WO2021203811A1 - 苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 - Google Patents

苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 Download PDF

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WO2021203811A1
WO2021203811A1 PCT/CN2021/074578 CN2021074578W WO2021203811A1 WO 2021203811 A1 WO2021203811 A1 WO 2021203811A1 CN 2021074578 W CN2021074578 W CN 2021074578W WO 2021203811 A1 WO2021203811 A1 WO 2021203811A1
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methyl
benzothiazinone
amino
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乔春华
范东光
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苏州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the technical field of the present invention is related to the application of antibacterial drugs, mainly for the research and development of bacilli, such as tuberculosis or leprosy, 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, in particular, it also has an inhibitory effect on Mycobacterium tuberculosis that is clinically resistant.
  • MDR-TB multi-drug resistant strains
  • the anti-tuberculosis drugs targeting DprE1 with benzothiazinone (BTZ) as the backbone are currently being developed at BTZ043 (phase I) and pBTZ169 (phase II).
  • the MICs of the two compounds against the standard strain of tuberculosis are 0.02 respectively.
  • ⁇ M and 0.004 ⁇ M, compared with the existing first-line clinical drug isoniazid (MIC 0.5 ⁇ M) have obvious in vitro antibacterial advantages.
  • the existing benzothiazinone anti-tuberculosis drugs have a high cLogP value and poor druggability.
  • the development of more drug candidates is worth looking forward to.
  • the present invention creatively changes the benzene ring of the benzothiazinone skeleton, especially the creative changes to the substituents, and obtains a series of compounds with unexpected technical effects; the compounds of the present invention have excellent inhibitory effects on tuberculosis bacteria ,
  • the reported activity of the compound is comparable to the current first-line clinical drug isoniazid (MIC 0.5 ⁇ M), it has a very big advantage. It is important to compare with the existing research-stage benzothiazinone anti-tuberculosis drug pBTZ Compared with 169, the compound of the present invention has a lower cLogP value and a better druggability.
  • the present invention adopts the following technical scheme: a benzothiazinone compound whose structure is as follows: .
  • 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, alkene, alkyne, alkoxy, hydroxyl, carboxyl, amino, and substituted amino groups , Preferably H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxy, amino, substituted amino, etc.; R 3 Including one of alkyl, cycloalkyl, alkene, alkynyl, alkoxy, hydroxy, carboxy, amino, substituted amino group, preferably C1-
  • n is 0 to 3;
  • X is O, NH or S;
  • R 6 includes hydrogen, alkyl, cycloalkyl, alkene, alkynyl, aryl, heterocyclic aromatic group, etc.;
  • R 7 includes hydrogen, alkyl One of, cycloalkyl, alkene, alkynyl, alkoxy, hydroxy, carboxy, amino, substituted amino, and heterocyclic aromatic group, preferably H, C1-C6 alkyl, C1-C6 cycloalkyl , C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, amino, substituted amino, etc.;
  • R 8 includes hydrogen, alkyl, cycloalkyl, alkene, alkynyl, One of alkoxy, hydroxy, carboxy, amino, substituted amino, and heterocyclic aromatic group, preferably H, C1-C6 alkyl, C
  • the preparation method of the benzothiazinone compound of the present invention includes the following steps: (1) reacting compound A5 with an amine compound to obtain a benzothiazinone compound; (2) reducing the benzothiazinone compound prepared in step (1) , To obtain compound A7, compound A7 undergoes substitution reaction to obtain benzothiazinone compound; or reduce the benzothiazinone compound prepared in step (1) to obtain compound A7, compound A7 undergoes substitution reaction and azide reaction to obtain A benzothiazinone compound; or the benzothiazinone compound prepared in step (1) undergoes an azide reaction to obtain a benzothiazinone compound.
  • compound A3 or 2-chloro-5-(methylsulfonyl)benzoic acid undergoes chlorination reaction to obtain compound A4; compound A4 is reacted with isothiocyanate to obtain compound A5.
  • Steps (1) and (2) of the present invention are carried out at room temperature, wherein the product of step (1) can be called compound A6, the product of step (2) can be called compound A8, and both compound A6 and compound A8 are
  • the benzothiazinone compound of the present invention the chemical structural formulas of compound A3, compound A4, compound A5, compound A6, compound A7, and compound A8 are as follows: .
  • the amine compound is selected according to the product structure, for example, the chemical structure of the amine compound is as follows: .
  • the present invention discloses the application of the above-mentioned benzothiazinone compound as a tuberculosis inhibitor, or an application in the preparation of anti-tuberculosis drugs.
  • the present invention discloses the application of a pharmaceutical composition containing the above-mentioned benzothiazinone compound as a tuberculosis inhibitor, or an application in the preparation of anti-tuberculosis drugs;
  • the tuberculosis includes active tuberculosis, single-drug-resistant tuberculosis, and multi-drug-resistant tuberculosis , Extensively multi-drug-resistant tuberculosis;
  • the tuberculosis includes tuberculosis and extrapulmonary tuberculosis.
  • the present invention discloses a pharmaceutical composition using the above-mentioned benzothiazinone compound as an active ingredient; the pharmaceutical composition is a tablet, capsule, granule, syrup, powder or injection; the benzothiazinone compound of the present invention can be The active ingredient is combined with a conventional pharmaceutical carrier to obtain a pharmaceutical composition.
  • the present invention discloses a series of structurally innovative compounds.
  • the results of the examples show that the benzothiazinone compound of the present invention has an obvious antibacterial effect, far exceeding the positive control isoniazid (existing clinical drugs), especially the present invention
  • the defect that the existing pBTZ169 has a high cLogP value is solved.
  • the preparation method of the benzothiazinone compound of the present invention is as follows: (1) Compound A5 is reacted with an amine compound to obtain a benzothiazinone compound; (2) the benzothiazinone compound prepared in step (1) is reduced to obtain Compound A7, compound A7 undergo substitution reaction to obtain benzothiazinone compound; or reduce the benzothiazinone compound prepared in step (1) to obtain compound A7, compound A7 undergoes substitution reaction and azide reaction to obtain benzothiazinone compound A thiazinone compound; or the benzothiazinone compound prepared in step (1) undergoes an azide reaction to obtain a benzothiazinone compound.
  • compound A3 is chlorinated to obtain compound A4; compound A4 is reacted with isothiocyanate to obtain compound A5; A4 to A6 are a one-pot reaction.
  • each compound of the present invention can refer to the following schematic route: .
  • the above reaction path can be exemplified as follows: the steps of A1 ⁇ A3 are: compound A1 is nitrated by potassium nitrate and concentrated sulfuric acid under the action of potassium peroxymonosulfonate to obtain compound A3; the steps of B1 ⁇ A3 are: Substituting thiol for the F atom on the benzene ring of the raw material compound B1 to obtain compound thioether B2, which is oxidized to prepare compound B3, then the nitro group in B3 is reduced to an amino group to obtain compound B4, and the amino group is protected with trifluoroacetic anhydride to obtain the compound B5, then nitrate with potassium nitrate and concentrated sulfuric acid to obtain compound B6, remove the trifluoroacetyl group in ammonia methanol solution to obtain compound B7, and use tert-butyl nitrite and cuprous chloride to convert the amino group into chlorine through diazotization.
  • Compound B8 finally under the action of potassium dichromate
  • A3 ⁇ A6 The steps of A3 ⁇ A6 are: compound A3 reacts with oxalyl chloride under the catalysis of N , N -dimethylformamide to form acid chloride compound A4, and then reacts with ammonium thiocyanate using polyethylene glycol as a catalyst to produce compound A5. Finally, the amine compound is added to generate different benzothiazin-4-ones, also known as compound A6.
  • the steps of A6 ⁇ A8 are: the nitro group of compound A6 is reduced to an amino group under the action of iron powder ammonium chloride to obtain compound A7, and then compound A8 is obtained through substitution reaction, such as substitution by tert-butyl nitrite and cuprous chloride
  • substitution reaction such as substitution by tert-butyl nitrite and cuprous chloride
  • 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 6-12 hours; the solvent used for B2 ⁇ B3 is methanol, the reaction temperature is room temperature, and the reaction time is 2 ⁇ 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 methylene chloride, the base used is triethylamine, and the reaction temperature is Ice bath, the reaction time is 0.5 hours; the solvent used for B5 ⁇ B6 is concentrated sulfuric acid, the reaction temperature is ice bath, and the reaction time is 2-10 hours; the solvent used for B6 ⁇ B
  • the time is overnight; the solvent used for B7 ⁇ B8 is acetonitrile, the reaction temperature is reflux, and the reaction time is 0.5 hours; the solvent used for A3 ⁇ A4 is dichloromethane (anhydrous), the reaction temperature is room temperature, and the reaction time is 1 hour; The solvent used in A4 ⁇ A5 is dichloromethane and acetone, the reaction temperature is room temperature, and the reaction time is 0.2 hours; the solvent used in A5 ⁇ A6 is dichloromethane and acetone, the reaction temperature is room temperature, and the reaction time is 2 hours; A6 ⁇ The solvent used in A7 is ethanol (75%), the reaction temperature is room temperature, and the reaction time is 1 hour; the solvent used in A7 ⁇ A8 is acetonitrile, the reaction temperature is reflux, and the reaction time is 0.5 hours.
  • the solvent used for A3 ⁇ A4 is dichloromethane (anhydrous), the reaction temperature is room temperature, and the reaction time is 1 hour;
  • the solvent used in A4 ⁇ A5 is
  • Example 1 Compound 1 : 2- ( 4- (cyclohexylmethyl)piperazin- 1 -yl) -6- (methylsulfonyl) -8- nitro- 4 H - 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 to dissolve to obtain isothiocyanate Ammonium solution; dissolve compound A3 (50 mg, 1eq, R 3 is methyl) in dichloromethane (anhydrous) (5 mL), and add N , N -dimethylformamide (0.05eq., with compound A3 as the benchmark), add oxalyl chloride (0.25 mL, 2.5eq.) dropwise, and stir at room temperature for 0.5 hours after the addition is complete.
  • Example 2-6 The preparation method of the following Examples 2-6 is the same as that of Example 1, except that the amine compound used is replaced, and the rest is unchanged, to obtain different benzothiazinone compounds.
  • Example 3 Compound 15 : 2- ((( 2,3 -dihydrobenzo [b] [1,4] dioxin -6- yl)methyl)(methyl)amino) -6- (methanesulfon Acyl) -8- nitro- 4 H -benzo [ e ] [1,3] thiazin- 4 -one: .
  • Example 2 The operation is the same as in Example 1, and the amine used is 1-(2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl) -N -methylmethylamine.
  • the compound 15 was obtained as a yellow solid (yield 60%).
  • Example 6 Compound 36: 2- ((( 5 -cyclohexyl- 1,3,4 -oxadiazol- 2- yl)methyl)amino) -6- (methylsulfonyl) -8- nitro- 4 H - benzo [ e ][1,3] thiazin -4- one: .
  • Example 7 Compound 30: 2- ((( 1- benzyl- 1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino) -6- (methylsulfonyl) -8- nitro- 4 H -benzo [ e ] [1,3] thiazin- 4 -one: .
  • Dissolve ammonium thiocyanate 46 mg, 1.2 eq
  • 5 mL of anhydrous acetone add polyethylene glycol (0.05 eq, based on compound A3) dropwise, and stir at room temperature to dissolve to obtain ammonium isothiocyanate Solution
  • Dissolve compound A3 50 mg, 1eq, R 3 is methyl
  • dichloromethane anhydrous
  • N , N -dimethylformamide 0.05eq, take compound A3 as Standard
  • add oxalyl chloride (2 mL, 2.5 eq) dropwise and stir at room temperature for 0.5 hours.
  • Example 8 Compound 31: 2- (Methyl(( 1- phenyl- 1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino) -6- (methylsulfonyl ) -8- nitro- 4 H -benzo [ e ] [1,3] thiazin- 4 -one: The same operation as in Example 7, the azide used is phenyl azide, and the rest remain unchanged to obtain compound 31 It is a yellow solid (40% yield).
  • Example 9 Compound 32: 2- ((( 1- ( 4- (dimethylamino)benzyl) -1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino ) -6- (methylsulfonyl) -8- nitro- 4 H -benzo [ e ] [1,3] thiazin- 4 -one: The operation is the same as in Example 7, and the azide used is 4-azide Nitrogen- N , N -dimethylaniline was used to obtain compound 32 as a yellow solid (yield 38%).
  • Example 10 Compound 33: 2- ((( 1 -cyclohexylmethyl- 1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino) -6- (methylsulfonyl ) -8- nitro- 4 H - benzo [ e ][1,3] thiazin- 4 -one: the same operation as in Example 7, the azide used is azidomethylcyclohexane to obtain compound 33 It is a yellow solid (40% yield).
  • Example 11 Compound 34: 2- ((( 1- ( 3 -chlorobenzyl) -1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino) -6- ( Methanesulfonyl) -8- nitro- 4 H -benzo [ e ] [1,3] thiazin- 4 -one: The operation is the same as in Example 7, the azide used is 1-azidomethyl-3 -Chlorobenzene, compound 34 is obtained as a yellow solid (yield 40%).
  • Example 12 Compound 37: 2- ((( 1 -cyclohexyl- 1 H -1,2,3- triazol- 4 -yl)methyl)(methyl)amino) -6- (methylsulfonyl) - 8 -Nitro - 4H - benzo [ e ][1,3] thiazin- 4 -one: The operation is the same as in Example 7 , and the azide used is cyclohexyl azide. Compound 37 was obtained as a yellow solid (yield 36%).
  • the minimum inhibitory concentration MIC ( ⁇ M) and cLogP value of the above compounds against Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) are as follows: .
  • Example 7 The operation is the same as in Example 7, wherein the amine compound and/or azide used are replaced to obtain the product and the minimum inhibitory concentration MIC ( ⁇ M) of the product against Mycobacterium tuberculosis (H37Rv, standard tuberculosis strain) as follows: .
  • reaction system was reacted at 80°C until TLC showed that the reaction was complete; the system was concentrated, the residue was partitioned between ethyl acetate and water, the ethyl acetate layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the product 3-3 was obtained by concentration , Directly used in the next reaction; 3-3 was dissolved in EtOH, 95% hydrazine hydrate was added under stirring, and reacted overnight at room temperature; the reaction system was diluted with water, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine , Dried with anhydrous sodium sulfate, filtered to remove the desiccant, concentrated to obtain 3-4 , directly used in the next reaction.
  • reaction system was diluted with water, extracted with ethyl acetate, the combined organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated by rotary evaporation to obtain 2-4 .
  • Compound 2-4 imidazole, triphenylphosphorus, and carbon tetrabromide were dissolved in DCM in an equivalent proportion.
  • the reaction mixture was stirred until TLC showed that the reaction was complete; the system was concentrated by rotary evaporation, and the residue was purified by column chromatography to obtain 2-5 .
  • the compound of the present invention has a significant antibacterial effect, and the antibacterial effect far exceeds the positive control isoniazid, especially compared with the positive control pBTZ169, the compound of the present invention has a significantly better cLogP value.

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Abstract

一类苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用，具体涉及一类具有苯并噻嗪酮骨架的化合物，该类化合物显示对结核杆菌具有抑制效果，尤其是其对具有临床抗药性的结核杆菌同样具有抑制效果。结果显示：化合物显示出了明显的抑菌效果，抑菌效果远超过阳性对照异烟肼，尤其是与阳性对照pBTZ169相比，化合物具有明显好的cLogP值。

Description

苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 技术领域
本发明的技术领域是有关抗菌药物的应用，主要针对杆菌， 如结核菌或者麻风杆菌，感染人体后的药物的研发；具体涉及一类新的具有苯并噻嗪酮骨架的化合物，该类化合物显示对结核杆菌具有抑制效果，尤其是其对具有临床抗药性的结核杆菌同样具有抑制效果。
 背景技术
针对结核病，现有临床用药的主要问题在于不能满足对耐多药以及广谱耐药菌的有效控制。研发结构新颖，作用机制与现有临床用药不同的新型抗结核药物的应用，是有效控制结核病的途径。由于结核菌生长繁殖缓慢，分裂一代通常需要18-24小时，这使得对结核病的筛查和诊断也变得困难。临床上对至少两种一线药物（异烟肼和利福平）耐药的称作耐多药菌株（MDR-TB）。以苯并噻嗪酮（BTZ)为骨架，靶向DprE1的抗结核药物，现在研发阶段的是BTZ043(phase I)和pBTZ169（phase II)，两个化合物对结核菌标准株的MIC分别为0.02μM和0.004μM，与现有临床一线用药异烟肼（MIC 0.5μM）相比，具有明显体外抗菌优势，但是，现有苯并噻嗪酮抗结核药物cLogP值高，成药性差。而且，临床评价期药物的高失败率，更多候选药物的研发值得期待。
 技术问题
本发明对苯并噻嗪酮骨架苯环进行创造性改变，尤其对取代基进行创造性变化，得到的一系列的化合物，取得预料不到的技术效果；本发明化合物具有优异的对结核菌的抑制效果，所报道的化合物活性与现有临床一线用药异烟肼（MIC 0.5 μM）相比，具有非常大的优势，重要的是，与现有研究阶段的苯并噻嗪酮抗结核药物pBTZ 169相比，本发明的化合物具有更低的cLogP值，具有更好的成药性。
 技术解决方案
本发明采用如下技术方案：一种苯并噻嗪酮化合物，其结构如下：
Figure 359365dest_path_image001
。
其中，R 1包括硝基、卤素、氰基、醛基或者酯基；比如为：硝基(NO 2)、卤素(F、Cl、Br、I)、氰基(CN)、醛基(CHO)、酯基(COOCH 3、COOC 2H 5)等；R 2包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 3包括烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为C1-C6烷基、C1-C6环烷基、C1-C6烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基或者取代的胺基等；R 4包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 5为以下取代基：
Figure 754574dest_path_image002
。
其中，n为0～3；X为O、NH或者S；R 6包括氢、烷基、环烷基、烯烃基、炔烃基、芳基、杂环芳香基等；R 7包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、杂环芳香基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 8包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、杂环芳香基中的一种，优选为H、C1-C6烷基、C1-C6环烷基、C1-C6的烯烃基、C1-C6炔烃基、C1-C6烷氧基、羟基、羧基、氨基、取代胺基等；R 9包括氢、烷基、环烷基、烯烃基、炔烃基、芳基、杂环芳香基等。
本发明苯并噻嗪酮化合物的制备方法包括以下步骤：（1）化合物A5与胺化合物反应，得到苯并噻嗪酮化合物；（2）将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应，得到苯并噻嗪酮化合物；或者将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应后叠氮反应，得到苯并噻嗪酮化合物；或者将步骤（1）制备的苯并噻嗪酮化合物发生叠氮反应，得到苯并噻嗪酮化合物。
进一步的，化合物A3或2-氯-5-(甲基磺酰基)苯甲酸进行氯代反应，得到化合物A4；化合物A4与异硫氰酸盐反应，得到化合物A5。
本发明的步骤（1）、步骤（2）在室温下进行，其中，步骤（1）的产物可称为化合物A6，步骤（2）的产物可称为化合物A8，化合物A6、化合物A8都是本发明苯并噻嗪酮化合物；化合物A3、化合物A4、化合物A5、化合物A6、化合物A7、化合物A8的化学结构式如下：
Figure 490318dest_path_image003
。
胺化合物根据产物结构选择，比如胺化合物的化学结构式如下：
Figure 843939dest_path_image004
 。
其中，取代基的定义同上文。
本发明公开了上述苯并噻嗪酮化合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用。
本发明公开了含有上述苯并噻嗪酮化合物的药物组合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用；所述结核包括活动性结核、单耐药结核、多耐药结核、广泛多耐药结核；所述结核包括肺结核、肺外结核。
本发明公开了以上述苯并噻嗪酮化合物为活性成分的药物组合物；所述药物组合物为片剂、胶囊、颗粒、糖浆、粉剂或者注射剂；可以将本发明苯并噻嗪酮化合物为活性成分与常规药物载体组合，得到药物组合物。
 有益效果
本发明公开了系列结构创新的化合物，实施例结果显示，本发明苯并噻嗪酮化合物显示出了明显的抑菌效果，远超过阳性对照异烟肼（现有临床药物），尤其是本发明解决了现有pBTZ169具有高的cLogP值的缺陷。
 本发明的实施方式
以下通过具体实施例对本发明的方法进行说明，但本发明并不局限于此。实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径或常规方法制备获得。
本发明苯并噻嗪酮化合物的制备方法如下：（1）化合物A5与胺化合物反应，得到苯并噻嗪酮化合物；（2）将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应，得到苯并噻嗪酮化合物；或者将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应后叠氮反应，得到苯并噻嗪酮化合物；或者将步骤（1）制备的苯并噻嗪酮化合物发生叠氮反应，得到苯并噻嗪酮化合物。
进一步的，化合物A3氯代反应，得到化合物A4；化合物A4与异硫氰酸盐反应，得到化合物A5；A4到A6为一锅反应。
具体的，本发明各化合物的制备可以参照以下示意路径：
Figure 845393dest_path_image005
。
其中，取代基的定义同上文。
更具体的，上述反应路径可举例如下：A1→A3的步骤为：化合物A1在过氧单磺酸钾的作用下，经过硝酸钾和浓硫酸进行硝化得到化合物A3；B1→A3的步骤为：用硫醇取代原料化合物B1苯环上的F原子得化合物硫醚B2，经氧化制备化合物B3，再将B3中的硝基还原成氨基得化合物B4，用三氟乙酸酐对氨基进行保护得化合物B5，然后用硝酸钾和浓硫酸硝化得化合物B6，在氨甲醇溶液中脱去三氟乙酰基得化合物B7，用亚硝酸叔丁酯与氯化亚铜通过重氮化将氨基转化成氯得到化合物B8，最后在重铬酸钾和浓硫酸的作用下，将甲基氧化成羧基得到化合物A3。
A3→A6的步骤为：化合物A3在 N ， N-二甲基甲酰胺的催化作用下与草酰氯反应生成酰氯化合物A4，再以聚乙二醇为催化剂与硫氰酸铵反应制备化合物A5，最后加入胺化合物，生成不同的苯并噻嗪-4-酮，也称为化合物A6。
A6→A8的步骤为：化合物A6的硝基在铁粉氯化铵的作用下还原成氨基得化合物A7，再经过取代反应得到化合物A8，比如通过亚硝酸叔丁酯和氯化亚铜发生取代反应生成氯代的苯并噻嗪-4-酮，也称为化合物A8（R1=Cl)，化合物A6和A8均为本发明产物。
比如，A1→A2使用的溶剂为甲醇，反应温度为室温，反应时间为3小时；A2→A3使用的溶剂为浓硫酸，反应温度为60℃，反应时间为2小时；B1→B2使用的溶剂为 N ， N-二甲基甲酰胺，使用的碱为碳酸钾，反应温度为室温，反应时间为6～12小时；B2→B3使用的溶剂为甲醇，反应温度为室温，反应时间为2～5小时；B3→B4使用的溶剂为乙醇（75%），反应温度为室温，反应时间约为1小时；B4→B5使用的溶剂为二氯甲烷，使用的碱为三乙胺，反应温度为冰浴，反应时间为0.5小时；B5→B6使用的溶剂为浓硫酸，反应温度为冰浴，反应时间为2～10小时；B6→B7使用的溶剂为氨甲醇溶液，反应温度为回流，反应时间为过夜；B7→B8使用的溶剂为乙腈，反应温度为回流，反应时间为0.5小时；A3→A4使用的溶剂为二氯甲烷（无水），反应温度为室温，反应时间为1小时；A4→A5使用的溶剂为二氯甲烷和丙酮，反应温度为室温，反应时间为0.2小时；A5→A6使用的溶剂为二氯甲烷和丙酮，反应温度为室温，反应时间为2小时；A6→A7使用的溶剂为乙醇（75%），反应温度为室温，反应时间为1小时；A7→A8使用的溶剂为乙腈，反应温度为回流，反应时间为0.5小时。
实施例 1  化合物 1 ： 2- （ 4- （环己基甲基）哌嗪 -1- 基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：
Figure 716397dest_path_image006
。
将硫氰酸铵（46 mg, 1.2 eq.）溶于 5 mL无水丙酮中，滴加聚乙二醇（0.05eq，以化合物A3为基准），室温下搅拌至溶解，得到异硫氰酸铵溶液；将化合物A3（50 mg，1eq，R 3为甲基）溶于二氯甲烷（无水）（5 mL），滴加 N ， N-二甲基甲酰胺（0.05eq.，以化合物A3为基准），滴加草酰氯（0.25 mL, 2.5eq.），滴加完成后室温下搅拌0.5小时，反应结束后，旋干溶剂和过量的草酰氯，得到相应的中间体酰氯化合物（化合物A4中，R 3为甲基）；再滴加上述异硫氰酸铵溶液，滴加完成后室温下搅拌20分钟，得到中间体A5（化合物A4中，R 3为甲基）；然后滴加1-（环己基甲基）-哌嗪（50 mg, 1.1eq.）的二氯甲烷溶液，滴加完成后室温下搅拌2小时，反应结束，旋干溶剂，直接柱层析纯化，得到化合物 1为黄色固体（20 mg，产率48%）。 1H 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 = 9.2 Hz, 2H), 0.85 (d, J = 10.8 Hz, 2H). 13C 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, 34.7, 31.6, 26.8, 25.9。MS-ESI (m/z): 466.7 [M+H] +。
以下实施例2-6制备方法与实施例1相同，将所用的胺化合物更换，其余不变，得到不同的苯并噻嗪酮化合物。
实施例 2 化合物 2 ： 2- （苄基（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：
Figure 119696dest_path_image007
。
与实施例1操作相同，所用的胺为 N-甲基-1-苯基甲胺，其余不变，得到化合物 2为黄色固体（产率52%）。
1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 9.04 (s, 1H), 7.33 – 7.26 (m, 5H), 5.13 – 4.94 (m, 2H), 3.40 – 3.29 (m, 3H), 3.19 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 165.8, 158.7, 144.0, 140.0, 136.0, 135.0, 129.3, 129.0, 128.3, 127.6, 127.1, 126.9, 54.6, 44.2, 30.0. MS-ESI (m/z): 405.7 [M+H] + 。
实施例 3 化合物 15 ： 2- （（（ 2,3- 二氢苯并 [b] [1,4] 二噁英 -6- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：
Figure 113060dest_path_image008
。
与实施例1操作相同，所用的胺为1-(2,3-二氢苯并[ b] [1,4]二噁英-6-基)- N-甲基甲胺。得到化合物 15为黄色固体（产率60%）。
1H NMR (400 MHz, CDCl 3) δ 9.35 (s, 1H), 9.05 (s, 1H), 6.82 (s, 3H), 5.02 (s, 1H), 4.82 (s, 1H), 4.25 (s, 4H), 3.38 (s, 1H), 3.27 (s, 2H), 3.19 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 165.4, 163.3, 144.5, 143.8, 139.8, 135.8, 133.9, 131.5, 129.0, 128., 126.3, 121.4, 117.6, 117.2, 64.5, 60.2, 53.5, 43.6, 36.4。MS-ESI (m/z): 463.7 [M+H] +。
实施例 4 化合物 26: 8- 硝基 -2- （（ 2- （（（环己基甲基）（甲基）氨基）乙基）（甲基）氨基） -6- （甲磺酰基） -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：
Figure 664127dest_path_image009
。
与实施例1操作相同，所用的胺为 N1-（环己基甲基）- N1, N2-二甲基乙烷-1,2-二胺。得到化合物 26为黄色固体（产率53%）。 1H NMR (400 MHz, CDCl 3) δ 9.28 (s, 1H), 9.03 (s, 1H), 4.13 (s, 1H), 3.77 – 3.64 (m, 2H), 3.48 (s, 2H), 3.40 (s, 1H), 3.19 (s, 3H), 2.97 (s, 1H), 2.69 (s, 1H), 2.50 (s, 3H), 2.31 (s, 2H), 1.78 – 1.64 (m, 4H), 1.55 (s, 1H), 1.38 –1.14 (m, 4H), 0.94 – 0.79 (m, 2H). MS-ESI (m/z): 468.7 [M+H] + 。
实施例 5 化合物 35: 2- （甲基（（ 5- 甲基 -1,3,4- 噁二唑 -2- 基）甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 - 4- 酮：
Figure 135560dest_path_image010
。
与实施例1操作相同，所用的胺为 N-甲基-1-（5-甲基-1,3,4-噁二唑-2-基）甲胺。得到化合物 35为白色固体（产率60%）。 1H NMR (400 MHz, CDCl 3) δ9.34 (s, 1H), 9.09 (s, 1H), 5.30 (s, 2H), 3.51 (s, 3H), 3.19 (s, 3H), 2.54 (s, 3H). MS-ESI (m/z): 412.2 [M+H] +。
实施例 6 化合物 36:  2- （（（ 5- 环己基 -1,3,4- 噁二唑 -2- 基）甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 - 4- 酮：
Figure 580316dest_path_image011
。
与实施例1操作相同，所用的胺为 N-甲基-1-（5-环己基-1,3,4-噁二唑-2-基）甲胺。得到化合物 36为白色固体（产率80%）。 1H NMR (400 MHz, CDCl 3) δ9.34 (s, 1H), 9.09 (s, 1H), 5.31 (s, 2H), 3.51 (s, 3H), 3.19 (s, 3H), 2.90 (d, J = 6.0 Hz, 1H), 2.06 (d, J = 6.0 Hz, 2H), 1.83 (d, J = 6.0 Hz, 2H), 1.70 (s, 1H), 1.41– 1.33 (m, 2H), 1.27 (m, 2H), 0.88 (s, 1H). MS-ESI (m/z): 479.6 [M+H] +。
实施例 7 化合物 30: 2- （（（ 1- 苄基 -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲基磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：
Figure 744582dest_path_image012
。
将硫氰酸铵（46 mg, 1.2 eq）溶于 5 mL无水丙酮中，滴加聚乙二醇（0.05eq，以化合物A3为基准），室温下搅拌至溶解，得到异硫氰酸铵溶液；将化合物A3（50 mg，1eq，R 3为甲基）溶于二氯甲烷（无水）（5 mL），滴加 N ， N-二甲基甲酰胺（0.05eq，以化合物A3为基准），滴加草酰氯（2 mL, 2.5 eq）室温下搅拌0.5小时，反应结束后，旋干溶剂和过量的草酰氯，得到相应的中间体酰氯A4，再加入异硫氰酸铵溶液，室温下搅拌20分钟，得到中间体A5。然后将 N-甲基炔丙胺（150 mg，1.5 eq）的二氯甲烷溶液缓慢滴加到A5 的溶液中。室温下搅拌2小时，反应结束，旋干溶剂，直接柱层析纯化，得到中间体A6 (350 mg，yield 65%)。将中间体A6（84.90 μmol）与苄基叠氮(127.35 μmol) 溶于乙醇（8 mL）中，搅拌下加入硫酸铜（13.73 μmol）、抗坏血酸钠（21.22 μmol）、碳酸钾（59.43 μmol）的水溶液；将反应体系在室温下搅拌24 h，硅藻土过滤，DCM（50 mL × 3）萃取，无水硫酸钠干燥，过滤，浓缩柱层析（D:M = 200:1）得到黄色固体化合物 30 (15 mg; Yield：36%）。 1H NMR (400 MHz, CDCl 3) δ9.22 (s, 1H), 8.95 (s, 1H), 7.72 (s, 1H), 7.26 (s, 2H), 7.17 (s, 3H), 5.41 (s, 2H), 5.04 (s, 2H), 3.44 (s, 3H), 3.09 (s, 3H). MS-ESI (m/z): 486.18 [M+H] +。
以下实施例制备方法与实施例7相同，将所用的叠氮化合物更换，其余不变，得到不同的苯并噻嗪酮化合物。
Figure 782945dest_path_image013
。
实施例 8 化合物 31: 2- （甲基（（ 1- 苯基 -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：与实施例7操作相同，所用的叠氮为苯基叠氮，其余不变得到化合物 31为黄色固体（产率40%）。 1H NMR (400 MHz, CDCl 3) δ9.35 (s, 1H), 9.05 (s, 1H), 8.27 (s, 1H), 7.71 (s, 2H), 7.52 (s, 2H), 7.45 (d, J = 4.0 Hz, 1H), 5.21 (s, 2H), 3.59 (s, 3H), 3.18 (s, 3H).MS-ESI (m/z): 472.6 [M+H] +。
实施例 9 化合物 32: 2- （（（ 1- （ 4- （二甲基氨基）苄基） -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：与实施例7操作相同，所用的叠氮为4-叠氮甲基- N, N-二甲基苯胺，得到化合物 32为黄色固体（产率38%）。 1H NMR (400 MHz, CDCl 3) δ9.32 (s, 1H), 9.03 (s, 1H), 7.63 (s, 1H), 7.17 (d, J = 4.0 Hz, 2H), 6.68 (d, J =2.0 Hz, 2H), 5.37 (s, 2H), 5.09 (s, 2H), 3.48 (s, 3H), 3.18 (s, 3H), 2.94 (s, 6H). MS-ESI (m/z): 529.6 [M+H] +。
实施例 10 化合物 33:  2- （（（ 1- 环己基甲基 -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：与实施例7操作相同，所用的叠氮为叠氮甲基环己烷，得到化合物 33为黄色固体（产率40%）。 1H NMR (400 MHz, CDCl 3) δ9.34 (s, 1H), 9.05 (s, 1H), 7.74 (s, 1H), 5.12 (s, 2H), 4.14 (d, J = 4.0 Hz, 2H), 3.53 (s, 3H), 3.19 (s, 3H), 1.86 (s, 2H), 1.60 – 1.70 (m, 4H), 1.37 (s, 1H), 1.18 (s, 2H), 1.04 – 0.91 (m, 2H). MS-ESI (m/z): 492.6 [M+H] +。
实施例 11 化合物 34: 2- （（（ 1- （ 3- 氯苄基） -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：与实施例7操作相同，所用的叠氮为1-叠氮甲基-3-氯苯，得到化合物 34为黄色固体（产率40%）。 1H NMR (400 MHz, CDCl 3) δ9.31 (s, 1H), 9.04 (s, 1H), 7.76 (s, 1H), 7.31 (s, 2H), 7.24 (s, 1H), 7.15 (d, J = 2.0 Hz, 1H), 5.46 (s, 2H), 5.10 (s, 2H), 3.53 (s, 3H), 3.18 (s, 3H). MS-ESI (m/z): 520.5 [M+H] +。
实施例 12 化合物 37: 2- （（（ 1- 环己基 -1 H-1,2,3- 三唑 -4- 基）甲基）（甲基）氨基） -6- （甲磺酰基） -8- 硝基 -4 H- 苯并 [ e] [1,3] 噻嗪 -4- 酮：与实施例 7操作相同，所用的叠氮为环己基叠氮。得到化合物 37为黄色固体（产率36%）。 1H NMR (400 MHz, CDCl 3) δ9.34 (s, 1H), 9.04 (s, 1H), 7.78 (s, 1H), 5.11 (s, 2H), 4.41 (s, 1H), 3.53 (s, 3H), 3.19 (s, 3H), 2.16 (s, 2H), 1.90 (d, J = 11.8 Hz, 2H), 1.76 –1.71 (m, 4H), 1.43 (m, 2H). MS-ESI (m/z):478.7[M+H] +。
抗结核分枝杆菌活性的测定：抗菌实验采用微孔阿尔玛蓝（Alamar Blue）显色法，为现有常规测试方法，实验步骤简述如下：滴2滴5% 吐温80于磨菌瓶中，刮取培养好的菌株H37Rv （购自ATCC的标准株）置入其中；将磨菌瓶拧紧，震荡5分钟使菌分离；静置20 min，加生理盐水，与1号比浊管比浊至相同浓度，测菌液OD（OD=1为3.8*10 8，OD=0.2为1*10 8），确定比浊管浓度；比浊，换算后稀释，混匀备用；加100 μL的7H9分枝杆菌培养基和OADC增菌液于96孔板第1-11孔中，第12列孔加190 μL 的7H9+OADC；取10 μL 配制好的化合物加入已加培养基的96孔板第12列孔中，混匀；将排枪调至100 μL 刻度，从第12列孔中吸取100 μL 混合液加入第11列孔中，混匀后从第11列孔中吸取100 μL 混合液加入第10列孔中...以此类推，直至加到第2列孔，混匀后废弃100 μL ，不加入第1列孔（对照孔）；吸取100 μL备用菌液加入96孔板中，注意枪头尽量不要接触孔里溶液；加好后将96孔板仔细放好，置于37℃孵育箱中培养8天；将5%吐温80：alamar blue=5:2的溶液配制好，取出96孔板，每孔加入70 μL配制液，再次于37℃孵育箱中孵育2天，观察结果，判读MIC值；现有PBTZ169以及异烟肼用作阳性对照；采用软件ChemDraw Professional 16.0 计算得到cLogP值，为常规测试方法。
上述化合物对结核分枝杆菌（H37Rv，标准结核菌株）的最小抑菌浓度MIC（μM）以及cLogP值如下：
Figure 58068dest_path_image014
。
与实施例7操作相同，其中将所用的胺化合物和/或叠氮更换，得到产物以及产物对结核分枝杆菌（H37Rv，标准结核菌株）的最小抑菌浓度MIC（μM）如下：
Figure 435960dest_path_image015
Figure 177651dest_path_image016
。
2-(乙基((1-苯基-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.33 (s, 1H), 9.04 (s, 1H), 8.31 (s, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.45 – 7.42 (m, 1H), 5.13 (s, 2H), 3.99 (q, J = 6.4 Hz, 2H), 3.18 (s, 3H), 1.51 (t, J = 6.4 Hz, 3H). MS (+ESI) m/z calcd for C 20H 19N 6O 5S 2 + [M+H] += 487.0853, found 487.0855.MIC:0.031μg/mL，0.064 μM。
(S)-6-(甲磺酰基)-8-硝基-2-((1-(1-苯基-1H-1,2,3-三氮唑-4-基)乙基)氨基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.24 (s, 1H), 9.00 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.0 Hz, 2H),7.49 – 7.43 (m, 1H), 5.93 (brs, 1H), 3.18 (s, 3H), 1.82 ( d, J = 8.0 Hz, 3H ). MS (+ESI) m/z calcd for C 19H 17N 6O 5S 2 + [M+H] += 473.0696, found 473.0689. MIC: 0.119μg/mL, 0.252μM。
2-(((1-(4-氟苯基-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 7.93 (br, 2H), 7.45 (t, J = 8.0 Hz, 2H), 5.19 (s, 2H), 3.44 (s, 6H). HRMS (+ESI) m/z calcd for C 19H 16FN 6O 5S 2 + [M+H] += 491.0602, found 491.0602. MIC: 0.031μM。
2-(((1-(3-氟苯基-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.85 (s, 1H), 7.85 – 7.79 (m, 2H), 7.64 (dd, J = 12.0Hz, J = 8.0Hz, 1H), 7.35 (br, 1H), 5.19 (s, 2H), 3.44 (s, 6H). HRMS (+ESI) m/z calcd for C 19H 16FN 6O 5S 2 + [M+H] += 491.0602, found 491.0601. MIC: 0.014μM。
2-(((1-(4-甲氧基苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 20H 19N 6O 6S 2 + [M+H] += 503.0802, found 503.0796. MIC: 0.200μM。
(R)-6-(甲磺酰基)-8-硝基-2-((1-(1-苯基-1H-1,2,3-三氮唑-4-基)乙基)氨基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 8.99 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 6.8 Hz, 2H), 7.54 – 7.52 (m, 2H), 7.49 – 7.47 (m, 1H), 5.93 (br, 1H), 3.18 (s, 3H), 1.82 (br, 3H). MS (+ESI) m/z calcd for C 19H 17N 6O 5S 2 + [M+H] += 473.0696, found 473.0686. MIC:>2μg/mL（>4.0μM）。
2-(甲基((1-吡啶-3-基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 18H 16N 7O 5S 2 + [M+H] += 474.0649, found 474.0647. MIC: 0.530μM。
2-(甲基(1-苯基)-1H-1,2,3-三氮唑-4-基)环丙基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 9.02 (s, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.51 – 7.49 (m, 2H), 7.45 – 7.43 (m, 1H), 3.59 (s, 3H), 3.18 (s, 3H), 2.15 – 1.81 (m, 4H). MS (+ESI) m/z calcd for C 21H 19N 6O 5S 2 + [M+H] += 499.0853, found 499.0854. MIC: >4.0μM。
6-(甲磺酰基)-8-硝基-2-((1-(1-苯基-1H-1,2,3-三氮唑-4-基)环丙基)氨基)-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H) , 7.58 (br, 2H), 7.35 (br, 3H), 3.05 (s, 3H), 1.48 – 1.09 (m, 4H). MS (+ESI) m/z calcd for C 20H 17N 6O 5S 2 + [M+H] += 485.0696, found 485.0696. MIC:> 4.0μM。
2-(((1-(4-氯苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.97 (s, 1H), 8.82 (s, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.66 (d, J = 7.3 Hz, 2H), 5.19 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 19H 16ClN 6O 5S 2 + [M+H] += 507.0307, found 507.0307. MIC: 0.031μM。
2-(甲基((1-(3-三氟甲基)苯基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 1.6 Hz, 2H), 8.27 – 8.25 (m, 2H), 7.88 – 7.82 (m, 2H), 5.21 (s, 2H), 3.43 (s, 6H). MS (+ESI) m/z calcd for C 20H 16F 3N 6O 5S 2 + [M+H] + = 541.0570, found 541.0573. MIC: 0.042μM。
2-(((1-(3-溴苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 14BrN 6O 5S 2 + [M+H] += 550.9801, found 550.9800. MIC: 0.044μM。
2-(((1-(2-氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 16FN 6O 5S 2 + [M+H] += 491.0602, found 491.0600. MIC: 0.024μM。
2-(((1-(3-甲氧基苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 8.97(s,1H),8.82 (s, 1H), 7.47 (br, 3H), 7.06 (br, 1H), 5.19 (s, 2H), 3.84 (s, 3H), 3.44 (s, 6H).  MS (+ESI) m/z calcd for C 20H 19N 6O 6S 2 + [M+H] += 503.0802, found 503.0801. MIC: 0.200μM。
2-(((1-(3-氰基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.04 (d, J = 1.8 Hz, 1H), 8.99 (d, J = 1.6 Hz, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 5.22 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 20H 16N 7O 5S 2 + [M+H] += 498.0649, found 498.0649. MIC: 0.048μM。
2-(甲基((1-( p-甲苯基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 20H 19N 6O 5S 2 + [M+H] += 487.0853, found 487.0853. MIC: 0.115μM。
2-(((1-(3-碘苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.85 (br, 1H), 8.27 (br, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 5.20 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 19H 16IN 6O 5S 2 + [M+H] += 598.9663, found 598.9661. MIC: 0.055μM。
2-(((1-(3-甲基苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 20H 19N 6O 5S 2 + [M+H] += 487.0853, found 487.0851. MIC: 0.100μM。
2-(((1-(2,5-二氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 15F 2N 6O 5S 2 + [M+H] += 509.0508, found 509.0508. MIC: 0.012μM。
2-(((1-(3,5-二氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.04 (s, 1H), 8.99 (s, 1H), 8.89 (s, 1H), 7.78 (d, J = 6.0 Hz, 2H), 7.43 (t, J = 9.2 Hz, 1H), 5.20 (s, 2H), 3.41 (s, 6H). MS (+ESI) m/z calcd for C 19H 15F 2N 6O 5S 2 + [M+H] += 509.0508, found 509.0506. MIC: 0.022μM。
2-(((1-(2,4-二氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 15F 2N 6O 5S 2 + [M+H] += 509.0508, found 509.0504. MIC: 0.024μM。
2-(((1-(3,4-二氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ9.03 (s, 1H), 8.98 (s, 1H), 8.82 (s, 1H), 8.10 (br, 1H), 7.80 (br, 1H), 7.74 – 7.64 (m, 1H), 5.19 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 19H 15F 2N 6O 5S 2 + [M+H] += 509.0508, found 509.0508. MIC: 0.022μM。
2-(((1-(2,6-二氟苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 15F 2N 6O 5S 2 + [M+H] += 509.0508, found 509.0507. MIC: 0.279μM。
2-(((1-(3,5-二氯苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.91 (s, 1H), 8.05 (br, 2H), 7.76 (br, 1H), 5.19 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 19H 13Cl 2N 6O 5S 2 + [M+H] += 540.9917, found 540.9917. MIC: 0.039μM。
2-(((1-(3,4-二氯苯基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.24 (br, 1H), 7.94 (br, 1H), 7.86 (d, J = 7.8 Hz, 1H), 5.19 (s, 2H), 3.44 (s, 6H). MS (+ESI) m/z calcd for C 19H 13Cl 2N 6O 5S 2 + [M+H] += 540.9917, found 540.9916. MIC: 0.068μM。
2-(甲基((1-(噻吩-2-基)甲基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 18H 17N 6O 5S 3 + [M+H] += 493.0417, found 493.0416. MIC: 0.123μM。
2-(甲基((1-((1-甲基-1H-吡咯-2-基)甲基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR indicates 3:7 atropisomeric ratio through the integral value of – CH proton of triazole); 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.13 (s, 0.3 H, minor), 8.00 (s, 0.7 H, major), 6.73 (br, 1H), 6.15 (br, 1H), 5.94 (t, J = 3.0 Hz, 1H), 5.58 (s, 2H), 5.06 (s, 2H), 3.56 (s, 3H), 3.44 (s, 3H), 3.36 (s, 3H). MS (+ESI) m/z calcd for C 19H 20N 7O 5S 2 + [M+H] += 490.0961, found 490.0961. MIC: 0.432μM。
2-(甲基((1-(噻唑-4-基甲基)-1H-1,2,3-三氮唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 17H 16N 7O 5S 3 + [M+H] += 494.0370, found 494.0370. MIC: 3.100μM。
2-(((1-(异噁唑-4-基甲基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 17H 15N 7O 5S 3 + [M+H] += 494.0370, found 494.0370. MIC: 2.012μM。
2-(((1-(异噁唑-4-基)-1H-1,2,3-三氮唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 16H 14N 7O 6S 2 + [M+H] += 464.0441, found464.0441. MIC: 0.065μM。
Figure 703310dest_path_image017
。
将原料酰胺或者硫代酰胺 3-1（1.0 当量），1，3-二氯丙酮（1.05当量）的THF/EtOH（1:2体积比）溶液，在常规搅拌下回流反应至TLC显示反应完成，将体系浓缩，残余物在乙酸乙酯和水中分配，乙酸乙酯层用无水硫酸钠干燥，过滤除去干燥剂，浓缩得到产物 3-2；将化合物 3-2（1.0 当量）溶于DMF中，常规搅拌下加入邻苯二甲酰亚胺钾（1.1当量）。将反应体系在80℃下反应至TLC显示反应完成；将体系浓缩，残余物在乙酸乙酯和水中分配，乙酸乙酯层用无水硫酸钠干燥，过滤除去干燥剂，浓缩得到产物 3-3，直接用于下一步反应;将 3-3溶于EtOH，搅拌下加入95%水合肼，室温下反应过夜；将反应体系用水稀释，乙酸乙酯萃取，合并的有机相用饱和的盐水洗涤后，无水硫酸钠干燥，过滤除去干燥剂，浓缩得到 3-4，直接用于下一步反应。将中间体 3-4（1.0当量），三乙胺（1.05当量）， Boc 2O（1.02当量）的DCM溶液，在室温下反应至TLC显示反应完成。将反应体系用水稀释，乙酸乙脂萃取，合并的有机相用饱和的盐水洗涤后，无水硫酸钠干燥，过滤除去干燥剂，浓缩得到 3-5，直接用于下一步反应。将中间体 3-5（1.0当量）溶于无水THF中，冰浴下常规加入四氢铝锂（4.0当量）。将反应体系升温至70℃，反应至TLC显示反应完成；将体系用1N NaOH的水溶液淬灭，乙酸乙酯萃取，合并的有机相用饱和的盐水洗涤后，无水硫酸钠干燥，过滤除去干燥剂，浓缩得到 3-6，直接用于下一步反应。采用制备三氮唑相同的环合步骤；中间体 A5 （1.0当量）与中间体 3-6（1.05当量）混合，搅拌至TLC显示反应完成，得到环化的终产物。
Figure 516546dest_path_image018
。
2-(甲基(((2-苯基噻唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR indicates 2:3 atropisomeric ratio through the integral value of − CH 2protons and – CH protonof thiazole ); 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.97 (s, 1H), 7.93 (br, 2H), 7.81 (s, 0.4 H, minor), 7.64 (s, 0.6 H, major), 7.48 (br, 3H), 5.19 (s, 1.2 H, major), 5.13 (s, 0.8 H, minor), 3.46 (s, 6H). MS (+ESI) m/z calcd for C 20H 17N 4O 5S 3 + [M+H] += 489.0356, found 489.0356. MIC: 0.014μM。
6-(甲磺酰基)-8-硝基-2-(((2-苯基噻唑-4-基)甲基)氨基)-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 14N 4O 5S 3Na + [M+Na] += 497.0019, found 497.0021，MIC: 2.600μM。
2-(乙基(((2-苯基噻唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 21H 19N 4O 5S 3 + [M+H] += 503.0512, found 503.0512. MIC: 0.030μM。
2-(((2-环己基噻唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 20H 23N 4O 5S 3 + [M+H] +=495.0825, found 495.0826. MIC: 0.061μM。
2-(((2-(3-氟苯基)噻唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR indicates 2:3 atropisomeric ratio through the integral value of −CH 2 protons and – CH protonof thiazole); 1H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H), 8.93 (s, 1H), 8.16 (br, 1H), 7.91 s, 0.4 H, minor), 7.74 (s, 0.6 H, major), 7.50 (br, 1H), 7.45 – 7.36 (m, 1H), 7.32 (br, 1H), 5.19 (s, 1.2 H, major), 5.14 (s, 0.8 H, minor), 3.45 (s, 3H), 3.40 (s, 3H). MS (+ESI) m/z calcd for C 20H 16FN 4O 5S 3 + [M+H] += 507.0261, found 507.0262. MIC: 0.057μM。
2-(((2-(4-氟苯基)噻唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 20H 16FN 4O 5S 3 + [M+H] += 507.0261, found 507.0263. MIC: 0.024μM。
6-(甲磺酰基)-8-硝基-2-(((2-苯基噁唑-4-基)甲基)氨基)-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for  C 19H 15N 4O 6S 2 + [M+H] += 459.0428, found 459.0428. MIC: 4.00μM。
2-(甲基(((2-苯基噁唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (ESI+)  calcd for  C 20H 17N 4O 6S 2 + [M + H] += 473.0584; found 473.0585. MIC: 0.021μM。
2-(((2-(4-氟苯基)噁唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR indicates 3:1 atropisomeric ratio through the integral value of – CH 2protons and – CH protonof oxazole); 1H NMR (400 MHz, CDCl 3) δ 9.33 (s, 1H), 9.04 (s, 1H), 8.00 (br, 2H), 7.83 (s, 0.75 H, minor), 7.77 (s, 0.25 H, major), 7.14 (t, J = 8.0 Hz, 2H), 5.03 (s, 1.5 H, minor), 4.86 (s,0.5 H, major), 3.56 (s, 3H), 3.19 (s, 3H). MS (+ESI) m/z calcd for C 20H 15FN 4O 6S 2 + [M+H] += 491.0490, found 491.0484. MIC: 0.030μM。
2-(((2-(4-氟苯基)噁唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS(ESI +)calcd for  C 19H 13FN 4O 6S 2Na +   [M+Na] +=499.0153; found 499.0145. MIC: 1.431μM。
2-(((2-(环己基甲基)噁唑-4-基)甲基)(甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for  C 20H 23N 4O 6S 2 + [M+H] += 479.1054, found 479.1055. MIC: 0.421μM。
2-(((2-(环己基甲基)噁唑-4-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.23 (s, 1H), 9.03 (s, 1H), 7.97 (br, 1H), 7.63 (s, 1H), 4.73 (s, 2H), 3.21 (s, 3H), 2.75 (t, J = 7.8Hz , 1H), 2.01 (d, J = 12.4 Hz, 2H), 1.71 (d, J = 12.4 Hz, 2H), 1.55 – 1.42 (m, 2H), 1.41 – 1.31 (m, 2H), 1.25 (t, J = 11.8 Hz, 2H). MS (+ESI) m/z calcd for C 19H 21N 4O 6S 2 + [M+H] += 465.0897, found 465.0895. MIC: 3.054μM。
Figure 935894dest_path_image019
。
将肌氨酸盐酸盐2-1（500 mg,3.26 mmol）溶于20 mL DCM中，加入三乙胺（362 mg,3.58 mmol），再加入Boc 2O（853 mg,3.90 mmol），室温下搅拌反应12 h；将反应体系倒入20 mL水中，乙酸乙脂（25 mL×3）萃取。合并的乙酸乙酯层用无水硫酸钠干燥，过滤除去干燥剂，旋蒸浓缩，残余物柱层析（石油醚：乙酸乙酯=5：1）纯化得无色油状物2-2（700 mg, 产率：95%）；将化合物2-2（700 mg,3.41 mmol）溶于30 mL乙醇中，加入水合肼（500 mg,10.2 mmol），将反应体系在回流条件下搅拌4 h。将反应混合物冷却，旋蒸浓缩除去溶剂和过量的水合肼。残余物柱层析（D:M=20:1）纯化得到无色油状物2-3(510 mg, 产率：75%)。MS-ESI (m/z) [M-Boc+H] +: 190.0。将羧酸（R 6COOH）和CDI按照1:1.1比例溶于乙腈中，将体系在搅拌至全部溶解。将反应体系降至室温，加入化合物2-3（1.0当量），搅拌至TLC显示反应完成。将反应体系用水稀释，乙酸乙脂萃取，合并的有机相用无水硫酸钠干燥，过滤除去干燥剂，旋蒸浓缩，得 2-4。将化合物 2-4 、咪唑、三苯基磷、四溴化碳按照等当量比例溶于DCM中。将反应混合物搅拌至TLC显示反应完成; 将体系旋蒸浓缩，残余物柱层析纯化得 2-5。将得到的化合物 2-5溶于DCM中，在冰浴下滴加三氟乙酸（20当量），在室温下搅拌至TLC显示反应完成。加水稀释反应液，用饱和碳酸钾溶液调至pH 10。用乙酸乙脂萃取，合并的有机相用无水硫酸钠干燥，过滤除去干燥剂，旋蒸浓缩得化合物 2-6。采用制备三氮唑相同的环合步骤；中间体 A5 （1.0当量）与中间体 2-6（1.05当量）混合，搅拌至TLC显示反应完成，得到环化的氧二唑或者噻二唑终产物。
Figure 441962dest_path_image020
。
2-(乙基((5-苯基-1,3,4-氧二唑-2-基)甲基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 2H), 7.98 (d, J = 5.8 Hz, 2H), 7.61 (d, J = 7.4 Hz, 3H), 5.34 (s, 2H), 3.96 (q, J = 6.2 Hz, 2H), 3.43 (s, 3H), 1.40 (br, 3H). MS (+ESI) m/z calcd for C 20H 18N 5O 6S 2 + [M+H] += 488.0693, found 488.0693. MIC: 0.029μM。
(S)-2-(甲基(1-(5-苯基-1,3,4-氧二唑-2-基)乙基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 20H 18N 5O 6S 2 + [M+H] += 488.0693, found 488.0689. MIC: 0.496μM。
(R)-2-(甲基(1-(5-苯基-1,3,4-氧二唑-2-基)乙基)氨基)-6-(甲磺酰基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, CDCl 3) δ 9.37 (s, 1H), 9.09 (s, 1H), 8.02 (d, J = 7.4 Hz, 2H), 7.56 – 7.49 (m, 3H), 7.02 (q, J = 5.2 Hz, 1H ), 3.33 (s, 3H), 3.20 (s, 3H), 1.83 (d, J = 5.2 Hz, 3H). MS (+ESI) m/z calcd for C 20H 18N 5O 6S 2 + [M+H] += 488.0693, found 488.0688. MIC: 0.064μM。
(S)-6-(甲磺酰基)- 8-硝基-2-((2-(1-(5-苯基-1,3,4-氧二唑-2-基)乙基)氨基)-4H-苯并[e][1,3]噻嗪-4-酮：MS (+ESI) m/z calcd for C 19H 16N 5O 6S 2 + [M+H] += 474.0537, found 474.0530. MIC: >68μM。
2-(甲基((5-(甲基-1,3,4-氧二唑-2-基)甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 14H 14N 5O 6S 2 + [M+H] += 412.0380, found 412.0382. MIC: 6.582μM。
2-(((5-环己基-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 19H 22N 5O 6S 2 + [M+H] += 480.1006, found 480.1007. MIC: 0.119μM。
2-(((5-环己基甲基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.99 (s, 1 H), 5.28 (s, 2 H), 3.48 (s, 3H), 3.43 (s, 3H), 2.73 (d, J = 4.0 Hz, 2H), 1.70 – 1.56 (m, 6H), 1, 1.23 – 1.07 (m, 3H), 1.01 – 0.93 (m, 2H). HRMS (+ESI) m/z calcd for C 20H 24N 5O 6S 2 + [M+H] += 494.1163, found 494.1163. MIC: 0.063μM。
2-(甲基((5-苯基-1,3,4-氧二唑-2-基)甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.99 (s, 1H), 7.99 (d, J = 6.2 Hz, 2H), 7.59 – 7.63 (m, 3H), 5.40 (s, 2H), 3.52 (d, J = 9.6 Hz, 3H), 3.43 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 16N 5O 6S 2 + [M+H] += 474.0537, found 474.0532. MIC: 0.030μM。
2-( ((5-(4-氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.98 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 5.38 (s, 2H), 3.54 (s, 3H), 3.13 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 15ClN 5O 6S 2 + [M+H] += 508.0147, found 508.0142. MIC: 0.028μM。
2-( ((5-(3-氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 19H 15ClN 5O 6S 2 - [M+H] += 508.0147, found508.0145. MIC: 0.022μM。
2-( ((5-(4-氟苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.99 (s, 1H), 8.10 (t, J = 6.0 Hz, 2H), 7.45 (t, J = 8.4 Hz, 2H), 5.39 (s, 2H), 3.53 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 15FN 5O 6S 2 + [M+H] += 492.0442, found 492.0441. MIC: 0.061μM。
2-( ((5-(3-氟苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.99 (s, 1H), 8.02 (br, 1H), 7.69 (br, 1H), 7.51 – 7.49 (m, 1H), 7.45 – 7.42 (m, 1H), 5.42 (s, 2H), 3.53 (s, 3H), 3.44 (s, 3H).  HRMS (+ESI) m/z calcd forC 19H 15FN 5O 6S 2 +  [M+H] +=  492.0442, found 492.0439. MIC: 0.049μM。
2-( ((5-(2,4-二氟苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.99 (s, 1H), 8.08 (d, J = 6.0 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H), 7.34 (br, 1H), 5.41 (s, 2H), 3.52 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14F 2N 5O 6S 2 + [M+H] += 510.0348, found 510.0345. MIC: 0.040μM。
2-( ((5-(3,5-二氟苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.99 (s, 1H), 7.70 (d, J = 4.4 Hz, 2H), 7.60 (t, J = 8.4 Hz, 1H), 5.40 (s, 2H), 3.54 (s, 3H), 3.43 (s, 3H). HRMS (+ESI) m/z calcd forC 19H 14F 2N 5O 6S 2 +   [M+H] +=  510.0348, found 510.0345. MIC: 0.020μM。
2-( ((5-(3,4-二氟苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (s, 1H), 9.00 (s, 1H), 8.06 (br, 1H), 7.87 (br, 1H), 7.70 (d, J = 7.1 Hz, 1H), 5.40 (s, 2H), 3.53 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14F 2N 5O 6S 2 + [M+H] += 510.0348, found 510.0346. MIC: 0.038μM。
2-( ((5-(3,4-二氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.99 (s, 1H), 8.18 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 5.41 (s, 2H), 3.53 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14Cl 2N 5O 6S 2 + [M+H] += 541.9757, found 541.9755. MIC: 0.043μM。
2-( ((5-(3,5-二氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.99 (s, 1H), 7.97 (br, 2H), 7.92 (br, 1H), 5.40 (s, 2H), 3.53 (s, 3H), 3.43 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14Cl 2N 5O 6S 2 + [M+H] += 541.9757, found541.9753. MIC: 0.022μM。
2-( ((5-(4-氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-(甲磺酰基)- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd forC 19H 15ClN 5O 6S 2 +   [M+H] +=  508.0147, found 508.0143. MIC: 0.089μM。
2-(甲基((5-苯基-1,3,4-氧二唑-2-基)甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.99 (s, 1H), 7.94 (d, J = 5.6 Hz, 2H), 7.58 – 7.54 (m, 3H), 5.45 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd forC 19H 16N 5O 5S 3 +   [M+H] +=  490.0308, found 490.0310. MIC: 0.037μM。
2-( ((5-(3-氯苯基)-1,3,4-氧二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.99 (s, 1H), 7.99 (br, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 5.46 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 15ClN 5O 5S 3 + [M+H] += 523.9918, found 523.9909. MIC: 0.004μM。
2-( ((5-(4-氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 19H 15FN 5O 5S 3 + [M+H] += 508.0214, found 508.0212. MIC: 0.047μM。
2-( ((5-(3-氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.94 (s, 1H) , 8.21 – 8.18 (m, 1H), 7.60 (dd, J = 11.2 Hz, J = 5.5 Hz, 1H), 7.46 – 7.37 (m, 2H), 5.44 (s, 2H), 3.45 (s, 3H), 3.39 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 15FN 5O 5S 3 + [M+H] += 508.0214, found 508.0209. MIC: 0.047μM。
2-( ((5-(2,4-二氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.06 (d, J = 0.4 Hz, 1H), 9.00 (d, J = 0.4 Hz, 1H), 8.33 – 8.27 (m, 1H), 7.65 – 7.55 (m, 1H), 7.38 – 7.28 (m, 1H), 5.49 (s, 2H), 3.50 (s, 3H), 3.45 (s, 3H).  HRMS (+ESI) m/z calcd for C 19H 14F 2N 5O 5S 3 + [M+H] += 526.0120, found 526.0119. MIC: 0.023μM。
2-(((5-(环己基甲基)-1,3,4-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮：HRMS (+ESI) m/z calcd for C 20H 24N 5O 5S 3 +  [M+H] +=510.0934, found 510.0937. MIC: 0.031μM。2-( ((5-(3,4-二氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 9.00 (s, 1H), 8.12 – 8.02 (m, 1H), 7.82 (s, 1H), 7.62 (dd, J = 18.0, 9.2 Hz, 1H), 5.46 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14F 2N 5O 5S 3 +  [M+H] +=526.0120, found: 526.0124. MIC: 0.030μM。2-( ((5-(3-氯-4-氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.99 (s, 1H), 8.17 (d, J = 5.4 Hz, 1H), 7.97 (s, 1H), 7.59 (t, J = 8.6 Hz, 1H), 5.46 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for    C 19H 14ClFN 5O 5S 3 +  [M+H] +=541.9824, found 541.9827. MIC: 0.029μM。2-( ((5-(3,5-二氟苯基)-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.05 (s, 1H), 9.00 (s, 1H), 7.72 (s, 2H), 7.51 (t, J = 8.2 Hz, 1H), 5.48 (s, 2H), 3.49 (s, 3H), 3.44 (s, 3H). HRMS (+ESI) m/z calcd for C 19H 14F 2N 5O 5S 3 +  [M+H] +=526.0120, found: 526.0124. MIC: 0.030μM。2-(((5-(环己基)-1,3,4-1,3,4-噻二唑-2-基)甲基)(甲基)氨基)-6-甲磺酰基- 8-硝基-4H-苯并[e][1,3]噻嗪-4-酮： 1H NMR (400 MHz, DMSO- d 6) δ 9.04 (s, 1H), 8.99 (s, 1H), 5.37 (s, 2H), 3.44 (s, 6H), 3.19 – 3.07 (m, 1H), 2.02 (d, J = 10.8Hz, 2H), 1.74 (d, J = 11.6 Hz, 2H), 1.65 (d, J = 12.2 Hz, 1H), 1.52 – 1.32 (m, 4H), 1.24 (t, J = 11.6 Hz, 1H). HRMS (+ESI) m/z calcd for C 19H 22N 5O 5S 3+ [M+H] +=496.0778, found 496.0780. MIC: 0.032μM 。
结果显示：本发明化合物显示出了明显的抑菌效果，抑菌效果远超过阳性对照异烟肼，尤其是与阳性对照pBTZ169相比，本发明化合物具有明显好的cLogP值。

Claims (10)

  1. 一种苯并噻嗪酮化合物，其特征在于，所述苯并噻嗪酮化合物，的化学结构式如下：
    Figure 590496dest_path_image001
    其中，R 5为以下取代基：
    Figure 38795dest_path_image002
    。
  2. 根据权利要求1所述苯并噻嗪酮化合物，其特征在于，R 1包括硝基、卤素、氰基、醛基或者酯基；R 2包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；R 3包括烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；R 4包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基中的一种；n为0～3；X为O、NH或者S；R 6包括氢、烷基、环烷基、烯烃基、炔烃基、芳基、杂环芳香基中的一种；R 7包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、杂环芳香基中的一种；R 8包括氢、烷基、环烷基、烯烃基、炔烃基、烷氧基、羟基、羧基、氨基、取代胺基、杂环芳香基中的一种；R 9包括氢、烷基、环烷基、烯烃基、炔烃基、芳基、杂环芳香基中的一种。
  3. 权利要求1所述苯并噻嗪酮化合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用。
  4. 含有权利要求1所述苯并噻嗪酮化合物的药物组合物作为结核菌抑制的应用，或者在制备抗结核药物中的应用。
  5. 根据权利要求3或者4的应用，其特征在于，所述结核包括活动性结核、单耐药结核、多耐药结核、广泛多耐药结核；所述结核包括肺结核、肺外结核。
  6. 以权利要求1所述苯并噻嗪酮化合物为活性成分的药物组合物。
  7. 根据权利要求6所述药物组合物，其特征在于，所述药物组合物为片剂、胶囊、颗粒、糖浆、粉剂或者注射剂。
  8. 权利要求1所述苯并噻嗪酮化合物的制备方法，其特征在于，包括以下步骤：
    （1）化合物A5与胺化合物反应，得到苯并噻嗪酮化合物；
    （2）将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应，得到苯并噻嗪酮化合物；
    或者将步骤（1）制备的苯并噻嗪酮化合物还原，得到化合物A7，化合物A7发生取代反应后叠氮反应，得到苯并噻嗪酮化合物；
    或者将步骤（1）制备的苯并噻嗪酮化合物发生叠氮反应，得到苯并噻嗪酮化合物。
  9. 根据权利要求8所述苯并噻嗪酮化合物的制备方法，其特征在于，化合物A3或2-氯-5-(甲基磺酰基)苯甲酸进行氯代反应，得到化合物A4；化合物A4与异硫氰酸盐反应，得到化合物A5。
  10. 根据权利要求8所述苯并噻嗪酮化合物的制备方法，其特征在于，反应在室温下进行。
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