. Ta.

'H-NMR (CDCI3): δ2.0 (s, 3H), 4.6 (s, 2 )I), 6.3(s, IH), 7.3(s, 5H)B Production 9 l, 2-dimethyl-2,3,4,7-titraazabicyclo(3,3,0 ) oct-3-ene-6°8-dione and 1. 4-dimethyl-2,3,4゜7 - Citraasahi cyclo(3,3,0)oct-3-ene-6,8-dione gamma Compound 31 3-loaf flask with thermometer, dropping funnel and condenser, 56.2g (0.8t3M) of sodium azide and 86.4g of NaHCO3 (11M) 1.8β of H2O was added and heated in an oil bath.

In another container, add 18 g (89.6 mM) of 1- to 360 yne of toluene. Pencil-3-methylmaleimide was dissolved in a dry ice-acetone bath. Cooled to 50--78°C.

These two containers are connected with a glass tube, and the generated methyl azide gas or maleimide is The solution was moved into the solution, and a NaOH trap was connected at a position between them.

Add 203g (1, GM) of dimethyl sulfate to a basic solution for 1 hour and 20 minutes. was added dropwise at 75-85°C and removed from the reaction solution in a dry ice-acetone bath. .

The reaction mixture was left at 80-85°C overnight and evaporated under vacuum. color the residue Purified by mucochromatography (eluent: ethyl acetate n-hexane = 13). , 21 g (yield: 9196) of the target compound was obtained as a blue-yellow solid.

Melting point: 86-88℃ 'H-NMR (CDCI3) δ 1.5 (s, 315 x 3H), 1.6 (s, 215 x 3H), 3.3 (s, 315 x 2Hj.

3.4 (s, 215 x 2H), 3.8 (s, 215 x IH), 4.6 (s, 2H).

5.1 (s, 315 x IH), 7.3 (s, 5H) Production 10 3-H sil-1,6-dimethyl-3,6-diazabicyclo(3,1,0)hexane- 2,4-dione [Production method 1. Photolysis reaction] 4. In a 500 m1' quartz reactor. Triazoline of Og (11,6mM) Compound (Production 9) or 300 mff of 1. Add what is contained in 4-dioxane and bubbled in N2 gas for 15 minutes.

The reaction solution was irradiated for 6 hours using a 254 nm UV lamp. 1δ medium is true Evaporate in vacuo and subject the residue to column chromatography (solvent, ethyl acetate, n -hexane=1.3) to obtain 2.3 g (yield: 6596) of the target compound. was obtained as a blue-yellow crystalline mass.

Melting point = 79-8 pC 'H-NMR (CDCI, ): δ1.5 (s, 1/4 x 3H), 1. 6 (s, 3/4 x 3H), 2.3 (s, IH).

2.4 (s, 3/4 x 3H), 2.5 (s, 1/4 x 3H), 4.6 (s, 2H).

7.3 (s, 5H).

[Production method 2. Pyrolysis reaction] 10. in 300ml diphenyl ether. 0g (29mM) of triazo The mixture containing the phosphorus compound (Production 9) was stirred at 170-180°C for 6 hours, and To remove the phenyl ether, the residue was subjected to column chromatography (eluent Purified with ethyl acetate, n-hexane-13) to give 6.7 g (yield 7596 ) was obtained as a pale yellow solid.

The melting point and 'H-NMR data are the same as in Production Method 1.

Production 11 3-benzyl-1,6-dimethyl-3,6-diazapisochloro(3,1 ,0) hexane 2. in 100 J of dry tetrahydrofuran. 0g (52,6mM) of Lithi Stir the solution in which aluminum aluminum hydride is dissolved, and add 25me dryite to it. 5.0 g (21,7 mM) of 3-hensyl-1,6-nome in trahydrofuran. Contains Chiru 3.6=diasahisochloro(3,1,O)hexane-2,4-dione The mixture was added dropwise at room temperature.

This anti-1. ; The TrL compound was heated to reflux for 3 hours, cooled in a water bath, and heated to 0.8 5 mff of water, 0.85 ml' of 1596-I ○H solution and 2. '6ml water was added continuously at about 10°C.

Tetrofuran was evaporated under vacuum and the residue was dissolved in 1007 nl of chloroform. Extracted using . Wash the chloroform extract with saturated thorium chloride solution. Cleaned, dried over magnesium sulphate, filtered and evaporated under vacuum.

The yellow residue was purified by column chromatography (eluent: ethanol, ethyl acetate = 1:4), and 2.2 g (yield: 5096) of the target compound was purified with a pale yellow oil. I got it.

'H-NMR (CDCI, ) 61.3 (s, 3H), 1.7 (s, LH ), 2.1-2.6 (m, 2H).

2.3 (s, 3H), 2.8-3.2 (m, 2I-1), 3.6 (s, 2H); 7.3 (s, 5H).

1. in 100ml methanol. 3-benzyl-1G in Og (5,0mM) -dimethyl-3,6-diasavinchlo[3,1゜0]hexane, 0.30g ( A mixture containing 5.0 mM) acetic acid and 1.0 g of 1096Pd-C catalyst was mixed with 60 Hydrogenated under H2 pressure of psi for 1.5 hours at room temperature.

The reaction mixture was filtered through a pad of Celite and evaporated under vacuum to a concentration of 0.80 g (yield: 95%) of the target compound was obtained as a pale yellow semi-solid.

'H-NMR (CDCI, ): δ1.3 (s, 3H), 1.9 (s, 4H ), 2.3(s, 3H).

2.9 (dd, 4H, J=12Hz), 8.5 (s, IH).

Preparation 13 +-benzyl-3-viroline 400d in benzene 12.　5g　 A solution containing (0.10 M) of cis-1,4-dichloro-2-butene was stirred; To this was added dropwise 33.2 g (0.31 M) of benzylamine at room temperature. reaction mixture The mixture was stirred for 1 hour and allowed to stand overnight. Remove solids by filtration and wash the filtrate with water. and dried over magnesium sulfate, purified by vacuum: n-hexane = 1.3), 13.5 g (yield: 8596) of the target compound was obtained as a pale yellow oil.

'H-NMR (CDCI, ): δ3.4 (s, 4H), 3.7 (s, 2H) , 5.8 (s, 2H), 7.2 (s, 5H)・Production 14 1-benzyl- 3,4-Epoxypyrrolidine 16g (0 , 1M) of 1=benzyl-3-pyrroline was stirred, and salt was added to it. Raw gas was bubbled through for 30 minutes at room temperature. Adjust the pH of the solution to 20% NaOH solution. 9-10 using evaporated under.

To the residue, 100 ml of 2096-NaOHiS solution was added and the resulting solution It was stirred overnight. This was extracted with 500 ml of methylene chloride, dried and evaporated under vacuum. I let it emanate. The residue was purified by column chromatography (eluent: ethyl acetate, n-hex Purified by San=2:1), 11.5 g (yield: 6696) of the target compound was obtained as a light brownish oil.

4.1-4.3 (m, IH), 7.3 (s, 5H).

Production +5 1-benzyl-1-lans-4-and-3-hydroxypyrrolidine 6.0 g (34 m Stir the solution in which 1-pencyl-3,4-epoxypyridine of M) is dissolved, To this was added 13.4 g (0.21 M) of sodium azide at room temperature. reaction The mixture was refluxed overnight and extracted twice with 200ml of chloroform. dried with nesium.

This is filtered, evaporated in vacuo and subjected to column chromatography (eluent: ethyl acetate). 6.8g (yield: 9296) The desired compound was obtained as a dark brownish oil.

'H-NMR (CDCI,) δ2.5 (d, 2H, J=12Hz), 3. 2 (d, 2H, J=12Hz).

3.5 (s, 2H), 3.7 (s, 2H), 7.3 (s, 5H).

5. in 150 mN tribenzene. 1-pencil-tra of Og (23mM) Stir the solution in which ence-4-azido-3-hydroxypyrrolidine is dissolved, and add 3. 0 g (30 mM) of triethylamine was added in a water bath, then 20 3.2g (28mM) of methanesulfonyl chloride in ml of dry benzene was added dropwise for 10 minutes.

The reaction mixture was stirred for 2 h, lyd water was added, transferred to a separatory funnel and washed with water. Ta. The benzene layer was collected, dried and evaporated under vacuum. Column chromatography of residue Purified by matography (eluent: ethyl acetate, n-hexane = 1:3), 6.4 g (yield 95%) of the target compound was obtained as a dark brownish oil.

'H-NMR (CDCI3) 62.4-3.2 (m, 4H), 3.0 (s , 3H), 3.6(s, 2H).

3.9-4.2 (m, IH), 4.8-5.1 (m, IH), 7.3 ( s, 5H).

Solution in which hensyl-trans-4-azido-3-mesyloxypyrrolidine is dissolved Stir and add 0.25g (6.8mM) of lithium aluminum hydride to this. was added in portions at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and 0,1 5 mff water, 0.5 ml 1596-KOH solution, 0.5 ml water and 20 mff 1 part of ether acetate (1:], V/V) was added continuously. Filter the resulting solution. Filtered, dried over magnesium sulphate and evaporated under vacuum.

The residue was purified by column chromatography (eluent: ethanol: ethyl acetate = 1:3). ) to obtain 0.5 g (yield: 8596) of the target compound as a yellow part. .

'H-NMR (CDCI, ): 6 1.8 (7 o-do, lH), 2.3 (d, 2H, J=10Hz), 2.4 (s, 2H).

3.1 (d, 2H, J=10Hz), 3.6 (s, 2H), 7.2 (s , 5H).

Production 18 3.6-diazabicyclo(3,1,0)hexane 0.5 g (2,9 mM) of 3-benzyl-3,6 in 60 m(!) methanol -Diazabicyclo[3,1,O)hexane, 170μ1. (2,9mM) vinegar A mixture containing acid and 0.5 g of 10% Pd-C catalyst was heated to a H2 pressure of 50 ps i. Below, hydrogenate for 1 hour at room temperature.

The reaction mixture was filtered through a Celite vat and evaporated under vacuum to give 0.39 g of The target compound was obtained as a crude sulfuric acid salt. This was then subjected to column chromatography (eluent, Purified with methanol:40%-methylamine=24:]), 0.12g The desired compound (yield: 4596) was obtained as a colorless oil.

'H-NMR (CDCL, ): δ1.4 (s, 2H), 2.5 (s, 2H) , 2.9 (q, 4H, J=12Hz).

Production +9 3-benzyl-6-methoxycarbonyl-3゜6-diazabicyclo[ 3,1,0) 3.5g (20mM ) of 3-hexane-3,6-diazabicyclo(3,1,0)hexane is dissolved. Stir the solution containing 2.4 g (24 m M) of triethylamine and 2.1 g (22rnM) of methyl chloroformate was added dropwise at room temperature for 15 minutes.

The reaction mixture was stirred for 2.5 hours at room temperature and filtered.

The filtrate was washed with water, dried over magnesium sulphate, filtered and evaporated under vacuum. . The residue was purified by column chromatography (eluent: ethyl acetate, n-hexane; ・Purified according to step 3), yielding 4.3 g (yield: 92%) of the target compound as a dark brownish product. Obtained as oil.

'H-NMR (CDCI, ): δ2.3 (d, 2H, J=10Hz), 2 ．． 9 (s, 2H), 3.3 (d, 2H, J=10Hzj.

3.6 (s, 2H), 3.7 (s, 3H), 7.3 (s, 5H).

Production 20 6-medoxycarbonyl-3,6-cyazabicyclo(3,1,0) hexane 1.5g (6.5mM) of 3-benzyl-6-methane in 100+J of methanol. Doxycarponyl-3,6-diazabicyclo[3,1,0)hexane and 0.7 A mixture containing 5 g of 1096Pd-C catalyst was heated at room temperature under 50 ps i of H2 pressure. Water for 4.5 hours, then column chromatography (eluent, ethanol:acetic acid) 0.60 g (yield: 6596) of the target compound was obtained as a white solid.

Melting point 80°C 'H-NMR (CDCI3): δ1.3 (broads, IH), 2. 7 (s, 2H), 3.3 (d, 2H, J=12Hz)B 3.6 (s, 28), 5.6 (d, 2H, J=12Hz).

1.5g (11mM) of 6-medoxycarbonyl in 35ml of methanol 3. Stir the solution in which 6-diazabicyclo[3,1,0)hexane is dissolved, and 3 g of sodium hydroxide was added to the mixture and stirred at 70-80°C overnight. reaction mixture The material was cooled in a water bath and 465 g of acetic acid was added dropwise and evaporated under vacuum. residue Extracted with chloroform in loomj and evaporated in vacuo, yielding 1.34g (yield The target compound (8896) was obtained in the form of a semi-solid.

’) (-NMR (CDCI, n・δ 1.9 (s, 3H), 2.7 (s, 2 H), 3.0 (q, 4H, J=12Hz).

3.4 (s, 2H), 5.6 (1 leaf, ll-1).

6.7g (0°18M) of lithium in 300+J of dry tetrahydrofuran The solution in which aluminum hydride was dissolved was stirred and 10.0g (0,089M ) was added dropwise at -20 to -10°C. The reaction mixture is 120~ = 1 hour at 0°C and adjust the pH of the solution to 7-8. 3096-H2'S04 solution, filtered and 300 mff of ether-acetone (1: 1, V/V) mixture. .

The saved filtrate was dried over anhydrous sodium sulfate, filtered and evaporated under vacuum.

The residue was prepared by column chromatography (eluent: ethyl acetate) and 1. 1 g (yield: 1296) of the target compound was obtained as a yellow part.

'H-NMR (CDCI, ): 61.7 (s, 3H), 3.2-3.8 ( m, 2H), 3.9-4.2 (m, 4H).

5.5Q, IH, J=8Hz) Production 23 Rus-1,4-dibromo-2-methyl-2-butene 30 me t], Og (9,8 mM) in dry methylene chloride-1,4- Stir the solution in which nitroquine-2-methyl-2-butene is dissolved, and add 5.9 g (22 mM) of tripromide phosphate was added dropwise in a water bath.

The reaction mixture was stirred for 1.5 hours, 7nff of water was added and this was poured into a separatory funnel. Moved to.

The organic layer was washed with lOm (!) of water, decomposed and dried. The solution was filtered and dried under vacuum. The residue was purified by column chromatography (eluent: ethyl acetate: n-helical). 1.5 g (yield: 67%) of the target compound was purified by Obtained as yellow part.

'H-NMR (CDCI, ): δ1.9 (s, 3H), 4.0-4.2 ( m, 4H), 5.6 (t, IH).

Production 24) -benzyl-3-methyl-3-viroline in Hensen's 120 mρ 3.0 g (13 mM) of cis-1,4-dibromo-2-methyl-2-butene The dissolved solution was stirred and removed by.

The filtrate was washed with water, dried and evaporated under vacuum. Column chromatograph the residue Purified by roughy (eluent: ethyl acetate:n-hexane=:l:3), 1. 6 g (yield near 09 ft) of the target compound was obtained as a yellow part.

'H-NMR (CDCI, ): 61.7 (s, 3)-1), 3.4 (s, 4H), 3.7 (s, 2H), 5.4 (s, 1H), @7.3 (s, 5H) )゛.

1.0 g (5.7 mM) of 1-ben in 10 me of water and ]me of concentrated hydrochloric acid. Stir the solution in which dill-3-methyl-3-viroline is dissolved, and add 2 chlorine gas to it. Bubble through at room temperature for 0 minutes.

Adjust the pi of the solution to 9-10 by adding 2096-NaOH solution. It was extracted with 50 ml of methylene chloride and evaporated under vacuum. 5me in the residue 2096-NaOH solution was added and stirred at room temperature overnight.

The resulting solution was extracted twice with 50 ml of methylene chloride, the extract was dried and vacuum evaporated under. The residue was purified by column chromatography (eluent: ethyl acetate: n -hexane=2:]) to produce 0.68 g (yield: 6296) The target compound was obtained as a yellow-brownish oil.

'H-NMR (CDCI, ): 61.5 (s, 3H), 2.2-2.7 ( m, 2H), 3.9'-3,3(m, 2H).

3.4 (s, LH), 3.7 (s, 2H), 7.3 (s, 5H).

Production 26 1-hensyl-trans-4-azido-3-hydroxy-3-methyl Pyrrolidine and l-benzyl-trans-4-azido-3-hydroxy-4-methane Mixture of tilpyrrolidine 1.0 g (5.3 mM) in 30 ml of N,N-dimethylformamide Stir a solution in which 1-benzyl-3,4-epoxy-3-methylpyrrolidine is dissolved. Stir and add 1.0 g (15 mM) of sodium azide and 0.03 g ( 0.56 mM) ammonium chloride was added and stirred overnight at 75-80°C.

To the reaction mixture was added 30 rnl of chloroform, filtered and the filtrate was evaporated under vacuum. I let it emanate. To the residue, 50 ml of chloroform was added again and filtered.

The filtrate was evaporated in vacuo and the residue was purified by column chromatography (eluent: acetic acid). Purified with chill:n-hexane=1:l), 0.92g (yield near 596) The desired compound was obtained as a red-brownish oil.

'H-NMR (CDCI, ): δ1.3 (s, 3H), 2.1-3.4 ( m, 5H), 3.6 (s, 2H).

3.8-4.1 (m, IH), 7.3 (s, 5H).

Production 27 1-benzyl-trans-4-azido-3-mesyloxy-3-methy Lupyrrolidine and l-benzyl-trans-4-azido-3-mesyloxy-4 -Mixtures of methylpyrrolidine 2.0 g (8.6 mM) azide alcohol in 60 ml dry benzene (Compound of Production 26) was stirred, and 10 mN of dry benzene was added to the solution. 1.1 g (11 mM) of triethylamine and 1.2 g (IO (mM) methanesulfonyl chloride was added for 5 minutes at 0-5°C.

The reaction mixture was stirred for 8 hours at room temperature and 0.5 ml of water was added dropwise and the solution was poured into a separate funnel. Transferred to a bowl and washed with water. Separate the benzene layer, dry with magnesium sulfate and vacuum evaporated under.

The residue was purified by column chromatography (eluent: ethyl acetate di-n-hexane = 1: 5) to obtain 1.7 g (yield: 6596) of the target compound as a red-brown Obtained as an oil.

'H-NMR (CDCI, ): δ1.4 (s, 3H), 2.5-3.5 ( m, 4H), 3.0 (s, 3H).

3.6 (s, 2H), 4.6-4.9 (m, IH), 7.3 (s, 5 H).

Production 28 3-benzyl-1-methyl-3,6-diazabicyclo[3,1,O) hexane 1.0 g (3.2 mM) azide mesylate in 30 mN dry ether A solution in which (compound of Production 27) was dissolved was stirred, and 0.24 g (6,5 lithium aluminum hydride (mM) was added in portions at room temperature. reaction mixture was stirred at room temperature for 4 hours, 0.15 mA' water, 0.5 tne 1596-KOH solution, 0.5 ml of water and 30 mρ of ether-acetyl(1:1.V) /V) was added continuously.

The resulting solution was filtered, dried over magnesium sulphate and evaporated under vacuum. residual The material was subjected to column chromatography (eluent: ethanol diacetate-ethyl 1:5). It was further purified to obtain 0.46 g (yield near 696) of the target compound as a yellow part.

'11-NMR (CDCI, ) δ1.2 (s, 3H), 1.8 (broa ds, IH), 2.2Q, 2H, J=10Hz).

2.9 (+, 2H, J=10Hz), 3.6 (s, 2H), 7.3 (s , 5H) 0.5 g (2.7 mM) 3-benzyl in 60 ml methanol -1-methyl-3,6-diazabicyclo(3,1,0)hexane, 157 μf A mixture containing (2.7mM) acetic acid and 0.5g 1096Pd-C catalyst was added to the room. Hydrogenated under 50 psi H2 pressure for 1.5 hours at room temperature.

The reaction mixture was filtered through a Celite pad and evaporated under vacuum to yield 0.38 g ( The desired compound (yield: 9196) was obtained as an oil.

'H-NMR (D20): δ 1.3 (s, 3H), 1.8 (s, 3H ), 2.7 (s, IH), 3.2-3.4 (m, 4g)- 1.0g (5.7mM) of 1-benzyl-3 in 5me of 1.4-dioxane, Stir the solution in which 4-epoxypyrrolidine is dissolved, and add 25 ml of 4096- Add methylamine solution and stir at 40-45°C overnight. Vacuum the reaction mixture Evaporate under water, add 30 ml of chloroform to this and dry with magnesium sulfate. and filtered.

The filtrate was evaporated under vacuum to give 1.1 g (yield: 9496) of the desired compound as a yellow- Obtained as a brownish oil.

'H-NMR (CDCI3): 62.2-3.2 (m, 7H), 2.3 (s ,'3H), 3.6(s, 2H).

3.8-4.1 (m, IH), 7.3 (s, 5H).

Production 31 3-benzyl-6-methyl-3,6-diazabicyclo(3,1,0) hexane 2. in 25 ml of dry tetrahydrofuran. 0g (9.7mM) of 1-bean The solution containing 3-trans-3-hydroxy-4-methylaminopyrrolidine Stir the solution and add 3.1g (12mM) of triphenylphosphine at 0 to 5°C. Added with C.

Add 1. to the above solution. 85mff (12mM) of diethyl azodicarboxylate DEAD was added and stirred at 0-5°C for 7 hours at room temperature.

The resulting solution was evaporated under vacuum and diluted with 30 ml of ethyl acetate-pet, ether ( 1:1, V/V) was added thereto and the precipitate was removed by filtration.

The filtrate was evaporated under vacuum and the residue was subjected to column chromatography (eluent, ethanol). ethanol:ethyl acetate=1:3) to obtain 1.25 g (yield: 6996) of The target compound was obtained as a red-brown color.

'H-NMR (CDCI3): δ2.0 (s, 2H), 2.2 (s, 3 H), 2.3 (dd, 2H), 3.1 (d, 2H, i=12Hz).

3.6 (s, 2H), 7.3 (s, 5H).

Production 32 1-benzyl-trans-4-methylamino-3-hydroxy-3- Methylpyrrolidine and l-benzyl-trans-4-methylamino-3-hydro A mixture of xy-4-methylpyrrolidine 1. Og (5,3mM) of 1-benzyl-3,4-evogycy-3-methylpyrrolidine Stir the dissolved solution and add 30ml of 4096-methylamine solution to it. , and stirred overnight at 50-60°C. The reaction solution was evaporated under vacuum and added to 30 m 1 of chloroform was added and dried over magnesium sulfate.

This was filtered and the filtrate was evaporated under vacuum to yield 1.1 g (yield: 9296). The compound was obtained as a yellow-brownish oil.

'I-1-NMR (Cl-1-N: δ1.3 (s, 3H), 2.0-3. 8 (m, 7H), 2.4 (s, 3H).

3.6 (s, 2H), 7.3 (s, 5H).

Production 33 3-benzyl-°1,6-dimethyl-3,6-diazabicyclo(3, 1,0) hexane 1.0g (4.5mM) of amino acid in 15ml of tritetrahydrofuran A solution in which alcohol (compound of production 33) was dissolved was stirred, and 1.4 g (5 , 5mM) and 0.9mρ (5,7mM) of diethyl phosphine. Luazodicarpochelate was added continuously at 0-5°C. Add the reaction solution to 0 for 1 hour. Stir at ~5°C and leave at room temperature overnight.

The resulting solution was evaporated under vacuum and 20 mj of ethyl acetate-1=-pet, ethylacetate ether (1:1.V/V) was added to this and the precipitate was removed by filtration.

The filtrate was evaporated under vacuum and the residue was purified by column chromatography (eluent: ethanol). 0.61 g (yield: 6696) The desired compound was obtained as a red-brown color.

'H-NMR data are the same as Preparation 11.

Production 34 1-benzyl-3,4-dimethylmaleimide 500ml in toluene A suspension containing 13.4 g (0.14 M) of sulfuric acid was cooled in a water bath and 4.6g (0.14M) of benzylamine was added dropwise to the bisbenzylamine. A monium sulfate slurry was obtained.

In another container, 30 g (0.23 M) of anhydrous 2.3 in 500 ml of toluene - 34 g (0.32 M) of hensylamine in a solution of dimethylmaleic acid was dripped.

This was stirred at room temperature for 2 hours to obtain N-benzylaleaminic acid as a slurry.

N-benzylmalea by the Dean-Stark apparatus Add the minic acid slurry to the bisbenzylammonium sulfate-1-slurry. , heated to reflux.

The extent of the reaction was monitored by measuring the amount of water collected in the Sheen-Stark apparatus. I watched it. After the reaction is completed, cool and filter to remove bisbenzylammonium Sulfate was removed.

The filtrate was washed three times with 500 ml of water, dried and evaporated under vacuum. crude product By column chromatography (eluent: ethyl acetate: n-hexane = l:3). Purification was performed to obtain 48.7 g (yield: 9596) of the target compound as a white crystalline solid. .

Melting point, 39-40℃ 'H-NMR (CDCI, ): δ1.9 (s, 6H), 4.6 (s, 2 H), 7.3 (s, 5H).

Production 35 2.7-dipendyl-1.5-dimethyl-2゜3.4.7-titraa Sabicyclo(3,3,0)oct-3-ene-6,8-dione 32 g (0.15 M) of 1-benzyl-3,4-di in 300 ml of toluene. Stir the solution containing methylmaleimide and add 20g (0.15M) of benzene to it. Luazide was added at room temperature and heated to reflux for 4 days.

The resulting solution was evaporated under vacuum and subjected to column chromatography (eluent, acetic acid). Purified with ethyl:n-hexane=1:3) to yield 14.2g (yield: 2796 ) was obtained as a blue-yellow solid.

Melting point, 108-109°C 'H-NMR (CDCI,) δ1.2 (s, 3H), 1.5 (s, 3H ), 4.6 (s, 2H), 4.9 (d, 2H, J=SHz).

7.3 (s, 10H).

Production 36 3.6-dipenzyl-1,5-dimethyl-3゜6-diazabicyclo( 3,1,0) 6.9 g (20 mM ) containing the triazoline compound (compound of Production 35) for 2 hours at 200 to 2 The mixture was stirred at 10°C. The reaction mixture was cooled to room temperature and subjected to column chromatography. (Eluent: 1st: n-hexane, 2nd: ethyl acetate 20-hexane = l:3) After purification, 5.8 g (yield: 9396) of the target compound was obtained as a blue-yellow syrup. Obtained.

'H-NMR (CDCI, ): δ 1.4 (s, 6H), 3.4 (s, 2H), 4.6 (s, 2H), 7.3 (1o-F gf+]OH).

Manufacturing method 2 300 m1CD I. Rue > Medium t] 9.5 g (0.09M) (7) l-ve Stir the solution in which dimethyl-3,4-dimethylmaleimide was dissolved, and add 24 g (0.18M) of benzyl azide was added dropwise at room temperature and the reaction mixture was heated for 1 week. It refluxed.

The toluene was evaporated under vacuum and the residue was subjected to column chromatography (eluent; vinegar Ethyl acid: n-hexane = 1 + 6) to produce 17.9 g (yield: 6 The target compound (296) was obtained as a blue-yellow syrup.

'H-NMR data are the same as in Preparation Method 1.

Manufacture 37 3.6-Dipendyru 1. 5-dimethyl-3゜6-diazabicyclo (3,1,0)hexane 1.37 in 100 mff of dry tetrahydrofuran Stir a mixture containing g (36mM) of lithium aluminum hydride, and 5.8g (18mM) of 3.6g in 25me of dry tetrohydrofuran - Dipenjiru 1. 5-dimethyl-3,6-diazabicyclo(3,1,O) Containing xane-2,4-dione was added dropwise at room temperature and the reaction mixture was heated for 2 days. and refluxed.

The resulting solution was cooled in a water bath, 0.8 ml water, 0.8 ml 1596-K OH solution and 2.5 mN water were added continuously. Filter this and filter cake was washed with tetrahydrofuran. Dry the mixed filtrate with thorium sulfate filtered and evaporated under vacuum to give 4.8 g (yield: 9096) of the desired compound. was obtained as a blue-yellow color.

'H-NMR (CDCI, ): δ1.2 (s, 6H), 2.6 (d, 2 H, J=10Hz), 3.1(d, 2H, J=10Hzj.

3.6 (s, 3H), 4.2 (s, 2H), 7.3 (s, 10H).

Production 38 1,5-dimethyl-3,6-diazabicyclo[3,1,0)hexane 2.7 g (9.2 mM) of 3.6-dipendyl in 80 ml of methanol 1. 5-methyl-3,6-diazabicyclo(3,1゜0)hexadi and 4. Stir a solution in which 3 g (84 mM) of ammonium horn-1 is dissolved. 2.7 g of 1096Pd-C catalyst was slowly added to the mixture and stirred at room temperature for 4.5 hours. Stirred.

The reaction mixture was filtered through Celite and the filtrate was evaporated under vacuum. the residue, Dissolved in 70 ml of chloroform, stirred for 30 minutes, filtered and the filtrate was removed under vacuum. Evaporation was performed to obtain 1.5 g of the target compound as Horn-1-.

Dissolve this in 40ynj' methanol and add 0.4g (10mM) hydroxyl and stirred at room temperature for 1 hour. Evaporate methanol under vacuum , 70 ml of chloroform were added for extraction. Vacuum chloroform extract 0.96 g (yield: 9396) of the desired compound was obtained as a blue-brown oil. Ta.

'H-NMR (CDCI, ): δ 1.2 (s, 6H), 1.6 (B o-F 5.2H), 2.8(q, 4H, J=12Hz).

Production 39 7-hensyl-1,2,5-trimethyl-2゜3.4.7-titraa Zabicyclo(3,1,0)oct-3-ene-6,8-dione 31g (0,144M) of 1-benzyl-2° in 300ml of toluene The mixture was stirred at 100-105°C for 5 days. 30g (0,52M) of methi Luando was added again and reacted at the same temperature for 5 days.

Evaporate the reaction mixture under vacuum and use the residue in the next step without further purification. did. A small amount of analysis sample was subjected to column chromatography (eluent: ethyl acetate: n-hexane=1:3).

'H-NMR (CDCI, ): δ1.4 (s, 3H), 1.5 (s, 3H) , 3.4 (s, 3H), 4.6 (s, 2H), 7.3 (sword A5I-1).

Production 40 3-benzyl-1,5,6-drimethyl-3゜6-diazabicyclo( 3,1,O)hexane-2,4-dione 0.144M triazoline compound in 40ml diphenyl ether (Preparation 3) The mixture containing compound 9) was stirred for 2 hours at 180-190°C. reaction mixture was cooled to room temperature and subjected to column chromatography (eluent: f!ethyl acetate: m- Hexane = 1:10) to obtain 34.7g (yield: 9996) The compound was obtained as a blue-yellow color.

Blind H-NMR (CDCI, ): δ 1.4 (s, 6H), 2.3 (s, 3H), 4.6 (s, 2H), 7.3 (s, 5H) | Production 41 3-benzyl-1,5,G-trimethyl-3゜6-diazabicyclo( 3,1,0) hexane 1.51 g in 200 mj' of dry tetrahydrofuran Stir a mixture containing (40mM) of lithium aluminum hydride, and add , 4.42g (18.1mM) in 20ml of Dragote 1-La Drofuran 3-hensyl-1,5,6-'I.rifthyl-3,6-diazabicyclo(3,1 ,0) containing hexane-2,4-dione was added dropwise at room temperature to dilute the reaction mixture. The mixture was heated to reflux for 0 hours.

The resulting solution was cooled in a water bath and diluted with 30 m(!) of a water-tetrahydrofuran mixture ( l:2, v/v) was added slowly. Filter the solid and add 50me of tetrahydrochloride. After washing with furan, the combined filtrates were dried over magnesium sulfate. Filter this and The filtrate was evaporated under vacuum. The residue was separated from column Chroma 1 to Graphie (eluent: vinegar). Purification using ethyl acid:ethanol = 3:l) yielded 3.34g.

85%) of the desired compound was obtained as a blue-yellow oil.

'H-NMR (CDCI,) δ1.2 (s, 6H), 2.5 (s, 3H ), 2.6 (2d, 4H), 3.6 (s, 2H), @7.3 (s, 5 H) Manufacturing 42 1,5. (i-1-dimethyl-3,6-diazabicyclo(3,1,0 ) hexane 4y67g (21.6mM) of 3-benzyl-1 in 230mj of methanol ,5,6-1-dimethyl-3,6-diazabicyclo[3゜l,0]hexane and A mixture containing 5 g of 1096Pd-C catalyst was heated (at room temperature under hydrogen pressure of i2Psi). Hydrogenation was carried out for 5 hours. Filter the reaction mixture through a pad of Celite and evacuate the filtrate under vacuum. Evaporate it at the bottom.

The residue was purified by ) J Lamb chroma I chromatography (eluent: methanol 4096-methylene Purify with amine solution = 24:1) and remove the blue-yellow surface. Further, Purified by vacuum distillation to yield 1.3 g (yield.

The target compound (4896) was obtained as a white solid.

Melting point: 39-40°C.

'H-NMR (CDCI,) δ1.1 (s, 6H), 2.1 (s, IH 7,2,2 (s, 3H), 2.6 (2d, 4H).

Example I Bicyclo(3,1,0)hexan-3-yl)-j,4-dihydro-4-oxo -3-quinolinecarboxylic acid 100 m in 2 mg acetonitrile and 1 bottle of N,N-dimethylformamide g (0,377mM) of 1-cyclopropyl-6°7-difluoro-1,4- Dihydro-4-oxo-3-quinolinecarfonic acid, 129mg (1,34mM ) of 6-methyl-3,6-diazabicyclo[3°1.0]hexane and 59m g (0,377mM) of 1,8-diazabicyclo[5,4,0)unde-7 The mixture containing 1sene was heated to reflux for 4 hours.

The resulting solution was cooled overnight, the precipitate was filtered, and the acetonitrile was reconstituted with ethanol. It was crystallized to obtain 60 mg (yield: 4696) of the target compound.

Melting point: 237-239°C 'H-NMR (CDCI,) δ1.1 - 1.4 (m, 4H), 2.4 (s, 5H), 3.4-3.8 (m, 3H).

4, 0 (dd, 2H, J=4Hz, 12Hz), 6.8 (d, IH, J=8Hz).

7, 7 (d, IH, J=16Hz), 8.5 (s, IH).

IR (KBr): 1723, 1630, 1544.　1507　cm” Example 2 l-cyclopropyl-6,8-difluoro-7-(6-methyl-3,6 -diazabicyclo(3.1.0)hexane-3-yl)-1.4-dihydro-4 -oxo-3=quinolinecarboxylic acid in 2 mg ace1-nitrile and 1 ml N,N-dimethylformalumide. , 100 mg (0. (i97 rnM) of 1-cyclopropyl-〇, 7. 8-1-Lifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid , 1 1 2 mg (0.707 mM) of 6-methyl-3,6-diazabisic B [3.1.0) Hexane acetate-1- and I OGmg (0,389mM ) containing 1,8-diazapiclo(5,4,0)unde-7-cene , heated to reflux for 4 hours.

The resulting solution was cooled overnight, the crystals were filtered off, and acetonitrile was added. was recrystallized from ethanol to obtain 60 mg (yield: 4896) of the target compound.

Melting point. 208~210°C 'H-NMR (CDCI,) δ1. l - 1.4 (m, 4H), 2.3 (s, 2H), 2.4 (s, 3H), 3.5 - S. 2 (m, 5H ).

7, 8 (d. IH, J=16Hz), 8.7 (s, IH) IR (KBr ): 1725.　1624. 1541. 1514 cm” Example 3 5-A Mino-l-cyclopropyl-6,8-difluoro-7-(G-methyl-3,6 -diazabicyclo (3.1.

0]Hexan-3-yl)-1,4-dihydro-4-year-old xo-3-quinolinecar bonic acid In a similar manner as described in Example 2, 100 mg (0.33 mM) of 5-amino No-l-cyclopropyl-6, 7. 8-trifluoro-1,4-dihydro-4 -Oxo-3-quinolinecarboxylic acid, 100mg (0.671mM) 6-methyl-3. 6-′) Asabincro (3.1.O) hexane acetate 38 mg (yield: 3096) of the target compound was obtained.

Melting point: 236-238°C 'H-NMR (CDCI, + DMSO-δ6) δ 1.1 - 1.4 ( m, 4H), 2.3 (s, 2H), 2.4 (s, RH).

3, 5 - 4.2 (m, 5H), 7.5 (bs, 2H), 8.6 (s , IH).

IR (FJlr): 1725, 1626, 1513. 1425cm “Example 4 l-cyclopropyl-6-fluoro-7-(6-methyl-3,6-dia zabicyclo(3.1.0)hexan-3-yl)-1,4-dihydro-4-oxy So-1. 8-naphthyridine-3-carboxylic acid In a manner similar to that described in Example 2, 100 mg (0.354 mM) of 1- Cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-year-old xo 1.8-naphthyridine-3-carboxylic acid, 2 mg (0.708 m M) 6-methyl-3,6-diazabicyclo(3.1.0)hexane acetate and recrystallized with n-butanol to give 81 mg (yield: 66 The target compound of 96) was obtained.

Melting point = 209-212°C 'H-NMR (CDCI, + DMSO-δ6) δ 1.1 - 1, 4 ( m, 4H), 2.4 (s, 5H), 3.5 - 4D0 (m, 3H) .

4, 2 (dd, 2H, J-4Hz, 12Hz).

7, 9 (d, IH,' J=12Hz), 8.7 (s, IH).

IR (KBr): 1723, 1631, 1604. 1454cm” example 5 G,8-difluoro-1-(2,4-difluorophenyl)-7-(6- Methyl-3,6-diazabicyclo[3.

1,0)hexan-3-yl)-1,4-dihydro-4-year-old xo-3-quinoline carboxylic acid 5 mN acetonitrile 4-difluorophenyl)-6. 7. 8-trifluoro-1.

4-dihydro-4-oxo-3-quinolinecarboxylic acid, 65mg (0.41 mM) of 6-methyl-3,6-diazabicyclo[3,1.0)hexane, acetate A mixture containing tate and 79 mg (0.56 mM) of triethylamine The mixture was heated to reflux for 8 hours.

The reaction mixture was cooled overnight and the crystals were filtered and washed with acetonitrile. filtrate Evaporate under vacuum and crystallize the residue with ethanol to give 25 mg (yield 20 The desired mixture of 96) was obtained.

Melting point: 150-152°C 'H-NMR (CDCI,) 62.3 (s, 2H), 2.4 (s, 3H ), 3.8 (dd, 4H, J=12Hz, 20Hz)B 6, 8 - 8.0 (m, 4H), 8.4 (s, IH) TR (TG3r) : 1728. 1627, 1538. 1510 cm” Example 6 1-Cyclo Propyl-8-chloro-6-fluoro-7-(6-methyl-3,6-diazabisi Chloro(3.1.0)hexan-3-yl)-1,4-dihydro-4-dihydro-3 -quinolinecarboxylic acid lOmg (0.334mM) of 1-cyclopropylene in 3mg of birinone. Pyr-8-chloro-6,7-difluoro-1. 4-dihydro-4-oxo-3 -quinolinecarboxylic acid, 158 mg (1.0 mM) of 6-methyl-3, 40 to a mixture containing 6-diazabicyclo(3.1.0) hexane acetate. Stir overnight at ~50°C.

Pyridine was evaporated under vacuum, 2 tJ of acetonitrile and 1-N,N-di Methylformamide was added to the residue and filtered to form crystals.

The filtrate was cooled overnight and filtered again. Add 2 crops of crystals to a small amount of acetonitrile. After drying, 44n+g (yield: 3596) of the target compound was obtained as a pale yellow solid. It's a good deal.

Melting point: 190~+91°C 1M-NMR (cDa,): δ0.8 - 1.4 (m, 4H), 2.2 (s, 2H), 2.3 (s, 3H).

3, 7 (q, 4H, J=12Hz), 4.0 - 4.5 (m, IH) .

7, 9 (d, IH, J=14Hz), 8.8 (s, IH).

IR (KBr) + 1726. 1617, 1500.　1446　cm” Example 7 9-fluoro-2,3-dihydro-3-methyl-10-(6-methyl-3 ．． 6-Diazabicyclo(3.1.0)hexan-3-yl)-7-oxo-7H -pyrid (1.

2,3-de)-1,4-benzoxazine-6-carboxylic acid 9,1O-diph of 1Omg (0.356mM) in 3ml of pyridine. fluoro-2,3-dihydro-3-methyl-7-oxo-7H-bilide (1.2. 3-de)-1,4-benzoxazine-〇-carboxylic acid and 169 mg ( 1.07mM) of 6-methyl3.6-diazabicyclo(3.1.0)hexane. The mixture containing acetate was stirred at 55-60°C for 2 days. Pyridine under vacuum The crude product was purified by column chromatography (eluent; chloroform:method). Tanol: water = 1 0: 3: 1') was purified to give 31 mg (yield :2496) was obtained.

Melting point: 206-210℃ 'H-NMR (CDCI,): δ1.5 (d, 3H, J=7Hz), 2 ．． 2 (s, 2H), 2.3 (s, 3H).

3, 4 - 3.8 (m, 2H), 3.9 - 4.7 (m, 5H).

7, 6 (d, IH, J=15Hz), 8.5 (s, IH).

IR(KEr): 1721, 1621, 1524.　1452cm"f f'1181-Cyclopropyl-6-fluoro-8-methoxy-7-(6-methy -3,6-diazabicyclo(3,1゜0]hexadi-3-yl)-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid In a similar manner as described in Example 7, 1-ink of I00mg (0,339mM) Lobrovir-6,7-difluoro-8-methyl-oxy-1゜4-dihydro-4-o Xo-3-quinolinecarboxylic acid was added to 175 mg of 6-methyl-3,6-diazabi 27 mg (yield: 2 1%) of the target compound was obtained.

Melting point, 193-195℃ 'H-NMR (CD'CI,) knee 50.8-1.2 (m, 4H), 2.2 ( s, '2H), 2.3(s, 3H).

3.3-4.2 (m, 5H), 3.6 (s, 3H).

7.7 (d, IH, J=15Hz), 8.7 (s, IH).

TR (KEr) + 17:28.1622.1513.1440 cm’ flight 9 1-Cyclopropyl-6-fluoro-7-(1,6-cymethyl-3,6-diaza Bicyclo(3,1,O)hexan-3-yl)-1,4-dihydro-4-oxo -1゜8-naphthyridine-3-carboxylic acid 100 mg (0,354 mM) of 1-cyc in 2me(1)T setonitrile. lopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 92 mg (0,533 mM) i, e- Dimethyl 3,6-diazabicyclo(3,1,0) hexane acetate and 4 9mg (0,320mM) of 1. 8-diazabicyclo(5,4,0) unde- The mixture containing 7-cene was stirred at room temperature overnight.

The solids are filtered and washed successively with acetonitrile, water and acetonitrile; 42 mg (yield: 409 ci) of the target compound was dried.

Melting point: 1813-188°C 'H-NMR (CDCI3) 60.9-1.4 (m, 4H), 1.5 (s, 3 H), 2.1 (s, IH), 2.4 (s, 3H).

□3.4-4.4 (m, 5H), 7.9 (d, IH, J=14Hz), 8.6 (s, IH).

IR (KBr): 1725.1629.1541.1452cm” flight 01 -cyclopropyl-6-fluoro-7-(1,6-cymethyl-3,6-diazabi cyclo(3,1,O)hexan-3-yl-1,4-dihydro-4-oxo-3 -quinolinecarboxylic acid 3mff (7) 100mg (0,337mM) (7) I-Si in pyridine Clopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quino phosphoruscarboxylic acid and 195 mg (1,13 mM) of 1°6-dimethyl-3.6- A mixture containing diazabicyclo(3,1,0)hexane acetate was added to Stir overnight at 0″C.

Pyridine was evaporated under vacuum and 3-methanol was added to the residue overnight at room temperature. Stirred. Filter the precipitate and add a small amount of methanol, water, and methanol continuously in that order. After washing and recrystallizing with acenitrile, 42 mg (yield: 31%) of the target compound was obtained. Obtained.

Melting point: 214~2+5°C 'H-NMR (CDCI, ): δ1.0-1.4 (m, 4H), 1.5 ( s, 3H), 2.1 (s, IH), 2.5 (s, RH).

3.2-4.2 (m, 5H), 6.7 (d, IH, J-8Hz).

7.8 (d, IH, J=16Hz), 8.5 (s, IH).

IR(KEr): 1725.1630.1511.1466cm” Example II 5-Amino-1-cyclopropyl-6,8-difluoro-7-(l,6-cymethylene) -3,6-diazabicyclo[3,1,O)hexan-3-yl)-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid 3me in pyridine, 100 mg (0,336mM) of 5-amino-1-cyclopropyl-6,7,8,- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1 73 mg (1,01 mM) of 1,6-dimethyl-3,6-diazabicyclo (3, 1,0) The mixture containing hexane acetate was stirred at 50-60°C overnight. .

The pyridine was evaporated under vacuum and the residue was dissolved in 2 mg acetonitrile overnight. Cooled. Filter the solids and add a small amount of acetonitrile, water and acetate. After successive washing and drying, 36 mg (yield: 2896) of the target compound I got it.

Melting point: 204-206℃ 'H-NMR (CDCI,) δ0.8 - 1.4 (m, 4H), 1.5 (s, 3H), 2.1 (s, IH), 2.5 (s, @3H).

3, 4 - 4.3 (m, 5I-1), 6.3 (u-FS, 2H), 8.5 (s, IH) IR (KBr): 1725, 1633, 1516. 14 36cm”I+12U 9-Fluoro-2,3-dihydro-3-methyl-10- (1.13-dimethyl-3.6-diazabicyclo[3.

1,0]hexan-3-yl)-7-oxo-7H-pyrido(1,2.3-de) -1,4-benzoxazine-6-carboxylic acid In 3 mg of pyridine, 100 mg (0.356 mM) of 9,10-di Fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2 ．． 3-de)-1,4-benzoxazine-6-carboxylic acid and 184 mg (1.07mM) i.p. e-dimethyl-3,6-diazabicyclo (3.1.0 ) The mixture containing hexane acetate was stirred at 50-60°C for 2 days.

The pyridine was evaporated under vacuum and the residue was purified by column chromatography (eluent: Loloform. Purified with methanol:water=10:3:l) to give 28 mg (yield :2296) was obtained.

Melting point = 162-164°C 'H-NMR (CDCI,): δ1.5 (d, 3H, J=7Hz), 1 ．． 9 (s, IH), 2.4 (s, 3H).

3, 2 - 4.5 (m, 7H), 7.5 (d, IH, J = 15Hz) , 8.5 (s, IH).

IR (KBr): 1722, 1621, 1525. 1466cm” example 131-Cyclopropyl-6-fluoro-8-methoxy-7-C1. G-dimethi -3,6-diazabicyclo(3.1.0)hexan-3-yl)-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid similar to that described in Example 12 In the method, l-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydrogen Dro-4-oxo-3-quinolinecarboxylic acid 100 mg (0,339mM) 1,6-dimethyl-3,6-diazabicyclo[3,1,0)hexane acetate React with 175 mg (1.02 mM) of 28 mg (yield: 2196 ) was obtained.

Melting point: 1136-168°C 'H-NMR (CDCI, ): 60.8-1.4 (m, 4H), 1.5 ( s, 3H), 1.9 (s, IH), 2.5 (s, RH).

3.2-4.2 (m, 5l-1), 3.6 (s, 3H), 7.7 (d, lH, J = 14Hz).

IR (KBr): 1728.1621.1512.1456cm 1 case + 4 1-chlorobrobyl-6,8-difluoro-7-(1゜6-dimethyl-3,6- Diazabicyclo(3,1,O)hexan-3-yl)-1,4-dihydro-4- 3-quinolinecarboxylic acid ■-Dicyclopropyl-67,8-1 in a manner similar to that described in Example 12. -Lifluoro-1,4-dihydro-4-oxo-3-ki-norinnoJ luponic acid 1 00mg (0,353mM) of G-dimethyl-3,6-diazabicyclo( 3,1,O) by reacting with 182 mg (1,0 GmM) of hexane acetate , 36 mg (yield: 2796) of the target compound was obtained.

Melting point: 230-231″C 'H-NMR (CDCI3): 61.0-1.4 (m, 4H), 1.5 ( s, 38), 2.1 (s, IH), 2.5 (s, 3g).

3.4-4.2 (m, 5H), 7.7 (d, 1.J = 14Hz), 8.7 ( s, IH) JR (KI3r): 1730.162G, 1517.1459 cm”ff11151-Cyclopropyl-8-chloro-6-fluoro-7-(1 ,6-dimethyl-3,6-diazabicyclo[3°1.0]hexadi-3-yl) -1,4-dihydro-4-oxo-3-gynolinecarboxylic acid In a manner similar to that described in Example 12, 1-cyclopropyl-8-chloro-6 ,7-difluoro-1,4-dihydro-4-oxy-3-quinolinecarboxylic acid 1 00mg (0,334mM) of 1,6-dimethyl-3,6-diazabicyclo( 3,1,O) Hexane acetate-1-172mg (1,0mM) was reacted with , 33 mg (yield: 2496) of the target compound was obtained.

Melting point: 198-202°C 'H-NMR (CDCI, ): 60.7-1.4 (m, 4H), 1.5 ( s, 3H), 1.9 (broad s, IH), 2D5 (s, 5H) .

3.4-4.0 (m, 4H), 4.0-4.4 (m, IH).

7.9 (d, IH, J=14Hz), 8.8 (s, IH) IR (KBr) : 1735.162], 1577, 1451 cm-'Example 16 1-sik lopropyl-7-(3,6-diazabicycloc3.1.Owl hexane-3-y 1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid 2mg acetonitrile Lopropyl-7-chloro-6-fluoro-1,4-dihydro-4=oxo-1. 8-naphthyridine-3-carboxylic acid, 27 mg (0.33 mM) of 3,6-dia Zapisik t: + l: 3.1.0) hexane and 3 4 mg (0.25 m M) 1,8-diazabicyclo (5.4.

0] The mixture containing unde-7-cene was stirred at room temperature for 6 hours.

The fixative was filtered, washed successively with small amounts of acetonitrile, and dried. , 55 mg (yield: 6706) of the target compound was injected into the stomach.

Melting point. 248-252°C 'H-NMR (CDCI3): 60.9 - 1.4 (m, 4H), 2J t (broad s, 2H), 3.4-4.3 (mC 5H).

7, 9 (cl, IH, J=14Hz), 8.5 (s, IH).

IR()03r): 1717. 1635, 1563.　1469cm” Example 17 1-cyclopropyl-7-(3.13-diazabicyclo(3.1.0) hexan-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-x Norincarphonic acid l00mg (0.38mM) of 1-cyclobu3 in 3mg of pyridine - quinoline carboxylic acid and 164 mg (1.1 mM) of 3.

6-diazabicyclo[3.1.0)hexane acetate-containing compound, ・1 Stir overnight at 5-55°C.

Pyridine was evaporated under vacuum, 4 J of methanol was added to the residue and 6 Stir for hours. Filter the solids and add methanol, water and methanol sequentially. After washing and drying, 70 mg (yield: 5696) of the target compound was obtained.

Melting point. 244-248°C 'H-NMR (DMSO-t16): 6 1.0 - 1.4 (m, 4H) , 2.3 (Broad S, 2H), 3.4-4.0 (Fragrance C5H).

7, 0 (d, IH, J=!3Hz), 7.8 (d, IH, J=16H z), 3.5 (s, LH).

IR (KJ3r): 1719, l (J32, 1508. 1473 c m”ff11181-cyclopropyl-7-(3.6-diazabicyclo(3.1 ．． O) hexan-3-yl)-13.8-difluoro-1. 4-dihydro-4 -oxo-3-gynolinecarphonic acid 1.5 mg of acetate nitrile and I,5tnj of N,N-dimethylformamide 1-cyclopropyl-6, 7.8 mg (0.35 mM) of -trifluoro-1,4-onehydro-4-oxo-3-quinolinecarboxylic acid, 8 7 mg (0.=I2mM) of 3,6-n-a → Nohi Sokuro (5.4.0) un The two-containing mixture containing De-7 was stirred at 40-50°C overnight.

The reaction mixture was cooled to room temperature, the crystals formed were filtered, and a small amount of acetonitrile was added. The solution was washed successively with water, water and acetonitrile. This is converted into N,N-dimethylene Recrystallize from chloroformamide to obtain 44 mg (yield: 3G-6) of the target compound as a white product. was obtained as a solid.

Melting point. 230~232°C 'H-NMR (CDCI,): δ0.9 - 1, 4 (m, 4H), 2 ．． 8 (s, 2H), 3.5 - 4.3 (m, IH)B 3, 8 (q, 4H, J = 121-1z), 7.8 (d, IH, J = 14Hz), 8.6 (s, IH).

IR (KI3r): 1727, 1628, 1517. 1464 cm 'Example 19 1-cycloprobyl-8-chloro-7-(3,6-diazabicyclo( 3.1.03hexan-3-yl)-1,4-dihydro-4-ogisoquinoline l-Cyclopropyl-8- Chloro-6,7-difluoro-1,4-dihydro-4-year-old xo-3-quinolinker 100 mg (0.33 mM) of rubonic acid was added to 3,6-diazabicyclo (3.1 ．． 0) Hexane acetate-1-144mg (1.0mM) and anti-1. Let me do it, 50 mg (yield: 4I96) of the target compound was obtained.

Melting point, 214-216°C 'H-NMR (CDCI, ): 60.8-1.6 (m, 4) 1), 2.7 (s, 2H), 3.7 (s, 4H), 4.2-4. T (m, IH).

8.0 (d, IH, J=14Hz), 8.8 (s, IH).

IR (KBr): 1726.1614.1502.1448 cm” Example 2 05-amino-1-cyclopropyl-7-(3,6-diazabicyclo(3,1, 0)Hexan-3-yl)6,8-difluoro-1,4-onehydro-4-oxo -3-quinocarboxylic acid in 1+J acetonyl-lyl and 2 mg N,N-dimethylpolamide] 7 mg (0.39 mM) of 5-amino-1-fuclopropyl-6, 8-1-Lifluoro-1,4-dihydro-4-year-old xo-3-quinolinecarboxylic acid , 68mg (0,47mM) of 3,6-soisosupinoclo(3,1,O) xane acetate)- and 131 mg (0.87 mM) of 1. 8-Diazabi Stir the mixture containing cyclo(5,4,0)unde-7-cene at 50-60°C. did.

The reaction mixture was cooled to room temperature and the solid was filtered to remove a small amount of acetonidonyl. After drying, 55 mg (yield 3996) of the desired mixture was obtained as a yellow solid.

Melting point: 218-220℃ 'jl-NMR (DMSOJ,): 60.9 - 1.2 (+n, 4tl), 2.6 (s, 2H).

34 ~ 4.2 (3.7 dd in f tsubium, 5H, J = 8Hz. 1 2Hz).

7, 0 (Broad s, 2H), 8.4 (s, III).

IR (KI3r): 1726, +638. 1542, 1517 cI 7+” Example 2+ 7-(3.6-diazabicyclo[:3.1.0)hexane-3 -yl)-6,8-difluoro-■-ethyl-1.4-onehydro-4-oxo- 3-quinolinecarboxylic acid l-Omg (0.37mg) of l-ethyl- in 3mg of pyridine. 6, 7. 8-trifluoro-1,4-dihy-1s-lo-4-oxo-3-quinoline carbonic acid and 158 mg (1.1 mM) of 3.

A mixture containing 6-diazabicyclo(3.1.0) hexane acetate from 55 to The mixture was stirred at 65°C.

The reaction mixture was cooled and the solids were filtered. Disperse this in 10ml of methanol filtered, recrystallized from chloroform to give 76 mg (yield 6196). It's a mixture of things.

Melting point = 222-224°C 1 NMR (DMSO-d,) δ l, 4 (+, 3H, J=6Hz) , 2.6 (s, 21]).

3, 7 (dd, 4H. J=8Hz, 12Hz).

4, 3 - 4.7 (m, 311).

'Noah ((+, Ill, J=14tlz.), 8.8 (s, III).

IR(KL+[): I’712.　1628. 1521, Il168, 14+15 am” Example 22 9-fluoro-2,3-dihydro-3-methyl- IO-(3.6-diazabicyclo(3.1.Owl hexane-3-yl)-7 -oxo-7H-pyrido (1.

2,3-de)-1,4-penzogisacin-6-carphonic acid In 3 mg of pyridine, 100 mg (0.36 mM) of 9,10-di Fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1, 2. 3-de)-1,4-penzoxanone = 6-carboxylic acid and 154mg (1.1mM) of 3.6-diazabicyclo(3.1.O)hexane acetate The mixture was stirred at 60-70°C overnight.

After cooling the reaction solution, the solids were removed by filtration, the filtrate was evaporated under vacuum, 5 mff of methanol was added to the residue and stirred for 2 hours at room temperature. filter solids Then, successively wash with a small amount of methanol, water and methanol, and dry. 38 mg (yield: 3196) of the target compound was obtained.

Melting point: 242-244°C 1 to 1-NlvlR (C DCI,) δ 1.5 (d, 311, J = 6 1-b. ), 2.6 (s, 2tl).

34-4.0 (+n, 51-I), 1.3-4.8 (m, 31-1).

7, 7((J, IH, J=14+1z), 8.6(s, 14-1)If( (KBr): 1712, I (1+21.1531.1474crn” Example 23 1-Fucloproyl-6.8-nofur-71 [l-methyl-3.6-dia Zabicyclo (3.l.

O] hex→non-3-yl)-, I,4-cyto- 4-oxo-3-quino phosphoric acid In 3me pyridine, 100mg (0.35mNi) of 1-chloride was added. Blobiru G. 7. 8-trifluoro-1,4-dihydro-4-year-old xo 3 -quinolinecarphonic acid and 1136 mg (1.1 mM) of 1-methyl-3,6- γ complex containing diazabicyclo(3.1.0) hexane acetate, 4 Stir overnight at 5-50"C.

The reaction solution was cooled and the solids were filtered. This was dispersed in methanol (!). filtered, recrystallized with chloroform to obtain 97 mg (yield 7G?6) The compound was obtained.

Melting point: 228-230°C 'H-NhlR (CDCI,) 6 0.9 - 1.4 (m, 4H), 1.5 (s,3H), 2.4(s,l)().

3, 4 - 4.2 (m, 51-1), 7.6 (d, IH, J = 14 Hz), 8.7 (m, l) ().

IJ ((K13r): 1721, +627. 1547. 1518. 1 449cm” Example 24 1-cyclopropyl-8-chloro-6-fluoro-7- (l-methyl-3,6-diazabicyclo[3.

1,0]hexan-3-yl)1,4-dihydro-4-oxo-3-quinoline In pyridine of J luponic acid 3me, 1 Omg (0.33mM) -fuclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4- Oxo-3-quinolinecarboxylic acid and lGImg (1.

0mg seasonal 1-methyl-3.6-diazabicyclo(3.1.O) hexane acetate The mixture containing tate was stirred at 60-65°C overnight.

The mixture was evaporated under vacuum and added to 3 m(!) of acetonidonyl distillate, The mixture was stirred at room temperature for 4 hours. The solid was filtered and dried to give 41 mg (yield: 3296 ) target compound? It's q.

Melting point: 216-218°C 'H-N81R to CDCI, ): 6 0.7-1.5 (m, 4H), 1.4 (s, 3H), 2.4 (s, IH).

3.6 (q, 4H, J=lOHz), 4.0-4.4 (m, IH).

7.9 (d, It-1, J=14Hz), 8.8 (s, IH) IR (Toko Br ): 1726.1617.1500.1452 cm” Example 255-amino -1-cyclopropyl-6,8-difluoro-7-(l-methyl-3,6-dia Zabicyclo(3,1,O)hexan-3-yl)-1,4-dihydro-4-o Xo-3-quinolinecarboxylic acid 100 mg (0.34 m M) 5-amino-1-cyclopropyl-6,7,8-1-refluoro-1,4 - Dipitrow 4-oxo-3-gynolinecarboxylic acid and 159 mg (1,0 mM ) of 1-methyl-3,6-diazabicyclo[3°I,0]hexane acetate The mixture containing the following was stirred at 65-70°C overnight.

The birinone was removed under vacuum and 3 mff of methanol was added to the residue for 5 h. Stir at room temperature. Filter the solids, add a small amount of methanol, then water and methanol. Continuously wash and dry, 2! Jmg (yield: 2396) of the target compound was obtained. .

Melting point, 224-226°C '+1-NMR (CDCI, ) 60.7-1.5 (m, 4t]), 1.4 (s, 3H), 2.4 (s, IH).

3.4-4.1 (m, 5) 1), 6.4 (11)-de s, 211), 8.7 (s, IH)lRfKBr+: 171R, 1632, 1516, 143Qc m” Example 26 1-cyclopropyl-6-fluoro-7-(1-methyl-3,6 -diazabicyclo(3,1,O)hexan-3-yl)-1,4-dihydro-4 -oxo-1,8-naphthyridine-3-carboxylic acid 3 mg acel-: l-t 74 mg (0,2i3mM) of 1-fuclopropylfur-chloro-6 -1,4-dihydro-4-oxo-1,8-naphthyridine-3-cal Bonic acid, 50 mg (0.32 mM) of 1-methyl-3,6-diazabicyclo( 1.3,1,O) hexane acetate and 86 μff (0,57 mM). A mixture containing 8-diazabicyclo[5,4,O)unde-7-cene was incubated for 6 hours at room temperature. Stir at warm temperature.

Filter the solids and remove a small amount of acetonitrile. The desired compound was obtained.

Melting point -249~251"C 1 TodoNMr+, (T)MS()-'1g) 6 0.9-1, 4(m, 4L]), 1, 4+ Ill-de s, 3H), 2.4 (Sword CIll).

3, 4 - 4.3 (m, 511), 7.9 (d, IN, J = 14 + ( z), 8′i(s, IH)IR(k+3r): 1718, 1635.　 1502. 146’/cln” Example 27 1-cyclopropyl-6-fluoro rho-7-(1-methyl-3.6-diazabicyclo(3.1.0)hexane-3- yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid In 5 ml of acel-:I-vine, add IO Omg (0.38rnM ) of 1-fucloprovir-6. Fushifluoro 1,4-jihi 1-low 4-oki So-3-quinolinecarboxylic acid, 72 mg (0.451 ntvI) of 1- Methyl-3,6-diazabicyclo(3.1.O)hexane acetate and l 25ul (0.83m'tXl[) of I, 8-diazabicyclo (5. 11. O) 1 kongo 1 nu including unde-7-sen, 5(]~Gt)”C to 8 Stir for hours.

Filter the solids and remove a small amount of acetonyl-lyl, water and acetonitrile. 06) Target compound? 1. It was.

Melting point: 267-269°C 1 to I-Kake IP4DMS () (1,) 8 1 0 to 1.4 (m, 4N), 1 (bleed s, 3H), 2.4 (s, I)-1).

3, 4-11. O(+n,5I(),7.0(d,lto1,J28Hz).

7, 8(d, III, J=I611zl 8.5CS, II()ll?. (KI3r): 1712, 1632, 1512. 1469 CIl+” Del-3,6-diazabicyclo(3.1.0)hexane'-3-yl)-1 ．． 4-dihydro-4-oxo-3-quinolinecarboxylic acid lactate 20me Chloropom and 0.15 g (0.4 I m M ) of 1-noclobrovir-6-fur-7-(1-methyl-3.6-naza) Hinocro(3.1.O)hexan-3-yl)-1.4-dihydro-4-oxo A solution of -3-quinolinecarphosic acid was stirred, and 36 mg (909 mg) was added to it. 6.

30 μC) of lactic acid was added and the resulting solution was stirred at room temperature for 30 minutes.

By evaporating lδwas2 with S'(I) and adding lomff of ether, It was crystallized by The solid was filtered and dried in vacuo to give 154 mg (yield 8 The target compound (296) was obtained as a white solid.

Melting point. 160~If32°C 'II NMR (CI) CI,) 6 1.0 - 1.5 (m, 411), 1 ．． 4(s,3)]), 2.7(s,IH).

3, (1 - 4.2 (m, I IH), 6.8 (d, IH, J = 8 Hz).

7, 7 (d.II-1.J=16Hz), 8. /I(ζ,iH) Example 29 9- Furu-10-2.3-dihydro-3-medy-10-(l-methyl-3,6-dia Zabishikuro [3.

1,0]hexan-3-yl)-7-oxo-7H-pyrido(], 2,3-de) -1,4-benzoxazine-6-noJrubonic acid In 3 ml of birinone, 100n+g (0.36mM) of 9,1O- Difluoro-2,3-Shihi I'low 3-methyl-7-oxo-7H-pyryl' (1. 2. 3-de)-1.4-benzoxazine-6-carboxylic acid and 16 9 mg (1.1 mM) of 1-methyl-3,6-na→nohisoclo(3.1.O ) The mixture containing hexane acetate was stirred at 60-70°C overnight.

The solution was evaporated under vacuum and the residue was subjected to column chromatography (eluent :Chloroborum. Purified with methanol water = 10:3:l) to give 30 mg ( The target compound (yield: 2396) was obtained as a yellow solid.

Melting point: 220-222°C 'II-NMR (CDCI, ): δ 1.4 (d, 3H, J=6Hz), 1.5(s, ](), 2.3(s, IH).

3.2-4.0 (m, 5H), 4. l -4,8 (m, 3H).

7.6 (d, IH, J=14Hz), 8.6 (s, IB) IR (KJ3r ): 1719.1623.1531.1476cm+Example 306.8-Diflu Oro-1-(2,4-difluorophenyl)-7-(3,G-diazabicyclo[ 3,IO]hexan-3-yl)-1,4-dihydro-4-quino-3-quino phosphorus carboxylic acid In 4me pyrinone, lOOmg (0,28mtv1) of 1-(2°4- difluorophenyl)-G, 7. 8-trifluoro-1゜4-di-1-low 3.6 of 4-oxo-3-quinolinecarboxylic acid and 121 mg (0,84 mM) - a mixture containing diazabicyclo(3,1,O)hexane acetate from 55 to The mixture was stirred at 60°C overnight.

The solids were removed by filtration and the filtrate was evaporated under vacuum. Residue, ether crystallized by adding, filtered, washed with water and dried to give 45 mg The target compound (yield: 3896) was obtained as a blue-yellow solid.

Melting point: 245-247°C 111-NMC11l-N, ) δ2.1 (s, IH), 27 (s, 2H ), 3. '7 (q, 411. J = 12Hz).

48 (10-s, II), 6.9-7.7 (ITI, 3 days).

743 (d, IH, 3=16Hz), 8.4 (s, IH) Example 31 1-S Clopropyl-6,8-nofluoro-7-(1,5-dimethyl-3,6-diaza Bicyclo[3°1.0]hexan-3-yl)-1,4-dihydro-4-negiso -3-quinolinecarboxylic acid 3n+j7 in pyridine, IOOmg (0, 35mM) of l-cyclopropyl-6,7,8-1-lifluoro-1,4-dihydrogen Dolo-4-oxo-3-quinolinecarboxylic acid and 93 mg (0.83 mM) of 1 , 5-dimethyl-3,6-diazabicyclo[3,1°0]hexane. was stirred at 40-65°C overnight.

The reaction mixture was cooled and filtered to obtain crystals. This crystal is mixed with lOmff methanol. The target compound was dispersed in 53 μg (yield: 4096) by dispersing the product in Obtained as a white solid.

Melting point 240-242°C 'H-NMR (CDCI, ): 60.9-1.5 (m, 4H), 1.4 ( s, 6H), 3.4-4.2 (m, 5) 1).

7.8 (d, IH, J=14Hz), 8.7 (s, IH).

rR(KBr): 1722.1625.1517.1450cnt” Example 32 1-so’) lobcopyru-8-chloro G-fluoro-7-(1,5-dimethyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-dipy 100 mg of Thoro-4-oxo-3-quinolinecarboxylic acid in 3 ml of pyridine (0,33mM) of 1-cyclopropyl-8-chloro-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 113 mg (1° 0mM) of 1,5-dimethyl-3,6-diazabicyclo[3°1.0]hexane The mixture was stirred at 50-60°C overnight.

Pyridine was evaporated under vacuum and 5 methanol was added to the residue. Precipitation The material was filtered, washed successively with methanol and acetate, and dried. A white solid compound (yield: 5996) was obtained.

Melting point: 220-222°C 'H-NMR (CDCI, ): 60.8-1.2 (m, 2H), 1.2- 1.5 (m, 2H), 1.4 (s, 6tl).

3.6 (s, 4H), 4.1-4.5f:m, 1l-1), 8.0 (d, IT- 1, J=141-Lzl).

IR (KBr): 1722, 1617.144-1 cm” Example 33 5-ami Nor-1-fuclopropyl-6,8-difluoro-7-(1,5-tmethyl-3, 6-diazapiclo(3,1,O)hex→J'-3-yl)-1°4-enhit Rho-4oxo-3-quinolinecarphonic acid In a similar manner to that described in Example 32, 10 0m(! (0,34mM) of 5-amino-1-cyclopropyl-6,7,8- trifluoride 1,4-sich 1-rho 4-oxo-3-quinolinecarphonic acid , ] II 3 mg (1, OmM) 1. 5-dimethyl-3,6-diazabisi By reacting with chloro(3,1,O)hexane, 1g of 68Il (yield: 5206) The target compound was obtained as a yellow solid.

Melting point: 219-22 pC 'H-N ~ IR (CI) CI3) 60.8-1.4 (m, 4H), 1.3 (s, 611), 3.4-4.1 (m, 5H).

64 (broad s, 2H), 8.6 (s, 1H) IR (f (Ilr): 1 723.1632.1516. +429c+n” Example 34 1-cyclopropyl -7-(1,5-dimethyl-3゜6 one noa one two socro (3,1,0) hexa (3-yl)-6-fluoro-1,4-nohythro-4-oxo1. 8-na Acetonitrile of phthyricin-3-carboxylic acid 3mC Socloprovir-7-chloro-6-fluro1,4-nohydro11-oxo -1. 8-nanothilinone-3-carboxylic acid, 41mg (0.2f3m M) 1,5-dimethyl-3,6-diazahincroC3.1.0'l hexane, 1. of porn-1-3-carboxylic acid and 27+ng (0.18mM). 8-Diazapiclo [5.

The mixture containing 4,0]unde-7-cene was stirred at room temperature for 4 hours.

Filter the precipitate and remove it with cetonitrile. After successive washing and drying, 46μ (yield: 7396) of the target compound was obtained as a white product. It's solid and it's the stomach.

Melting point: 256-257°C 'H-NklR (1) MSO- (16) 6 0.9 - 15 (m, 4+- 1), 1.4(s, 6I().

3, 4 - 4.4 (m, 51 - (), 7.9 (d.l) (, J = l / lHz) , 8.6(s,IH) Example 35 1-cyclopropyl-7-(1.5-tmethyl- 3,6-Diazabicyclo(3.1.O)hegizacy-3-yl)-6-fluoro- 1,・1-nohythro-4-oxo-3-quinolinecarboxylic acid G Omg (0.23mM) of 1-cyclopropylene in 3me of pyrinone. Ru-6,7-difluoro-1,4-difluoro-4-difluoro-3-quinolinecarbo 7 mg (0.68 mM) of 1,5-trimethyl-3,6- A compound containing diazabicyclo[3.1,0]hexane polmate was added to the Stir overnight at 80°C.

1, L; The mixture was cooled to room temperature and the precipitate was filtered. Add this to methanol , water and methanol in this order, and dried to give 43cm (yield: 539cm). The target compound i) was obtained as a white solid.

Melting point, 258-260°C 'I-LNMR (CF+C02) 1) δ 1.2-1.8 (IIL 48), l, 9(s, (d-().

3.8-4.2 (m, IH), 4.1 (d, 2H, J=14Hz).

4.8 (d, 2H, J=14Hz), 7.5 (d, IH, J=8Hz).

8.2 (d, IH, J=14to1z), 9.2 (s, IH).

IR (Kllr): 1711.1631.1512.1471 cm” Example 36 1-ethyl-7-(1,5-dimethyl-3,6-diazabicyclo(3,1,0 )hexan-3-yl)-6,8-difluoro-1,4-dihydro-4-ox So-3-quinolinecarboxylic acid In 3 mg of pyridine, [i0rng (0,22mM) of 1-ethyl-6, 7,8-trifluoro-1,4-dihydro-4-year-old xo-3-quinolinecarvone acid and 74 mg (0,66 mM) of 1°5-trimethyl-3,6-diazabisic The mixture containing RO[3,1,O)hensan was stirred at 40-50°C overnight.

Anti-1. Cool the mixture, evaporate under vacuum and add the residue to methanol. Ta. Filter the precipitate, wash successively with methanol, water and methanol, and dry. Then, 54 +++ g (yield f38?6) of the target compound was obtained as a white solid. .

Melting point: 240-241℃ To '1111・IR (CI) CI, no δ 1.4 (s, GII), 1.5 (+ , 3tl, J=6Hz).

3.7 (q, 1II-1, J=14Hz), 4.2-4.7 (m, 2H).

1.9 (d, IH, J = group (z), 8.5 (s, IH).

IR (lI3r): 1722.1627.1521.1447 can”I J37 9-fluoro-2,3-dihydro-3-methyl-1O-(1,5-dimethyl to thyl-3,6-diazabicyclo(3,1,O); tosan-3-yl)-7-o xo-78-pyrido N,2,3-de)-1,4-benzoxazine-6-carbo acid I00+ng (0.36mM) of 9,10-diflu in 3mg of pyridine. Oro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (L2,3 -de)-1,4-penzoxane-6-carboxylic acid and I 20mg (1, ImM) of 1. 5-dimethyl-3,6-diazabicyclo(3,1,0)hex The mixture containing the sun was stirred at 60-75°C for 30 hours.

The precipitate was obtained by filtration and the filtrate was evaporated under vacuum leaving 3 mg of methanol. It was added to the liquid and crystallized. Mix 2 crops of sediment and add 5 Dispersed in methanol, filtered and dried to give 79 mg (yield: 5996) The desired compound was obtained as a blue-green solid.

Melting point: 286-288°C 'H-Nh4R (CDCI, ) 6 1.3 (s, 6) 1), ], 6 (d, 31J, J=7)1z), 3.3-4.8 (rn, 7H).

7, (i (d, 1) 1. J = 14 Hz), 8.6 (s, LH) JR (KB r): IF8.1622.1525.14118 c+η゛1 Example 38 6. 8-difluoro-1-(2,4-difluorophenyl)-7-(1,5-dimethyl -3,6-diazabicyclo(3,1,0)hexan-3-yl)-1,4-one Hitro 4-oxo 3-quinolinecarboxylic acid In 4tne of pyrinone, lUOmg ((1,28mM) of 1-(2° 4-difluorophenyl)-G, 7. 8-1-refluoro-1゜4-inpi1 ~Rho-11-oxo-3-quinolinecarboxylic acid and 95mg (0,85mM) 1. Contains 5-dimethyl-3,6-diazabicyclo[3,1,O)hexane The gamma mixture was stirred at 45-55°C overnight.

The reaction mixture was evaporated under vacuum and methanol was added to the residue. Filter the precipitate Filtered, washed with methanol and dried to obtain 85 mg (yield: [1896)] The compound was obtained as a blue-yellow solid.

Melting point: 230-232°C 'H-NMR (CDCI δ 1.3 (s, 68), 3.6 (q, 4H1J= I211z).

6.8-7.6 (m, 3) (), 7.9 (d, IH, J=14Hz), 8.4(s, II().

IR (KBr): 1725.1622.1508.1441 cm” (1, 5,13-trimethyl-3,6-diazabicyclo(3,1,0)hexane-3- 2 ml of methyl)-1,4-ene 4-oxo-3-quinoline In lysine, 0.22g (0.78mM) of 1-cyclopropyl-6,7,8 -1-lifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and and 0. 2g (1,58mM) of 1. Gai 6-1-rifutyl-3,6-diaza Stir the mixture containing bicyclo[3,1,O)hexane at 50-60°C for 2 hours. did.

3 mg of methanol was added to the reaction mixture and gradually cooled to room temperature. precipitation The material was filtered, washed with methanol, and diluted with chloroform-methanol (1.3.V/ V) several times to obtain 0.2 g (yield: 6696) of the target compound as a white solid. I got it.

Melting point, 212-213°C 'H-NMR (CDCL, ): 61.1-1.5 (+n, 4H), 1.3 (s, 6H), 2.4 (s, 3H).

3.4-4.2 (m, 5H), 7.7 (d, IH, J=14Hz), 8.7 (s , IH).

IF, (KBr): 1730.1627.1541.1452cm'(P+ 40 8-chloro-1-cyclopropyl-6-fluoro-7-(1,5,6-1 -dimethyl-3,6-diazabicyclo(3,1,0)hexan-3-yl)-1 ゜4-dihydro-4-oxo-3-quinolinecarboxylic acid In a manner similar to that described in Example 39, 8-chloro-1-cyclopropyl-6 ,7-difluoro-1,4-dihyto'rho-4-oxo-3-quinolinecarboxylic acid 0.22g (0.7mM) 1. 5. 6-drimethyl-3,6-diazabi React with 0.19 g (1,48 mM) of cyclo[3,1O]hexane 1 g (yield near 096) of the target compound was obtained.

Melting point 202-203°C 'H-NMR (CDCI, ): δ1.1 (m, 4H), 1.3 (s, 6 H), 2.4 (s, 3H), 3.8 (m, 4H).

11.3 (m, IH), 7.8 (d, IH, J=14Hz), 8.8 ( s, IH).

IR (Kko3r): 1731.1616.1550.1497. 1438 cm” Oro 7-(1,5,6i-rifutyl-3,6-diazapisochloro(3 ,1,0)hexan-3-yl)-1,4-dihydro-4-oxo-3-quinoli carboxylic acid In a manner similar to that described in Example 39, 5-amino-l-noclobrovir G, 7.8-1-Lifluoro-1,4-dihydro-4-year-old xo-3-quinolinecarbo acid 0. 22g (0.74mM) of 1,5.6-drimethyl-3,6-dia React with 0.91g (1,48mM) of zabicyclo(3,1,O)hexane , O,: 2 g (yield: 6796) of the target compound was obtained as a yellow solid.

Melting point 203-204°C 'H-NMR (CDCI+): δ 1.1 (m, 4H), 1.3 (s, 6H ), 2.4 (s, 3H), 3.9 (m, 5H).

64 (Broad s, 2H), 8.6 (s, IH) TR (KBr): 1726 ．． 1633.1515.1434 cm'Example 42 1-cyclopropyl-6-ph fluoro-7-(1,5゜6-drimethyl-3,6-diazabicyclo(3,1゜0 ]Hexan-3-yl)-1,4-dihydro-4-oxo-1,8-naphthyridi l-Cyclopropylene-3-carboxylic acid in a similar manner to that described in Example 39. -7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naph 0.2 g (0.71 mM) of tyridine-3-carboxylic acid Chiru 3,6-diazabicyclo3.1.0]hexane 0.18g (1,42m M) to obtain 0.1 g (yield: 3896) of the target compound.

Melting point 230-231℃ 'H-NMR (CDCI, ): 61.0-1.3 (n+, 4H), 1.3 (s, 6H), 2.3 (s, 3H).

3.4-4.3 (m, 5H), 8.0 (cl, IH, J=14Hz), 8.7 (s, IH).

IR (KBr): 177-5.1631. +561.1505.1452 cm” colored soil 31-cyclopropyl-6-fluoro-7-(1,5,7-drimethyl Ru-3,6-diazabicyclo[3゜1.0]hexan-3-yl)-1,4-di Hydro-4-oxo-3-quinolinecarboxylic acid similar to that described in Example 39 In the method, ■-dicyclopropyl-67-difluoro-1,4-dihydro-4-o Xo-3-quinolinecarboxylic acid 0. I 8g (0.68mM) at 1.5゜6- Dolimethyl-3,6-diazabicyclo(3,1,0)hexane O,l 7g ( 1.36, mM) to obtain 0.2 g (yield 79%) of the target compound.

Melting point = 238-239℃ 'H-NMR (CDCI, ): 61.1-1.7 (m, 4H), 1.4 ( s, 6H), 2.3(s, 3H).

3.2-4.1 (m, 5H), 6.8 (d, IH, J=6Hz).

7.9 (d, IH, J=16H7,), 8.7 (s, IH).

IR (KBr): 1729.1631. +511.1469.1404 cm-' 6-difluoro-7-(1,5゜6-difluoro-7-ethyl-6,8-difluoro-7-(1,5°6-difluoro) Thiru-3,6-diazabicyclo[3,1゜0]hexan-3-yl)-1,4- Dihydro-4-year-old xo-3-quinolinecarboxylic acid In a manner similar to that described in Example 39, ■-ethyl-6°7.8-trifluoro Lo-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 0.17g (0 , 63mM) at 1. 5. 6-drimethyl-3,6-diazabicyclo(3,1 , 0) Hexane 0. React with 6 g (1,26m,'M) of 0.1 4 g (yield 62%) of the target compound was obtained.

Melting point 204-205°C '11-N 4R (CDCIρ, δ 1.3 (s, 6l-1), 1.5 (t , 3H, J=6Hz).

2.4 (s, 3H), 3.4-4.6 (m, 6H).

7.8 (d, IH, J=14Hz), 8.5 (s, IH).

The following Examples 45-47 illustrate medical straw compositions containing compounds of the invention as active ingredients.

Example 45 Example II or the compound of 18’t! ! 1 25 g Following the conventional method, convert the above ingredients into ethanol. The mixture was crushed and filled into a lOO-h package.

Example 46 Compound of Example 11 or 18 25g Starch 5.4g Calcium Calhokit Methyl Cellulose 4.0g Microcrystalline Cellulose base 5.0g Magnesium stearate 0.6g According to conventional methods, the above ingredients are blended with ethanol and crushed to produce 100 tablets. Prepared as a cut.

Example 47 Compound of Example 22 0.5g Lactic acid 1.2g Dissolve the above ingredients in 100 ml of distilled water and ply using thorium hydroxide solution. Adjusted to H4 and then filled into ampoules (10mj) to produce an injection solution .

Copy and translation of written amendment) Submission (Article 184-8 of the Patent Law) July 14, 1992

Claims (5)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is hydrogen or a protecting group, R2 is hydrogen, amino, alkylamino having 1 to 4 carbon atoms, hydroxy Ci, alkoxy with 1 to 4 carbon atoms, mercapto, 1 to 4 carbon atoms alkylthio or halogen, R3 is alkyl having 1 to 4 carbon atoms, alkyl having 2 to 4 carbon atoms; rukenyl, cycloalkyl with 3 to 6 carbon atoms, haloalkyl, 2 to 4 hydroxyalkyl, methoxy, amino, 1-2 carbon atoms Alkylamino, dimethylamino or halogen atom or 1- phenyl optionally substituted with one or more alkyls having 3 carbon atoms; Z is the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein R4 is hydrogen or alkyl having 1 to 4 carbon atoms, R5 and R7 are the same or different and have hydrogen or 1 to 2 carbon atoms amine represented by (representing alkyl), X is N or C-R6 (wherein R6 is hydrogen, hydroquine, methyl, cyano, nitro The following formula with B, methoxy, halogen or R3 -NH-CH2-CH-CH2, -O-CH2CH-CH2-S-CH2-CH -CH2, or -CH2-CH2-CH-CH2) A novel quinolone compound represented by Salt acceptable above. 2. A compound of formula (II) is added to an amine of formula (III) or its like in the presence of a solvent and a base. react with an acid addition salt of ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)▲There are mathematical formulas, chemical formulas, tables, etc.▼( II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R1, R2, R3 , X and Z are the same as those described in claim 1, and Y represents halogen). A method for producing a compound of formula (I). 3. Solvents include acetonitrile, N,N-dimethylformamide, dimethylsulfonate. - or more selected from the group consisting of oxide, alcohol, water, pyridine and picoline 3. The method according to claim 2, wherein the solvent is 4. Bases include sodium hydroxide, potassium hydroxide, triethylamine, and pyridine. , picoline, lutidine, 1,4-diazabicyclo[2.2.2]octane [DA BCO], 1,8-diazabicyclo[5.4.0] unde-7-cene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) 3. The method according to claim 2, wherein the base is - or more selected from the group. 5. Compound of formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1, R2, R3, Z and is the same as that described in claim 1) or its pharmaceutically acceptable active ingredient 1. An antimicrobial composition comprising one or more salts.