CN108484601A - Benzothiazine -4- ketone compounds and preparation method thereof containing 2,8- diaza spiros [4.5] decane segment - Google Patents

Abstract

The invention relates to benzothiazine-4-ketone compounds containing 2,8-diazaspiro[4.5]decane fragments and a preparation method thereof, in particular, the invention relates to a class of 6-trifluoromethyl- 8‑nitro‑4H‑benzo[e][1,3]thiazin‑4‑ketones whose 2‑position substituent is 2,8‑diazaspiro[4.5]decane‑8‑yl , wherein: Z represents alkane (1-6 carbon atoms) oxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl; or, Z represents phenyl, pyridyl, naphthyl, quinolinyl, pyrazinyl, pyrimidinyl, pyrimidyl Azolyl, imidazolyl, furyl or thienyl, and optionally, the hydrogen atoms at any position of these groups can be replaced by R groups; R is selected from alkyl groups with 1-4 carbon atoms, with 1-4 carbon atoms Alkoxy of 3 carbon atoms, halogen, -CF ₃ , -OCF ₃ , -NO ₂ or -CN.

Description

Benzothiazin-4-ones containing 2,8-diazaspiro[4.5]decane fragments and its preparation method

technical field

The invention belongs to the field of medicinal chemistry, and relates to benzothiazin-4-one compounds containing basic 2,8-diazaspiro[4.5]decane fragments with anti-tuberculosis activity and a preparation method thereof, and a compound containing them Anti-tuberculosis pharmaceutical composition; more specifically, the present invention relates to 6-trifluoromethyl-8-nitro-4H-benzo[e][1,3]thiazin-4-one compound, its 2- The substituent is a 2,8-diazaspiro[4.5]decane fragment.

Background technique

In recent years, tuberculosis (TB), especially the rising incidence of multidrug-resistant TB (MDR-TB) and the emergence of extensively drug-resistant TB (XDR-TB), has become a major public health and social issue of global concern. According to the World Health Organization (WHO), in 2015, there were 10.4 million new cases of TB worldwide, and 1.4 million people died of TB. In addition, nearly 1/3 of the world's population carries latent Mycobacterium tuberculosis, which is a potential risk of disease. Traditional anti-TB drugs, such as streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide, can cure more than 85% of newly diagnosed pulmonary tuberculosis patients, but there is a long treatment cycle (more than 6 months). months) and is ineffective against MDR-TB, and has weak effect on latent Mycobacterium tuberculosis (MTB). Therefore, it is imminent to develop new anti-TB drugs to achieve effective treatment and control of TB (Adv Drug Deliv Rev.2016, 102,55-72).

Bedaquiline (ATP synthase inhibitor) with a new mechanism of action is the first new anti-TB drug approved by the US FDA (for the treatment of MDR-TB) in the past 40 years. Encouraged by this, in recent years, many large pharmaceutical companies and research institutes around the world have stepped up the research and development of new anti-TB drugs, and have publicly reported several anti-TB candidate compounds with different mechanisms of action. These candidate compounds are currently either in clinical trials or in preclinical studies.

In 2007, Swiss scientist Makarova disclosed a class of 4H-benzo[e][1,3]thiazine-4 whose 2-position substituent is 4,4-dialkoxypiperidin-1-yl. -Synthesis and antituberculous activity of ketones (WO 2007/134625 A1). Its representative BTZ043 has broad-spectrum anti-tuberculosis activity in vitro (Antimicrob Agent Chemother, 2010, 54(4): 1616-1618; 2012, 56(7): 3984-3985), but due to poor water solubility, the in vivo activity of BTZ043 Much worse than expected (EMBO Mol Med, 2014, 6:372–383).

In 2011, the research team further disclosed the synthesis and anti-tuberculosis activity of a class of 4H-benzo[e][1,3]thiazin-4-one compounds whose 2-position substituent is piperazin-1-yl (CN 201180055813.5). Its representative, PBTZ169, also has broad-spectrum anti-tuberculosis activity in vitro, and its in vivo activity is significantly stronger than that of BTZ043 (EMBOMol Med, 2014, 6: 372-383). As a second-generation benzothiazin-4-one anti-tuberculosis candidate, PBTZ169 is currently in phase I clinical research.

The present inventors conducted extensive research, designed and synthesized benzothiazinone compounds containing various basic azaspiro ring fragments at the 2-position, and determined their anti-tuberculosis activity. It is finally found that the 2-position substituent of the present invention is 2,8-diazaspiro[4.5]decane-8-yl 6-trifluoromethyl-8-nitro-4H-benzo[e][1 ,3] Thiazin-4-ones have unexpectedly strong anti-tuberculosis activity, compared with the same kind of benzothiazin-4-one candidate compound PBTZ169 and the first-line anti-tuberculosis drugs isoniazid and rifampicin. More superior anti-tuberculosis activity.

Contents of the invention

The object of the present invention is to provide a class of 6-trifluoromethyl-8-nitro-4H-benzo[e] containing 2,8-diazaspiro[4.5]decane fragments represented by general formula ][1,3]thiazin-4-ones,

in:

Z represents alkane (1-6 carbon atoms) oxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl; or, Z represents phenyl, pyridyl, naphthyl, quinolinyl, pyrazinyl, pyrimidyl, pyrazolyl, imidazolyl, furyl or thienyl, and optionally, hydrogen atoms at any position of these groups can be replaced by R groups;

R is selected from alkyl having 1-4 carbon atoms, alkoxy having 1-3 carbon atoms, halogen, -CF ₃ , -OCF ₃ , -NO ₂ or -CN.

Preferably, the compound shown in the formula (I) of the present invention, wherein:

Z represents: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl; or, Z represents phenyl, pyridyl, pyrimidinyl, and optionally, any of these groups The hydrogen atom in position can be replaced by R group;

The R group is selected from: methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ or -CN.

More preferably, the compound represented by formula (I) of the present invention, wherein:

Z represents: ethoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, benzyl, fluorophenyl, chlorophenyl, bromophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxy phenyl, 4-cyanophenyl), 4-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoro Methoxyphenyl, 3-cyanophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2 ,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-4-bromophenyl, 3-fluoro -4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-bromo-4-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-bromo-4-trifluoromethylphenyl, 3-fluoro-4-cyanophenyl, 3-bromo-4-nitrophenyl, 2- Fluoro-5-methylphenyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-2-ylmethyl.

Most preferably, the compound shown in the formula (I) of the present invention, wherein:

Z represents: ethoxycarbonyl, benzyloxycarbonyl, chlorophenyl, 4-trifluoromethylphenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 4-chloro-3-tri Fluoromethylphenyl.

Concrete compounds of the present invention are:

2-(2-Ethoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e][ 1,3] Thiazin-4-one;

2-(2-tert-butoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e] [1,3]thiazin-4-one;

2-(2-Phenoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e][ 1,3] Thiazin-4-one;

2-(2-Benzyloxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e][ 1,3] Thiazin-4-one;

2-(2-Benzyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e][1,3 ]thiazin-4-one;

2-[2-(4-Fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(4-Chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(4-Bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(4-Trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(4-Trifluoromethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(4-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[ e] [1,3] Thiazin-4-one;

2-[2-(4-Nitrobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[ e] [1,3] Thiazin-4-one;

2-[2-(3-Fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(3-Chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(3-Bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[e ][1,3]thiazin-4-one;

2-[2-(3-Trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(3-Trifluoromethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(3-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo[ e] [1,3] Thiazin-4-one;

2-[2-(2,4-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(2,6-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(3,4-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(3,5-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(2,4-Dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(3,4-Dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one;

2-[2-(2-fluoro-3-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(2-fluoro-4-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(2-Fluoro-4-bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(3-fluoro-4-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(2-Chloro-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(2-Bromo-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(3-Chloro-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one;

2-[2-(4-Chloro-3-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one;

2-[2-(3-fluoro-4-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one;

2-[2-(3-Bromo-4-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one;

2-[2-(3-Fluoro-4-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H - Benzo[e][1,3]thiazin-4-one;

2-[2-(3-Bromo-4-nitrobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H - Benzo[e][1,3]thiazin-4-one;

2-[2-(2-fluoro-5-methylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H - Benzo[e][1,3]thiazin-4-one;

2-[2-(Pyridin-2-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one;

2-[2-(Pyridin-3-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one;

2-[2-(Pyridin-4-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one;

2-[2-(Pyrimidin-2-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one.

The present invention further provides the preparation method of the compound of formula (I) described in this side, comprising the following steps:

The compound of formula (II) and the compound of formula (III), in the presence of a protic solvent and adding an acid-binding agent, are stirred and reacted at -5°C to 60°C for 0.5 to 10 hours to obtain the compound of formula (I),

in:

The definition of Z is the same as claim 1. The protic solvent is selected from water, alcohol or alcohol-water mixed solvent; the acid-binding agent is selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

Preferably, the preparation method of the compound of formula (I) of the present invention comprises the following steps:

Combine the compound of formula (II) and compound of formula (III) in the presence of a protic solvent and add an acid-binding agent, and use an excess of compound of formula (III) to meet the needs, at -5 ° C to 60 ° C, with or without pressure conditions The reaction was carried out under stirring for 0.5-10 hours to obtain the compound of formula (I).

The compound of formula (II) used as a starting material in the present invention is a known compound, and can be easily prepared by referring to known methods in existing publications, such as CN 201180055813.5.

According to the method shown in the following reaction scheme 2, the compound of formula (III) which is another starting material of the present invention can be prepared.

Reaction route 2:

In Scheme 2, Z is as defined above.

Add an acid-binding agent in an aprotic solvent to make the compound of formula (IV) condense with the compound of formula (V). The generated intermediate does not need to be separated, and the protecting group is directly removed with trifluoroacetic acid to obtain the compound of formula (III ) compounds. The aprotic solvent that is used for this reaction is selected from acetonitrile, acetone, methylene dichloride, chloroform, ether or cyclohexane; Described acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, hydrogen potassium oxide or triethylamine.

The compounds of the formula (IV) and the compound of the formula (V) used as starting materials are all known compounds, which are commercially available in China.

The present invention also provides an anti-tuberculosis composition comprising a compound of formula (I) as defined above as an active ingredient. The weight ratio of the compound of the invention contained in the pharmaceutical composition is 0.1-99.9% in the composition, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%. The pharmaceutical compositions are in the form of formulations suitable for pharmaceutical use. The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, the pharmaceutical preparations are tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, and powders.

In the pharmaceutical composition of the present invention, as a preparation form, the effective amount of the compound of the present invention contained in each dose is 0.1 to 1000 mg, and each dose refers to each preparation unit, such as each tablet, each capsule Granules may also refer to each dosage, such as 100 mg each time.

When the pharmaceutical composition of the present invention is prepared into solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, and cachets, solid carriers can be used. The solid carrier that can be used is preferably one or more substances selected from diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, swelling agents, etc., or can be encapsulated substances. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets and capsules etc. represent the most advantageous oral solid preparations.

It is especially advantageous to formulate the aforementioned pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit form can be in packaged form, such as tablets, capsules, or powders in vials or vials.

Although the amount of active ingredient contained in dosage unit forms may vary, it will generally be adjusted within the range of 1 to 800 mg, depending on the potency of the active ingredient chosen.

When the active compound of formula (I) of the present invention is used as a drug for the treatment of Mycobacterium tuberculosis infection, it is preferred to administer 6-14 mg/kg body weight in the first stage. However, the dosage administered will vary with the needs of the patient, the severity of the infection to be treated, the compound selected, and the like.

Those skilled in the art can routinely determine the preferred dosage for a particular situation. Generally, the initial treatment dose is lower than the optimum dose of the active ingredient, and then the dose is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dosage may be divided and administered in divided doses.

The present invention also provides the application of the compound represented by formula (I) or the pharmaceutical composition containing the compound in the preparation of medicine for treating tuberculosis.

The tuberculosis described in the present invention includes active tuberculosis, monodrug-resistant tuberculosis, multidrug-resistant tuberculosis and extensively multidrug-resistant tuberculosis.

Tuberculosis in the present invention includes pulmonary tuberculosis and extrapulmonary tuberculosis.

As mentioned above, the activity of the compound of the present invention against Mycobacterium tuberculosis is much higher than that of the same kind of benzothiazin-4-one candidate compound PBTZ169 and the first-line anti-tuberculosis drugs isoniazid and rifampicin. In particular, the in vitro activity of the compounds of Examples 1, 4, 7, 9, 20, 28 and 32 on the Mycobacterium tuberculosis standard strain H37Rv ATCC 27294 is more than 2-7 times that of the compound PBTZ169, and on the clinical isolate MDR-MTB 20161 (resistant to rifampicin and isoniazid) in vitro activity is more than 2-3 times that of compound PBTZ169.

Compared with the existing products, the compound of the present invention has better curative effect on anti-tuberculosis, higher activity, lower side effects, simpler synthesis process operation, effective cost reduction, and is suitable for large-scale production.

Detailed ways

In the following examples, the present invention will be explained more specifically. However, it should be understood that the following examples are intended to illustrate the present invention and not to limit the scope of the present invention.

Example 1. 2-(2-ethoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one

To a solution of tert-butyl 2,8-azaspiro[4,5]decane-8-carboxylate (192 mg, 0.88 mmol) in acetonitrile (15 mL) was added ethyl bromoacetate (181 mg, 1 mmol) and Potassium carbonate (276 mg, 2 mmol), stirred at room temperature for 2 hours. Distilled water (30 mL) was added to the reaction liquid, and extracted with ethyl acetate (20 mL×3). Several layers were combined, dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography (DCM:MeOH:NH ₃ H ₂ O=200:10:0.2) to obtain a light yellow oil (260 mg).

At room temperature, the above oil (260 mg) was dissolved in anhydrous dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added dropwise with stirring, stirred at the same temperature for 1 hour, and concentrated to obtain a yellow oil.

Add 2-methylthio-6-trifluoromethyl-8-nitro-benzothiazin-4-one (257 mg, 0.8 mmol) to a solution of the above yellow oil in absolute ethanol (10 mL), triethyl Amine (333 μL, 2.4 mmol), stirred at 40°C for 3 hours, concentrated, separated and purified on a silica gel column to give a pale yellow solid, mp: 116-118°C.

¹ H NMR (400MHz, CDCl ₃ )δ9.14(s,1H),9.78(s,1H),4.24(q,J=7.2Hz,2H),4.12(brs,2H),3.88(brs,2H) , 3.39 (s, 2H), 2.88 (brs, 2H), 2.72 (brs, 2H), 1.83-1.81 (m, 6H), 1.32 (t, J=7.2Hz, 3H).

¹³ C NMR (400MHz, CDCl ₃ ) δ170.48, 166.57, 161.73, 143.95, 134.26, 133.39(q, J=3.5Hz), 129.60(q, J=35.2Hz), 126.74, 126.00(q, J=3.5Hz) , 122.50 (q, J=274.2Hz), 64.61, 60.70, 56.26, 52.94, 44.85, 41.02, 37.20, 36.52, 14.27.

HRMS- _ESI (m/ _{z )} : Calcd. for _{C21H24N4O5F3S} (M+H) ₊ ^: 501.1414; Found: 501.1417.

Example 2. 2-(2-tert-butoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzene And[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced with tert-butyl bromoacetate to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.14(s,1H),9.78(s,1H),4.12(brs,2H),3.88(brs,2H),3.39(s,2H),2.88(brs, 2H), 2.72 (brs, 2H), 1.83-1.81 (m, 6H), 1.42 (s, 9H).

MS-ESI (m/z): 529.1 (M+H) ⁺ .

Example 3. 2-(2-Phenoxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced with phenyl bromoacetate to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.14(s,1H),9.78(s,1H),7.45-7.40(m,1H),7.37-7.30(m,2H),7.08-7.00(m,2H ), 4.12 (brs, 2H), 3.88 (brs, 2H), 3.39 (s, 2H), 2.88 (brs, 2H), 2.72 (brs, 2H), 1.83-1.81 (m, 6H).

MS-ESI(m/z):549.1(M+H) ⁺ .

Example 4. 2-(2-Benzyloxycarbonylmethyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo [e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced with benzyl bromoacetate to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.14(s, 1H), 9.78(s, 1H), 7.35-7.33(m, 5H), 5.20(s, 2H), 4.12(brs, 2H), 3.88( brs, 2H), 3.39 (s, 2H), 2.88 (brs, 2H), 2.72 (brs, 2H), 1.83-1.81 (m, 6H).

MS-ESI(m/z):563.1(M+H) ⁺ .

Example 5. 2-(2-Benzyl-2,8-diazaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-4H-benzo[e] [1,3]thiazin-4-one

The preparation method was the same as in Example 1, and the ethyl bromoacetate in Example 1 was replaced with benzyl bromide to obtain a light yellow solid, mp: 98-100°C.

¹ H NMR (500MHz,DMSO-d ₆ )δ8.85(s,1H),8.79(s,1H),7.33(brs,5H),4.06(brs,2H),3.80(brs,2H),3.58( brs,2H), 2.54(brs,2H), 2.48(brs,2H), 1.68(brs,6H).

¹³ C NMR (400 MHz, CD ₃ OD) 167.46, 162.81, 144.49, 134.59 (q, J=35.4 Hz), 131.63, 129.48, 129.39, 128.31, 65.44, 59.41, 52.92, 40.53, 28.87, 26.64.

HRMS-ESI(m/z): Calcd.for C ₂₄ H ₂₄ N ₄ O ₃ F ₃ S(M+H) ⁺ :505.1515; Found: 505.1515.

Example 6. 2-[2-(4-Fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and 4-fluorobromobenzyl is used instead of ethyl bromoacetate in Example 1 to obtain a light yellow solid, mp: 154-156°C.

¹ H NMR (400MHz, CDCl ₃ ) δ9.14(d, J=2.2Hz, 1H), 8.79(d, J=2.2Hz, 1H), 7.34(brs, 2H), 7.05(t, J=8.7Hz ,2H), 4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

¹³ C NMR (400MHz, CDCl ₃ ) δ166.57, 161.72, 143.94, 134.24, 133.39, 133.38(q, J=3.6Hz), 130.17, 129.81, 129.20(q, J=35.4Hz), 126.74, 126.00(q, J = 3.5 Hz), 122.50 (q, J = 274.2 Hz), 115.20 (d, J = 21.2 Hz), 59.35, 53.15, 44.79, 40.72, 37.28, 37.28, 36.18.29.35.

HRMS- _ESI (m/ _{z )} : Calcd. for _{C24H23N4O4F4S} (M+H) ⁺ : 523.1421; Found _: 523.1411.

Example 7. 2-[2-(4-Chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-chlorobromobenzyl to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.39(d, J=8.4Hz, 2H), 7.22(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 539.1 (M+H) ⁺ .

Example 8. 2-[2-(4-Bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-bromobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.85(d, J=8.4Hz, 2H), 7.17(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI(m/z):583.1,585.1(M+H) ⁺ .

Example 9. 2-[2-(4-Trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-trifluoromethylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.54(d, J=8.4Hz, 2H), 7.17(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI(m/z):573.1(M+H) ⁺ .

Example 10. 2-[2-(4-Trifluoromethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-trifluoromethoxybenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.12(d, J=8.4Hz, 2H), 6.89(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 589.1 (M+H) ⁺ .

Example 11. 2-[2-(4-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H -Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-cyanobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.76(d, J=8.4Hz, 2H), 7.46(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 530.1 (M+H) ⁺ .

Example 12. 2-[2-(4-nitrobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H -Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-nitrobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 8.32(d, J=8.4Hz, 2H), 7.95(d, J=8.4Hz, 2H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 550.1 (M+H) ⁺ .

Example 13. 2-[2-(3-Fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-fluorobromobenzyl to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.36-7.30(m,1H),7.08-6.90(m,3H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 523.1 (M+H) ⁺ .

Example 14. 2-[2-(3-Chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-chlorobromobenzyl to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.43-7.35(m,3H),7.18-7.10(m,1H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 539.1 (M+H) ⁺ .

Example 15. 2-[2-(3-Bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H- Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-bromobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.53-7.45(m,2H),7.28-7.15(m,2H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 583.1, 585.1 (M+H) ⁺ .

Example 16. 2-[2-(3-Trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-trifluoromethylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.50-7.40(m,3H),7.31-7.25(m,1H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 573.1 (M+H) ⁺ .

Example 17. 2-[2-(3-Trifluoromethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-trifluoromethoxybenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.25-7.18(m,1H),7.00-6.92(m,3H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 589.1 (M+H) ⁺ .

Example 18. 2-[2-(3-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro-4H -Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-cyanobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.89-7.80(m,1H),7.79(s,1H),7.59-7.45(m,1H), 7.20-7.10 (m, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 530.1 (M+H) ⁺ .

Example 19. 2-[2-(2,4-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2,4-difluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.24-7.18(m,1H),7.24-7.15(m,1H),6.96-6.88(m,1H ), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 541.1 (M+H) ⁺ .

Example 20. 2-[2-(2,6-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2,6-difluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.74-7.60(m,1H),7.40-7.30(m,2H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 541.1 (M+H) ⁺ .

Example 21. 2-[2-(3,4-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3,4-difluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.21-7.15(m,2H),6.95-6.88(m,1H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 541.1 (M+H) ⁺ .

Example 22. 2-[2-(3,5-Difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3,5-difluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),6.74-6.70(m,2H),6.65-6.60(m,1H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 541.1 (M+H) ⁺ .

Example 23. 2-[2-(2,4-Dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2,4-dichlorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.70(s, 1H), 7.26(d, J=8Hz, 1H), 7.16(d, J=8Hz ,1H), 4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 573.1 (M+H) ⁺ .

Example 24. 2-[2-(3,4-Dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro -4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3,4-dichlorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.65(d, J=8Hz, 1H), 7.40(s, 1H), 7.20(d, J=8Hz ,1H), 4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 573.1 (M+H) ⁺ .

Example 25. 2-[2-(2-Fluoro-3-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-fluoro-3-chlorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.37-7.30(m,1H),7.14-7.10(m,2H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 557.1 (M+H) ⁺ .

Example 26. 2-[2-(2-Fluoro-4-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-fluoro-4-chlorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.81-7.70(m,1H),7.20-7.10(m,2H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 557.1 (M+H) ⁺ .

Example 27. 2-[2-(2-Fluoro-4-bromobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-fluoro-4-bromobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.62-7.50(m,1H),7.40-7.30(m,1H),7.18-7.10(m,1H ), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 601.1, 603.1 (M+H) ⁺ .

Example 28. 2-[2-(3-Fluoro-4-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-fluoro-4-chlorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.40-7.30(m,1H),7.18-7.10(m,1H),7.00-6.91(m,1H ), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 557.1 (M+H) ⁺ .

Example 29. 2-[2-(2-Chloro-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-chloro-4-fluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.81(d, J=9.0Hz, 1H), 7.18-7.10(m, 1H), 7.00-6.91( m, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 557.1 (M+H) ⁺ .

Example 30. 2-[2-(2-Bromo-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-bromo-4-fluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.41(d, J=9.0Hz, 1H), 7.18-7.10(m, 2H), 4.19(brs, 4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 601.1, 603.1 (M+H) ⁺ .

Example 31. 2-[2-(3-Chloro-4-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitrate yl-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-chloro-4-fluorobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 7.81(d, J=9.0Hz, 1H), 7.18-7.10(m, 1H), 7.05-7.00( m, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 557.1 (M+H) ⁺ .

Example 32. 2-[2-(4-Chloro-3-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl- 8-Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-chloro-3-trifluoromethylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.44-7.30(m,3H),4.19(brs,4H),3.85(s,2H),2.70( brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 607.1 (M+H) ⁺ .

Example 33. 2-[2-(3-Fluoro-4-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl- 8-Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as that in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-fluoro-4-trifluoromethylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.44-7.38(m,1H),6.94-6.85(m,2H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 591.1 (M+H) ⁺ .

Example 34. 2-[2-(3-Bromo-4-trifluoromethylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl- 8-Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-bromo-4-trifluoromethylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.44-7.38(m,2H),7.11-7.00(m,1H),4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 651.1, 653.1 (M+H) ⁺ .

Example 35. 2-[2-(3-Fluoro-4-cyanobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8- Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-fluoro-4-cyanobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.61-7.55(m,1H),7.23-7.15(m,1H),7.20-7.15(m,1H ), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 548.1 (M+H) ⁺ .

Example 36. 2-[2-(3-Bromo-4-nitrobenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8- Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-bromo-4-nitrobenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 8.09(d, J=8Hz, 1H), 7.89(d, J=8Hz, 1H), 7.70(s ,1H), 4.19(brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 628.1, 630.1 (M+H) ⁺ .

Example 37. 2-[2-(2-Fluoro-5-methylbenzyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8- Nitro-4H-benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-fluoro-5-methylbenzyl bromide to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),7.17-7.05(m,3H),4.19(brs,4H),3.85(s,2H),2.70( brs, 2H), 2.49 (brs, 2H), 2.31 (s, 3H), 1.80 (brs, 6H).

MS-ESI (m/z): 537.1 (M+H) ⁺ .

Example 38. 2-[2-(Pyridin-2-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro- 4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-bromomethylpyridine to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),8.50-7.45(m,1H),7.74-7.68(m,1H),7.32-7.26(m,2H ), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 506.1 (M+H) ⁺ .

Example 39. 2-[2-(Pyridin-3-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro- 4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 3-bromomethylpyridine to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ )δ9.13(s,1H),8.79(s,1H),8.59(s,1H),8.38-8.30(m,1H),7.86-7.70(m,1H), 7.37-7.30 (m, 1H), 4.19 (brs, 4H), 3.85 (s, 2H), 2.70 (brs, 2H), 2.49 (brs, 2H), 1.80 (brs, 6H).

MS-ESI (m/z): 506.1 (M+H) ⁺ .

Example 40. 2-[2-(Pyridin-4-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro- 4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 4-bromomethylpyridine to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 8.55(d, J=8.2Hz, 1H), 7.35(d, J=8.2Hz, 1H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 506.1 (M+H) ⁺ .

Example 41. 2-[2-(Pyrimidin-2-ylmethyl)-2,8-diazaspiro[4.5]decane-8-yl]-6-trifluoromethyl-8-nitro- 4H-Benzo[e][1,3]thiazin-4-one

The preparation method is the same as in Example 1, and the ethyl bromoacetate in Example 1 is replaced by 2-bromomethylpyrimidine to obtain the target compound.

¹ H NMR (400MHz, CDCl ₃ ) δ9.13(s, 1H), 8.79(s, 1H), 8.70(d, J=8.2Hz, 2H), 7.39(t, J=8.2Hz, 1H), 4.19 (brs,4H), 3.85(s,2H), 2.70(brs,2H), 2.49(brs,2H), 1.80(brs,6H).

MS-ESI (m/z): 507.1 (M+H) ⁺ .

Biological Example 1

In vitro anti-mycobacterial activity test

The anti-tuberculosis activity of the compound of the present invention is by measuring its minimum inhibitory concentration (MIC, μg/ mL) to express. In this test, the same kind of benzothiazin-4-one candidate compound PBTZ169 and the first-line anti-tuberculosis drugs isoniazid and rifampicin were used as control drugs. The minimum inhibitory concentration was determined as follows: sterile 48-well plate (special microculture plate for rapid drug susceptibility of Mycobacterium tuberculosis), according to the design requirements of the drug susceptibility test, each well was added with 2 times concentration medium (improved Michaelis 7H9 liquid culture medium) base) diluted drug. Each compound was made into an initial solution of appropriate concentration, diluted with culture medium (2×) to double the concentration of each compound used, each compound had 10 gradients, added 100 μL per well of a 48-well plate, and the final concentrations of the test drugs were respectively It is 8, 4, 2...0.015μg/mL. The standard strain H37Rv ATCC 27294 and the clinical isolate MDR-MTB 20161 were inoculated with 100 μl per well, and the amount of bacteria per well was 4×10 ^-3 mg. Each plate was equipped with two growth positive control wells without antibacterial drugs and two growth negative control wells with distilled water instead of medium. The 48-well plate was sealed with scotch tape and placed in a humid box for incubation at 37°C. After the third day, observe the positive growth control well and the negative growth control well. When a clear difference is observed between the two, observe the number and form of bacterial growth in each test well, determine inhibition or drug resistance and record the results, and then observe after the seventh day Record it once to confirm. The minimal inhibitory concentration (MIC) was the minimum concentration of the drug contained in the sterile growth control wells. The measurement results are listed in Table 1.

The in vitro activity of table 1 part embodiment compound to 2 strains of Mycobacterium tuberculosis

MTB ^a :MTB H37Rv ATCC 27294

MDR-MTB ^b : MDR-MTB 20161 (resistance to rifampicin and isoniazid)

The above table only lists the in vitro activities of some compounds of the present invention. Other compounds of the present invention are similar in structure and have the same or similar in vitro activities as the above compounds, which are not listed here.

Biological Example 2

Oral acute toxicity test

In order to measure the oral acute toxicity of the compound of the present invention, the compound of Example 1 and the compound of Example 4 have carried out an acute toxicity experiment, and the solution containing these two compounds of different concentrations is orally given to male mice, and the dose is 0.1ml/10g After 7 days, the body weight of the dead mice was counted, and the median lethal dose (LD ₅₀ ) of each compound was calculated using the Bliss program. The results are listed in Table 2.

The mouse oral acute toxicity of table 2 embodiment 1 and 4 compounds

experimental compound _LD50 (mg/kg) Example 1 >2000 Example 4 >2000

Experimental results show that these compounds have very low toxicity and are very suitable for medicinal use.

Composition Example

Example 1 Coated tablet

Tablet prescription:

Take the above ingredients and mix evenly, granulate, sieve and adjust the granules, dry and tablet to make 100 tablet cores. Prescription of coating liquid: Opadry (Opadry) 5g, appropriate amount of 80% ethanol for coating.

Example 2 Capsules

prescription:

Preparation:

Take the raw and auxiliary materials of the prescription amount, sieve them separately, add 5% polyvinylpyrrolidone alcohol solution and Tween 80 soft material, granulate with a 20-mesh sieve, dry at room temperature at 15°C, add sodium lauryl sulfate, mix Evenly, according to 0.27g/S, put into No. 0 stomach-soluble capsules, take a sample for testing, the dissolution limit is Q=80%, and the content should be 90-110% of the labeled amount.

Example 3 Granules

Take 100 g of the compound of Example 24, add appropriate amount of dextrin and stevioside, dry granulate, size the granules, and pack separately to obtain the product.

Example 4 Injection

Take 150 g of the compound of Example 28 and dissolve it in water, and then dissolve sodium chloride and ethyl p-hydroxybenzoate in heated water, mix well, and adjust the pH value to 5-7. Dilute it with water for injection to 1000ml, filter it with a hollow fiber membrane, fill it, and sterilize it.

Example 5 Freeze-dried powder for injection

Take 150 g of the compound of Example 32 and dissolve it in water, add 500 g of mannitol to dissolve in heated water, mix well, dilute to 5000 ml with water for injection, filter through a hollow fiber membrane, fill, sterilize, and lyophilize to obtain a lyophilized powder injection.

Embodiment 6 Dropping pills

Take 20g of the compound of Example 39 as the raw material for later use; weigh 200g of the dropping pill matrix, heat to 80°C to melt, and stir evenly; add the raw material into the excipient matrix while stirring, stir for 30min to make it uniform, and keep the temperature of the liquid medicine not low At 60°C; pour the prepared medicine into the dripping pill machine, and drop it into a dripping pill.

Although the present invention has been described in detail with general descriptions and specific embodiments above, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (10)

1. compound shown in formula (I),

Wherein：

Z represents alkane (1-6 carbon atom) oxygen carbonyl, carbobenzoxy and benzyloxycarbonyl group；Alternatively, Z represent phenyl, pyridyl group, naphthalene, Quinolyl, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl, and optionally, any position of these groups The hydrogen atom set can be replaced by R group；

R is selected from the 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：

Z is represented：Methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butoxy carbonyl, carbobenzoxy, benzyloxycarbonyl group；Alternatively, Z represents benzene Base, pyridyl group, pyrimidine radicals and optionally, the hydrogen atom of any position of these groups can be replaced by R group；

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 1, which is characterized in that wherein：

Z is represented：Carbethoxyl group, tertbutyloxycarbonyl, carbobenzoxy, benzyloxycarbonyl group, benzyl, fluorophenyl, chlorphenyl, bromophenyl, 4- Trifluoromethyl, 4- Trifluoromethoxyphen-ls, 4- cyano-phenyls), 4- nitrobenzophenones, 3- fluorophenyls, 3- chlorphenyls, 3- bromobenzenes Base, 3- trifluoromethyls, 3- Trifluoromethoxyphen-ls, 3- cyano-phenyls, 2,4 difluorobenzene base, 2,6- difluorophenyls, 3,4- The fluoro- 3- chlorphenyls of difluorophenyl, 3,5- difluorophenyls, 2,4 dichloro benzene base, 3,4- dichlorophenyls, 2-, the fluoro- 4- chlorphenyls of 2-, The fluoro- 4- bromophenyls of 2-, the fluoro- 4- chlorphenyls of 3-, the chloro- 4- fluorophenyls of 2-, the bromo- 4- fluorophenyls of 2-, the chloro- 4- fluorophenyls of 3-, the chloro- 3- of 4- The fluoro- 4- trifluoromethyls of trifluoromethyl, 3-, the bromo- 4- trifluoromethyls of 3-, the fluoro- 4- cyano-phenyls of 3-, the bromo- 4- of 3- The fluoro- 5- aminomethyl phenyls of nitrobenzophenone, 2-, pyridine -2- ylmethyls, pyridin-3-yl methyl, pyridin-4-yl methyl, pyrimidine -2-base Methyl.

4. compound shown in formula (I) according to claim 1, which is characterized in that

Z is represented：The fluoro- 4- chlorphenyls of carbethoxyl group, benzyloxycarbonyl group, chlorphenyl, 4- trifluoromethyls, 2,6- difluorophenyls, 3-, The chloro- 3- trifluoromethyls of 4-.

5. compound shown in formula (I) according to claim 1, which is characterized in that be selected from following compound：

2- (2- ethoxycarbonylmethyl group -2,8- diaza spiros [4.5] decane -8- bases) -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- (2- tert-Butoxycarbonylmethyl -2,8- diaza spiros [4.5] decane -8- bases) -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- (2- carbobenzoxies methyl -2,8- diaza spiros [4.5] decane -8- bases) -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- (2- benzyloxycarbonyl-methyl -2,8- diaza spiros [4.5] decane -8- bases) -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- (2- benzyl -2,8- diaza spiros [4.5] decane -8- bases) -6- trifluoromethyls -8- nitro -4H- benzos [e] [1,3] thiophene Piperazine -4- ketone；

2- [2- (4- luorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (4- chlorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (4- bromobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (4- trifluoromethyl benzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (4- trifluoro-methoxybenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；

2- [2- (4- cyanobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (4- nitrobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3- luorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3- chlorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3- bromobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3- trifluoromethyl benzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (3- trifluoro-methoxybenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；

2- [2- (3- cyanobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (2,4- difluorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (2,6- difluorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3,4- difluorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3,5- difluorobenzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (2,4- dichloro benzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (3,4- dichloro benzyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 3- chlorobenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 4- chlorobenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 4- bromobenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 4- chlorobenzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the chloro- 4- luorobenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the bromo- 4- luorobenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the chloro- 4- luorobenzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (the chloro- 3- trifluoromethyl benzyls of 4-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 4- trifluoromethyl benzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (the bromo- 4- trifluoromethyl benzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros - 4H- benzos [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 4- cyanobenzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；

2- [2- (the bromo- 4- nitrobenzyls of 3-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；

2- [2- (the fluoro- 5- methylbenzyls of 2-) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitros -4H- Benzo [e] [1,3] thiazine -4- ketone；

2- [2- (pyridine -2- ylmethyls) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (pyridin-3-yl methyl) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (pyridin-4-yl methyl) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [e] [1,3] thiazine -4- ketone；

2- [2- (pyrimidine -2-base methyl) -2,8- diaza spiros [4.5] decane -8- bases] -6- trifluoromethyl -8- nitro -4H- benzene And [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 Z is the same as claim 1.

7. preparation method 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 is 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.