CN108530448A - Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and preparation method thereof - Google Patents

Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and preparation method thereof Download PDF

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CN108530448A
CN108530448A CN201710121414.3A CN201710121414A CN108530448A CN 108530448 A CN108530448 A CN 108530448A CN 201710121414 A CN201710121414 A CN 201710121414A CN 108530448 A CN108530448 A CN 108530448A
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trifluoromethyl
ketone
thiazine
bases
hendecane
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刘明亮
郭慧元
吕凯
汪阿鹏
柴芸
黄国成
王洪建
陶泽宇
张俊
陈仕洪
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Institute of Medicinal Biotechnology of CAMS
Zhejiang Starry Pharmaceutical Co Ltd
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Institute of Medicinal Biotechnology of CAMS
Zhejiang Starry Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

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Abstract

The present invention relates to 4 ketone compounds of benzothiazine and preparation method thereof containing alkaline azaspiro segment, specifically, the present invention relates to 8 nitro 4H benzos [e] [1 of a kind of 6 trifluoromethyl, 3] 4 ketone compounds of thiazine, its 2 bit substituent is the loop coil segment containing 2 nitrogen-atoms, wherein：N1, n2 represent 0 or 1, and wherein n1 and n2 are identical or different；W is saturated or unsaturated, halogenated or not halogenated straight chain, branch or cricoid fat-based with 3 10 carbon atoms, wherein if it does, optional 12 methines are replaced by O or S；Alternatively, W represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl, and optionally, wherein 03 hydrogen atoms are replaced by R group；R is selected from the alkyl with 14 carbon atoms, the alkoxy with 13 carbon atoms, halogen, CF3、‑OCF3、‑NO2Or CN.

Description

Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and its preparation Method
Technical field
The invention belongs to medicinal chemistry arts, it is related to the benzo containing alkaline azaspiro segment with anti-tubercular Thiazine ketone compounds and preparation method thereof, and the antitubercular pharmaceutical composition containing them；More specifically, the present invention relates to And 6- trifluoromethyls -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone compounds, 2- bit substituents are containing 2 nitrogen The alkaline azaspiro segment of atom.
Background technology
Tuberculosis (TB) be by seriously endanger caused by mycobacterium tuberculosis (MTB) serious infectious diseases of human health it One.Since the 1980s, drug resistance TB, the incidence of especially multi-drug resistant TB (MDR-TB) constantly rise and TB with HIV/AIDS, which is combined, makes TB epidemic situations rise once again, becomes the great public health problem and social concern of global concern.According to system Meter, the whole world have 8,000,000 newly-increased TB patients, nearly 3,000,000 people to die of tuberculosis every year, and nearly 1/3 population carries latent form tubercle bacillus, tool There is potential initiation potential.Traditional anti-TB drugs, such as streptomysin, isoniazid, rifampin, ethambutol and pyrazinamide connection Sharing medicine can make 85% or more first control lunger's recovery from illness, but there are treatment cycle length (be more than 6 months) and to MDR-TB Invalid disadvantage, at the same it is not strong to the effect of latent form MTB, therefore anti-TB new drugs are researched and developed, realize effective treatment and control to TB Make extremely urgent (external medicine-antibiotic fascicle 2009,30 (1)：19-24).
Fortunately, quinoline (ATP is reached as the 1st in the past 40 years anti-TB new drugs shellfish with completely new mechanism of action Synthetase inhibitors) treatment MDR-TB was approved by the fda in the United States in 2012.It is inspired by this, multiple big systems global in recent years Medicine company and research unit increase the R＆D intensity of Antituberculous new drug, and it is several with different role mechanism to disclose report Treating tuberculosis candidate compound.These candidate compounds are at present or in clinical experimental stage or in the preclinical study stage.
2007, it was 4,4- dialkoxy piperidines -1- that Switzerland scientist Ma Kaluowa etc., which discloses a kind of 2- bit substituents, The synthesis of 4H- benzos [e] [1,3] thiazine -4- ketone compounds of base and anti-tubercular (2007/134625 A1 of WO).Its Representing object BTZ043 has external wide spectrum anti-tubercular (Antimicrob Agent Chemother, 2010,54 (4): 1616-1618；2012,56(7):3984-3985), but because water-soluble poor, the activity in vivo of BTZ043 can not show a candle to be expected (EMBO Mol Med, 2014,6：372–383).
2011, Switzerland scientist Ma Kaluowa etc. further disclosed the 4H- that a kind of 2- bit substituents are piperazine -1- bases The synthesis of benzo [e] [1,3] thiazine -4- ketone compounds and anti-tubercular (CN 201180055813.5).It represents object PBTZ169 equally has an external wide spectrum anti-tubercular, activity in vivo be significantly stronger than BTZ043 (EMBO Mol Med, 2014, 6：372–383).As second generation benzothiazine -4- ketone treating tuberculosis candidates, PBTZ169 enters clinical I phase research at present.
Present inventor has performed extensive research, design has synthesized the 2- benzos containing various alkaline azaspiro segments Thiazine ketone compounds, and determine their anti-tubercular.It finally found that, 2- bit substituents of the invention are to contain alkalinity 6- trifluoromethyls -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone compounds of azaspiro segment have unexpected Strong anti-tubercular, with similar benzothiazine -4- ketone candidate compound PBTZ169 and a line anti-tubercular drug isoniazid and Rifampin is compared, and has more superior anti-tubercular.
Invention content
The 6- fluoroforms containing alkaline azaspiro segment that the object of the present invention is to provide one kind to be indicated by leading to formula (I) Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone compounds,
Wherein：
N1, n2 represent 0 or 1, and wherein n1 and n2 are identical or different；
W is saturated or unsaturated, halogenated or not halogenated straight chain, branch or cricoid fat with 3-10 carbon atom Fat base, wherein 1-2 optional methine is replaced by O or S；
Or W represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl Or thienyl, and optionally, the hydrogen atom of any position of these groups can be replaced by R group；
The R group is selected from：Alkyl with 1-4 carbon atom, the alkoxy with 1-3 carbon atom, halogen ,- CF3、-OCF3、-NO2Or-CN.
Preferably, compound shown in formula (I) of the present invention, wherein：
Wherein：N1, n2 simultaneously for 1 or n1 be 0, n2 1, n1 1, n2 0 or n1, n2 simultaneously be 0；
W represents phenyl, pyridyl group, pyrimidine radicals and optionally, and the hydrogen atom of any position of these groups can be by R Group replaces；The R group is selected from：Methyl, ethyl, propyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine ,-CF3、-OCF3、-NO2 Or-CN.
It is furthermore preferred that compound shown in formula (I) of the present invention, wherein：N1, n2 represent for 1, W simultaneously：4- benzyl ethyls Base, 4- methoxybenzyls, 4- nitrobenzyls, 4- luorobenzyls, 4- methoxy-benzyls, 4- chlorobenzyls, 4- bromobenzyls, 4- trifluoromethyl benzyls Base, 4- trifluoro-methoxybenzyls, 4- cyanobenzyls, 4- nitrobenzyls, 3- luorobenzyls, 3- chlorobenzyls, 3- bromobenzyls, 3- fluoroforms Base benzyl, 3- trifluoro-methoxybenzyls, 3- cyanobenzyls, pyridine -2- ylmethyls, pyridin-3-yl methyl, pyridin-4-yl methyl, Pyrimidine -2-base methyl, 3,5- difluorobenzyls, 2,4- difluorobenzyls, 3,4- difluorobenzyls, 2,6- difluorobenzyls, 2,4- benzyl dichlorides The fluoro- 3- chlorobenzyls of base, 3,4- dichloro benzyls, 2-, the fluoro- 4- chlorobenzyls of 2-, the fluoro- 4- bromobenzyls of 2-, the fluoro- 4- chlorobenzyls of 3-, 2- are chloro- The bromo- 4- luorobenzyls of 4- luorobenzyls, 2-, the chloro- 4- luorobenzyls of 3-, the chloro- 3- trifluoromethyl benzyls of 4-, the fluoro- 4- trifluoromethyl benzyls of 3-, The bromo- 4- trifluoromethyl benzyls of 3-, the fluoro- 4- cyanobenzyls of 3-, the bromo- 4- nitrobenzyls of 3-, the fluoro- 5- methylbenzyls of 2-.
Most preferably, compound shown in formula (I) of the present invention, wherein：N1, n2 represent for 1, W simultaneously：4- bromobenzyls The fluoro- 4- of the chloro- 4- luorobenzyls of base, 4- trifluoromethyl benzyls, 3- chlorobenzyls, 3,5- difluorobenzyls, 3,4- dichloro benzyls, 3-, 3- tri- Methyl fluoride benzyl.
The specific compound of the present invention is：
2- [7- (4- Ethylbenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [7- (4- methoxybenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [7- (4- nitrobenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [7- (4- cyclohexyl methyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [8- (4- luorobenzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [8- (4- methoxy-benzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (4- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (4- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (4- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (4- nitrobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (3- luorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (3- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (3- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (3- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (pyridine -2- ylmethyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (pyridin-3-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (pyridin-4-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (pyrimidine -2-base methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3,5- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (2,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (2,6- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (2,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 3- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- bromobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- chlorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 4- luorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 3- trifluoromethyl benzyls of 4-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- cyanobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- nitrobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 5- methylbenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone.
The present invention further provides the preparation methods of we's formula (I) compound, include the following steps：
By formula (II) compound and formula (III) compound, in the presence of protonic solvent and be added acid binding agent, -5 DEG C~ It 60 DEG C, is stirred to react 0.5~10 hour, obtains formula (I) compound,
Wherein：
The definition of n1, n2 and W are the same as claim 1.
The protonic solvent is selected from water, alcohol or alcohol-water mixed solvent；The acid binding agent is selected from triethylamine, carbonic acid Sodium, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Preferably, preparation method of the invention, includes the following steps：
By formula (II) compound and formula (III) compound, in the presence of protonic solvent and acid binding agent is added, use is excessive Formula (III) compound meets needs, at -5 DEG C~60 DEG C, with or without being stirred to react under pressure condition 0.5~10 hour, obtains formula (I) compound.
Formula (II) compound for being used as starting material in the present invention is known compound, and with reference to known in existing publication Method can easily be made, such as CN 201180055813.5.
According to method shown in following reaction routes 2, formula (III) compound of another starting material of the present invention can be prepared.
Reaction route 2：
In reaction route 2, n1, n2 and W are defined as the aforementioned.
Acid binding agent is added in non-protonic solvent, makes formula (IV) compound that condensation reaction, institute occur with formula (V) compound The intermediate of generation directly sloughs protecting group to get to formula (III) compound without separation with trifluoroacetic acid.For this reaction Non-protonic solvent be selected from acetonitrile, acetone, dichloromethane, chloroform, ether or hexamethylene；The acid binding agent is selected from carbonic acid Sodium, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or triethylamine.
Formula (IV) compound and formula (V) compound as starting material are known compound, and there is supply of commodities in the country.
The present invention also provides contain treating tuberculosis composition of formula as defined above (I) compound as active constituent.Medicine The weight ratio of the compounds of this invention that compositions contain in the composition is 0.1~99.9%, and pharmaceutically acceptable carrier exists Weight ratio in composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.The drug of the present invention Composition can be prepared into any pharmaceutical dosage form.Preferably, medicinal preparation be tablet, sugar coated tablet, film coated tablet, Enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, Duracaps, powder.
The pharmaceutical composition of the present invention, as dosage form, the effective quantity of the compounds of this invention contained in every dose is 0.1 ~1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking agent Amount, such as each taking 100mg.
The pharmaceutical composition of the present invention is in the solid for being prepared into pulvis, tablet, dispersible pulvis, capsule, cachet form When pharmaceutical preparation, solid carrier can be used.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubrication One or more substances in agent, suspending agent, adhesive, swelling agent etc., or can be encapsulating substance.Suitable solid carrier includes Magnesium carbonate, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, carboxymethyl cellulose Sodium, cocoa butter etc..Since they are easy to be administered, tablet, pulvis, cachet and capsule etc. represent best oral administration solid system Agent.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous. The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control The active constituent for the predetermined amount of therapeutic effect calculated.This dosage unit form can be packaged form, such as tablet, capsule or dress Pulvis in tubule or bottle.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent Effect is adjusted within the scope of 1~800mg.
When formula (I) reactive compound of the present invention is used as the drug for the treatment of mycobacterium tuberculosis infection, preferably first Stage gives the amount of 6~14mg/kg weight.But dosage can be with sick human needs, the seriousness of the infection to be treated, institute It selects compound etc. and changes.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active constituent.It rises for convenience See, total daily dose can be divided into several parts, score time administration.
The present invention also provides compounds shown in formula (I) or the pharmaceutical composition containing the compound to prepare treatment tuberculosis Drug in application.
Tuberculosis of the present invention includes active tuberculosis, single resistant tuberculosis, more resistant tuberculosis and resistance to extensively Multiple medicine tuberculosis.
Tuberculosis of the present invention includes pulmonary tuberculosis, the outer tuberculosis of lung.
As described above, the compounds of this invention is candidate higher than similar benzothiazine -4- ketones to the activity of mycobacterium tuberculosis Compound PBTZ169 and a line anti-tubercular drug isoniazid and rifampin.For example, embodiment 8,9,14,23,28,35 and 37 is changed 2-7 times or more that object is compound PBTZ169 to the external activity of mycobacterium tuberculosis type strain H37Rv ATCC 27294 is closed, External activity to clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant) is the 2-3 of compound PBTZ169 Times or more.
The compound of the present invention is for existing product, the better efficacy in terms for the treatment of tuberculosis, active higher, side effect Lower, building-up process operation is also simpler, effectively reduces cost, and is suitble to large-scale production.
Specific implementation mode
In the examples below, the present invention will be more specifically explained.It should be understood that the following example is intended to illustrate hair It is bright without to the scope of the present invention constitute any restrictions.
1. 2- of embodiment [7- (4- Ethylbenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
At room temperature, to the acetonitrile of 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters (200mg, 0.88mmol) 4- ethyls bromobenzyl (199mg, 1mmol) and potassium carbonate (276mg, 2mmol) are added in (15mL) solution, is stirred at room temperature 2 hours.To Distilled water (30mL) is added in reaction solution, ethyl acetate extracts (20mL × 3).It is associated with several layers of, anhydrous magnesium sulfate drying, it is dense Contracting, through silica gel column chromatography (DCM:MeOH:NH3H2O=200:10:0.2) pale yellow oil (260mg) is obtained.
At room temperature, the above grease (260mg) is dissolved in anhydrous methylene chloride (10mL), stirs lower dropwise addition trifluoroacetic acid (3mL), equality of temperature stir 1 hour, are concentrated to give yellow oil.
2- methyl mercapto -6- trifluoromethyl -8- nitros-are added into absolute ethyl alcohol (10mL) solution of above-mentioned yellow oil Benzothiazine -4- ketone (257mg, 0.8mmol), triethylamine (333 μ L, 2.4mmol), 40 DEG C are stirred 3 hours, concentration, silicagel column It isolates and purifies, obtains target compound.
1H NMR(400MHz,CDCl3) δ 9.20 (s, 1H), 8.82 (s, 1H), 7.24 (d, J=8Hz, 2H), 7.08 (d, J =8.0Hz, 2H), 4.18 (brs, 2H), 4.10 (brs, 2H), 3.66 (s, 2H), 3.38 (brs, 4H), 2.72 (q, J= 8.1Hz, 2H), 1.88 (brs, 4H), 1.18 (t, J=8.1Hz, 3H).
ESI-MS(m/z):519.1(M+H)+。
2. 2- of embodiment [7- (4- methoxybenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the 4- ethyl bromobenzyls in embodiment 1 to get targeted with 4- methoxyl group bromobenzyls Close object.
1H NMR(400MHz,CDCl3) δ 9.18 (s, 1H), 8.78 (s, 1H), 7.12 (d, J=8Hz, 2H), 6.89 (d, J =8.0Hz, 2H), 4.18 (brs, 2H), 4.10 (brs, 2H), 3.81 (s, 3H), 3.66 (s, 2H), 3.38 (brs, 4H), 1.88 (brs,4H)。
ESI-MS(m/z):521.1(M+H)+。
3. 2- of embodiment [7- (4- nitrobenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the 4- ethyls bromobenzyl in embodiment 1 to get target chemical combination with 4- nitro bromobenzyls Object.
1H NMR(400MHz,CDCl3) δ 9.19 (s, 1H), 8.75 (s, 1H), 8.32 (d, J=8Hz, 2H), 7.95 (d, J =8.0Hz, 2H), 4.18 (brs, 2H), 4.10 (brs, 2H), 3.65 (s, 2H), 3.39 (brs, 4H), 1.88 (brs, 4H).
ESI-MS(m/z):536.1(M+H)+。
4. 2- of embodiment [7- (4- cyclohexyl methyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, replaces the 4- ethyl bromobenzyls in embodiment 1 to get target with (bromomethyl) hexamethylene Compound.
1H NMR(400MHz,CDCl3) δ 9.14 (d, J=1.5Hz, 1H), 8.78 (d, J=1.5Hz, 1H)), 4.18 (brs,2H),4.10(brs,2H),3.39(brs,4H),2.09-2.06(m,2H),1.88(brs,4H),1.65-1.30(m, 11H)。
ESI-MS(m/z):497.1(M+H)+。
5. 2- of embodiment [8- (4- luorobenzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, is distinguished with 2,8- diaza spiros [4,5] certain herbaceous plants with big flowers alkane -2- carboxylic acid tert-butyl esters and 4- fluorine bromobenzyls Instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target compound.
1H NMR(400MHz,CDCl3) δ 9.21 (s, 1H), 8.82 (s, 1H), 7.38 (d, J=8.2Hz, 2H), 7.07 (d, J=8.2Hz, 2H), 4.04 (t, J=17.8Hz, 1H), 3.87 (s, 1H), 3.83 (t, J=17.8Hz, 1H), 3.69-3.63 (m, 1H), 3.57 (m, 1H), 3.53-3.51 (m, 2H), 3.35-3.32 (m, 1H), 2.10 (t, J=17.7Hz, 1H), 2.00 (t, J=17.9Hz, 1H), 1.70-1.60 (m, 4H).
ESI-MS(m/z):523.1(M+H)+。
6. 2- of embodiment [8- (4- methoxy-benzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 2,8- diaza spiros [4,5] certain herbaceous plants with big flowers alkane -2- carboxylic acid tert-butyl esters and 4- methoxyl group bromobenzyls Respectively instead of 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl ester 4- ethyls bromobenzyls in embodiment 1 to get target chemical combination Object.
1H NMR(400MHz,CDCl3) δ 9.21 (s, 1H), 8.82 (s, 1H), 7.12 (d, J=8.2Hz, 2H), 6.89 (d, J=8.2Hz, 2H), 4.04 (t, J=17.8Hz, 1H), 3.87 (s, 1H), 3.83 (t, J=17.8Hz, 1H), 3.69-3.63 (m, 1H), 3.57 (m, 1H), 3.53-3.51 (m, 2H), 3.35-3.32 (m, 1H), 2.10 (t, J=17.7Hz, 1H), 2.00 (t, J=17.9Hz, 1H), 1.70-1.60 (m, 4H).
ESI-MS(m/z):535.1(M+H)+。
7. 2- of embodiment [9- (4- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- chlorine bromobenzyls point Not instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyls bromobenzyl to get target chemical combination Object.
1H NMR(400MHz,CDCl3) δ 9.21 (s, 1H), 8.82 (s, 1H), 7.39 (d, J=8.2Hz, 2H), 7.32 (d, J=8.2Hz, 2H), 4.04 (t, J=17.8Hz, 1H), 3.87 (s, 1H), 3.83 (t, J=17.8Hz, 1H), 3.69-3.63 (m, 1H), 3.57 (m, 1H), 3.53-3.51 (m, 2H), 3.35-3.32 (m, 1H), 2.10 (t, J=17.7Hz, 1H), 2.00 (t, J=17.9Hz, 1H), 1.70-1.60 (m, 4H).
ESI-MS(m/z):539.1(M+H)+。
8. 2- of embodiment [9- (4- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- bromine bromobenzyls point Not instead of 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls in embodiment 1, light yellow solid is obtained, mp:142-144℃。
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 7.48 (d, J=8.4Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 4.00 (brs, 4H), 3.54 (s, 2H), 2.48 (brs, 4H), 1.66 (brs, 8H)13C NMR(400MHz, CDCl3) δ 166.52,161.73,143.92,134.23,133.36,133.34,131.43,130.84,129.60 (q, J= 34.6Hz), 126.75,125.98,125.96,122.30 (q, J=272Hz), 62.42,48.88,35.1635.16,30.19.
HRMS-ESI(m/z):Calcd.for C25H25N4O3F3SBr(M+H)+:597.0777；Found:597.0773.
9. 2- of embodiment [9- (4- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- trifluoromethyls Bromobenzyl replaces 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters in embodiment 1 and 4- ethyl bromobenzyls respectively, obtains pale yellow Color solid, mp:170-172℃.
1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.79(s,1H),7.64-7.62(m,2H),7.51(m,2H), 4.14(brs,2H),3.86(brs,2H),3.63(brs,2H),2.50(brs,4H),1.68(brs,8H).13C NMR (400MHz,CDCl3)δ166.55,161.77,143.94,134.24,133.40,129.82,129.47,129.28, (126.76,126.02,125.29,122.50 q, J=272.1Hz), 62.61,49.03,43.01,35.29,30.19.
HRMS-ESI(m/z):Calcd.for C26H25N4O3F6S(M+H)+:587.1546；Found:587.1541.
10. 2- of embodiment [9- (4- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- three Methyl fluoride -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- trifluoro methoxies Bromide benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyls bromobenzyl to get Target compound.
1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.79(s,1H),7.12(m,2H),6.89(m,2H),4.14 (brs,2H),3.86(brs,2H),3.63(brs,2H),2.50(brs,4H),1.68(brs,8H)。
ESI-MS(m/z):603.1(M+H)+。
11. 2- of embodiment [9- (4- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- cyano-benzyl bromides Instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target compound.
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 7.76 (d, J=7.8Hz, 2H), 7.46 (d, J=7.8Hz, 2H), 4.14 (brs, 2H), 3.86 (brs, 2H), 3.63 (brs, 2H), 2.50 (brs, 4H), 1.68 (brs, 8H)。
ESI-MS(m/z):544.1(M+H)+。
12. 2- of embodiment [9- (4- nitrobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 4- nitro bromobenzyls Respectively instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get targeted Close object.
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 8.32 (d, J=7.8Hz, 2H), 7.95 (d, J=7.8Hz, 2H), 4.14 (brs, 2H), 3.86 (brs, 2H), 3.63 (brs, 2H), 2.50 (brs, 4H), 1.68 (brs, 8H)。
ESI-MS(m/z):564.1(M+H)+。
13. 2- of embodiment [9- (3- luorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- fluorine bromobenzyls point Not instead of 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls in embodiment 1, light yellow solid is obtained, mp:122-124℃。
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.33-7.27(m,2H),7.13-7.07 (m,1H),6.99-6.94(m,1H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64 (brs,8H).13C NMR(400MHz,CD3OD) δ 167.42,162.86 (d, J=243Hz), 162.60,144.46,140.11, (134.70,131.63,130.85,129.59,128.60 d, J=35.4Hz), 125.99,124.99,122.50 (q, J= 272.1Hz), 115.60 (d, J=21.5Hz), 113.60 (d, J=21.4Hz), 62.05,48.51,41.97,34.45, 29.79。
HRMS-ESI(m/z):Calcd.for C25H25N4O3F4S(M+H)+:537.1578；Found:537.1592.
14. 2- of embodiment [9- (3- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- chlorine bromobenzyls point Not instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyls bromobenzyl to get target chemical combination Object.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.43-7.41(m,1H),7.35-7.29 (m,2H),7.10-7.00(m,1H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):553.1(M+H)+。
15. 2- of embodiment [9- (3- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls -8- Nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- bromine bromobenzyls point Not instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyls bromobenzyl to get target chemical combination Object.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.54-7.41(m,2H),7.35-7.20 (m,2H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):597.1,599.1 (M+H)+。
16. 2- of embodiment [9- (3- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoros Methyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- trifluoromethyls Bromobenzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.56-7.41(m,3H),7.35-7.20 (m,1H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):587.1(M+H)+。
17. 2- of embodiment [9- (3- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- three Methyl fluoride -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- trifluoro methoxies Bromide benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyls bromobenzyl to get Target compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.25-7.20(m,1H),7.00-6.80 (m,3H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):603.1(M+H)+。
18. 2- of embodiment [9- (3- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyls - 8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3- cyano-benzyl bromides Respectively instead of in embodiment 12,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get targeted Close object.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.31(s,1H),7.89-7.60(m,2H),7.50-7.43 (m,1H),7.00-6.80(m,1H),4.07(brs,2H),3.86(brs,2H),3.56(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):544.1(M+H)+。
19. 2- of embodiment [9- (pyridine -2- ylmethyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and (2- bromomethyls) Pyridine respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.51-8.45(m,1H),8.31(s,1H),7.89-7.60 (m,1H),7.31-7.24(m,2H),4.07(brs,2H),3.96(s,2H),3.86(brs,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):520.1(M+H)+。
20. 2- of embodiment [9- (pyridin-3-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and (3- bromomethyls) Pyridine respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),8.59-8.50(m,1H),8.37-8.33(m,1H),8.31 (s,1H),7.89-7.60(m,1H),7.37-7.30(m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H), 2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):520.1(M+H)+。
21. 2- of embodiment [9- (pyridin-4-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and (4- bromomethyls) Pyridine respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD) δ 8.91 (s, 1H), 8.59 (d, J=9.0Hz, 2H), 8.31 (s, 1H), 7.37 (d, J=9.0Hz, 1H), 4.15 (s, 2H), 4.07 (brs, 2H), 3.86 (brs, 2H), 2.49 (brs, 4H), 1.64 (brs, 8H).
ESI-MS(m/z):520.1(M+H)+。
22. 2- of embodiment [9- (pyrimidine -2-base methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, phonetic with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 2- bromomethyls Pyridine respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 8.70 (d, J=8.1Hz, 2H), 7.39- 7.34(m,1H),4.14(brs,2H),3.86(brs,2H),3.63(brs,2H),2.50(brs,4H),1.68(brs,8H)。
ESI-MS(m/z):521.1(M+H)+。
23. 2- of embodiment [9- (3,5- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3,5- difluoro bromines Benzyl replaces 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters in embodiment 1 and 4- ethyl bromobenzyls respectively, obtains light yellow Solid, mp:178-180℃.
1H NMR(500MHz,CDCl3) δ 9.07 (s, 1H), 8.72 (s, 1H), 6.85 (dd, J=9.1Hz, J=2.1Hz, 2H), 6.66 (tt, J=9.1Hz, J=2.3Hz, 1H), 4.07 (brs, 2H), 3.80 (brs, 2H), 3.48 (s, 2H), 2.43 (brs,4H),1.61(brs,8H).13C NMR(500MHz,CDCl3) δ 166.48,162.97 (dd, J=272.1Hz, J= 12.6Hz), 143.92,142.82,134.26,133.29,129.60 (d, J=35.5Hz), 126.76,125.93,111.30 (d, J=18.3Hz), 102.40 (t, J=25.6Hz), 62.29,48.98,35.34,30.17,29.69.
MS-ESI(m/z):555.6[M+H]+；HRMS-ESI(m/z):Calcd.for C25H24N4O3F5S(M+H)+: 555.1483；Found:555.1474.
24. 2- of embodiment [9- (2,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 2,4- difluoro bromines Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.24-7.20(m,1H),6.96-6.86 (m,1H),6.80-6.75(m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):555.1(M+H)+。
25. 2- of embodiment [9- (3,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3,4- difluoro bromines Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.24-7.00(m,3H),4.07(brs, 2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):555.1(M+H)+。
26. 2- of embodiment [9- (2,6- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 2,6- difluoro bromines Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD) δ 8.91 (s, 1H)), 8.31 (s, 1H), 7.74 (t, J=9Hz, 1H), 7.40- 7.30(m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):555.1(M+H)+。
27. 2- of embodiment [9- (2,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 2,4- dichloro bromines Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.75-7.70(m,1H),7.26-7.16 (m,1H),7.10-7.00(m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):587.1(M+H)+。
28. 2- of embodiment [9- (3,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and 3,4- dichloro bromines Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.65-7.60(m,1H),7.40-7.26 (m,1H),7.25-7.15(m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):587.1(M+H)+。
29. 2- of embodiment [9- (the fluoro- 3- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 3- chlorine bromines of 2- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.40-7.30(m,1H),7.15-7.10 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):571.1(M+H)+。
30. 2- of embodiment [9- (the fluoro- 4- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 4- chlorine bromines of 2- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.81-7.75(m,1H),7.25-7.10 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):571.1(M+H)+。
31. 2- of embodiment [9- (the fluoro- 4- bromobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 4- bromines bromines of 2- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.60-7.50(m,1H),7.40-7.30 (m,1H),7.20-7.15(m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64 (brs,8H)。
ESI-MS(m/z):615.1,617.1 (M+H)+。
32. 2- of embodiment [9- (the fluoro- 4- chlorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 4- chlorine bromines of 3- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.40-7.30(m,1H),7.15-6.90 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):571.1(M+H)+。
33. 2- of embodiment [9- (the chloro- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the chloro- 4- fluorine bromines of 2- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.81-7.60(m,1H),7.20-7.07 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):571.1(M+H)+。
34. 2- of embodiment [9- (the bromo- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the bromo- 4- fluorine bromines of 2- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.41-7.30(m,1H),7.15-7.07 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):615.1(M+H)+。
35. 2- of embodiment [9- (the chloro- 4- luorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- fluoroforms Base -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the chloro- 4- fluorine bromines of 3- Benzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get target Compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.71-7.60(m,1H),7.20-7.01 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):571.1(M+H)+。
36. 2- of embodiment [9- (the chloro- 3- trifluoromethyl benzyls of 4-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- Trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the chloro- 3- trifluoros of 4- Methyl bromobenzyl replaces 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters in embodiment 1 and 4- ethyl bromobenzyls respectively, i.e., Obtain target compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.44-7.32(m,3H),4.07(brs, 2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):621.1(M+H)+。
37. 2- of embodiment [9- (the fluoro- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- Trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 4- trifluoros of 3- Methyl bromobenzyl replaces 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters in embodiment 1 and 4- ethyl bromobenzyls respectively, i.e., Obtain target compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.48-7.40(m,1H),7.05-6.92 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):605.1(M+H)+。
38. 2- of embodiment [9- (the bromo- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- Trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the bromo- 4- trifluoros of 3- Methyl bromobenzyl replaces 2,7- diaza spiros [3, the 5] nonane -2- carboxylic acid tert-butyl esters in embodiment 1 and 4- ethyl bromobenzyls respectively, i.e., Obtain target compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.39-7.30(m,2H),7.15-7.10 (m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):665.1,667.1(M+H)+。
39. 2- of embodiment [9- (the fluoro- 4- cyanobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoros Methyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 4- cyano of 3- Bromobenzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),7.61-7.40(m,1H),7.23-7.10 (m,2H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):562.1(M+H)+。
40. 2- of embodiment [9- (the bromo- 4- nitrobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoros Methyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the bromo- 4- nitros of 3- Bromobenzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(400MHz,CD3OD)δ8.91(s,1H),),8.31(s,1H),8.09-7.89(m,2H),7.73-7.60 (m,1H),4.07(brs,2H),3.86(brs,2H),3.76(s,2H),2.49(brs,4H),1.64(brs,8H)。
ESI-MS(m/z):642.1(M+H)+。
41. 2- of embodiment [9- (the fluoro- 5- methylbenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoros Methyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone
The preparation method is the same as that of Example 1, with 3,9- diaza spiros [5,5] hendecane -3- carboxylic acid tert-butyl esters and the fluoro- 5- methyl of 2- Bromobenzyl respectively replace embodiment 1 in 2,7- diaza spiros [3,5] nonane -2- carboxylic acid tert-butyl esters and 4- ethyl bromobenzyls to get mesh Mark compound.
1H NMR(500MHz,CDCl3) δ 9.14 (s, 1H), 8.79 (s, 1H), 7.21 (d, J=8.1Hz, 1H), 6.89- 6.80(m,2H),4.14(brs,2H),3.86(brs,2H),3.63(brs,2H),2.50(brs,4H),2.36(s,3H)1.68 (brs,8H)。
ESI-MS(m/z):551.1(M+H)+。
Biological Examples 1
External anti-mycobacteria activity test
The anti-tubercular of the compounds of this invention is by measuring it to mycobacterium tuberculosis type strain MTB H37Rv Minimal inhibitory concentration (MIC, the μ of ATCC 27294 and clinical separation strain MDR-MTB 20161 (to rifampin and Isoniazid-resistant) G/mL it) indicates.In this experiment, with similar benzothiazine -4- ketone candidate compound PBTZ169 and a line treating tuberculosis Drug isoniazid and rifampin compare medicine.Minimal inhibitory concentration measures as follows：Sterile 48 orifice plate (tulase quick medicine-sensitive Special microtest plate), by drug sensitive test design requirement, each hole is separately added into 2 times of concentration cultures (improvement Michaelis 7H9 liquid Body culture medium) diluted drug.The first solution of debita spissitudo is made in each compound, is diluted to culture medium (2 ×) each used 48 orifice plates are added per 100 μ L of hole in two times of concentration of compound, each 10 gradients of each compound, and the final concentration of investigational agent is distinguished For 8,4,2 ... 0.015 μ g/mL.Type strain H37Rv ATCC 27294 and clinical separation strain MDR-MTB20161 are inoculated with per hole 100 μ l are 4 × 10 per hole bacterium amount-3mg.Per plate be all provided with 2 without antimicrobial growth Positive control wells and two with distilled water The growth negative control hole of substitutive medium, surrounding is sealed with adhesive tape after 48 orifice plates are capped, and is placed in 37 DEG C of incubations of wet box. Growth positive control wells and negative growth control wells are observed after 3rd day, when observing that the two has clear difference, to each test hole The quantity and form of bacterial growth are observed, judgement inhibit or drug resistance and record as a result, observed and recorded again after the 7th day once into Row confirms.The concentration of contained drug minimum is minimal inhibitory concentration (MIC) in the control wells of asepsis growth.Measurement result is listed in Table 1.
The external activity of 12 plants of mycobacterium tuberculosis of section Example compound pair of table
MTBa:MTB H37Rv ATCC 27294
MDR-MTBb：MDR-MTB 20161 (to rifampin and Isoniazid-resistant)
The external activity of part of compounds of the present invention is only enumerated in above-mentioned table, other compound structures of the invention are similar, It is numerous to list herein with the external activity effect same or similar with above compound.
Biological Examples 2
Oral Acute Toxicity is tested
To measure the Oral Acute Toxicity of the compounds of this invention, 8 compound of embodiment and 9 compound of embodiment are carried out The solution of the two compounds containing various concentration is taken orally and awards male mice, dosage 0.1ml/10g by acute toxicity testing Weight, count dead mouse amount respectively after 7 days, and the median lethal dose (LD of each compound is calculated with Bliss programs50).As a result it is listed in table 2 In.
The Mouse oral acute toxicity of table 2 embodiment 8 and 9 compounds
Experimental compound LD50(mg/kg)
Embodiment 8 >2000
Embodiment 9 >2000
The experimental results showed that these toxicity of compound are very low, it is very suitable for medicinal.
Composition embodiment
1 coating tablet of embodiment
Core formulation：
Mentioned component is taken to be uniformly mixed, 100 labels are made in whole grain of being sieved after granulation, dry, tabletting.
Coating fluid prescription：Opadry (Opadry) 5g, the coating of 80% appropriate amount of ethanol.
2 capsule of embodiment
Prescription：
Preparation method：
Recipe quantity supplementary material is taken, is sieved respectively, 5% polyvinylpyrrolidone alcohol liquid and Tween 80 softwood is added, with 20 Mesh sieve granulation, dries at 15 DEG C of room temperature, lauryl sodium sulfate is added, be uniformly mixed, and No. 0 glue soluble in the stomach is packed by 0.27g/S Capsule, sample examination, dissolution limit are Q=80%, and content should be the 90~110% of labelled amount.
3 granule of embodiment
The compound 100g of Example 28, is added appropriate dextrin, Steviosin, dry granulation, whole grain, packing to get.
4 injection of embodiment
The compound 150g of Example 35 is dissolved in water, and another sodium chloride, ethyl-para-hydroxybenzoate heat water dissolution, mix It is even, adjust pH value 5-7.Water for injection is diluted to 1000ml, is filtered with hollow-fibre membrane, filling, sterilizing to get.
5 freeze-dried powder of embodiment
The compound 150g of Example 37 is dissolved in water, and separately plus mannitol 500g heats water dissolution, mixing, water for injection It is diluted to 5000ml, is filtered with hollow-fibre membrane, filling, sterilizing is lyophilized up to freeze-dried powder.
6 dripping pill of embodiment
The compound 20g of Example 40 is spare as bulk pharmaceutical chemicals；Dripping pill matrix 200g is weighed, 80 DEG C of thawings are heated to, It stirs evenly；It adds raw materials into excipient matrix while stirring, stirring 30min is allowed to uniform, and fluid temperature is kept to be not less than 60 ℃；Prepared liquid is injected in pill dripping machine, is dripped into dripping pill, you can.
Although above the present invention is described in detail with a general description of the specific embodiments, On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.

Claims (10)

1. compound shown in formula (I),
Wherein：
N1, n2 represent 0 or 1, and wherein n1 and n2 are identical or different；
W is saturated or unsaturated, halogenated or not halogenated straight chain, branch or cricoid fat with 3-10 carbon atom Base, wherein 1-2 optional methine is replaced by O or S；
Or W represents phenyl, pyridyl group, naphthalene, quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thiophene Pheno base, and optionally, the hydrogen atom of any position of these groups can be replaced by R group；
The R group is selected from：Alkyl with 1-4 carbon atom, the alkoxy with 1-3 carbon atom, halogen ,-CF3、- OCF3、-NO2Or-CN.
2. compound shown in formula (I) according to claim 1, which is characterized in that
Wherein：N1, n2 simultaneously for 1 or n1 be 0, n2 1, n1 1, n2 0 or n1, n2 simultaneously be 0；
W represents phenyl, pyridyl group, pyrimidine radicals and optionally, and the hydrogen atom of any position of these groups can be by R group Substitution；The R group is selected from：Methyl, ethyl, propyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine ,-CF3、-OCF3、-NO2Or-CN.
3. compound shown in formula (I) according to claim 2, which is characterized in that wherein：N1, n2 represent for 1, W simultaneously： 4- Ethylbenzyls, 4- methoxybenzyls, 4- nitrobenzyls, 4- luorobenzyls, 4- methoxy-benzyls, 4- chlorobenzyls, 4- bromobenzyls, 4- tri- Methyl fluoride benzyl, 4- trifluoro-methoxybenzyls, 4- cyanobenzyls, 4- nitrobenzyls, 3- luorobenzyls, 3- chlorobenzyls, 3- bromobenzyls, 3- trifluoromethyl benzyls, 3- trifluoro-methoxybenzyls, 3- cyanobenzyls, pyridine -2- ylmethyls, pyridin-3-yl methyl, pyridine - 4- ylmethyls, pyrimidine -2-base methyl, 3,5- difluorobenzyls, 2,4- difluorobenzyls, 3,4- difluorobenzyls, 2,6- difluorobenzyls, 2, The fluoro- 3- chlorobenzyls of 4- dichloro benzyls, 3,4- dichloro benzyls, 2-, the fluoro- 4- chlorobenzyls of 2-, the fluoro- 4- bromobenzyls of 2-, the fluoro- 4- benzyl chlorides of 3- The chloro- 4- luorobenzyls of base, 2-, the bromo- 4- luorobenzyls of 2-, the chloro- 4- luorobenzyls of 3-, the chloro- 3- trifluoromethyl benzyls of 4-, the fluoro- 4- trifluoros of 3- The bromo- 4- trifluoromethyl benzyls of methylbenzyl, 3-, the fluoro- 4- cyanobenzyls of 3-, the bromo- 4- nitrobenzyls of 3-, the fluoro- 5- methylbenzyls of 2-.
4. compound shown in formula (I) according to claim 3, which is characterized in that wherein, W is represented：4- bromobenzyls, 4- tri- The chloro- 4- luorobenzyls of methyl fluoride benzyl, 3- chlorobenzyls, 3,5- difluorobenzyls, 3,4- dichloro benzyls, 3-, the fluoro- 4- trifluoromethyls benzyls of 3- Base.
5. compound shown in formula (I) according to claim 1, which is characterized in that be selected from following compound：
2- [7- (4- Ethylbenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [7- (4- methoxybenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [7- (4- nitrobenzyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [7- (4- cyclohexyl methyls) -2,7- diaza spiros [3.5] nonane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [8- (4- luorobenzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [8- (4- methoxy-benzyls) -2,8- diaza spiros [4.5] decane -2- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (4- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (4- nitrobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- luorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- chlorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- bromobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- trifluoromethyl benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (3- trifluoro-methoxybenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (3- cyanobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (pyridine -2- ylmethyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (pyridin-3-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (pyridin-4-yl methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (pyrimidine -2-base methyl) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (3,5- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (2,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (3,4- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (2,6- difluorobenzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (2,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (3,4- dichloro benzyls) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 3- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- chlorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- bromobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- chlorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- luorobenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 4- luorobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；
2- [9- (the chloro- 3- trifluoromethyl benzyls of 4-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- trifluoromethyl benzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitre Base -4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 4- cyanobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the bromo- 4- nitrobenzyls of 3-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；
2- [9- (the fluoro- 5- methylbenzyls of 2-) -3,9- diaza spiros [5.5] hendecane -3- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone.
6. the preparation method of formula (I) compound described in a kind of claim 1, which is characterized in that include the following steps：
By formula (II) compound and formula (III) compound, in the presence of protonic solvent and acid binding agent is added, -5 DEG C~60 DEG C, it is stirred to react 0.5~10 hour, obtains formula (I) compound,
Wherein：
The definition of n1, n2 and W are the same as claim 1.
7. the preparation method of formula (I) compound according to claim 6, which is characterized in that the protonic solvent is selected from Water, alcohol or alcohol-water mixed solvent；The acid binding agent be selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or Potassium hydroxide.
8. compound described in claim 1 is preparing the application in treating tuberculosis.
9. application according to claim 8, which is characterized in that the tuberculosis includes pulmonary tuberculosis, the outer tuberculosis of lung, activity Tuberculosis, single resistant tuberculosis, more resistant tuberculosis and extensive multi-drug resistance tuberculosis.
10. the pharmaceutical composition containing compound described in claim 1.
CN201710121414.3A 2017-03-02 2017-03-02 Benzothiazine -4- ketone compounds containing alkaline azaspiro segment and preparation method thereof Pending CN108530448A (en)

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