CN111303075A - Benzothiazinone derivatives and their preparation methods and their application as anti-tuberculosis drugs - Google Patents

Abstract

The invention discloses a benzothiazinone derivative, a preparation method thereof and application thereof as an antituberculosis drug, and particularly relates to a novel compound with a benzothiazinone skeleton, wherein the compound has an inhibition effect on tubercle bacillus, especially on tubercle bacillus with clinical drug resistance. The invention creatively changes the benzene ring of the benzo buprofezin skeleton, particularly creatively changes the substituent group to obtain a series of compounds, thereby achieving unexpected technical effects; the compound has excellent effect of inhibiting tubercle bacillus, has great advantages compared with the prior clinical first-line drug isoniazid (MIC 0.5 mu M) in the activity of the reported compound, and importantly has lower cLogP value and better druggability compared with the prior benzothiazinone antituberculous drug pBTZ169 in the research stage.

Description

Benzothiazinone derivatives and their preparation methods and their application as anti-tuberculosis drugs

technical field

The technical field of the present invention is related to the application of antibacterial drugs, mainly aimed at the research and development of bacteria, such as Mycobacterium tuberculosis or Bacillus leprae, after infecting the human body; specifically, it relates to a new class of compounds with a benzothiazinone skeleton, such compounds It is shown to have an inhibitory effect on Mycobacterium tuberculosis, especially, it also has an inhibitory effect on Mycobacterium tuberculosis with clinical drug resistance.

Background technique

Tuberculosis is one of the infectious diseases and remains one of the leading causes of death in developing countries. There are many Mycobacterium tuberculosis carriers. On average, one out of every three people is a Mycobacterium tuberculosis carrier, that is, there are nearly 2 billion Mycobacterium tuberculosis carriers in the world. In addition, due to the slow growth and reproduction of TB bacteria, the split generation usually takes 18-24 hours, which makes the screening and diagnosis of TB difficult. Bacteria that are clinically resistant to at least two first-line drugs (isoniazid and rifampicin) are called multidrug-resistant strains (MDR-TB). XDR-TB has now spread to all continents. The discovery of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) bacteria has been closely associated with an increase in the number of deaths from tuberculosis worldwide ( Science 1992, 257, 1055-1064). Moreover, the continued development of multidrug-resistant (MDR) and extensively drug-resistant (XDR-TB) mycobacteria is extremely dangerous, with the proportion of XDR-TB exceeding 20% in some countries ( Nature Med . 2007, 13, 295-298). As the number of tuberculosis patients continues to increase, about 3 million people worldwide die of tuberculosis every year.

As a developing country, China has about 4.5 million tuberculosis patients, the second largest number of tuberculosis patients in the world, and about 450,000 people die of tuberculosis every year. Tuberculosis has become a serious public health problem. The main problem of the existing clinical drugs is that they cannot meet the effective control of multi-drug-resistant and broad-spectrum drug-resistant bacteria. The application of new anti-tuberculosis drugs with novel structures and different mechanisms of action from existing clinical drugs is an effective way to control tuberculosis.

With benzothiazinone (BTZ) as the backbone, anti-tuberculosis drugs targeting DprE1 are currently in the development stage of BTZ043 (phase I) and pBTZ169 (phase II). The two compounds have MICs of 0.02 for standard TB strains respectively Compared with the existing clinical first-line drug isoniazid (MIC 0.5 μM), μM and 0.004 μM have obvious in vitro antibacterial advantages. However, the existing benzothiazinone anti-tuberculosis drug has a high cLogP value and poor druggability. Moreover, due to the high failure rate of drugs in the clinical evaluation period, the development of more candidate drugs is worth looking forward to.

SUMMARY OF THE INVENTION

The invention makes creative changes to the benzene ring of the benzothiazinone skeleton, especially makes creative changes to the substituents, and obtains a series of compounds, which achieves unexpected technical effects; the compounds of the invention have excellent inhibitory effect on Mycobacterium tuberculosis , the reported activity of the compound has a very great advantage compared with the existing clinical first-line drug isoniazid (MIC 0.5 μM), and importantly, it is comparable to the current research stage of the benzothiazinone anti-tuberculosis drug pBTZ 169. The compounds of the present invention have lower cLogP values and better druggability.

The present invention adopts following technical scheme:

A kind of benzothiazinone derivative, its structure is as follows:

Wherein, R ₁ includes nitro, halogen, cyano, aldehyde or ester group; for example: nitro (NO ₂ ), halogen (F, Cl, Br, I), cyano (CN), aldehyde (CHO) ), ester group (COOCH ₃ , COOC ₂ H ₅ ), etc.; R ₂ includes one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, hydroxyl, carboxyl, amino, and substituted amino groups R ₃ Including one of alkyl, cycloalkyl, alkene, alkynyl, alkoxy, hydroxyl, carboxyl, amino, substituted amine, preferably C1-C6 alkyl, C1-C6 cycloalkyl, C1- C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, amino or substituted amine, etc.; R ₄ includes hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy , one of hydroxyl, carboxyl, amino, and substituted amine groups, preferably H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkene, C1-C6 alkynyl, C1-C6 alkoxy group, hydroxyl group, carboxyl group, amino group, substituted amino group, etc.; R ₅ is the following substituent group:

Wherein, n1=1～3; n2=1～3; R ₆ includes hydrogen, alkyl group, cycloalkyl group, alkene group, alkynyl group, alkoxy group, hydroxyl group, carboxyl group, amino group, substituted amino group, benzyl group, sulfonic group One of the acyl groups, preferably H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, benzyl, sulfonyl etc.; R ₉ includes hydrogen, alkyl, cycloalkyl or carbonyl, preferably C1-C6 alkyl, C1-C6 cycloalkyl, ketone, etc.; R ₁₀ includes alkyl, cycloalkyl, heterocyclyl, substituted heterocycle A cyclic group or an aryl group, preferably a C1-C6 alkyl group, a C1-C6 cycloalkyl group, a phenyl group, a substituted phenyl group, etc.; R ₁₁ includes an alkyl group, a cycloalkyl group or an aryl group, preferably a C1-C6 alkyl group, C1-C6 cycloalkyl, phenyl, substituted phenyl, etc.; R ₁₂ includes alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl or aryl, preferably C1-C6 alkyl, C1-C6 cycloalkane base, phenyl, substituted phenyl, etc., for example R ₅ is the following substituent:

。

.

The preparation method of benzothiazinone derivative of the present invention comprises the following steps:

(1) Compound A5 reacts with an amine compound to obtain a benzothiazinone derivative;

(2) Reducing the benzothiazinone derivative prepared in step (1) to obtain compound A7; compound A7 undergoes a substitution reaction to obtain the benzothiazinone derivative.

Further, compound A3 or 2-chloro-5-(methylsulfonyl)benzoic acid is subjected to chlorination reaction to obtain compound A4; compound A4 is reacted with isothiocyanate to obtain compound A5.

In the present invention, the product of step (1) may be referred to as compound A6, and the product of step (2) may be referred to as compound A8. Compound A6 and compound A8 are both benzothiazinone derivatives of the present invention; compound A3 and compound A4 , Compound A5, Compound A6, Compound A7, Compound A8 The chemical structural formulas are as follows:

The chemical structural formula of the amine compound is as follows:

Wherein, the definition of the substituent is the same as above.

The invention discloses the application of the above-mentioned benzothiazinone derivatives as tuberculosis inhibition or in the preparation of anti-tuberculosis drugs.

The invention discloses the application of a pharmaceutical composition containing the above-mentioned benzothiazinone derivatives as tuberculosis inhibition, or in the preparation of anti-tuberculosis drugs; the tuberculosis includes active tuberculosis, monodrug-resistant tuberculosis and multidrug-resistant tuberculosis Tuberculosis, extensively multidrug-resistant tuberculosis; the tuberculosis includes pulmonary tuberculosis, extrapulmonary tuberculosis.

The present invention discloses a pharmaceutical composition using the above-mentioned benzothiazinone derivatives as active ingredients; the pharmaceutical compositions are tablets, capsules, granules, syrups, powders or injections; the benzothiazinone derivatives of the present invention can be derivatized The compound is an active ingredient combined with a conventional pharmaceutical carrier to obtain a pharmaceutical composition.

The present invention discloses a series of compounds with innovative structures. The results of the examples show that the benzothiazinone derivatives of the present invention show obvious bacteriostatic effect, far exceeding that of the positive control isoniazid (existing clinical drug), especially the present invention. The invention solves the defect that the existing pBTZ169 has a high cLogP value.

Detailed ways

The method of the present invention will be described below through specific examples, but the present invention is not limited thereto. The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials can be prepared from commercial channels or conventional methods unless otherwise specified.

The preparation method of benzothiazinone derivative of the present invention is as follows:

(1) Compound A5 reacts with an amine compound to obtain a benzothiazinone derivative;

(2) Reducing the benzothiazinone derivative prepared in step (1) to obtain compound A7; compound A7 undergoes a substitution reaction to obtain the benzothiazinone derivative.

Further, compound A3 is chlorinated to obtain acid chloride A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are one-pot reactions.

Specifically, the preparation of each compound of the present invention can refer to the following schematic routes:

The chemical structural formula of the amine compound is as follows:

Wherein, the definition of the substituent is the same as above.

More specifically, the above reaction path can be exemplified as follows:

The steps of A1→A3 are: oxidation of compound A1 in potassium peroxymonosulfonate, and then nitrification by potassium nitrate and concentrated sulfuric acid to obtain compound A3;

The steps of B1→A3 are: replacing the F atom on the benzene ring of the starting compound B1 with thiol to obtain compound thioether B2, and then oxidizing to prepare compound B3, and then reducing the nitro group in B3 to amino group to obtain compound B4, using trifluoroethyl The amino group is protected by acid anhydride to obtain compound B5, which is then nitrated with potassium nitrate and concentrated sulfuric acid to obtain compound B6, and the trifluoroacetyl group is removed in ammonia methanol solution to obtain compound B7. The amino group is converted into chlorine to obtain compound B8, and finally, under the action of potassium dichromate and concentrated sulfuric acid, the methyl group is oxidized into a carboxyl group to obtain compound A3;

The steps from A3 to A6 are as follows: compound A3 reacts with oxalyl chloride under the catalysis of N,N -dimethylformamide to form acid chloride compound A4, and then uses polyethylene glycol as a catalyst to react with ammonium thiocyanate to prepare compound A5, Finally, the amine compound is added to generate different benzothiazin-4-ones, also known as compound A6, which is the product of the present invention;

The steps of A6→A8 are: the nitro group of compound A6 is reduced to an amino group under the action of iron powder and ammonium chloride to obtain compound A7, and then compound A8 is obtained through a substitution reaction, for example, through tert-butyl nitrite and cuprous chloride. The substitution reaction generates chlorinated benzothiazin-4-one, which is the product of the present invention.

For example, the solvent used in A1→A2 is methanol, the reaction temperature is room temperature, and the reaction time is 3 hours; the solvent used in A2→A3 is concentrated sulfuric acid, the reaction temperature is 60 °C, and the reaction time is 2 hours; The solvent used in B1→B2 It is N,N -dimethylformamide, the base used is potassium carbonate, the reaction temperature is room temperature, and the reaction time is 6 to 12 hours; the solvent used for B2→B3 is methanol, the reaction temperature is room temperature, and the reaction time is 2～12 hours. 5 hours; the solvent used for B3→B4 is ethanol (75%), the reaction temperature is room temperature, and the reaction time is about 1 hour; the solvent used for B4→B5 is dichloromethane, the base used is triethylamine, and the reaction temperature is Ice bath, the reaction time is 0.5 hour; the solvent used for B5→B6 is concentrated sulfuric acid, the reaction temperature is ice bath, and the reaction time is 2 to 10 hours; the solvent used for B6→B7 is ammonia methanol solution, the reaction temperature is reflux, the reaction The time was overnight; the solvent used for B7→B8 was acetonitrile, the reaction temperature was reflux, and the reaction time was 0.5 hour; the solvent used for A3→A4 was dichloromethane (anhydrous), the reaction temperature was room temperature, and the reaction time was 1 hour; The solvents used in A4→A5 were dichloromethane and acetone, the reaction temperature was room temperature, and the reaction time was 0.2 hours; the solvents used in A5→A6 were dichloromethane and acetone, the reaction temperature was room temperature, and the reaction time was 2 hours; A6→ The solvent used in A7 was ethanol (75%), the reaction temperature was room temperature, and the reaction time was 1 hour; the solvent used in A7→A8 was acetonitrile, the reaction temperature was reflux, and the reaction time was 0.5 hours.

Example 1 Compound 1: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][1,3 ]thiazin-4-one

Ammonium thiocyanate (46 mg, 1.2 eq.) was dissolved in 5 mL of anhydrous acetone, polyethylene glycol (0.05 eq., based on compound A3) was added dropwise, and stirred at room temperature until dissolved to obtain isothiocyanate Ammonium acid solution;

Compound A3 (50 mg, 1eq., _R3 is methyl) was dissolved in dichloromethane (anhydrous) (5 mL), and N,N -dimethylformamide (0.05eq. was added dropwise, taking compound A3 as standard), add oxalyl chloride (0.25 mL, 2.5eq.) dropwise, and stir at room temperature for 0.5 hours after the completion of the dropwise addition. After the reaction, spin dry the solvent and excess oxalyl chloride to obtain the corresponding intermediate acid chloride compound (in compound A4) , R ₃ is methyl); then add the above ammonium isothiocyanate solution dropwise, and stir at room temperature for 20 minutes after the completion of the dropwise addition, and the reaction ends to obtain intermediate A5 (in compound A5, R ₃ is methyl); then dropwise Add a solution of 1-(cyclohexylmethyl)-piperazine (50 mg, 1.1 eq.) in dichloromethane, and after the completion of the dropwise addition, stir at room temperature for 2 hours, the reaction is completed, spin dry the solvent, and purify directly by column chromatography to obtain Compound 1 was a yellow solid (20 mg, 48% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.95 (s, 1H), 3.89 (s, 4H), 3.43 (s, 3H), 2.46 (s, 4H), 2.13 ( d, J = 10.8 Hz, 2H), 1.75 (d, J = 10.8 Hz, 2H), 1.65 (s, 4H), 1.50 (s, 1H), 1.19 (d, J = 9.2Hz, 2H), 0.85 ( d, J = 10.8 Hz, 2H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 165.6, 161.8, 144.6, 139.7, 135.6, 133.7, 128.2, 126.4, 64.7, 52.8, 46.1, 43.5, 34.6.7, 3 , 26.8, 25.9. MS-ESI (m/z): 466.7 [M+H] ⁺ .

The preparation methods of the following Examples 2 to 18 are the same as those of Example 1, except that the amine compound used is replaced, and the rest remain unchanged to obtain different benzothiazinone derivatives.

Example 2 Compound 3: 2-(3-(Methoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][ 1,3]thiazin-4-one

The same operation as in Example 1, the amine used was azetidine-3-monooxy-methyl oxime, and the rest remained unchanged, to obtain compound 3 as a white solid (yield 46%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 9.08 (s, 1H), 5.05 - 5.04 (m, 4H), 3.93 (s, 3H), 3.19 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 165.3, 162.0, 146.0, 144.1, 139.8, 135.6, 134.3, 128.3, 126.1, 62.5, 60.2, 43.52. MS-ESI (m/z): 384.6 [M+H] ⁺ .

Example 3 Compound 4: 2-(3-(Ethoxyimino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][ 1,3]thiazin-4-one

The same operation as in Example 1, the amine used was azetidine-3-mono-oxo-ethyl oxime, and the rest remained unchanged to obtain compound 4 as a white solid (yield 36%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 9.06 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.16 (d, J = 7.0 Hz, 2H) , 3.18 (s, 3H), 1.30 – 1.22(m, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 165.6, 162.0, 143.6, 142.2, 140.2, 135.6, 135.4, 127.8, 126.7, 70.8, 49.6, 44.1, 14.4. MS-ESI (m/z): 398.7 [M+H] ⁺ .

Example 4 Compound 5: 2-(3-((benzyloxy)imino)azetidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ] [1,3]thiazin-4-one

The same operation as in Example 1, the amine used is azetidine-3-monooxy-benzyl oxime. Compound 5 was obtained as a white solid (41% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.98 (s, 1H), 7.39-7.34 (m, 5H), 5.18 (s, 2H), 5.12 (s, 2H), 5.05 (s, 2H), 3.44 (s, 3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ 165.3, 144.1, 139.8, 134.3, 128.8, 128.6, 128.4, 128.3, 126.1, 76.2, 43.5. MS- ESI (m/z): 460.6 [M+H] ⁺ .

Example 5 Compound 6: 2-(7-(Cyclohexylmethyl)-2,7-diazaspiro[3.5]nonyl-2-yl)-6-(methylsulfonyl)-8-nitro -4H -benzo[ e ][1,3]thiazin-4-one

The same operation as in Example 1, the amine used was 7-(cyclohexylmethyl)-2,7-diazaspiro[3.5]nonane. Compound 6 was obtained as a yellow solid (31% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.99 (s, 1H), 3.89 – 3.67 (m, 4H), 3.29 (s, 3H), 2.97 – 2.87 (m, 4H) , 2.57 – 2.52 (m, 2H), 2.23 – 2.21 (m, 2H), 2.13 – 2.01 (m, 2H), 1.85 (d, J = 11.6 Hz, 2H), 1.77 – 1.68 (m, 3H), 1.60 (s, 2H), 1.29 – 1.20 (m, 2H), 1.02 – 0.88 (m, 2H). MS(+ESI) m/z calcd for C ₂₃ H ₃₁ N ₄ O ₅ S ₂ [M+H] ⁺ = 507.17, found 506.8.

Example 6 Compound 7: ( E )-2-(3-(ethoxyimino)pyrrolidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ] [1,3]thiazin-4-one

The same operation as in Example 1, the amine used is ( E )-pyrrolidone-3-mono-oxo-ethyloxime. Compound 7 was obtained as a yellow solid (30% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 2H), 9.03 (s, 2H), 4.60 (s, 2H), 4.43 (s, 2H), 4.19-4.22 (m, 2H), 4.15 ( s, 2H), 4.14 (s, 2H), 3.99 (s, 2H), 3.19 (s, 3H), 3.00-3.04 (m, 2H), 2.91 (s, 2H), 1.24-1.27 (m, 3H) , (s,3H). HRMS (ESI+) m/z [M+Na] ⁺ calcd for C ₁₅ H ₁₆ N ₄ O ₆ S ₂ Na: 435.0403; found: 435.0401.

Example 7 Compound 8: ( E )-2-(3-(ethoxyimino)pyrrolidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ] [1,3]thiazin-4-one

The same operation as in Example 1, the amine used was ( E )-pyrrolidone-3-mono-oxy-benzyl oxime. Compound 8 was obtained as a yellow solid (35% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 2H), 9.03 (s, 2H), 4.60 (s, 2H), 4.43 (s, 2H), 4.20 (s, 2H), 4.15 (s, 2H), 4.14 – 4.06 (m, 2H), 3.99 (s, 2H), 3.19 (s, 3H), 3.19 – 3.13 (m, 3H), 3.03 (s, 2H), 2.91 (d, J = 7.2 Hz , 2H), 1.27 (s, 3H), 1.24 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 165.5, 160.3, 143.6, 139.8, 136.3, 135.1, 127.5, 127.2, 63.9, 63.1, 18.7, 53.8, 49.9, 48.6, 47.0, 37.7, 36.7, 36.7, 36.74. , 35.1, 35.0, 29.6, 29.3, 26.6 , 26.0, 22.7. MS-ESI (m/z): 474.6 [M+H] ⁺ .

Example 8 Compound 9: 6-(Methylsulfonyl)-8-nitro-2-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)piperidin-1-yl ) -4H -benzo[ e ][1,3]thiazin-4-one

The same operation as in Example 1, the amine used was 1-(piperidin-4-ylmethyl)-4-(trifluoromethyl)piperidine. Compound 9 was obtained as a yellow solid (31% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (s, 1H), 9.02 (s, 1H), 3.18 (s, 3H), 2.94 (d, J = 10.0 Hz, 2H), 2.22 (d, J = 6.4 Hz, 2H), 1.99 – 1.93 (m, 8H), 1.83 (d, J = 12.4 Hz, 2H), 1.64 – 1.61 (m, 2H), 1.36 – 1.24 (m, 4H). ¹³ C NMR(151 MHz, CDCl ₃ ) δ 166.1, 161.3, 144.0, 139.8, 136.1, 134.7, 127.6, 127.4 (q, J = 278.6 Hz), 127.1, 63.6, 44.1, 40.3 (q, J = 27.3 Hz), 33.8, 31.5 30.1, 29.7, 24.6. HRMS (ESI+) m/z [M+H] ⁺ calcd for C ₂₁ H ₂₆ F ₃ N ₄ O ₅ S ₂ : 535.1291; found: 535.1269.

Example 9 Compound 10: 2-(4-(Methoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][1, 3] Thiazin-4-one

The same operation as in Example 1, the amine used is piperidine-4-mono-oxy-methyl oxime. Compound 10 was obtained as a yellow solid (47% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 (br, 2H), 4.09 (br, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 2.78 (s, 2H), 2.64 (s, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 165.9, 162.5, 144.1, 140.5, 135.4, 135.1, 127.9, 127.0, 44.5, 44.2, 39.9. MS(+ESI) m/z calcd for C ₁₅ H ₁₇ N ₄ O ₆ S ₂ [M+H] ⁺ = 413.06, found412.7.

Example 10 Compound 11: 2-(4-(ethoxyimino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][1, 3] Thiazin-4-one

The same operation as in Example 1, the amine used is piperidine-4-mono-oxo-ethyl oxime. Compound 11 was obtained as a yellow solid (yield 49%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 9.04 (s, 1H), 4.18 – 4.01 (m, 6H), 3.19 (s, 3H), 2.79 (s, 2H), 2.64 ( s, 2H), 1.24 – 1.28 (m, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 165.9, 144.0, 140.1, 135.7, 134.9, 127.7, 128.0, 69.5, 44.2, 25.2, 14.5. MS(+ESI) m/z calcd for C ₁₆ H ₁₉ N ₄ O ₆ S ₂ [M+H] ⁺ = 427.07, found426.7.

Example 11 Compound 12: 2-(4-((benzyloxy)imino)piperidin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ][ 1,3]thiazin-4-one

The same operation as in Example 1, the amine used is piperidine-4-monooxo-benzyl oxime. Compound 12 was obtained as a yellow solid (44% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.35 (s, 5H), 5.10 (s, 2H), 4.19 (br, 2H), 3.99 (br, 2H), 3.19 (s, 3H), 2.83 (br, 2H), 2.65(br, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 165.9, 153.2 144.1 140.2, 137.5, 135.7, 135.0, 128.5, 128.2 , 128.0, 127.7, 127.1, 44.2, 29.9, 25.4. MS(+ESI) m/zcalcd for C ₂₁ H ₂₁ N ₄ O ₆ S ₂ [M+H] ⁺ = 489.09, found488.6.

Example 12 Compound 13: 2-(4-(Cyclohexylmethyl)-3-oxapiperazin-1-yl)-6-(methylsulfonyl)-8-nitro- 4H -benzo[ e ] [1,3]thiazin-4-one

The same operation as in Example 1, the amine used was 1-(cyclohexylmethyl)piperazin-2-one. Compound 13 was obtained as a yellow solid (yield 68%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 9.06 (s, 1H), 4.51 (s, 1H), 4.29 (s, 1H), 4.11 (dd, J = 14.2, 7.2 Hz, 1H), 3.53 (s, 2H), 3.32 (d, J = 7.0 Hz, 2H), 3.19 (s, 3H), 2.04 (s, 1H), 1.72 (s, 2H), 1.67 – 1.64 (m, 5H) ), 1.27 (s, 2H), 1.00 (s, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 144.0, 140.4, 135.1, 127.8, 127.0, 53.6, 45.8, 44.2, 35.9, 30.7, 26.2, 25.7. MS-ESI (m/z): 480.6 [M+H] ⁺ .

Example 13 Compound 14: ( R )-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-(methylsulfonyl)-8 -Nitro- 4H -benzo[ e ][1,3]thiazin-4-one

The same operation as in Example 1, the amine used is (R-)-2methyl-1,4-dioxo-8-azaspirodecane. Compound 14 was obtained as a yellow solid (27% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 9.04 (s, 1H), 4.29 (s, 2H), 4.13 (d, J = 7.6 Hz, 2H), 3.97 (s, 2H) , 3.51 (t, J = 7.9 Hz, 3.18(s, 3H), 1.87 (s, 4H), 1.32 (d, J = 5.9 Hz, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 165.2, 160.5 , 143.0, 139.0, 135.0, 134.9, 126.6, 126.1, 105.3, 71.6, 69.9, 43.2, 43.2, 28.7, 17.3. MS-ESI (m/z): 441.6 [M+H] ⁺ .

Example 14 Compound 27: 2-(4-(2-(2-methyl-5-nitro- 1H -imidazol-1-yl)ethyl)piperazin-1-yl)-6-(methanesulfonic acid acyl)-8-nitro- 4H -benzo[ e ][1,3]thiazin-4-one

The same procedure as in Example 1, the amine used was 1-(2-(2-methyl-5-nitro- 1H -imidazol-1-yl)ethyl)piperazine. Compound 27 was obtained as a yellow solid (51% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 9.05 (s, 1H), 7.94 (s, 1H), 4.48 (s, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 3.18 (s, 3H), 2.75 – 2.62 (m, 6H), 2.53 (s, 3H). MS(+ESI) m/z calcd for C ₁₉ H ₂₂ N ₇ O ₇ S ₂ [M+H ] ⁺ =524.10, found 523.6.

Example 15 Compound 28: 2-(4-(Cyclohexylmethyl)-4,7-diazaspiro[2.5]octyl-7-yl)-6-(methylsulfonyl)-8-nitro -4H -benzo[ e ][1,3]thiazin-4-one

The same operation as in Example 1, the amine used was 4-(cyclohexylmethyl)-4,7-diazaspiro[2.5]octane. Compound 28 was obtained as a yellow solid (52% yield). . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 9.02 (s, 1H), 4.10 – 3.68 (m, 4H), 3.18 (s, 3H), 3.14 (s, 2H), 2.67 ( d, J = 4.8 Hz, 2H), 1.77 – 1.70 (m, 4H), 1.43 (s, 1H), 1.25 – 1.19 (m, 4H), 0.91 – 0.88 (m, 4H), 0.73 (s, 2H) . MS(+ESI) m/z calcd for C ₂₂ H ₂₉ N ₄ O ₅ S ₂ [M+H] ⁺ = 493.16, found 492.7.

Example 16 Compound 29: 2-(7-Isobutyl-4,7-diazaspiro[2.5]octyl-4-yl)-6-(methylsulfonyl)-8-nitro- 4H -Benzo[ e ][1,3]thiazin-4-one

The same operation as in Example 1, the amine used was 7-isobutyl-4,7-diazaspiro[2.5]octane. Compound 29 was obtained as a yellow solid (60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (s, 1H), 9.02 (s, 1H), 3.18 (s, 3H), 2.87 - 2.68 (m, 2H), 2.21 (s, 2H), 2.07 ( s, 2H), 2.03 (s, 2H), 1.74- 1.70 (m, 2H), 1.67 (s, 1H), 1.04 (m, 2H), 0.88 – 0.87 (m, 6H). MS-ESI (m/ z): 452.6 [M+H] ⁺ .

Example 17 Compound 38: 6-(Methylsulfonyl)-8-nitro-2-(4-phenylpiperidin-1-yl) -4H -benzo[ e ][1,3]thiazine- 4-keto

The same operation as in Example 1, the amine used is 4-phenylpiperidine. Compound 38 was obtained as a yellow solid (44% yield). ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 9.04 (s, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 10.2 Hz, 3H), 5.47 ( s, 1H), 4.54 (s, 1H), 3.44 (s 1H), 3.20 (s, 4H), 2.98 – 2.92 (m, 1H), 2.11 (s, 2H), 1.83 (dd, J = 22.8, 11.8 Hz, 2H),1.62 (s, 1H). MS(+ESI) m/z calcd for C ₂₀ H ₂₁ N ₃ O ₅ S ₂ [M+H] ⁺ = 446.08, found445.6.

Example 18 Compound 20: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl) -4H -benzo[ e ][1,3]thiazine-4 -ketone

In the same operation as in Example 1, compound A3 was replaced with 2-chloro-5-(methylsulfonyl)benzoic acid, the amine was 1-cyclohexylmethylpiperazine, and the rest were unchanged, and compound 20 was obtained as a white solid (product). rate 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.97 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 4.11 (s, 2H), 3.71 (s, 2H), 3.11 (s, 3H), 2.52 (s, 4H), 2.19 (s, 2H), 1.78 – 1.62 (m, 6H), 1.50 (s, 1H), 1.25 – 1.20 (m, 2H) ), 0.89 – 0.87 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.4, 160.9, 140.5, 138.7, 129.7, 129.6, 126.8, 123.8, 65.1, 53.0, 46.2, 44.3, 35.0, 3 26.7, 26.0. MS(+ESI) m/z calcd for C ₂₀ H ₂₈ N ₃ O ₃ S ₂ [M+H] ⁺ =422.16, found 421.7.

Example 19 Compound 21: 8-Chloro-2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(methylsulfonyl)-4hydro-benzo[ e ][1,3] Thiazin-4-one

The preparation of this compound was prepared from compound 1 of the 8-nitro group.

To a solution of compound 1 (46.6 mg, 1 eq.) in EtOH/water (v/v3: 1, 4 mL) was added NH ₄ Cl (21.2 mg, 4 eq.) and iron powder (22.4 mg, 4 eq.), the resulting The mixture was heated to reflux with stirring for 1 hour, after cooling to room temperature, the mixture was filtered through celite, washed with MeOH, the filtrate was concentrated under reduced pressure and the mixture was partitioned with DCM and water, the organic phase DCM was washed with brine, dried , filtered and concentrated to give the intermediate product; a mixture of tert-butyl nitrite (10.3 mg, 1 eq.), copper chloride dihydrate (17 mg, 1 eq.) and acetonitrile preheated at 60°C was added at 60°C. was stirred at ℃ for 2 hours, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, filtered, and concentrated. The residue was purified by column chromatography to give compound 21 as a yellow solid (24 mg, yield 53%) . ¹ HNMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.11 (s, 1H), 4.12 (s, 2H), 3.79 (s, 2H), 3.11 (s, 3H), 2.53 (s, 4H) ), 2.18 (d, J = 6.4 Hz, 2H), 1.78 – 1.68 (m, 6H), 1.48 (s, 1H), 1.27 – 1.21 (m, 2H), 0.91 – 0.82 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 167.3 , 160.4, 140.3, 138.2, 131.4, 129.9, 127.7, 125.9, 65.0, 52.9, 44.3, 34.9, 31.7, 29.6, 26.7, 26.0 calcd MS(+ESI) m/z for C ₂₀ H ₂₇ ClN ₃ O ₃ S ₂ [M+H] ⁺ = 456.12, found 455.7.

The preparation methods of the following Examples 20 to 22 are the same as those of Example 20, except that the starting compounds used are replaced, and the rest remain unchanged to obtain different benzothiazinone derivatives.

Example 20 Compound 22: 8-Chloro-2-(3-( ethoxyimino )azetidin-1-yl)-6-(methylsulfonyl)-4H-benzo[ e ][ 1,3]thiazin-4-one

The same operation as in Example 19, the starting material used is compound 4. Compound 22 was obtained as a yellow solid (60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 8.18 (s, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 4.18 (d, J = 6.8 Hz, 2H) , 3.13 (s, 3H), 1.63 – 1.25 (m, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.8, 160.5, 142.6, 140.7, 137.9, 131.4, 130.0, 128.1,125.6, 70.7, 44.3, 29.6, 14.5. HRMS (ESI+) m/z [M+Na] ⁺ calcd for C ₁₄ H ₁₄ ClN ₃ O ₄ S ₂ Na: 410.0006; found: 409.9986.

Example 21 Compound 23: 8-Chloro-2-(4-(methoxyimino)piperidin-1-yl)-6-(methylsulfonyl) -4H -benzo[ e ][1, 3] Thiazin-4-one

The same operation as in Example 20 was carried out, and the starting material used was compound 10. Compound 23 was obtained as a yellow solid (90% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (s, 1H), 8.15 (s, 1H), 4.17 (s, 2H), 3.87 (s, 5H), 3.13 (s, 3H), 2.77 (s, 2H), 2.62 (s, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 167.2, 140.6, 138.0, 131.5, 130.0, 127.8, 125.9, 61.6, 46.0, 44.3, 29.9, 25.1. MS(+ESI) m/z calcd for C ₁₅ H ₁₇ ClN ₃ O ₄ S ₂ [M+H] ⁺ = 402.03, found401.6.

Example 22 Compound 24: 8-Chloro-2-(4-( ethoxyimino )piperidin-1-yl)-6-(methylsulfonyl)-4H-benzo[ e ][1, 3] Thiazin-4-one

The same operation as in Example 20 was carried out, and the starting material used was compound 11. Compound 24 was obtained as a yellow solid (60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 8.14 (s, 1H), 4.33 – 4.05 (m, 4H), 3.93 (s, 2H), 3.13 (s, 3H), 2.77 ( s, 2H), 2.62 (s, 2H), 1.28 – 1.22 (m, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 167.0, 149.9, 140.5, 138.1, 131.5, 130.0, 127.8, 124.5, 120.7, 69.4, 46.0, 44.3, 29.9, 25.2, 14.5. MS(+ESI) m/z C ₁₅ H ₁₉ ClN ₃ O ₄ S ₂ [M+H] ⁺ =416.05, found 415.6.

Example 23 Compound 16: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(isopropylsulfonyl)-8-nitro- 4H -benzo[ e ][1 ,3]thiazin-4-one

4-Fluoro-2-methyl-1-nitrobenzene (500 mg, 3.22 mmol) was dissolved in 20 mL of dry DMF, potassium carbonate (757 mg, 5.48 mmol) was added, followed by dropwise addition of isopropylthiol (378 mg, 3.55 mmol), and the system was stirred at room temperature for 12 h. The system was placed in an ice bath, potassium peroxomonosulfonate (757 mg, 5.48 mmol) was added in batches, the system was stirred at room temperature for 6 h again; 50 mL of water was added to the system, ethyl acetate (50 mL × 3 ) extraction, the organic phase was washed successively with aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid B3 (726 mg, yield 90%, substituent R ₃ is isopropyl);

Compound B3 (622 mg, 2.42 mmol) was dissolved in 12 mL of ethanol and 4 mL of water, iron powder (1350 mg, 24.17 mmol) and ammonium chloride (1290 mg, 24.17 mmol) were added with stirring, and the system was heated to 80 °C, Stirred for 3 h; the system was filtered with celite, extracted with DCM (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain yellow solid B4 (500 mg, yield 90%);

Compound B4 (500 mg, 2.2 mmol) was dissolved in 50 mL of DCM, triethylamine (445 mg, 4.4 mmol) and trifluoroacetic anhydride (540 mg, 4.4 mmol) were added with stirring, and the system was stirred at room temperature for 3 h The system was extracted with 50 mL of water, DCM (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid B5 (700 mg, yield 99%);

Compound B5 (368 mg, 1.14 mmol) was dissolved in 5 mL of concentrated sulfuric acid, potassium nitrate (357 mg, 3.53 mmol) was slowly added under an ice bath, and the mixture was stirred for 2 h. The reaction system was slowly poured into an ice-water bath, a white solid was precipitated, filtered, washed with ice-water three times, and dried to obtain white crystals B6 (385 mg, yield 90%);

Compound B6 (385 mg, 0.96 mmol) was dissolved in 10 mL of 2M ammonia solution in methanol, and the system was heated to 80 °C for 12 h. The mixture was cooled to room temperature, concentrated, and subjected to column chromatography (PE:EA=2:1) to obtain yellow solid B7 (208 mg, yield 80%);

Compound B7 (200 mg, 0.74 mmol) was dissolved in 10 mL of acetonitrile, cupric chloride dihydrate (140 mg, 0.92 mmol) and tert-butyl nitrite (95 mg, 0.92 mol) were added under stirring, and the system was heated to 65 ℃, stirred for 2 h; the system was filtered with celite, extracted with DCM (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (PE:EA=1:1) to obtain yellow solid B8 (130 mg, yield 60%);

Compound B8 (100 mg, 0.34 mmol) was added to a solution of potassium dichromate (201 mg, 0.69 mmol) in glacial acetic acid (10 mL). After stirring for 15 minutes, concentrated sulfuric acid (336 mg, 1.836 mmol) was added and the solution was heated to reflux for 4 hours. The mixture was then cooled, water (50 mL) was added, and extracted with ethyl acetate (3 x 50 mL). The organic phase was collected, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 20 mL of ethyl acetate, the organic phase was washed with 2M sodium hydroxide (20 mL), the aqueous phase was adjusted to pH 2 with 12N HCl, extracted with ethyl acetate (3 × 50 mL), the organic phase was collected, washed with anhydrous sulfuric acid Dry over sodium and concentrate to give white solid compound A3 (65 mg, 60% yield), MS-ESI (m/z): 329.7 [M+Na] ⁺ ;

Ammonium thiocyanate (46 mg, 1.2 eq.) was dissolved in 5 mL of anhydrous acetone, polyethylene glycol (0.05 eq., based on compound A3) was added dropwise, and stirred at room temperature until dissolved to obtain isothiocyanate Ammonium acid solution;

Compound A3 (65 mg, 0.2 mmol) was dissolved in DCM (20 mL), a catalytic amount of DMF was added, oxalyl chloride (134 mg, 1.06 mmol) was slowly added dropwise under nitrogen protection, and the mixture was reacted at room temperature for 2 h. Concentrated to obtain a white solid; the white solid obtained in the previous step was dissolved in dry DCM (20 mL), added to ammonium isothiocyanate solution, reacted under nitrogen protection for 0.5 h, and then added 1-(cyclohexylmethyl)piperidine oxazine (60 mg, 0.3 mmol), react at room temperature for 5 h, spin dry the solvent, filter with cyclohexane/ethyl acetate (10:1), and wash with water (30 mL×3) to obtain yellow solid compound 16 ( 40 mg, 55% yield). ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.23 (s, 1H), 8.95 (s, 1H), 4.14 (s, 2H), 3.87 (s, 2H), 3.38 – 3.30 (m, 1H), 2.54 (s , 4H), 2.18 (d, J = 8.0 Hz, 2H), 1.83 – 1.66(m, 6H), 1.49 (s, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.24 ( s, 2H), 0.93 – 0.85 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.1, 161.7, 144.1, 136.1, 129.0, 127.0, 77.2, 76.9, 76.8, 64.9, 55.8, 34.7, 31.6, 31.3, 26.5, 25.9, 25.5. ^. MS-ESI (m/z): 494.7 [M+H] ⁺ .

The preparation methods of the following Examples 24 to 26 are the same as those of Example 25, except that the thiol used is replaced, and the rest remain unchanged to obtain different benzothiazinone derivatives.

Example 24 Compound 17: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(ethanesulfonyl)-8-nitro- 4H -benzo[ e ][1,3 ]thiazin-4-one

The same operation as in Example 24, the thiol used was ethanethiol. Compound 17 was obtained as a yellow solid (yield 61%). ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.23 (s, 1H), 8.95 (s, 1H), 4.14 (s, 2H), 3.87 (s, 2H), 3.38 – 3.30 (m, 1H), 2.54 (br , 4H), 2.18 (d, J = 8.0 Hz, 2H), 1.83 –1.66 (m, 6H), 1.49 (s, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.24 (d, J = 10.4 Hz, 2H), 0.93 – 0.85 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.1, 161.6, 144.0, 138.2, 135.9, 135.4, 128.3, 127.1, 65.0, 50.4, 35.0, 31.7, 26.7, 26.0, 7.3. MS-ESI (m/z): 480.6 [M+H] ⁺ .

Example 25 Compound 18: 6-(tert-Butylsulfonyl)-2-(4-(cyclohexylmethyl)piperazin-1-yl)-8-nitro- 4H -benzo[ e ][1 ,3]thiazin-4-one

The same operation as in Example 24, the thiol used was tert-butyl mercaptan. Compound 18 was obtained as a yellow solid (yield 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.93 (s, 1H), 4.14 (s, 2H), 3.88 (s, 2H), 2.54 (br, 4H), 2.18 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 15.2 Hz, 4H), 1.70 (s, 2H), 1.49 (s, 1H), 1.40 (s, 9H), 1.24 (s, 2H), 0.88 ( s, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.0, 161.5, 143.7, 137.4, 135.7, 135.3, 130.0, 126.6, 65.0, 60.7, 53.0, 46.5, 34.9, 31.6, 26.6, 25.9. MS-ESI (m/z): 508.7 [M+H] ⁺ .

Example 26 Compound 19: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-8-nitro-6-(benzenesulfonyl) -4H -benzo[ e ][1,3 ]thiazin-4-one

The same operation as in Example 24, the thiol used was thiophenol. Compound 19 was obtained as a yellow solid (55% yield). ¹ HNMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 9.03 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 6.7 Hz, 1H), 7.57 ( d, J = 7.0 Hz, 2H), 3.98 (br, 4H), 2.52 (br,4H), 2.17 (s, 2H), 1.84 – 1.64 (m, 6H), 1.48 (s, 1H), 1.21 (s , 2H), 0.87 (s, 2H). ¹³ C NMR (151 MHz, CDCL ₃ ) Δ 166.1, 161.6, 160.6, 144.0, 141.4, 139.7, 135.0, 134.3, 129.8, 127.6, 65.4, 54.0, 45.6, 39.9, 35.0, 26.7. MS-ESI (m/z): 528.6 [M+H] ⁺ .

Example 27 Compound 25: 2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(isopropylsulfonyl) -4H -benzo[ e ][1,3]thiazine -4-keto

The same operation was performed as in Example 23, except that 4-fluoro-2-methyl-1-nitrobenzene was replaced with 3-fluorotoluene, and the rest remained unchanged to obtain compound 25 as a yellow solid (yield 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.07 (s, 1H), 4.13 (s, 2H), 3.79 (s, 2H), 3.28 (dt, J = 13.4, 6.8 Hz, 1H), 2.52 (s, 4H), 2.18 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 16.0 Hz, 3H), 1.65 (d, J = 20.0 Hz, 3H), 1.49 (s, 1H), 1.33 (s, 3H), 1.32 (s, 3H), 1.24 (s, 2H), 0.87 (s, 2H). ¹³ CNMR (151 MHz, DMSO-d ₆ ) δ 165.4, 163.4, 144.5, 133.9 , 128.2 , 121.4 , 117.6 ,117.2, 64.5, 60.2, 53.5, 43.6, 36.4, 21.0, 14.5. MS-ESI (m/z): 449.7 [M+H] ⁺ .

Determination of activity against Mycobacterium tuberculosis

The antibacterial experiment adopts the microporous Alamar Blue color development method, which is the existing conventional test method. The experimental steps are briefly described as follows: drop 2 drops of 5% Tween 80 in the grinding bottle, scrape the cultured strain H37Rv (Standard strain purchased from ATCC) into it; screw the grinding bottle tightly, shake it for 5 minutes to separate the bacteria; let it stand for 20 minutes, add normal saline, turbidity with No. 1 turbidimetric tube to the same concentration, and measure the OD of the bacterial solution (OD=1 is 3.8*10^8, OD=0.2 is 1*10^8), determine the concentration of the turbidimetric tube; turbidity, dilute after conversion, and mix for use; add 100 μL of 7H9 mycobacterial medium and Add OADC enrichment solution to the 1-11 wells of the 96-well plate, add 190 μL of 7H9+OADC to the 12th column; take 10 μL of the prepared compound and add it to the 12th column of the 96-well plate to which the medium has been added. Homogenize; adjust the spray gun to the 100 μL scale, pipette 100 μL of the mixture from the 12th column of wells and add it to the 11th column of wells. .And so on, until added to the second column of wells, after mixing, discard 100 μL, do not add the first column of wells (control wells); pipette 100 μL of the standby bacterial solution into the 96-well plate, be careful not to touch the hole as much as possible with the pipette tip After adding the 96-well plate carefully, place it in a 37°C incubator for 8 days; prepare a solution of 5% Tween 80:alamar blue=5:2, take out the 96-well plate, and each well Add 70 μL of the preparation solution, incubate again in a 37°C incubator for 2 days, observe the results, and interpret the MIC value; the existing PBTZ169 and isoniazid are used as positive controls; the software ChemDrawProfessional 16.0 is used to calculate the cLogP value, which is a routine test method.

The minimum inhibitory concentration MIC (μM) and cLogP value of the above compounds against Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) are as follows:

The results showed that the compound of the present invention showed obvious bacteriostatic effect, and the antibacterial effect far exceeded that of the positive control isoniazid, especially compared with the positive control pBTZ169, the compound of the present invention had a significantly better cLogP value.

Claims (10)

1. A benzothiazinone derivative, characterized in that, the chemical structural formula of the benzothiazinone derivative is as follows:

wherein R is₅Are the following substituents:

、

、

、

、

、

、

。

2. benzothiazinone derivative according to claim 1, wherein R₁Including nitro, halogen, cyano, aldehyde or ester groups; r₂Comprises one of hydrogen, alkyl, naphthenic base, alkylene, alkynyl, alkoxy, hydroxyl, carboxyl, amino and substituted amino; r₃Comprises one of alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, hydroxyl, carboxyl, amino and substituted amino; r₄Comprises one of hydrogen, alkyl, naphthenic base, alkylene, alkynyl, alkoxy, hydroxyl, carboxyl, amino and substituted amino; n1= 1-3; n2= 1-3; r₆Comprises one of hydrogen, alkyl, naphthenic base, alkylene, alkynyl, alkoxy, hydroxyl, carboxyl, amino, substituted amino, benzyl and sulfonyl; r₉Including hydrogen, alkyl, cycloalkyl or carbonyl; r₁₀Including alkyl, cycloalkyl, heterocyclyl, substituted heterocyclylsA group or an aryl group; r₁₁Including alkyl, cycloalkyl or aryl; r₁₂Including alkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl, or aryl.

3. Use of the benzothiazinone derivative according to claim 1 as a tubercle bacillus inhibitor or in the manufacture of an anti-tubercular agent.

4. Use of a pharmaceutical composition comprising a benzothiazinone derivative according to claim 1 as a tubercle bacillus inhibitor or in the manufacture of an anti-tubercular drug.

5. The use according to claim 3 or 4, characterized in that said tuberculosis comprises active tuberculosis, single-resistant tuberculosis, multi-resistant tuberculosis, extensive multi-resistant tuberculosis; the tuberculosis includes pulmonary tuberculosis and extrapulmonary tuberculosis.

6. A pharmaceutical composition comprising the benzothiazinone derivative according to claim 1 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet, capsule, granule, syrup, powder or injection.

8. A process for preparing a benzothiazinone derivative according to claim 1 comprising the steps of:

(1) reacting the compound A5 with an amine compound to obtain a benzothiazinone derivative;

(2) reducing the nitro of the benzothiazinone derivative prepared in step (1) to obtain a compound A7; and carrying out substitution reaction on the compound A7 to obtain the benzothiazinone derivative.

9. The process for producing a benzothiazinone derivative according to claim 8 wherein compound A3 or 2-chloro-5- (methylsulfonyl) benzoic acid is subjected to chlorination reaction to give compound a 4; reaction of compound a4 with isothiocyanate affords compound a 5.

10. A process for preparing a benzothiazinone derivative according to claim 8 wherein the reduction is carried out under the action of iron powder, ammonium chloride.