CN112759560B

CN112759560B - Benzothiazine-4-ketone compound containing N-aminopiperazine segment and preparation method thereof

Info

Publication number: CN112759560B
Application number: CN202110045987.9A
Authority: CN
Inventors: 刘明亮; 汪阿鹏; 吕凯; 许世捷; 马超; 王奥雨; 秦晓瑜
Original assignee: Institute of Medicinal Biotechnology of CAMS
Current assignee: Institute of Medicinal Biotechnology of CAMS
Priority date: 2021-01-14
Filing date: 2021-01-14
Publication date: 2022-06-21
Anticipated expiration: 2041-01-14
Also published as: CN112759560A

Abstract

The invention relates to benzothiazine-4-ketone compounds shown in formula (I), a preparation method and medical application thereof, and an antituberculous pharmaceutical composition taking the compounds as effective components. More particularly, the invention relates to a 6-trifluoromethyl-8-nitro-4H-benzo [ e][1,3]Thiazine-4-ketone compound, wherein the 2-position substituent is N-aminopiperazine fragment, and the substituent R₁And R₂As indicated in the specification.

Description

Benzothiazine-4-ketone compound containing N-aminopiperazine segment and preparation method thereof

Technical Field

The invention belongs to the field of medical chemistry, and relates to a benzothiazine-4-ketone compound containing an N-aminopiperazine fragment and having antitubercular activity, a preparation method thereof and an antitubercular pharmaceutical composition containing the compound; more particularly, the invention relates to 6-trifluoromethyl-8-nitro-4H-benzo [ e ] [1,3] thiazin-4-one compounds, wherein the substituent at the 2-position is an N-aminopiperazine fragment.

Background

In recent years, the increasing incidence of Tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), and the emergence of widely-resistant TB (XDR-TB) have become significant public health and social concerns worldwide. 1040 million new TB patients are added globally in 2015 according to the World Health Organization (WHO), and 140 million people die of TB. In addition, the near 1/3 population carries latent tubercle bacillus, which has potential risk of morbidity. Traditional anti-TB drugs, such as streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide and the like, can cure more than 85% of patients with primary tuberculosis, but have the defects of long treatment period (more than 6 months) and no effect on MDR-TB, and simultaneously have weak effect on latent Mycobacterium Tuberculosis (MTB), so that new anti-TB drugs are developed, and effective treatment and control on TB are urgently needed (Adv Drug Deliv Rev.2016,102, 55-72).

Bedaquiline (ATP synthase inhibitor) with a completely new mechanism of action is the 1 st new anti-TB drug approved by the FDA (for the treatment of MDR-TB) in the united states for over 40 years. Encouraged by this, a plurality of large pharmaceutical companies and research units worldwide have increased the development of new anti-TB drugs in recent years, 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.

The Swiss scientist MaCarlo W.equaled 2007 to disclose the synthesis and antitubercular activity of a class of 4H-benzo [ e ] [1,3] thiazin-4-ones having a 4, 4-dialkoxypiperidin-1-yl substituent in the 2-position (WO2007/134625A 1). Its representative BTZ043 has broad spectrum antitubercular activity in vitro (Antimicrob Agent Chemother,2010,54(4): 1616-.

The research team further disclosed in 2011 the synthesis and antitubercular activity (CN 201180055813.5) of 4H-benzo [ e ] [1,3] thiazine-4-one compounds with piperazine-1-yl as a 2-position substituent. The PBTZ169 represented by the compound also has in vitro broad-spectrum anti-tuberculosis activity, and the in vivo activity of the compound is remarkably stronger than that of BTZ043(EMBO Mol Med, 2014, 6: 372-383). As a second generation benzothiazine-4-one antitubercular candidate, PBTZ169 has been withdrawn from phase II clinical studies for unknown reasons.

The inventor researches and discovers that PBTZ169 has short half-life and drug exposure (C)_max，AUC_0-∞) Is smaller. Therefore, the inventors of the present invention conducted extensive studies to design and synthesize benzothiazinone compounds containing N-aminopiperazine fragment at 2-position, and measured their anti-tuberculosis activity. Finally, the 6-trifluoromethyl-8-nitro-4H-benzo [ e ] is different from the prior literature report that the substituent at the 2-position is an N-aminopiperazine fragment][1,3]The thiazine-4-ketone compound has excellent broad-spectrum antitubercular activity. More importantly, they show superior pharmacokinetic properties in vivo compared to PBTZ 169.

Disclosure of Invention

The invention aims to provide a 6-trifluoromethyl-8-nitro-4H-benzo [ e ] [1,3] thiazine-4-ketone compound containing N-aminopiperazine fragments represented by a general formula (I) or medicinal salts thereof,

wherein:

R₁and R₂Identical or different, each represents H, substituted phenyl or benzyl/phenethyl, straight-chain or branched or cyclic alkyl having 1 to 8 carbon atoms, where the cycloalkyl group, if present, may contain 1 oxime group.

The non-toxic pharmaceutically acceptable salts of the compound of formula (I) in the invention include salts with inorganic acids, such as hydrochloric acid and sulfuric acid, and salts with organic acids, such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid and amino acids.

Preferably, the present invention specifically includes the following compounds, or pharmaceutically acceptable salts thereof:

2- (4- (cyclohexylamino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((cyclohexylmethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((2-cyclohexylethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((cyclopentylmethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- (diisobutylamino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((cyclohexylmethyl) (methyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (methoxyimino) cyclohexyl) (methyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (trifluoromethoxy) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (trifluoromethyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((3- (trifluoromethyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4-fluorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((3, 5-difluorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4-chlorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4-bromobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4-methylbenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4-methoxybenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (tert-butyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((2-fluoro-6-methylbenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((1- (4- (trifluoromethyl) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ E ] [1,3] thiazin-4-one

2- (4- ((1- (4- (trifluoromethoxy) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- (methyl (1- (4- (trifluoromethoxy) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (trifluoromethyl) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- ((4- (trifluoromethoxy) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

2- (4- (methyl (4- (trifluoromethoxy) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

It is another object of the present invention to provide a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as shown in scheme 1.

Scheme 1:

in scheme 1, R₁And R₂As previously defined.

Adding an acid-binding agent into a protic solvent, and carrying out a condensation reaction between the compound of the formula (II) and the compound of the formula (III) to prepare the compound of the formula (I). The protic solvent used in the present reaction 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 comprises the following steps:

adding an acid binding agent into a protic solvent, adding a compound of a formula (II) and a compound of a formula (III) into the solvent to complete a condensation reaction, using an excessive amount of the compound of the formula (III) to meet the requirement, and stirring and reacting for 0.5-10 hours at-5-60 ℃ under the condition of pressure or no pressure to obtain the compound of the formula (I).

The compounds of formula (II) used as starting materials in the present invention are known compounds and can be readily prepared by reference to methods known in prior publications, for example CN 201180055813.5.

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

With reference to the related methods (EJMC, 2020, 31, 409-.

The invention also aims to provide application of the compound shown in the formula (I) or a pharmaceutical composition containing the compound in preparing a medicament for treating tuberculosis.

The tuberculosis comprises active tuberculosis, single-drug-resistant tuberculosis, multi-drug-resistant tuberculosis and wide-drug-resistant tuberculosis.

The tuberculosis of the invention comprises pulmonary tuberculosis and extrapulmonary tuberculosis.

Another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the pharmaceutical composition, the weight ratio of the compound shown in the formula (I) or the medicinal salt thereof is 0.1-99.9%, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%.

The pharmaceutical compositions of the present invention are in the form of preparations suitable for pharmaceutical use. The pharmaceutical composition of the invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, the medicinal preparation is tablet, sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule, sustained-release capsule, powder, granule, syrup, powder for injection, and injection.

The pharmaceutical composition of the present invention is in the form of a preparation, wherein each preparation contains 0.1-1000 mg of the compound of the present invention, and each preparation unit, such as each tablet of a tablet, each capsule, or each dose, such as 100mg per dose.

Solid carriers are used in the preparation of solid or semi-solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories, and ointments. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. In the powdery preparation, 5-70% of micronized active ingredients are contained in a carrier. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling waxes, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, capsules and the like represent the most advantageous oral solid dosage forms.

Liquid formulations of the present invention include solutions, suspensions and emulsions. For example, parenteral injection preparations may be in the form of water or water-propylene glycol solutions, which are adjusted in isotonicity, pH, etc. to suit the physiological conditions of the living body. The liquid preparation can also be prepared into solution in polyethylene glycol or water solution. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water, followed by the addition of suitable amounts of coloring, flavoring, stabilizing and thickening agents. Aqueous suspensions suitable for oral administration can be prepared by dispersing the micronized active ingredient in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

It is particularly advantageous to formulate the above pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a 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 forms may be in the form of a pack, such as a tablet, capsule or powder in a small tube or vial, or an ointment, gel or cream in a tube or bottle.

Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted within the range of 1 to 800mg, depending on the potency of the active ingredient selected.

The preferred dosage for a given situation can be determined by one skilled in the art in a routine manner. Generally, the amount of the active ingredient to be initially treated is lower than the optimum dose of the active ingredient, and then the dose to be administered is gradually increased until the optimum therapeutic effect is achieved. The total daily dose may be administered once or in divided doses for therapeutic purposes.

As described above, the compounds of the present invention have excellent in vitro broad-spectrum anti-Mycobacterium tuberculosis activity. For example, similar to PBTZ169, they were both more active than rifampicin and isoniazid against the standard strain H37Rv ATCC 27294 in vitro and very sensitive to both clinical isolates MDR-MTB 1699 and MDR-MTB16833 (resistant to rifampicin and isoniazid). More importantly, the compounds of the examples tested had longer half-lives (i.e., longer duration of action, less frequent dosing) and drug exposures (C) compared to PBTZ169_max，AUC_0-∞) Greater (i.e., more efficacious at the same dose administered).

Compared with the existing products, the compound of the invention has better curative effect on tuberculosis resistance, higher activity, lower side effect, simpler operation in the synthesis process, effectively reduced cost and suitability for large-scale production.

Detailed Description

In the following examples, the present invention will be explained more specifically. It is to be understood, however, that the following examples are intended to illustrate the present invention without limiting the scope of the present invention in any way.

Example 1.2- (4- (cyclohexylamino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

The compound 1-tert-butyloxycarbonyl-4-aminopiperazine IV (201mg,1.0mmol) was dissolved in 10mL of a dichloromethane solution, followed by addition of cyclohexanone (108mg,1.2mmol) and acetic acid (72mg, 1.2mmol), stirring at room temperature for 0.5 hour, addition of sodium triacetoxyborohydride (318mg, 1.5mmol), and further stirring for 1.5 hours. And (3) post-treatment: the reaction solution was washed with water, and the dichloromethane layer was dried over anhydrous sodium sulfate.

After the above-mentioned dried solution was filtered, trifluoroacetic acid (342mg, 3.0mmol) was added to the system, and the mixture was stirred at room temperature for 1 hour. And (3) post-treatment: the reaction solution is directly spun dry to carry out the next reaction.

The concentrate was dissolved in 5mL of methanol, and triethylamine (303mg, 3.0mmol) and compound II (321mg, 1.0mmol) were added to the solution to react at 40 ℃ for 1 hour. And (3) post-treatment: and (3) directly spin-drying the reaction solution, adding a dichloromethane solution for dissolving, washing with water, concentrating a dichloromethane layer, and performing column chromatography to obtain a light yellow solid.

¹H NMR(600MHz,CDCl₃):δ9.21(s,1H),8.89(s,1H),4.30-4.08(m,4H),2.93(s,4H),2.39(s，1H),2.00-1.98(m,2H),1.90-1.88(m，2H)，1.79-1.77(m,1H),1.48-1.29(m,4H),1.27-2.21(m,2H).¹³C NMR(150MHz,CDCl₃):δ166.53,162.21,144.03,134.17,133.44(q,J＝2.3Hz),129.80(q,J＝35.1Hz),126.14(q,J＝2.4Hz),122.50(q,J＝273.2Hz),55.80,46.40,32.40,26.38,24.72.MS-ESI(m/z):458.1(M+H)⁺.

Example 2.2- (4- ((cyclohexylmethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with cyclohexylformaldehyde, de-Boc protection, and then reacted with compound II to give a pale yellow solid.

¹H NMR(600MHz,CDCl₃):δ9.10(s,1H),8.76(s,1H),4.20-3.88(m,4H),2.78(brs,4H),2.66(d,J＝6.7Hz,2H),1.78-1.66(m,5H),1.49-1.44(m,1H),1.28-1.16(m,3H),0.97-0.90(m,2H).¹³C NMR(150MHz,CDCl₃):δ166.61,162.28,144.08,134.13,133.57(q,J＝4.1Hz),129.94(q,J＝35.3Hz),126.81,126.20(q,J＝4.4Hz),122.51(q,J＝273.1Hz),55.16,51.03,46.39,37.10,31.72,26.81,26.18.MS-ESI(m/z):472.2(M+H)⁺.

Example 3.2- (4- ((2-cyclohexylethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with cyclohexylacetaldehyde, de-Boc protection, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:27％；¹H NMR(600MHz,CDCl₃):δ9.10(d,J＝2.0Hz,1H),8.76(d，J＝2.1Hz,1H),4.15-3.94(m，4H),2.85-2.79(m,6H),1.72-1.62(m,5H),1.38-1.30(m,4H),1.22-1.19(m,2H),0.95-0.89(m,2H).¹³C NMR(150MHz,CDCl₃):δ166.59,162.28,144.09,134.11,133.43(q,J＝3.5Hz),129.96(q，J＝35.0Hz),126.82,126.05(q，J＝3.4Hz),122.52(q,J＝273.5Hz)，55.26，46.22,36.20，35.91,33.60,29.84,26.72,26.45.MS-ESI(m/z):486.2(M+H)⁺.

Example 4.2- (4- ((cyclopentylmethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with cyclopentylaldehyde, deputy-protected, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:30％；¹H NMR(600MHz,CDCl₃):δ9.08(d,J＝2.0Hz,1H),8.75(d,J＝2.1Hz,1H),4.15-3.92(m,4H),2.79-2.74(m,6H),2.02-1.94(m,1H),1.79-1.73(m,2H),1.63-1.51(m,4H),1.21-1.15(m,2H).¹³C NMR(150MHz,CDCl₃):δ166.56,162.26,144.05,134.11,133.52(q,J＝3.3Hz),129.90(q,J＝35.6Hz),126.77,126.17(q,J＝3.3Hz),122.48(q,J＝273.2Hz),55.19,54.15,46.37,38.76,31.08,25.38.MS-ESI(m/z):458.2(M+H)⁺.

Example 5.2- (4- (diisobutylamino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with two molecules of isobutyraldehyde, de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:29％；¹H NMR(600MHz,CDCl₃):δ9.16-8.85(m,1H),8.79-8.58(m,1H),4.06-3.87(m,4H),2.71(brs,4H),2.19-2.09(m,4H),1.77-1.63(m,2H),0.82(d,J＝6.4Hz,12H).¹³C NMR(150MHz,CDCl₃):δ165.46,160.92,142.92,133.11,132.34(q,J＝3.3Hz),128.67(q,J＝35.5Hz),125.71,124.97(q,J＝3.8Hz),121.38(q,J＝273.1Hz),57.28,25.41,19.76.MS-ESI(m/z):487.2(M+H)⁺.

Example 6.2- (4- ((cyclohexylmethyl) (methyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with cyclohexylformaldehyde, N-methylated, Boc-deprotected, and reacted with compound II to give a pale yellow solid.

Yellow solid；yield:35％；¹H NMR(600MHz,CDCl₃):δ9.08(d,J＝1.7Hz,1H),8.74(d,J＝1.7Hz,1H),4.15-3.90(m,4H),2.79(brs,4H),2.32(s,2H),2.31(s,3H),1.77-1.75(m,2H),1.72-1.64(m,4H),1.51-1.49(m,1H),1.25-1.14(m,4H).¹³C NMR(150MHz,CDCl₃):δ166.47,162.00,143.94,134.08,133.37(q,J＝3.3Hz),129.71(q，J＝35.4Hz),126.70,126.01(q,J＝3.8Hz)，122.38(q，J＝273.1Hz),60.83,36.75,35.78,31.70,26.85,26.13.MS-ESI(m/z):486.2(M+H)⁺.

Example 7.2- (4- ((4- (methoxyimino) cyclohexyl) (methyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with 4- (methoxyimino) cyclohexanone, N-methylated, de-Boc protected, and reacted with compound II to give a pale yellow solid.

Yellow solid；yield:29％；¹H NMR(500MHz,CDCl₃):δ9.10(d,J＝1.6Hz,1H),8.76(d,J＝1.7Hz,1H),4.27-3.85(m,4H),3.82(s,3H),2.80(brs,4H),2.76-2.67(m,2H),2.45-2.39(m,1H),2.33(s,3H),2.32-2.24(m,1H),2.17-2.07(m,1H),1.97-1.81(m,2H),1.81-1.64(m,2H).¹³C NMR(125MHz,CDCl3):δ166.52,162.11,159.42,143.94,134.04,133.45(q,J＝3.4Hz),129.79(q,J＝35.4Hz),126.68,126.09(q,J＝3.6Hz),122.54(q,J＝273.5Hz),61.10,58.93,31.59,29.87,28.68,28.62,21.74.MS-ESI(m/z):515.2(M+H)⁺.

Example 8.2- (4- ((4- (trifluoromethoxy) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with p-trifluoromethoxybenzaldehyde, deprotected to Boc, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:33％；¹H NMR(600MHz,CDCl₃):δ9.08(s,1H),8.75(s,1H),7.38(d,J＝8.5Hz,2H),7.17(d,J＝8.3Hz,2H)，4.23-3.83(m,4H),3.99(s,2H),2.84(s,4H).¹³C NMR(150MHz,CDCl₃):δ166.57,162.33,148.53,144.06,137.67,134.04,133.55(q,J＝4.3Hz),130.07,129.82,126.75,126.21(q，J＝3.5Hz),122.48(q,J＝273.0Hz),120.60(q,J＝260.1Hz),121.05,55.28,52.01,46.24.MS-ESI(m/z):550.1(M+H)⁺.

Example 9.2- (4- ((4- (trifluoromethyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with p-trifluoromethylbenzaldehyde and deprotected to Boc, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:33％；¹H NMR(600MHz,CDCl₃):δ9.10(d,J＝1.7Hz,1H),8.76(d,J＝1.7Hz,1H),7.59(d,J＝8.1Hz,2H),7.49(d,J＝8.0Hz,2H),4.10-4.01(m,6H),2.85(brs,4H).¹³C NMR(150MHz,CDCl₃):δ166.46,162.21,143.94,143.06,133.91,133.44(q,J＝3.3Hz),128.55,126.62,126.09(q，J＝3.4Hz),125.31(q,J＝3.4Hz),122.35(q，J＝273.1Hz),55.16,52.09,46.13.MS-ESI(m/z):534.2(M+H)⁺.

Example 10.2- (4- ((3- (trifluoromethyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with m-trifluoromethylbenzaldehyde and de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:27％；¹H NMR(600MHz,CDCl₃):δ9.09(d,J＝1.8Hz,1H),8.76(d,J＝1.8Hz,1H),7.65(s,1H),7.55(d,J＝7.7Hz,2H),7.46(d,J＝7.7Hz,1H),4.10-4-01(m,6H),2.85(brs,4H).¹³C NMR(150MHz,CDCl₃):δ166.43,162.21,143.94,139.94,133.91,133.41(q,J＝3.2Hz),131.69,130.71(q,J＝32.1Hz),129.83(q,J＝35.4Hz),128.80,126.63,126.07(q,J＝3.4Hz),125.13(q,J＝4.1Hz),124.07(q,J＝3.5Hz),123.28,122.35(q,J＝273.1Hz),55.15,52.16,46.13,29.69,20.50.MS-ESI(m/z):534.2(M+H)⁺.

Example 11.2- (4- ((4-Fluorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-fluorobenzaldehyde, de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:34％；¹H NMR(600MHz,CDCl₃):δ9.08(d,J＝2.1Hz,1H),8.75(d,J＝2.1Hz,1H),7.34-7.29(m,2H),7.03-6.98(m,2H),4.29-3.77(m,6H),2.92-2.72(m,4H).¹³C NMR(150MHz,CDCl₃):δ166.58,163.06,162.31,161.43,144.05,134.52(d,J＝3.2Hz),134.06,133.54(q,J＝3.4Hz),130.14(d,J＝8.2Hz),129.93(q,J＝35.6Hz),128.18(q,J＝8.3Hz),126.74,126.20(q,J＝4.2Hz),122.48(q,J＝273.2Hz),115.81(q,J＝21.6Hz),115.42,115.28,55.27,52.13,46.26,29.81.MS-ESI(m/z):483.1(M+H)⁺.

Example 12.2- (4- ((3, 5-difluorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with 3, 5-difluorobenzaldehyde and deprotected to Boc, followed by reaction with compound II to give a pale yellow solid.

Yellow solid；yield:37％；¹H NMR(600MHz,CDCl₃):δ9.08(s,1H),8.75(s,1H),6.90(d,J＝6.4Hz,2H),6.74-6.66(m,1H),4.24-3.74(m,6H),2.92-2.77(m,4H).¹³C NMR(150MHz,CDCl₃):δ166.45,163.86(d,J＝12.8Hz),162.22,162.22(t,J＝6.2Hz),143.93,143.31(t,J＝8.8Hz),133.90,133.42(q,J＝3.2Hz),129.84(q,J＝35.3Hz),126.60,126.10(q,J＝3.4Hz),122.35(q,J＝273.2Hz),110.90(dd,J＝15.3Hz,4.7Hz),102.60(t,J＝25.5Hz),55.16,51.78,46.09,29.69.MS-ESI(m/z):502.1(M+H)⁺.

Example 13.2- (4- ((4-chlorobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one (2f)

Referring to example 1, compound IV was subjected to reductive amination with p-chlorobenzaldehyde, de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:30％；¹H NMR(600MHz,CDCl₃):δ9.22(s,1H),8.90(s,1H),7.44(s,4H),4.49-3.95(m,6H),3.00(s,4H).¹³C NMR(150MHz,CDCl₃):δ166.50,162.28,143.99,137.49,134.08,133.46,133.01,129.86,128.59,126.67,126.18，122.47(q,J＝273.0Hz)，55.22，52.05,46.24.MS-ESI(m/z):500.1(M+H)⁺.

Example 14.2- (4- ((4-bromobenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-bromobenzaldehyde, de-Boc protection, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:39％；¹H NMR(600MHz,CDCl₃):δ9.03(s,1H),8.71(s,1H),7.39(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),4.25-3.91(m,6H),2.81(brs,4H).¹³C NMR(150MHz,CDCl₃):δ169.58,165.36,147.08,141.12,137.17,136.55,134.62,133.31,132.90(q，J＝35.5Hz),129.76,129.27,125.56(q,J＝273.3Hz),124.20,58.30,55.17,49.29.MS-ESI(m/z):544.1(M+H)⁺.

Example 15.2- (4- ((4-methylbenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-tolualdehyde, de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:21％；¹H NMR(600MHz,CDCl₃):δ9.09(d,J＝1.8Hz,1H),8.76(d,J＝1.8Hz,1H),7.24(d,J＝7.9Hz,2H),7.14(d,J＝7.8Hz,2H),4.20-3.95(m,6H),2.84(brs,4H),2.35(d,J＝7.7Hz,3H).¹³C NMR(150MHz,CDCl₃):δ166.57,162.27,144.04,137.14,135.63,134.09,133.53(q,J＝4.0Hz),129.90(q,J＝35.4Hz),129.27,128.56,126.76,126.18(q,J＝4.2Hz),122.48(q,J＝273.2Hz),55.30,52.74,46.31,21.24.MS-ESI(m/z):480.1(M+H)⁺.

Example 16.2- (4- ((4-methoxybenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-methoxybenzaldehyde and Boc removal protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:29％；¹H NMR(600MHz,CDCl₃):δ9.09(d,J＝1.8Hz,1H),8.76(d,J＝1.8Hz,1H),7.29-7.26(m,2H),6.87-6.86(m,2H),4.19-3.93(m,6H),3.80(s,3H),2.84(brs,4H).¹³C NMR(150MHz,CDCl₃):δ166.55,162.26,159.05,144.03,134.08,133.51(q，J＝3.3Hz),130.74,129.81,126.75,126.17(q，J＝3.5Hz),122.48(q，J＝273.1Hz),113.97,55.34,52.42,46.31,29.80.MS-ESI(m/z):496.1(M+H)⁺.

Example 17.2- (4- ((4- (tert-butyl) benzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-tert-butylbenzaldehyde, de-Boc protection, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:30％；¹H NMR(600MHz,CDCl₃):δ9.08(d,J＝1.7Hz,1H),8.75(d,J＝1.7Hz,1H),7.36-7.35(m,2H),7.28-7.26(m,2H),4.21-3.97(m,6H),2.85(brs,4H)，1.32(s，9H).¹³C NMR(150MHz,CDCl₃):δ166.58,162.29,150.50，144.04,135.51，134.09,133.52(q,J＝3.4Hz),129.90(q,J＝35.4Hz),128.31,126.74,126.18(q,J＝3.7Hz),125.53,122.48(q,J＝273.1Hz),55.18,52.64,50.92,46.30,34.62,31.47.MS-ESI(m/z):522.2(M+H)⁺.

Example 18.2- (4- ((2-fluoro-6-methylbenzyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with 2-fluoro-6-methylbenzaldehyde, deputy-protected, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:24％；¹H NMR(600MHz,CDCl₃):δ9.10(d,J＝1.8Hz,1H),8.76(d,J＝1.9Hz,1H),7.20-7.17(m,1H),7.05(s,1H),6.94-6.89(m,1H),4.25-3.89(m,6H),2.85(brs,4H),2.32(s,3H).¹³C NMR(150MHz,CDCl₃):δ166.43,162.16,160.25,158.64,143.95,133.95,133.62(d,J＝4.0Hz),133.43(q,J＝3.1Hz),131.33(d,J＝4.4Hz),129.82(q,J＝35.6Hz),129.52(d,J＝8.3Hz),126.68,126.05(q,J＝3.4Hz),124.85(d,J＝15.4Hz),122.37(q,J＝273.2Hz),114.96(d,J＝22.0Hz),55.15,46.63,46.16,29.70,20.65.MS-ESI(m/z):498.1(M+H)⁺.

Example 19.2- (4- ((1- (4- (trifluoromethyl) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ E ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-trifluoromethylphenethylketone, de-Boc protection, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:30％；¹H NMR(600Mz,CDCl₃):δ9.13(d,J＝1.8Hz,1H),8.77(d,J＝1.9Hz,1H),7.82(d,J＝8.7Hz,2H),7.23(d,J＝8.6Hz,2H),4.24-4.20(m,5H),3.02(brs,4H),2.43(s,3H).¹³C NMR(150MHz,CDCl₃):δ166.43,163.57,162.34,150.45,143.95,136.68,133.98,133.42(q,J＝3.3Hz),129.80(q,J＝35.5Hz),128.11,126.71,126.07(q,J＝3.5Hz),122.37(q,J＝273.2Hz),120.64,120.40(q,J＝257.7Hz),54.04,53.93,45.13,15.56.MS-ESI(m/z):548.1(M+H)⁺.

Example 20.2- (4- ((1- (4- (trifluoromethoxy) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was subjected to reductive amination with p-trifluoromethoxyacetophenone, de-Boc protection, and then reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:32％；¹H NMR(600MHz,CDCl₃):δ9.29(s,1H),8.96(s,1H),7.58(d,J＝8.2Hz,2H),7.37(d,J＝8.0Hz,2H),4.31-3.90(m,5H),3.03-2.91(m,4H),1.53(d,J＝6.2Hz,3H).¹³C NMR(150MHz,CDCl₃):δ166.61,163.66,162.30,148.38,144.06,134.10,133.56(q,J＝3.5Hz),129.95(q,J＝35.5Hz),128.29,126.76,126.22(q,J＝3.6Hz),122.50(q,J＝272.5Hz),121.03,120.65(q,J＝258.4Hz),56.43,55.46,46.25,22.44.MS-ESI(m/z):564.1(M+H)⁺.

Example 21.2- (4- (methyl (1- (4- (trifluoromethoxy) phenyl) ethyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 1, compound IV was reductively aminated with p-trifluoromethoxyacetophenone, N-methylated, de-Boc protected, and then reacted with compound II to give a pale yellow solid.

Yellow solid；yield:37％；¹H NMR(600MHz,CDCl₃):δ9.26(s,1H),8.93(s,1H),7.51(d,J＝8.0Hz,2H),7.33(d,J＝7.8Hz,2H),4.01-3.95(m,5H),2.96(s,4H),2.41(s,3H),1.56(d,J＝5.9Hz,3H).¹³C NMR(150MHz,CDCl₃):δ166.58,162.20,148.16,143.95(d,J＝22.4Hz),134.16,133.50(d,J＝3.6Hz),129.85(d,J＝35.5Hz),128.52,126.77,126.16(d,J＝3.7Hz),122.62(d,J＝242.7Hz),120.84,63.33,32.46,21.97.MS-ESI(m/z):578.1(M+H)⁺.

Example 22.2- (4- ((4- (trifluoromethyl) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Compound IV (334mg,1.66mmol), p-trifluoromethylbromobenzene (200mg,0.83mmol), Pd₂(dba)₃(23mg,0.025mmol), Xphos (20mg, 0.042mmol) and sodium tert-butoxide (120mg, 1.25mmol) were dissolved in 10mL of anhydrous dioxane and the reaction refluxed for 5 hours under argon. And (3) post-treatment: adding dichloromethane into the reaction solution, washing with water, and mixingThe layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to deprotection of Boc and then reacted with Compound II to obtain a pale yellow solid, referring to example 1.

Yellow solid；yield:27％；¹H NMR(600MHz,CDCl₃):δ9.08(d,J＝1.7Hz,1H),8.76(d,J＝1.8Hz,1H),7.45(d,J＝8.5Hz,2H)，6.95(d,J＝8.5Hz,2H),4.94(s,1H),4.14(brs,4H),2.92(brs,4H).¹³C NMR(150MHz,CDCl₃):δ166.52,162.53，149.45,144.09，133.89,133.52,129.95(q,J＝35.5Hz),126.69(q,J＝3.5Hz),126.13(q，J＝3.4Hz),124.62(q，J＝270.8Hz),123.23,,121.73(q,J＝32.4Hz)121.42,112.69,55.07,46.15.MS-ESI(m/z):520.1(M+H)⁺.

Example 23.2- (4- ((4- (trifluoromethoxy) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 22, compound IV was reacted with compound II after coupling reaction with p-trifluoromethoxybenzobenzene and de-Boc protection to give a pale yellow solid.

Yellow solid；yield:25％；¹H NMR(600MHz,CDCl₃):δ9.10(s,1H),8.77(s,1H),7.08(d,J＝8.3Hz,2H),6.90(d,J＝8.7Hz,2H),4.64(s,1H),4.11-4.08(m,4H)，2.91(brs，4H).¹³C NMR(150MHz,CDCl₃):δ166.57,162.47,145.42,143.94,142.34,133.94,133.51,129.91(q,J＝35.4Hz),126.40(q,J＝32.6Hz),122.51,122.39(q,J＝273.4Hz),120.67(q,J＝255.6Hz),114.17,55.00,46.17.MS-ESI(m/z):536.1(M+H)⁺.

Example 24.2- (4- (methyl (4- (trifluoromethoxy) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one

Referring to example 22, compound IV was coupled with p-trifluoromethoxybenzene, N-methylated, de-Boc protected, and reacted with compound II to obtain a pale yellow solid.

Yellow solid；yield:38％；¹H NMR(500MHz,CDCl₃):δ9.11(s,1H),8.78(s,1H),7.12(d,J＝8.8Hz,2H),7.03(d,J＝9.0Hz,2H),4.17(brs,4H),2.94(brs,4H),2.85(s,3H).¹³C NMR(125MHz,CDCl₃):δ166.49,162.37,148.03,143.95,141.52(q,J＝1.9Hz),133.88,133.48(q,J＝3.5Hz),129.91(q,J＝35.4Hz),126.59,126.17(q,J＝3.6Hz),122.36(q,J＝273.1Hz),122.11,120.70(q,J＝255.6Hz),113.66,48.96,46.43,28.99.MS-ESI(m/z):550.1(M+H)⁺.

Biological example 1

In vitro anti-mycobacterial Activity assay

The antitubercular activity of the compounds of the invention is indicated by determining the minimum inhibitory concentration (MIC, μ g/mL) for the standard strain of Mycobacterium tuberculosis MTB H37Rv ATCC 27294, the clinical isolates MDR-MTB 1699 and MDR-MTB16833 (resistant to rifampicin and isoniazid). In this test, the congenic benzothiazine-4-one candidate compound, PBTZ169, was used as a control with the first line antitubercular drugs isoniazid and rifampicin. The minimum inhibitory concentration was determined as follows: the medicines diluted by the culture medium with 2 times concentration (improved Mie's 7H9 liquid culture medium) are respectively added into each sterile 48-hole plate (special micro-culture plate for fast drug sensitivity of tubercle bacillus) according to the design requirement of drug sensitivity test. The compounds were prepared as a primary solution of appropriate concentration, diluted in medium (2X) to twice the concentration of each compound used, with 10 gradients for each compound, and added to a 48-well plate at 100. mu.L per well, with final concentrations of test drug of 8, 4, and 2 … … 0.015. mu.g/mL, respectively. Standard strains H37Rv ATCC 27294, clinical isolates MDR-MTB 1699 and MDR-MTB16833, inoculated with 100. mu.l of the bacterial load 4X 10 per well^-3And (5) mg. Each plate was provided with 2 growth positive control wells containing no antimicrobial and two growth negative control wells using distilled water instead of the culture medium, the 48-well plate was covered and sealed with a transparent tape around, and placed in a wet box for incubation at 37 ℃. And observing the positive growth control holes and the negative growth control holes after 3 days, observing the number and the shape of the bacteria growing in each test hole when a clear difference is observed between the positive growth control holes and the negative growth control holes, judging inhibition or drug resistance, recording the result, and observing and recording the result once again after 7 days for confirmation. The minimum concentration of drug contained in the control wells grown aseptically was the Minimum Inhibitory Concentration (MIC). The results are shown in Table 1.

TABLE 1 in vitro Activity of example Compounds 1-24 against 3 strains of Mycobacterium tuberculosis

^aMDR-MTB 1699 and MDR-MTB16833 (resistant to rifampicin and isoniazid) were isolated from the chest Hospital of Beijing

The results of the experiments show that, similarly to PBTZ169, the compounds of the invention have a greater in vitro activity against the standard strain H37Rv ATCC 27294 than against rifampicin and isoniazid, and are very sensitive against the clinical isolates MDR-MTB 1699 and MDR-MTB16833 (resistant to rifampicin and isoniazid).

Biological example 2

Pharmacokinetic Properties in vivo

1. Sample pretreatment method

Taking 10.0 μ l of plasma sample (sample taken from refrigerator at-80 deg.C, vortex at room temperature for 30 s after natural dissolution) into 1.5ml centrifuge tube, adding 100 μ l of internal standard solution (dexamethasone (60.0 ng. ml)^-1) .); and transferring 75 mul of supernatant to a 96-hole sample inlet plate filled with equal volume of water, oscillating, mixing uniformly, and performing LC-MS/MS sample injection analysis, wherein the sample injection amount is 10 mul.

2. Standard curve and quality control sample preparation

2.1. Internal standard: a proper amount of dexamethasone standard substance is precisely weighed, dissolved and diluted by dimethyl sulfoxide (DMSO), shaken up, prepared into stock solution with mass concentration of 5000 mug/ml, and diluted into internal standard working solution with concentration of 60 ng/ml.

2.2. Stock solution: an appropriate amount of the compound was precisely weighed and prepared into a 5.0mg/ml stock solution with DMSO.

2.3. Working fluid: and (4) diluting the stock solution according to a gradient to obtain a standard working solution with corresponding gradient concentration and a low-medium and high-quality control working solution. To 45.0. mu.l of blank plasma was added 5.00. mu.l of control standard curve working solution. Then, the treatment was carried out according to the method described in the section "sample treatment method".

3. Sample collection

Isoflurane anesthesia was performed before and after dosing by intraorbital bleeding of 0.03ml, placed in EDTAK2 centrifuge tubes and placed on an ice bath. Centrifuging at 5000rpm and 4 deg.C for 10min, and collecting plasma.

PO blood sampling point: 15,30min,1,2,4,6,8,24h, all plasma samples were stored at-80 ℃ before assay detection.

4. Data processing

The data acquisition and control system software is analyst1.5.1 software (Applied Biosystem). The peak integration mode of the atlas sample is automatic integration; and (4) taking the ratio of the peak area of the sample to the peak area of the internal standard as an index, and performing regression with the concentration of the sample. The regression mode is as follows: linear regression with weight coefficient of 1/X². Pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin Professional v6.3(Pharsight, USA). C_maxThe area AUC under the blood concentration-time curve is the maximum blood concentration measured_(0→t)Calculated by the trapezoidal method, T_maxIs the time of peak blood concentration after administration. The experimental data are expressed as "Mean. + -. standard deviation" (Mean. + -. ICR, n. gtoreq.3) or "Mean" (Mean, n. gtoreq.2).

From the plasma concentration data, post-dose pharmacokinetic parameters were calculated using the WinNonlin V6.3 non-atrioventricular model, see table below.

TABLE 2 oral pharmacokinetic Properties of some of the example compounds (3 mice/group)

The results of the experiments show that the compounds of the 3 examples have a longer half-life (i.e. longer duration of action and less frequent administration) and a drug exposure (C) compared to PBTZ169_max，AUC_0-∞) Greater (i.e., more efficacious at the same dose administered).

Composition examples

EXAMPLE 1 coated tablet

Tablet core prescription:

mixing the above materials, granulating, sieving, grading, drying, and tabletting to obtain 100 tablet cores.

The prescription of the coating liquid is as follows: opadry (Opadry)5g, 80% ethanol in appropriate amount.

EXAMPLE 2 capsules

Prescription:

the preparation method comprises the following steps:

taking the formula amount of raw and auxiliary materials, respectively sieving, adding 5% of polyvinylpyrrolidone alcohol solution and tween 80 to prepare soft materials, granulating by using a 20-mesh sieve, airing at room temperature of 15 ℃, adding sodium dodecyl sulfate, uniformly mixing, filling 0.27g/S into a No. 0 gastric soluble capsule, sampling and testing, wherein the dissolution limit is 80% and the content is 90-110% of the marked amount.

Example 3 granules

Taking 100g of the compound in the embodiment 13, adding a proper amount of dextrin and steviosin, carrying out dry granulation, finishing granules and subpackaging to obtain the compound.

EXAMPLE 4 injection

150g of the compound of example 18 was dissolved in water, and sodium chloride and ethyl p-hydroxybenzoate were dissolved in hot water, followed by mixing and adjusting the pH to 5-7. Diluting the injection water to 1000ml, filtering with hollow fiber membrane, bottling, and sterilizing.

EXAMPLE 5 lyophilized powder for injection

150g of the compound in the embodiment 21 is taken and dissolved in water, 500g of mannitol is additionally added and dissolved in hot water, the mixture is evenly mixed, water for injection is diluted to 5000ml, a hollow fiber membrane is used for filtration, filling, sterilization and freeze-drying are carried out, and the freeze-dried powder injection is obtained.

EXAMPLE 6 dropping pills

Taking 20g of the compound in the embodiment 24 as a raw material medicine for standby; weighing 200g of dripping pill matrix, heating to 80 deg.C for melting, and stirring; adding the raw materials into the adjuvant matrix while stirring, stirring for 30min to homogenize, and keeping the temperature of the liquid medicine not lower than 60 deg.C; injecting the prepared medicinal liquid into a dripping pill machine, and dripping into dripping pills.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A compound for the treatment of tuberculosis, or a pharmaceutically acceptable salt thereof, wherein the compound is:

2- (4- (methyl (4- (trifluoromethoxy) phenyl) amino) piperazin-1-yl) -8-nitro-6- (trifluoromethyl) -4H-benzo [ e ] [1,3] thiazin-4-one.

2. Use of a compound according to any one of claims 1 in the manufacture of a medicament for the treatment of tuberculosis.

3. Use of a pharmaceutical composition comprising a compound according to any one of claims 1 in the manufacture of a medicament for the treatment of tuberculosis.

4. Use according to claim 2 or 3, characterized in that said tuberculosis comprises active tuberculosis, single-drug resistant tuberculosis, multi-drug resistant tuberculosis and extensive multi-drug resistant tuberculosis.

5. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is formulated into any pharmaceutically acceptable dosage form selected from the group consisting of: tablet, capsule, granule, syrup, powder for injection, and injection.