WO2021073629A1 - Compound having effect of agonizing sirt6 acetylation activity, sirt6 agonist and use thereof - Google Patents

Compound having effect of agonizing sirt6 acetylation activity, sirt6 agonist and use thereof Download PDF

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WO2021073629A1
WO2021073629A1 PCT/CN2020/121732 CN2020121732W WO2021073629A1 WO 2021073629 A1 WO2021073629 A1 WO 2021073629A1 CN 2020121732 W CN2020121732 W CN 2020121732W WO 2021073629 A1 WO2021073629 A1 WO 2021073629A1
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compound
sirt6
nmr
dmso
agonist
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张健
赵明珠
魏嘉呈
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上海交通大学医学院
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This application relates to the technical field of medicinal chemistry, in particular to a compound that has the activity of agonizing SIRT6 acetylation, as well as the SIRT6 agonist obtained by using the compound and the application of the SIRT6 agonist in the preparation of drugs for the treatment of SIRT6-mediated diseases application.
  • SIRT6 belongs to the III family of Histone deacetylases (HDACs) and contains 7 members (SIRT1-7). SIRT6 is widely expressed in various tissues of mammals. In organisms, SIRT6 is mainly involved in the maintenance of genome stability, DNA repair, inflammation, and glucose and Lipid metabolism is closely related to heart disease, diabetes, obesity, cancer, aging and other diseases. Up-regulation of SIRT6 activity is considered to be one of the new strategies for the treatment of various diseases mentioned above. Therefore, the research on SIRT6 small molecule agonists is of great significance to the development of SIRT6-mediated drugs for related diseases.
  • HDACs Histone deacetylases
  • Patent CN109384694A discloses a SIRT6 small molecule agonist with triphenyl ring bissulfonamide as the core, but the acetylation activity of the SIRT6 small molecule agonist still needs to be improved.
  • the purpose of this application is to provide a compound with the activity of agonizing SIRT6 acetylation, or a pharmaceutically acceptable salt thereof, which can significantly improve the deacetylation activity of SIRT6, and then can be used as a SIRT6 agonist and applied to drugs for related diseases In preparation.
  • the present application provides a compound having the activity of agonizing SIRT6 acetylation, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (I):
  • X 1 , X 2 , X 3 , and X 4 each independently represent a hydrogen atom or a halogen; Y represents a hydrogen atom, a methyl group or a halogen; and R represents a carboxamido group, a cyano group or a nitrogen-containing heterocyclic ring.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • the formamide group is formamide, formyl fatty amine or formyl aromatic amine.
  • the nitrogen-containing heterocyclic ring is triazole, tetrazole, imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole or thiadiazole.
  • R represents
  • the pharmaceutically acceptable salt of the compound represented by formula (I) has a structure represented by formula (II) or formula (III):
  • the compound having the activity of agonizing SIRT6 acetylation has the structure shown in formula (Compound 1) to (Compound 29):
  • the application also provides a SIRT6 agonist, comprising any of the above-mentioned compounds or pharmaceutically acceptable salts thereof.
  • the application also provides the use of any of the aforementioned compounds and their pharmaceutically acceptable salts, or SIRT6 agonists, in the preparation of medicines for the treatment of SIRT6-mediated diseases.
  • the compound or pharmaceutically acceptable salt thereof that has the activity of stimulating SIRT6 acetylation described in the present application can significantly stimulate the deacetylation activity of SIRT6 in in vitro experiments, and is of great significance to the development of drugs for SIRT6-mediated related diseases .
  • Figure 1 Fluorescence quantitative method to detect the multiple of SIRT6 deacetylation activity activated by preferred compounds at 100 ⁇ M.
  • Figure 2 Fluorescence quantitative method detection shows that compound 1 activates SIRT6 deacetylation activity in a concentration-dependent manner, and its half maximum effect concentration (EC 50 ) is 1.5 ⁇ 0.2 ⁇ M; compound 2 activates SIRT6 deacetylation activity in a concentration-dependent manner. Its half maximum effect concentration (EC 50 ) is 2.3 ⁇ 0.3 ⁇ M; compound 8 activates SIRT6 deacetylation activity in a concentration-dependent manner, and its half maximum effect concentration (EC 50 ) is 3.3 ⁇ 0.3 ⁇ M; compound 23 activates concentration-dependently The deacetylation activity of SIRT6 has a half maximum effect concentration (EC 50 ) of 60.1 ⁇ 4.5 ⁇ M. When 400 ⁇ M, the deacetylation activity of SIRT6 is activated nearly 40 times.
  • This application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 , X 3 , and X 4 are the same or different and represent a hydrogen atom or a halogen
  • Y represents a hydrogen atom, a methyl group, or a halogen.
  • the halogen refers to fluorine, chlorine, bromine or iodine.
  • R represents a formamide group, a cyano group, or a nitrogen-containing heterocyclic ring.
  • the compound represented by formula (I) has specific structures represented by formulas (compound 1) to (compound 29).
  • the specific preparation method is as follows.
  • the raw material aniline compound (10 g, 49.0 mmol) was dissolved in 20 mL of pyridine, the raw material 4-nitro-2-carboxylic acid methyl ester benzenesulfonyl chloride (16.45 g, 58.8 mmol) was added, and the reaction was carried out at room temperature for more than 8 hours. After the completion of the reaction monitored by TLC, the reaction was cooled to room temperature, 1N hydrochloric acid was added, the pH was adjusted to 3-4, a pale yellow precipitate was precipitated, and the intermediate Int I (18.6 g, yield: 84.9%) was obtained by filtration and drying. It can be used directly in the next reaction.
  • the intermediate Int II (13.9 g, 33.32 mmol) was dissolved in 30 mL of pyridine, and the raw material 3,5-dichlorobenzenesulfonyl chloride (16.45 g, 58.8 mmol) 1) was added at 0° C. and reacted for 1 hour. Raise to room temperature and react for 6 hours. After TLC monitoring the completion of the reaction, at 0°C, 2N hydrochloric acid was added to adjust the pH to 3-4, and a solid was precipitated. The white intermediate Int III (16.5 g, yield: 79.0%) was obtained by silica gel column chromatography.
  • the other compounds can be prepared by the similar method described in Example 1, and will not be repeated here.
  • Example 1 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonylamino) Benzamide
  • Example 3 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-Dimethylbenzamide
  • Example 4 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-ethylbenzamide
  • Example 5 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N- Propylbenzamide
  • Example 6 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-methyl-N-ethylbenzamide
  • Example 7 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclopropyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
  • Example 8 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclobutyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
  • Example 9 2-(azetidine-1-carbonyl)-N-(5-bromo-4-fluoro-2-methylphenyl)-4-((3,5-dichloro (Phenyl)sulfonamido)benzenesulfonamide
  • Example 10 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(3-oxetanyl)benzamide
  • Example 11 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclopentyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
  • Example 12 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(pyrrolidine-1-carbonyl)benzenesulfonamide
  • Example 13 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(piperidine-1-carbonyl)benzenesulfonamide
  • Example 14 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(morpholine-4-carbonyl)benzenesulfonamide
  • Example 15 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(4-methylpiperazine-1-carbonyl)benzenesulfonamide
  • Example 16 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-Hydroxybenzamide
  • Example 17 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(2-propynyl)benzamide
  • Example 18 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(1,3,4-thiadiazol-2-yl)benzamide
  • Example 19 N-(5-bromo-4-fluoro-2-methylphenyl)-2-cyano-4-((3,5-dichlorophenyl)sulfonamido)benzenesulfon Amide
  • the preparation method is specifically listed below.
  • compound 1 300 mg, 0.49 mmol was added to 3 mL POCl 3 and reacted at 100° C. for 16 hours. Concentrate under reduced pressure to remove excess POCl 3 to obtain a crude product.
  • Example 20 N-(5-bromo-4-fluoro-2-methylphenyl)-4-((3,5-dichlorophenyl)sulfonamido)-2-(2H-tetra (Azol-5-yl)benzenesulfonamide
  • the above-mentioned compound having the structure shown in compound 21 is provided.
  • the preparation method is as follows.
  • the raw material aniline compound (1.0 g, 5.0 mmol) was dissolved in 5 mL of pyridine, the raw material 4-nitro-2-aminobenzenesulfonyl chloride (1.4 g, 6.0 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by TLC, the reaction was cooled to room temperature, 1N hydrochloric acid was added, the pH was adjusted to 3-4, a pale yellow precipitate was precipitated, filtered and dried to obtain the intermediate Int 21-I (1.5g, yield: 75.0%) . It can be used directly in the next reaction. MS (ESI) m/z: 403.9 (M+H) + .
  • the above-mentioned compound having the structure shown in compound 22 is provided.
  • the preparation method is as follows.
  • the above-mentioned compound having the structure shown in compound 28 is provided.
  • the preparation method is as follows.
  • the above-mentioned compound having the structure shown in compound 29 is provided.
  • the preparation method is as follows.
  • Example 9 Fluorescence quantitative experiment to detect SIRT6 deacetylation activity and agonist EC 50
  • SIRT6 deacetylation activity and agonist EC 50 .
  • the C-terminal of the acetylated polypeptide acetyl-Arg-His-Lys-Lys ( ⁇ -acetyl) is labeled with the fluorescent group AMC (coumarin).
  • SIRT6 can deacetylate this peptide (RHKK-Ac-AMC), and then it is further cleaved by trypsin (Trypsin) to produce free AMC, and then the reaction is fluorescently quantified.
  • the 50 ⁇ L reaction system contains 2.5 mM NAD+, 75 ⁇ M RHKK-Ac-AMC, 5 ⁇ M SIRT6, compound or DMSO, and reaction buffer (50 mM Tris-HCl, pH 8, 137 mM NaCl, 2.7 mM KCl, 1.0 mM MgCl 2 ).
  • reaction buffer 50 mM Tris-HCl, pH 8, 137 mM NaCl, 2.7 mM KCl, 1.0 mM MgCl 2 .
  • DMSO was used for both dissolution and dilution of the compound.
  • 40mM NAM nicotinamide
  • 6mg/mL trypsin was added to perform a color reaction at 25°C for 30 minutes.

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Abstract

Provided in the present application is a compound having the effect of agonizing the SIRT6 acetylation activity or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I). Further provided in the present application are an SIRT6 agonist obtained by means of using the compound and the use of the SIRT6 agonist, especially the use thereof in the preparation of a drug for treating SIRT6-mediated related diseases.

Description

具有激动SIRT6乙酰化活性的化合物、SIRT6激动剂及其应用Compounds with activity to agonize SIRT6 acetylation, SIRT6 agonists and applications thereof 技术领域Technical field
本申请涉及药物化学技术领域，特别涉及一种具有激动SIRT6乙酰化活性的化合物，以及应用该化合物获得的SIRT6激动剂及该SIRT6激动剂在尤其是制备治疗SIRT6介导的相关疾病的药物中的应用。This application relates to the technical field of medicinal chemistry, in particular to a compound that has the activity of agonizing SIRT6 acetylation, as well as the SIRT6 agonist obtained by using the compound and the application of the SIRT6 agonist in the preparation of drugs for the treatment of SIRT6-mediated diseases application.
背景技术Background technique
SIRT6属于组蛋白去乙酰化转移酶(Histone deacetylases，HDACs)第III家族，含有7个成员(SIRT1-7)。SIRT6广泛表达于哺乳动物的各种组织，在生物体内，SIRT6主要通过催化细胞内相关蛋白进行去乙酰化和单腺苷二磷酸核糖基化而参与基因组稳定性维持，DNA修复，炎症以及葡萄糖和脂质代谢，并与心脏疾病、糖尿病、肥胖症、癌症、衰老等疾病密切相关。SIRT6活性上调被认为是治疗上述多种疾病的新策略之一，因此对SIRT6小分子激动剂的研究对SIRT6介导相关疾病药物的开发具有重要的意义。SIRT6 belongs to the III family of Histone deacetylases (HDACs) and contains 7 members (SIRT1-7). SIRT6 is widely expressed in various tissues of mammals. In organisms, SIRT6 is mainly involved in the maintenance of genome stability, DNA repair, inflammation, and glucose and Lipid metabolism is closely related to heart disease, diabetes, obesity, cancer, aging and other diseases. Up-regulation of SIRT6 activity is considered to be one of the new strategies for the treatment of various diseases mentioned above. Therefore, the research on SIRT6 small molecule agonists is of great significance to the development of SIRT6-mediated drugs for related diseases.
专利CN109384694A公开了一种三苯环双磺酰胺为母核的SIRT6小分子激动剂，然该SIRT6小分子激动剂的乙酰化活性依然有待提高。Patent CN109384694A discloses a SIRT6 small molecule agonist with triphenyl ring bissulfonamide as the core, but the acetylation activity of the SIRT6 small molecule agonist still needs to be improved.
因此，需要一种新的SIRT6激动剂，以克服上述现有SIRT6激动剂的缺陷。Therefore, a new SIRT6 agonist is needed to overcome the above-mentioned shortcomings of existing SIRT6 agonists.
技术解决方案Technical solutions
本申请的目的在于提供一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，可显著提高SIRT6去乙酰化活性，进而可以用作SIRT6激动剂，并应用于相关疾病的药物制备中。The purpose of this application is to provide a compound with the activity of agonizing SIRT6 acetylation, or a pharmaceutically acceptable salt thereof, which can significantly improve the deacetylation activity of SIRT6, and then can be used as a SIRT6 agonist and applied to drugs for related diseases In preparation.
为了达到上述目的，本申请提供一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，具有式(I)所示的结构：In order to achieve the above-mentioned objective, the present application provides a compound having the activity of agonizing SIRT6 acetylation, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (I):
Figure PCTCN2020121732-appb-000001
Figure PCTCN2020121732-appb-000001
其中，X 1、X 2、X 3、X 4分别独立地表示氢原子或卤素；Y表示氢原子、甲基或卤素；R表示甲酰胺基、氰基或含氮杂环。 Wherein, X 1 , X 2 , X 3 , and X 4 each independently represent a hydrogen atom or a halogen; Y represents a hydrogen atom, a methyl group or a halogen; and R represents a carboxamido group, a cyano group or a nitrogen-containing heterocyclic ring.
在一实施例中，所述卤素为氟、氯、溴或碘。In one embodiment, the halogen is fluorine, chlorine, bromine or iodine.
在一实施例中，所述甲酰胺基为甲酰胺、甲酰脂肪胺或甲酰芳香胺。In one embodiment, the formamide group is formamide, formyl fatty amine or formyl aromatic amine.
在一实施例中，所述含氮杂环为三氮唑、四氮唑、咪唑、吡咯、吡唑、噁唑、异噁唑、 噻唑或噻二唑。In one embodiment, the nitrogen-containing heterocyclic ring is triazole, tetrazole, imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole or thiadiazole.
在一实施例中，R表示
Figure PCTCN2020121732-appb-000002
In one embodiment, R represents
Figure PCTCN2020121732-appb-000002
在一实施例中，式(I)所示化合物的药学上可接受的盐具有式(II)或式(III)所示的结构：In one embodiment, the pharmaceutically acceptable salt of the compound represented by formula (I) has a structure represented by formula (II) or formula (III):
Figure PCTCN2020121732-appb-000003
Figure PCTCN2020121732-appb-000003
在一较佳实施例中，所述具有激动SIRT6乙酰化活性的化合物，具有式(化合物1)～(化合物29)所示的结构：In a preferred embodiment, the compound having the activity of agonizing SIRT6 acetylation has the structure shown in formula (Compound 1) to (Compound 29):
Figure PCTCN2020121732-appb-000004
Figure PCTCN2020121732-appb-000004
Figure PCTCN2020121732-appb-000005
Figure PCTCN2020121732-appb-000005
本申请还提供一种SIRT6激动剂，包含上述任意所述的化合物或其药学上可接受的盐。The application also provides a SIRT6 agonist, comprising any of the above-mentioned compounds or pharmaceutically acceptable salts thereof.
本申请所述还提供上述任意所述的化合物及其药学上可接受的盐，或SIRT6激动剂，在制备治疗SIRT6介导的相关疾病的药物中的应用。The application also provides the use of any of the aforementioned compounds and their pharmaceutically acceptable salts, or SIRT6 agonists, in the preparation of medicines for the treatment of SIRT6-mediated diseases.
本申请所述的具有激动SIRT6乙酰化活性的化合物或其药学上可接受的盐，在体外实验中能够明显激动SIRT6的去乙酰化活性，对SIRT6介导的相关疾病药物的开发具有重要的意义。The compound or pharmaceutically acceptable salt thereof that has the activity of stimulating SIRT6 acetylation described in the present application can significantly stimulate the deacetylation activity of SIRT6 in in vitro experiments, and is of great significance to the development of drugs for SIRT6-mediated related diseases .
附图说明Description of the drawings
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。In order to more clearly describe the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings that need to be used in the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present application. For those skilled in the art, other drawings can be obtained based on these drawings without creative work.
图1：荧光定量方法检测优选化合物在100μM时激活SIRT6去乙酰化活性的倍数。Figure 1: Fluorescence quantitative method to detect the multiple of SIRT6 deacetylation activity activated by preferred compounds at 100 μM.
图2：荧光定量方法检测表明，化合物1浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC 50)为1.5±0.2μM；化合物2浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC 50)为2.3±0.3μM；化合物8浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC 50)为3.3±0.3μM；化合物23浓度依赖性地激活SIRT6去乙酰化活性，其半数最大效应浓度(EC 50)为60.1±4.5μM，在400μM时激活SIRT6去乙酰化活性的倍数近40倍。 Figure 2: Fluorescence quantitative method detection shows that compound 1 activates SIRT6 deacetylation activity in a concentration-dependent manner, and its half maximum effect concentration (EC 50 ) is 1.5±0.2 μM; compound 2 activates SIRT6 deacetylation activity in a concentration-dependent manner. Its half maximum effect concentration (EC 50 ) is 2.3 ± 0.3 μM; compound 8 activates SIRT6 deacetylation activity in a concentration-dependent manner, and its half maximum effect concentration (EC 50 ) is 3.3 ± 0.3 μM; compound 23 activates concentration-dependently The deacetylation activity of SIRT6 has a half maximum effect concentration (EC 50 ) of 60.1±4.5 μM. When 400 μM, the deacetylation activity of SIRT6 is activated nearly 40 times.
具体实施方式Detailed ways
下面详细描述本申请的实施方式，所述实施方式的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施方式是示例性的，仅用于解释本申请，而不能理解为对本申请的限制。The embodiments of the present application are described in detail below. Examples of the embodiments are shown in the accompanying drawings, in which the same or similar reference numerals indicate the same or similar elements or elements with the same or similar functions. The following embodiments described with reference to the drawings are exemplary, and are only used to explain the present application, and should not be understood as a limitation to the present application.
下文的公开提供了许多不同的实施方式或例子用来实现本申请的不同化合物。此外，本申请提供了的各种特定的工艺和材料的例子，但是本领域普通技术人员可以意识到其他工艺的应用和/或其他材料的使用。The following disclosure provides many different embodiments or examples for realizing different compounds of the present application. In addition, this application provides examples of various specific processes and materials, but those of ordinary skill in the art may be aware of the application of other processes and/or the use of other materials.
本申请提供结构式为式(I)所示的化合物或其药学上可接受的盐。This application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
Figure PCTCN2020121732-appb-000006
Figure PCTCN2020121732-appb-000006
其中，X 1、X 2、X 3、X 4相同或不同，表示氢原子、卤素，Y表示氢原子、甲基、卤素。所述卤素指氟、氯、溴或碘。R表示甲酰胺基、氰基、含氮杂环。 Wherein, X 1 , X 2 , X 3 , and X 4 are the same or different and represent a hydrogen atom or a halogen, and Y represents a hydrogen atom, a methyl group, or a halogen. The halogen refers to fluorine, chlorine, bromine or iodine. R represents a formamide group, a cyano group, or a nitrogen-containing heterocyclic ring.
在本实施例中，式(I)所示的化合物具有式(化合物1)～(化合物29)所示的具体结构。In this example, the compound represented by formula (I) has specific structures represented by formulas (compound 1) to (compound 29).
Figure PCTCN2020121732-appb-000007
Figure PCTCN2020121732-appb-000007
Figure PCTCN2020121732-appb-000008
Figure PCTCN2020121732-appb-000008
实施例1：化合物1～18的合成Example 1: Synthesis of Compounds 1-18
在本实施例中，提供上述具有式(化合物1～18)所示结构的化合物。反应路线如下：In this embodiment, the above-mentioned compounds having the structures represented by formulas (compounds 1-18) are provided. The reaction route is as follows:
Figure PCTCN2020121732-appb-000009
Figure PCTCN2020121732-appb-000009
具体制备方法如下几步。The specific preparation method is as follows.
合成中间体I：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-硝基苯甲酸甲酯Synthesis Intermediate I: Methyl 2-(N-(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-nitrobenzoate
Figure PCTCN2020121732-appb-000010
Figure PCTCN2020121732-appb-000010
室温下，将原料苯胺类化合物(10g，49.0mmol)溶解于20mL吡啶中，加入原料4-硝基-2-甲酸甲酯基苯磺酰氯(16.45g，58.8mmol)，室温反应8小时以上。TLC监测反应完全后，将反应冷却至室温，加入1N的盐酸，调pH至3-4，析出淡黄色沉淀，过滤、干燥即得中间体Int I(18.6g，收率：84.9％)。可直接用于下一步反应。 1H NMR(400MHz,DMSO-d 6)δ10.08(s,1H),8.50-8.47(m,2H),7.98-7.96(dd,J＝2.0Hz,J＝8.0Hz,1H),7.36-7.34(d,J＝8.0Hz,1H),7.29-7.27(d,J＝8.0Hz,1H),3.78(s,3H),1.96(s,3H)。 At room temperature, the raw material aniline compound (10 g, 49.0 mmol) was dissolved in 20 mL of pyridine, the raw material 4-nitro-2-carboxylic acid methyl ester benzenesulfonyl chloride (16.45 g, 58.8 mmol) was added, and the reaction was carried out at room temperature for more than 8 hours. After the completion of the reaction monitored by TLC, the reaction was cooled to room temperature, 1N hydrochloric acid was added, the pH was adjusted to 3-4, a pale yellow precipitate was precipitated, and the intermediate Int I (18.6 g, yield: 84.9%) was obtained by filtration and drying. It can be used directly in the next reaction. 1 H NMR (400MHz, DMSO-d 6 ) δ 10.08 (s, 1H), 8.50-8.47 (m, 2H), 7.98-7.96 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 7.36 7.34 (d, J=8.0 Hz, 1H), 7.29-7.27 (d, J=8.0 Hz, 1H), 3.78 (s, 3H), 1.96 (s, 3H).
合成中间体II：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-氨基苯甲酸甲酯Synthesis Intermediate II: 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-aminobenzoic acid methyl ester
Figure PCTCN2020121732-appb-000011
Figure PCTCN2020121732-appb-000011
在室温下，将中间体Int I(18.6g，41.6mmol)用乙酸溶解，加入铁粉(14.0g,250mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤3次，再用饱和食盐水洗涤3次后，有机相用无水硫酸钠 进行干燥，用柱层析分离纯化得到白色固体，即为中间体Int II(13.9g，收率：80.3％)。 1H NMR(400MHz,DMSO-d 6)δ8.89(s,1H),7.30-7.20(m,2H),6.73(s,1H),6.64-6.59(m,2H),6.30(s,2H),3.73(s,3H),2.02(s,3H)。 At room temperature, the intermediate Int I (18.6 g, 41.6 mmol) was dissolved with acetic acid, iron powder (14.0 g, 250 mmol) was added, and then reacted at 50° C. for 3 hours. The solvent was distilled under reduced pressure, ethyl acetate was added, sonicated for 10 minutes and then filtered with suction. The filtrate was washed with saturated sodium bicarbonate 3 times and then with saturated brine for 3 times. The organic phase was dried with anhydrous sodium sulfate. Column chromatography was separated and purified to obtain a white solid, which was the intermediate Int II (13.9 g, yield: 80.3%). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 7.30-7.20 (m, 2H), 6.73 (s, 1H), 6.64-6.59 (m, 2H), 6.30 (s, 2H) ), 3.73(s, 3H), 2.02(s, 3H).
合成中间体III：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰氨基)苯甲酸甲酯Synthesis intermediate III: 2-(N-(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzoic acid Methyl ester
Figure PCTCN2020121732-appb-000012
Figure PCTCN2020121732-appb-000012
室温下，中间体Int II(13.9g,33.32mmol))溶解于30mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(16.45g,58.8mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3-4，析出固体，硅胶柱层析纯化得白色中间体Int III(16.5g，收率：79.0％)。 1H NMR(400MHz,DMSO-d 6)δ11.36(s,1H),9.46(s,1H),8.01(s,1H),7.81(d,J＝2.0Hz,2H),7.60-7.58(d,J＝8.0Hz,1H),7.44-7.40(dd,J＝2.0Hz,J＝8Hz,1H),7.27(d,J＝2.0Hz,1H),7.24-7.22(d,J＝8.0Hz,1H),7.18-7.16(d,J＝8.0Hz,1H),3.74(s,3H),1.82(s,3H)。 At room temperature, the intermediate Int II (13.9 g, 33.32 mmol) was dissolved in 30 mL of pyridine, and the raw material 3,5-dichlorobenzenesulfonyl chloride (16.45 g, 58.8 mmol) 1) was added at 0° C. and reacted for 1 hour. Raise to room temperature and react for 6 hours. After TLC monitoring the completion of the reaction, at 0°C, 2N hydrochloric acid was added to adjust the pH to 3-4, and a solid was precipitated. The white intermediate Int III (16.5 g, yield: 79.0%) was obtained by silica gel column chromatography. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.36 (s, 1H), 9.46 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.60-7.58 ( d,J=8.0Hz,1H),7.44-7.40(dd,J=2.0Hz,J=8Hz,1H),7.27(d,J=2.0Hz,1H),7.24-7.22(d,J=8.0Hz , 1H), 7.18-7.16 (d, J=8.0 Hz, 1H), 3.74 (s, 3H), 1.82 (s, 3H).
合成化合物1-18：Synthesis of compounds 1-18:
Figure PCTCN2020121732-appb-000013
Figure PCTCN2020121732-appb-000013
在封管中，将Int III用甲醇溶解，加入5倍当量的胺类化合物，然后将反应温度升高到100℃反应4小时以上。TLC监测反应完全后，将反应冷却至室温，加入2摩尔/毫升的盐酸，调pH至3-4，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤3次，有机相用无水硫酸钠干燥。然后用柱层析分离纯化得到式(I)的化合物1-18。In the sealed tube, dissolve Int III with methanol, add 5 times equivalent of amine compound, and then raise the reaction temperature to 100°C for more than 4 hours of reaction. After the reaction was monitored by TLC, the reaction was cooled to room temperature, 2 mol/ml hydrochloric acid was added to adjust the pH to 3-4, ethyl acetate was added for extraction 3 times, the organic phases were combined, washed with saturated brine 3 times, Dry with anhydrous sodium sulfate. Then, it is separated and purified by column chromatography to obtain compound 1-18 of formula (I).
其余化合物均可以通过实施例1记载的相似的方法制备，此处不再赘述。The other compounds can be prepared by the similar method described in Example 1, and will not be repeated here.
实例1(化合物1)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰氨基)苯甲酰胺Example 1 (Compound 1): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonylamino) Benzamide
1H NMR(400MHz,DMSO-d 6)δ11.28(s,1H),8.78(s,1H),8.35(s,1H),7.97(t,J＝1.9Hz,1H),7.94(s,1H),7.77(d,J＝2.0Hz,2H),7.39(d,J＝8.6Hz,1H),7.28–7.12(m,4H), 1.89(s,3H). 13C NMR(101MHz,DMSO)δ170.69,156.65(d,J＝244.3Hz),137.24,136.67,136.60,135.59,134.35(d,J＝4.1Hz),133.12,133.04,133.02,130.80,125.60,120.21,118.89,118.55(d,J＝22.9Hz),104.65(d,J＝22.1Hz),17.46.MS(ESI)m/z:609.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.28(s,1H),8.78(s,1H),8.35(s,1H),7.97(t,J=1.9Hz,1H),7.94(s, 1H), 7.77(d,J=2.0Hz,2H), 7.39(d,J=8.6Hz,1H), 7.28–7.12(m,4H), 1.89(s,3H). 13 C NMR(101MHz,DMSO )δ170.69,156.65(d,J=244.3Hz),137.24,136.67,136.60,135.59,134.35(d,J=4.1Hz),133.12,133.04,133.02,130.80,125.60,120.21,118.89,118.55(d,J = 22.9 Hz), 104.65 (d, J = 22.1 Hz), 17.46. MS (ESI) m/z: 609.9 (M+H) + .
实例2(化合物2)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-甲基苯甲酰胺Example 2 (Compound 2): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-Methylbenzamide
1H NMR(400MHz,DMSO-d 6)δ11.30(s,1H),8.85(d,J＝6.3Hz,1H),8.80(s,1H),8.01(dt,J＝6.4,1.9Hz,1H),7.85(d,J＝1.9Hz,2H),7.47(dd,J＝8.9,1.7Hz,1H),7.35(dd,J＝8.6,2.4Hz,1H),7.28(t,J＝2.4Hz,1H),7.21(d,J＝6.7Hz,1H),7.12(dd,J＝9.6,3.1Hz,1H),2.68(s,3H),1.90(s,3H). 13C NMR(101MHz,DMSO)δ167.90,156.75(d,J＝244.6Hz),142.22,141.74,137.41,136.91(d,J＝7.9Hz),135.81,133.72,132.83(d,J＝3.1Hz),131.92,131.21,130.90,125.73,119.65,118.73,118.50(d,J＝23.0Hz),104.62(d,J＝22.1Hz),34.68,17.57.MS(ESI)m/z:623.9(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ11.30 (s, 1H), 8.85 (d, J = 6.3 Hz, 1H), 8.80 (s, 1H), 8.01 (dt, J = 6.4, 1.9 Hz, 1H), 7.85 (d, J = 1.9 Hz, 2H), 7.47 (dd, J = 8.9, 1.7 Hz, 1H), 7.35 (dd, J = 8.6, 2.4 Hz, 1H), 7.28 (t, J = 2.4 Hz, 1H), 7.21 (d, J = 6.7 Hz, 1H), 7.12 (dd, J = 9.6, 3.1 Hz, 1H), 2.68 (s, 3H), 1.90 (s, 3H). 13 C NMR (101MHz ,DMSO)δ167.90,156.75(d,J=244.6Hz),142.22,141.74,137.41,136.91(d,J=7.9Hz),135.81,133.72,132.83(d,J=3.1Hz),131.92,131.21,130.90 , 125.73, 119.65, 118.73, 118.50 (d, J = 23.0 Hz), 104.62 (d, J = 22.1 Hz), 34.68, 17.57. MS (ESI) m/z: 623.9 (M+H) + .
实例3(化合物3)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-二甲基苯甲酰胺Example 3 (Compound 3): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-Dimethylbenzamide
1H NMR(400MHz,DMSO-d 6)11.36(s,1H),9.46(s,1H),8.01(s,1H),7.81(d,J＝2.0Hz,2H),7.60-7.58(d,J＝8.0Hz,1H),7.44-7.40(dd,J＝2.0Hz,J＝8Hz,1H),7.27(d,J＝2.0Hz,1H),7.24-7.22(d,J＝8.0Hz,1H),7.18-7.16(d,J＝8.0Hz,1H),2.96(s,3H),2.62(s,3H),1.97(s,3H). 13C NMR(101MHz,DMSO)δ169.66,156.55(d,J＝244.2Hz),152.16,148.28,136.96(d,J＝7.7Hz),136.63,134.82,133.19(d,J＝3.1Hz),130.93,130.62,130.14,125.17,124.51,120.11,118.41(d,J＝22.6Hz),117.98,104.50(d,J＝21.9Hz),34.85,34.79,17.62.MS(ESI)m/z:637.9(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) 11.36 (s, 1H), 9.46 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.60-7.58 (d, J=8.0Hz,1H),7.44-7.40(dd,J=2.0Hz,J=8Hz,1H),7.27(d,J=2.0Hz,1H),7.24-7.22(d,J=8.0Hz,1H ), 7.18-7.16(d, J=8.0Hz, 1H), 2.96(s, 3H), 2.62(s, 3H), 1.97(s, 3H). 13 C NMR(101MHz,DMSO)δ169.66,156.55(d ,J=244.2Hz),152.16,148.28,136.96(d,J=7.7Hz),136.63,134.82,133.19(d,J=3.1Hz),130.93,130.62,130.14,125.17,124.51,120.11,118.41(d , J = 22.6 Hz), 117.98, 104.50 (d, J = 21.9 Hz), 34.85, 34.79, 17.62. MS (ESI) m/z: 637.9 (M+H) + .
实例4(化合物4)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-乙基苯甲酰胺Example 4 (Compound 4): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-ethylbenzamide
1H NMR(400MHz,DMSO-d 6)δ11.34(s,1H),8.88(d,J＝6.3Hz,1H),8.81(s,1H),8.03(dt,J＝6.4,1.9Hz,1H),7.82(d,J＝1.9Hz,2H),7.45(dd,J＝8.9,1.7Hz,1H),7.33(dd,J＝8.6,2.4Hz,1H),7.27(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),3.34–3.26(m,2H),1.88(s,3H),1.15(t,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO)δ167.93,156.78(d,J＝244.6Hz),142.24,141.74,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.1Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.0Hz),104.67(d,J＝22.1Hz),34.65,17.45,14.66.MS(ESI)m/z:637.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.34(s,1H), 8.88(d,J=6.3Hz,1H), 8.81(s,1H), 8.03(dt,J=6.4,1.9Hz, 1H), 7.82 (d, J = 1.9 Hz, 2H), 7.45 (dd, J = 8.9, 1.7 Hz, 1H), 7.33 (dd, J = 8.6, 2.4 Hz, 1H), 7.27 (t, J = 2.4 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 7.15 (dd, J = 9.6, 3.1 Hz, 1H), 3.34–3.26 (m, 2H), 1.88 (s, 3H), 1.15 (t , J = 7.2 Hz, 3H). 13 C NMR (101MHz, DMSO) δ 167.93, 156.78 (d, J = 244.6 Hz), 142.24, 141.74, 137.45, 136.97 (d, J = 7.9 Hz), 135.86, 133.77, 132.80 (d,J=3.1Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J=23.0Hz),104.67(d,J=22.1Hz),34.65,17.45,14.66.MS (ESI ) m/z: 637.9(M+H) + .
实例5(化合物5)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N- 丙基苯甲酰胺Example 5 (Compound 5): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N- Propylbenzamide
1H NMR(400MHz,Chloroform-d)δ8.48(d,J＝13.7Hz,1H),8.28–8.20(m,1H),7.70(t,J＝2.0Hz,2H),7.54(dt,J＝3.6,1.8Hz,1H),7.34(d,J＝8.5Hz,1H),7.29(s,1H),7.14(dd,J＝6.5,2.5Hz,1H),7.07(dd,J＝8.7,3.4Hz,1H),6.95–6.82(m,2H),3.37(q,J＝6.4Hz,2H),2.04(s,3H),1.64(d,J＝7.2Hz,2H),0.98(q,J＝7.2,6.6Hz,3H). 13C NMR(101MHz,CDCl 3)δ168.38,157.46(d,J＝248.1Hz),141.37,140.67,136.65,136.50,136.48,136.17(d,J＝7.3Hz),133.80,132.81(d,J＝12.7Hz),131.35,130.89,125.50,119.32,119.12,118.20(d,J＝22.9Hz),105.59(d,J＝22.1Hz),42.35,22.35,17.84,11.45.MS(ESI)m/z:651.9(M+H) +。 1 H NMR (400MHz, Chloroform-d) δ8.48 (d, J = 13.7Hz, 1H), 8.28-8.20 (m, 1H), 7.70 (t, J = 2.0Hz, 2H), 7.54 (dt, J ＝3.6,1.8Hz,1H),7.34(d,J＝8.5Hz,1H),7.29(s,1H),7.14(dd,J＝6.5,2.5Hz,1H), 7.07(dd,J＝8.7, 3.4Hz, 1H), 6.95–6.82 (m, 2H), 3.37 (q, J = 6.4 Hz, 2H), 2.04 (s, 3H), 1.64 (d, J = 7.2 Hz, 2H), 0.98 (q, J = 7.2, 6.6 Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ 168.38, 157.46 (d, J = 248.1 Hz), 141.37, 140.67, 136.65, 136.50, 136.48, 136.17 (d, J = 7.3 Hz) ,133.80,132.81(d,J=12.7Hz),131.35,130.89,125.50,119.32,119.12,118.20(d,J=22.9Hz),105.59(d,J=22.1Hz),42.35,22.35,17.84,11.45 .MS (ESI) m/z: 651.9 (M+H) + .
实例6(化合物6)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-甲基-N-乙基苯甲酰胺Example 6 (Compound 6): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-methyl-N-ethylbenzamide
1H NMR(400MHz,Chloroform-d)δ7.71(t,J＝1.5Hz,2H),7.53(t,J＝1.9Hz,1H),7.46(dd,J＝8.6,2.6Hz,1H),7.23(dd,J＝14.4,2.3Hz,1H),7.18(dd,J＝6.6,1.4Hz,1H),7.05(ddd,J＝8.6,2.3,1.1Hz,1H),6.87(d,J＝9.0Hz,1H),2.84(s,3H),2.08(s,3H),1.28(q,J＝6.8Hz,3H),1.14(t,J＝7.1Hz,2H). 13C NMR(101MHz,CDCl 3)δ169.39,157.37(d,J＝249.5Hz),142.42,142.28,137.45,136.97(d,J＝7.9Hz),135.86,133.77,132.80(d,J＝3.1Hz),131.99,131.22,130.91,125.78,119.68,118.77,118.52(d,J＝23.0Hz),104.67(d,J＝22.1Hz),105.42(d,J＝22.1Hz),36.51,32.21,17.79,12.86.MS(ESI)m/z:637.9(M+H) +。 1 H NMR (400MHz, Chloroform-d) δ7.71 (t, J = 1.5Hz, 2H), 7.53 (t, J = 1.9Hz, 1H), 7.46 (dd, J = 8.6, 2.6Hz, 1H), 7.23 (dd, J = 14.4, 2.3 Hz, 1H), 7.18 (dd, J = 6.6, 1.4 Hz, 1H), 7.05 (ddd, J = 8.6, 2.3, 1.1 Hz, 1H), 6.87 (d, J = 9.0Hz, 1H), 2.84 (s, 3H), 2.08 (s, 3H), 1.28 (q, J = 6.8 Hz, 3H), 1.14 (t, J = 7.1 Hz, 2H). 13 C NMR (101MHz, CDCl 3 )δ169.39,157.37(d,J=249.5Hz),142.42,142.28,137.45,136.97(d,J=7.9Hz),135.86,133.77,132.80(d,J=3.1Hz),131.99,131.22,130.91 ,125.78,119.68,118.77,118.52(d,J=23.0Hz),104.67(d,J=22.1Hz),105.42(d,J=22.1Hz),36.51,32.21,17.79,12.86.MS(ESI)m /z:637.9(M+H) + .
实例7(化合物7)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环丙基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺Example 7 (Compound 7): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclopropyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
1H NMR(400MHz,DMSO-d 6)δ11.29(s,1H),8.87(d,J＝4.2Hz,1H),8.80(s,1H),8.05(t,J＝1.8Hz,1H),7.81(d,J＝1.9Hz,2H),7.43(d,J＝8.7Hz,1H),7.30(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝6.8Hz,1H),7.19(d,J＝2.3Hz,1H),7.15(d,J＝9.5Hz,1H),2.82(tq,J＝7.6,3.9Hz,1H),1.87(s,3H),0.73(td,J＝7.1,4.8Hz,2H),0.61–0.50(m,2H). 13C NMR(101MHz,DMSO)δ169.26,156.80(d,J＝244.7Hz),142.27,141.75,137.34,137.06(d,J＝7.7Hz),135.86,133.78,132.77(d,J＝3.0Hz),131.84,131.36,130.92,125.78,119.55,118.74,118.52(d,J＝22.7Hz),104.67(d,J＝22.0Hz),23.31,17.45,6.13.MS(ESI)m/z:649.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.29(s,1H), 8.87(d,J=4.2Hz,1H), 8.80(s,1H), 8.05(t,J=1.8Hz,1H) ,7.81(d,J=1.9Hz,2H),7.43(d,J=8.7Hz,1H), 7.30(dd,J=8.7,2.3Hz,1H), 7.21(d,J=6.8Hz,1H) ,7.19(d,J=2.3Hz,1H),7.15(d,J=9.5Hz,1H), 2.82(tq,J=7.6,3.9Hz,1H),1.87(s,3H),0.73(td, J = 7.1, 4.8 Hz, 2H), 0.61-0.50 (m, 2H). 13 C NMR (101MHz, DMSO) δ 169.26, 156.80 (d, J = 244.7 Hz), 142.27, 141.75, 137.34, 137.06 (d, J =7.7Hz),135.86,133.78,132.77(d,J=3.0Hz),131.84,131.36,130.92,125.78,119.55,118.74,118.52(d,J=22.7Hz),104.67(d,J=22.0Hz) ,23.31,17.45,6.13.MS(ESI)m/z:649.9(M+H) + .
实例8(化合物8)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环丁基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺Example 8 (Compound 8): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclobutyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
1H NMR(400MHz,Chloroform-d)δ7.71(d,J＝1.8Hz,2H),7.54(t,J＝1.8Hz,1H),7.35(d,J＝8.6Hz,1H),7.30(d,J＝2.3Hz,1H),7.15(d,J＝6.5Hz,1H),7.07(dd,J＝8.6,2.3Hz,1H),6.98(d,J＝7.3Hz,1H),6.90–6.85(m,1H),4.47(dt,J＝16.0,8.0Hz,1H),2.43– 2.34(m,2H),2.12–1.99(m,2H),2.06(s,3H),1.82–1.75(m,2H). 13C NMR(101MHz,CDCl 3)δ167.51,157.43(d,J＝247.8Hz),141.74,141.18,136.47,136.41,136.21(d,J＝7.2Hz),133.61,132.64,131.47(d,J＝3.3Hz),130.93,130.89,125.50,119.44,119.25,118.15(d,J＝22.8Hz),105.55(d,J＝22.2Hz),45.85,30.41,17.86,15.45.MS(ESI)m/z:663.9(M+H) +。 1 H NMR (400MHz, Chloroform-d) δ 7.71 (d, J = 1.8 Hz, 2H), 7.54 (t, J = 1.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.30 ( d, J = 2.3 Hz, 1H), 7.15 (d, J = 6.5 Hz, 1H), 7.07 (dd, J = 8.6, 2.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.90- 6.85 (m, 1H), 4.47 (dt, J = 16.0, 8.0 Hz, 1H), 2.43-2.34 (m, 2H), 2.12-1.99 (m, 2H), 2.06 (s, 3H), 1.82-1.75 ( m, 2H). 13 C NMR (101MHz, CDCl 3 ) δ 167.51, 157.43 (d, J = 247.8 Hz), 141.74, 141.18, 136.47, 136.41, 136.21 (d, J = 7.2 Hz), 133.61, 132.64, 131.47 ( d, J = 3.3 Hz), 130.93, 130.89, 125.50, 119.44, 119.25, 118.15 (d, J = 22.8 Hz), 105.55 (d, J = 22.2 Hz), 45.85, 30.41, 17.86, 15.45.MS (ESI) m/z: 663.9(M+H) + .
实例9(化合物9)：2-(氮杂环丁烷-1-羰基)-N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰胺基)苯磺酰胺Example 9 (Compound 9): 2-(azetidine-1-carbonyl)-N-(5-bromo-4-fluoro-2-methylphenyl)-4-((3,5-dichloro (Phenyl)sulfonamido)benzenesulfonamide
1H NMR(400MHz,DMSO-d 6)δ11.56(s,1H),9.06(s,1H),8.05–7.96(m,1H),7.85(d,J＝1.9Hz,2H),7.52(d,J＝8.5Hz,1H),7.37–7.30(m,1H),7.26(d,J＝6.8Hz,1H),7.23(d,J＝6.6Hz,1H),7.17(d,J＝8.8Hz,1H),4.06(t,J＝7.6Hz,2H),3.71(t,J＝7.4Hz,2H),2.25(p,J＝7.4Hz,2H),1.90(s,3H). 13C NMR(101MHz,DMSO)δ168.22,156.85(d,J＝244.6Hz),142.25,142.03,137.30(d,J＝7.6Hz),135.79,134.90,133.65,132.47(d,J＝3.0Hz),132.11,131.50,131.09,125.82,120.05,118.54(d,J＝23.0Hz),118.52,104.69(d,J＝22.0Hz),51.26,48.89,17.50,15.63.MS(ESI)m/z:649.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.56(s,1H),9.06(s,1H),8.05-7.96(m,1H),7.85(d,J=1.9Hz,2H),7.52( d,J=8.5Hz,1H), 7.37–7.30(m,1H), 7.26(d,J=6.8Hz,1H), 7.23(d,J=6.6Hz,1H), 7.17(d,J=8.8 Hz, 1H), 4.06 (t, J = 7.6 Hz, 2H), 3.71 (t, J = 7.4 Hz, 2H), 2.25 (p, J = 7.4 Hz, 2H), 1.90 (s, 3H). 13 C NMR(101MHz,DMSO)δ168.22,156.85(d,J=244.6Hz),142.25,142.03,137.30(d,J=7.6Hz),135.79,134.90,133.65,132.47(d,J=3.0Hz),132.11, 131.50,131.09,125.82,120.05,118.54(d,J=23.0Hz),118.52,104.69(d,J=22.0Hz),51.26,48.89,17.50,15.63.MS(ESI)m/z:649.9(M+ H) + .
实例10(化合物10)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(3-氧杂环丁烷基)苯甲酰胺Example 10 (Compound 10): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(3-oxetanyl)benzamide
1H NMR(400MHz,DMSO-d 6)δ10.70(s,1H),8.12(d,J＝7.0Hz,1H),7.75(t,J＝2.0Hz,1H),7.69(t,J＝1.9Hz,2H),7.63–7.55(m,1H),7.28(d,J＝9.7Hz,1H),7.24(d,J＝2.4Hz,1H),7.03(dd,J＝8.4,2.4Hz,1H),4.65(t,J＝6.9Hz,1H),3.47–3.39(m,J＝17.2,7.0Hz,4H),1.91(s,3H). 13C NMR(101MHz,DMSO)δ167.38,161.54,155.36(d,J＝240.7Hz),147.67,135.19(d,J＝3.1Hz),134.90,134.67,133.97,133.90,131.03,128.25,127.81,125.35,122.16,121.00,118.11(d,J＝22.5Hz),104.29(d,J＝21.4Hz),61.47,55.75,45.92,17.96.MS(ESI)m/z:665.9(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.12 (d, J = 7.0 Hz, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.69 (t, J = 1.9Hz,2H), 7.63–7.55(m,1H), 7.28(d,J=9.7Hz,1H), 7.24(d,J=2.4Hz,1H), 7.03(dd,J=8.4,2.4Hz, 1H), 4.65 (t, J = 6.9 Hz, 1H), 3.47–3.39 (m, J = 17.2, 7.0 Hz, 4H), 1.91 (s, 3H). 13 C NMR (101MHz, DMSO) δ 167.38, 161.54, 155.36(d,J=240.7Hz),147.67,135.19(d,J=3.1Hz),134.90,134.67,133.97,133.90,131.03,128.25,127.81,125.35,122.16,121.00,118.11(d,J=22.5Hz ), 104.29 (d, J=21.4 Hz), 61.47, 55.75, 45.92, 17.96. MS (ESI) m/z: 665.9 (M+H) + .
实例11(化合物11)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-N-环戊基-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺Example 11 (Compound 11): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-N-cyclopentyl-5-((3,5-dichlorobenzene Group) sulfonamide group) benzamide
1H NMR(400MHz,Chloroform-d)δ8.23(s,1H),8.19(s,1H),7.69(d,J＝1.9Hz,2H),7.55(t,J＝1.8Hz,1H),7.35(d,J＝8.5Hz,1H),7.25(d,J＝2.2Hz,1H),7.14(d,J＝6.5Hz,1H),7.03(dd,J＝8.5,2.1Hz,1H),6.87(d,J＝8.9Hz,1H),6.71(d,J＝7.2Hz,1H),4.30(h,J＝6.5Hz,1H),2.07(s,6H),2.10–2.00(m,2H),1.76–1.70(m,2H),1.67–1.53(m,4H). 13C NMR(101MHz,CDCl 3)δ168.04,157.46(d,J＝247.8Hz),141.37,140.45,136.84,136.51,136.28(d,J＝7.3Hz),133.82,133.00,131.40(d,J＝3.3Hz),130.95,130.89,125.51,119.26, 119.06,118.18(d,J＝22.8Hz),105.57(d,J＝22.1Hz),52.55,32.67,23.87,17.88.MS(ESI)m/z:677.9(M+H) +。 1 H NMR (400MHz, Chloroform-d) δ 8.23 (s, 1H), 8.19 (s, 1H), 7.69 (d, J = 1.9 Hz, 2H), 7.55 (t, J = 1.8 Hz, 1H), 7.35(d,J=8.5Hz,1H), 7.25(d,J=2.2Hz,1H), 7.14(d,J=6.5Hz,1H), 7.03(dd,J=8.5,2.1Hz,1H), 6.87(d,J=8.9Hz,1H), 6.71(d,J=7.2Hz,1H), 4.30(h,J=6.5Hz,1H), 2.07(s,6H), 2.10–2.00(m,2H ), 1.76–1.70 (m, 2H), 1.67–1.53 (m, 4H). 13 C NMR (101MHz, CDCl 3 ) δ168.04,157.46(d,J=247.8Hz),141.37,140.45,136.84,136.51,136.28 (d,J=7.3Hz),133.82,133.00,131.40(d,J=3.3Hz),130.95,130.89,125.51,119.26, 119.06,118.18(d,J=22.8Hz),105.57(d,J=22.1 Hz), 52.55, 32.67, 23.87, 17.88. MS (ESI) m/z: 677.9 (M+H) + .
实例12(化合物12)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(吡咯烷-1-羰基)苯磺酰胺Example 12 (Compound 12): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(pyrrolidine-1-carbonyl)benzenesulfonamide
1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),7.71(d,J＝1.8Hz,2H),7.61(s,1H),7.54(t,J＝1.8Hz,1H),7.50(d,J＝8.5Hz,1H),7.37(s,1H),7.19(d,J＝6.5Hz,1H),7.12(d,J＝8.5Hz,1H),6.86(d,J＝9.0Hz,1H),3.66(t,J＝6.5Hz,2H),3.21(t,J＝6.5Hz,2H),2.07(s,3H),2.03–1.90(m,4H). 13C NMR(101MHz,CDCl 3)δ168.01,157.45(d,J＝247.7Hz),141.50,140.84,137.31,136.46(d,J＝7.2Hz),136.41,133.62,132.09,131.37(d,J＝3.3Hz),131.06,130.85,125.48,119.55,118.14(d,J＝23.8Hz),118.02,105.52(d,J＝22.1Hz),49.55,46.39,25.83,24.49,17.81.MS(ESI)m/z:663.9(M+H) +。 1 H NMR(400MHz, Chloroform-d)δ8.77(s,1H), 7.71(d,J=1.8Hz,2H), 7.61(s,1H), 7.54(t,J=1.8Hz,1H), 7.50(d,J=8.5Hz,1H),7.37(s,1H),7.19(d,J=6.5Hz,1H),7.12(d,J=8.5Hz,1H), 6.86(d,J=9.0 Hz, 1H), 3.66 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 2.07 (s, 3H), 2.03-1.90 (m, 4H). 13 C NMR (101MHz ,CDCl 3 )δ168.01,157.45(d,J=247.7Hz),141.50,140.84,137.31,136.46(d,J=7.2Hz),136.41,133.62,132.09,131.37(d,J=3.3Hz),131.06, 130.85,125.48,119.55,118.14(d,J=23.8Hz),118.02,105.52(d,J=22.1Hz),49.55,46.39,25.83,24.49,17.81.MS(ESI)m/z:663.9(M+ H) + .
实例13(化合物13)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(哌啶-1-羰基)苯磺酰胺Example 13 (Compound 13): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(piperidine-1-carbonyl)benzenesulfonamide
1H NMR(400MHz,Chloroform-d)δ7.71(d,J＝1.9Hz,2H),7.55(d,J＝1.8Hz,1H),7.49(d,J＝8.6Hz,1H),7.26(d,J＝2.2Hz,1H),7.18(d,J＝6.6Hz,1H),7.10(dd,J＝8.6,2.3Hz,1H),6.87(d,J＝9.0Hz,1H),3.92–3.86(m,1H),3.64–3.52(m,1H),3.24(dt,J＝8.4,4.1Hz,2H),2.07(s,3H),1.84–1.53(m,6H). 13C NMR(101MHz,CDCl 3)δ167.90,157.41(d,J＝247.4Hz),141.65,140.65,136.41,136.40(d,J＝7.3Hz),133.60,132.74,131.56(d,J＝3.4Hz),131.02,130.99,125.50,125.45,119.38,118.10(d,J＝23.0Hz),117.82,105.48(d,J＝22.2Hz),48.87,43.32,25.57,25.00,24.34,17.79.MS(ESI)m/z:677.9(M+H) +。 1 H NMR (400MHz, Chloroform-d) δ 7.71 (d, J = 1.9 Hz, 2H), 7.55 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.26 ( d, J = 2.2 Hz, 1H), 7.18 (d, J = 6.6 Hz, 1H), 7.10 (dd, J = 8.6, 2.3 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 3.92- 3.86(m,1H), 3.64–3.52(m,1H), 3.24(dt,J=8.4,4.1Hz,2H),2.07(s,3H),1.84–1.53(m,6H). 13 C NMR( 101MHz, CDCl 3 )δ167.90, 157.41 (d, J=247.4Hz), 141.65, 140.65, 136.41, 136.40 (d, J=7.3Hz), 133.60, 132.74, 131.56 (d, J=3.4Hz), 131.02, 130.99 ,125.50,125.45,119.38,118.10(d,J=23.0Hz),117.82,105.48(d,J=22.2Hz),48.87,43.32,25.57,25.00,24.34,17.79.MS(ESI)m/z:677.9 (M+H) + .
实例14(化合物14)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(吗啉-4-羰基)苯磺酰胺Example 14 (Compound 14): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(morpholine-4-carbonyl)benzenesulfonamide
1H NMR(400MHz,DMSO-d 6)δ7.74(t,J＝1.9Hz,1H),7.63(d,J＝1.9Hz,2H),7.21(d,J＝1.3Hz,1H),7.19(s,1H),7.16(d,J＝9.6Hz,1H),6.85(dd,J＝8.8,2.3Hz,1H),6.79(d,J＝2.3Hz,1H),3.84–3.74(m,4H),3.11–3.03(m,4H),2.00(s,3H). 13C NMR(101MHz,DMSO)δ168.50,156.55(d,J＝244.3Hz),148.97,148.94,137.10(d,J＝7.9Hz),135.70,134.74,133.23(d,J＝3.0Hz),130.93,130.38,130.15,125.13,124.14,120.44,118.44(d,J＝23.1Hz),117.84,104.47(d,J＝22.1Hz),63.71,43.13,17.67.MS(ESI)m/z:679.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ7.74(t,J=1.9Hz,1H), 7.63(d,J=1.9Hz,2H), 7.21(d,J=1.3Hz,1H), 7.19 (s, 1H), 7.16 (d, J = 9.6 Hz, 1H), 6.85 (dd, J = 8.8, 2.3 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 3.84–3.74 (m, 4H), 3.11–3.03(m,4H),2.00(s,3H). 13 C NMR(101MHz,DMSO)δ168.50,156.55(d,J=244.3Hz),148.97,148.94,137.10(d,J=7.9 Hz),135.70,134.74,133.23(d,J=3.0Hz),130.93,130.38,130.15,125.13,124.14,120.44,118.44(d,J=23.1Hz),117.84,104.47(d,J=22.1Hz) , 63.71, 43.13, 17.67. MS (ESI) m/z: 679.9 (M+H) + .
实例15(化合物15)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-4-((3,5-二氯苯基)磺酰胺基)-2-(4-甲基哌嗪-1-羰基)苯磺酰胺Example 15 (Compound 15): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-4-((3,5-dichlorophenyl)sulfonamido) -2-(4-methylpiperazine-1-carbonyl)benzenesulfonamide
1H NMR(400MHz,DMSO-d 6)δ7.84(t,J＝1.9Hz,1H),7.74(d,J＝1.9Hz,2H),7.34(d,J＝8.8Hz,1H),7.19(d,J＝6.8Hz,1H),7.16(d,J＝9.6Hz,1H),7.08(dd,J＝8.7,2.3Hz,1H),7.00(d,J＝2.3Hz,1H),3.88–3.61(m,2H),3.24–3.08(m,2H),2.83(br,2H),2.66–2.56(m,2H),2.49(s,3H),1.95(s,3H). 13C NMR(101MHz,DMSO)δ167.66,156.73(d,J＝244.4Hz),146.29,137.46(d,J＝7.3Hz),135.70,135.12,132.81(d,J＝3.0Hz),131.69,131.43,130.51,127.14,125.41,120.19,118.46(d,J＝22.9Hz),117.99,104.53(d,J＝21.9Hz),72.70,60.66,53.07,45.27,44.24,17.60.MS(ESI)m/z:692.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ7.84(t,J=1.9Hz,1H), 7.74(d,J=1.9Hz,2H), 7.34(d,J=8.8Hz,1H), 7.19 (d,J=6.8Hz,1H), 7.16(d,J=9.6Hz,1H), 7.08(dd,J=8.7,2.3Hz,1H), 7.00(d,J=2.3Hz,1H), 3.88 –3.61(m,2H), 3.24–3.08(m,2H), 2.83(br,2H), 2.66–2.56(m,2H), 2.49(s,3H),1.95(s,3H). 13 C NMR (101MHz,DMSO)δ167.66,156.73(d,J=244.4Hz),146.29,137.46(d,J=7.3Hz),135.70,135.12,132.81(d,J=3.0Hz),131.69,131.43,130.51,127.14 ,125.41,120.19,118.46(d,J=22.9Hz),117.99,104.53(d,J=21.9Hz),72.70,60.66,53.07,45.27,44.24,17.60.MS(ESI)m/z:692.9(M +H) + .
实例16(化合物16)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-羟基苯甲酰胺Example 16 (Compound 16): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-Hydroxybenzamide
1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),7.77(d,J＝1.9Hz,1H),7.67(dd,J＝4.5,2.2Hz,2H),7.28(d,J＝8.0Hz,1H),7.24(d,J＝6.7Hz,1H),7.16(d,J＝8.9Hz,1H),7.03(d,J＝7.5Hz,2H),1.98(s,3H). 13C NMR(101MHz,DMSO)δ166.02,156.35(d,J＝245.3Hz),136.01(d,J＝5.8Hz),134.97,134.10,133.59,131.14,130.65,129.92,125.18,121.82(d,J＝2.6Hz),119.27,118.53(d,J＝23.1Hz),104.64(d,J＝22.3Hz),17.61.MS(ESI)m/z:625.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ9.35(s,1H), 7.77(d,J=1.9Hz,1H), 7.67(dd,J=4.5,2.2Hz,2H), 7.28(d, J = 8.0Hz, 1H), 7.24 (d, J = 6.7 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 7.5 Hz, 2H), 1.98 (s, 3H) . 13 C NMR(101MHz,DMSO)δ166.02,156.35(d,J=245.3Hz),136.01(d,J=5.8Hz),134.97,134.10,133.59,131.14,130.65,129.92,125.18,121.82(d,J = 2.6 Hz), 119.27, 118.53 (d, J = 23.1 Hz), 104.64 (d, J = 22.3 Hz), 17.61. MS (ESI) m/z: 625.9 (M+H) + .
实例17(化合物17)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(2-丙炔基)苯甲酰胺Example 17 (Compound 17): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(2-propynyl)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.31(s,1H),9.31(q,J＝5.4,4.6Hz,1H),8.76(s,1H),8.03(ddt,J＝9.6,3.8,1.7Hz,1H),7.81(d,J＝1.8Hz,2H),7.44(dd,J＝8.7,2.0Hz,1H),7.33(dd,J＝8.7,2.2Hz,1H),7.26(q,J＝2.2Hz,1H),7.21(d,J＝6.7Hz,1H),7.14(dd,J＝9.7,4.4Hz,1H),4.09(dt,J＝5.2,2.5Hz,2H),3.23(d,J＝2.6Hz,1H),1.86(s,3H). 13C NMR(101MHz,DMSO)δ167.69,156.85(d,J＝244.7Hz),142.18,141.66,137.19(d,J＝8.9Hz),136.73,135.86,133.80,132.66(d,J＝3.1Hz),132.12,131.55,131.06,125.77,119.81,119.02,118.50(d,J＝22.4Hz),104.68(d,J＝22.3Hz),80.66,74.13,29.12,17.43.MS(ESI)m/z:647.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.31(s,1H), 9.31(q,J=5.4,4.6Hz,1H), 8.76(s,1H), 8.03(ddt,J=9.6,3.8 ,1.7Hz,1H),7.81(d,J=1.8Hz,2H),7.44(dd,J=8.7,2.0Hz,1H),7.33(dd,J=8.7,2.2Hz,1H),7.26(q ,J=2.2Hz,1H),7.21(d,J=6.7Hz,1H),7.14(dd,J=9.7,4.4Hz,1H),4.09(dt,J=5.2,2.5Hz,2H),3.23 (d,J=2.6Hz,1H),1.86(s,3H). 13 C NMR(101MHz,DMSO)δ167.69,156.85(d,J=244.7Hz),142.18,141.66,137.19(d,J=8.9Hz ),136.73,135.86,133.80,132.66(d,J=3.1Hz),132.12,131.55,131.06,125.77,119.81,119.02,118.50(d,J=22.4Hz),104.68(d,J=22.3Hz), 80.66, 74.13, 29.12, 17.43. MS (ESI) m/z: 647.9 (M+H) + .
实例18(化合物18)：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)-N-(1,3,4-噻二唑-2-基)苯甲酰胺Example 18 (Compound 18): 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido) -N-(1,3,4-thiadiazol-2-yl)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),7.92(t,J＝1.9Hz,1H),7.76(d,J＝1.9Hz,2H),7.43(s,1H),7.35(d,J＝8.5Hz,1H),7.17(d,J＝9.6Hz,1H),7.10(d,J＝8.8Hz,1H),7.05(d,J＝6.8Hz,1H),2.04(s,3H). 13C NMR(101MHz,DMSO)δ167.95,156.76(d,J＝244.8Hz),142.25,141.74,137.47,136.98(d,J＝7.9Hz),135.87,133.75,132.83(d,J＝3.0Hz), 131.97,131.21,130.92,125.75,119.67,118.76,118.54(d,J＝22.0Hz),104.37(d,J＝22.0Hz),17.93.MS(ESI)m/z:693.9(M+H) +。 1 H NMR(400MHz,DMSO-d 6 )δ11.48(s,1H),7.92(t,J=1.9Hz,1H),7.76(d,J=1.9Hz,2H),7.43(s,1H) ,7.35(d,J=8.5Hz,1H), 7.17(d,J=9.6Hz,1H), 7.10(d,J=8.8Hz,1H), 7.05(d,J=6.8Hz,1H), 2.04 (s,3H). 13 C NMR(101MHz,DMSO)δ167.95,156.76(d,J=244.8Hz),142.25,141.74,137.47,136.98(d,J=7.9Hz),135.87,133.75,132.83(d, J=3.0Hz), 131.97,131.21,130.92,125.75,119.67,118.76,118.54(d,J=22.0Hz),104.37(d,J=22.0Hz), 17.93.MS(ESI)m/z:693.9( M+H) + .
实施例2：化合物19的合成Example 2: Synthesis of compound 19
在本实施例中，提供上述具有化合物19所示结构的化合物。In this embodiment, the above-mentioned compound having the structure shown in compound 19 is provided.
实例19(化合物19)：N-(5-溴-4-氟-2-甲基苯基)-2-氰基-4-((3,5-二氯苯基)磺酰胺基)苯磺酰胺Example 19 (Compound 19): N-(5-bromo-4-fluoro-2-methylphenyl)-2-cyano-4-((3,5-dichlorophenyl)sulfonamido)benzenesulfon Amide
Figure PCTCN2020121732-appb-000014
Figure PCTCN2020121732-appb-000014
制备方法具体如下所列。The preparation method is specifically listed below.
在封管中，将化合物1(300mg,0.49mmol)加入到3mL POCl 3中，100℃反应16小时。减压浓缩除去过量的POCl 3得到粗产物，Pre-HPLC(Ultimate XB-C18,50*250mm,10um；elution：A＝H 2O,B＝MeCN,Rate＝80mL/min,B/A＝20％-90％in 40mins)分离纯化得到化合物19(220mg，收率：75.6％)。 1H NMR(400MHz,DMSO-d 6)δ11.51(br s,1H),10.18(s,1H),8.04(s,1H),7.84(s,2H),7.81-7.77(m,1H),7.62-7.56(m,2H),7.19-7.15(m,2H),1.75(s,3H).ES-API:[M-H] -＝591.92。 In the sealed tube, compound 1 (300 mg, 0.49 mmol) was added to 3 mL POCl 3 and reacted at 100° C. for 16 hours. Concentrate under reduced pressure to remove excess POCl 3 to obtain a crude product. Pre-HPLC (Ultimate XB-C18, 50*250mm, 10um; elution: A = H 2 O, B = MeCN, Rate = 80 mL/min, B/A = 20 %-90% in 40mins) was separated and purified to obtain compound 19 (220mg, yield: 75.6%). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.51 (br s, 1H), 10.18 (s, 1H), 8.04 (s, 1H), 7.84 (s, 2H), 7.81-7.77 (m, 1H) , 7.62-7.56 (m, 2H), 7.19-7.15 (m, 2H), 1.75 (s, 3H). ES-API: [MH] - =591.92.
实施例3：化合物20的合成Example 3: Synthesis of compound 20
在本实施例中，提供上述具有化合物20所示结构的化合物。In this embodiment, the above-mentioned compound having the structure shown in compound 20 is provided.
实例20(化合物20)：N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰胺基)-2-(2H-四唑-5-基)苯磺酰胺Example 20 (Compound 20): N-(5-bromo-4-fluoro-2-methylphenyl)-4-((3,5-dichlorophenyl)sulfonamido)-2-(2H-tetra (Azol-5-yl)benzenesulfonamide
Figure PCTCN2020121732-appb-000015
Figure PCTCN2020121732-appb-000015
化合物19(200mg,0.34mmol)，NH 4Cl(92mg,1.70mmol)，NaN 3(111mg,1.70mmol)加入到5mL DMF中。100℃反应18小时。反应液冷却至室温后倒入30mL水中，乙酸乙酯萃取(30mL×3)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。减压浓缩得到粗产物，Pre-HPLC(Ultimate XB-C18,50*250mm,10um；elution：A＝H 2O,B＝MeCN,Rate＝80mL/min,B/A＝20％-90％in 40mins)分离纯化得到化合物20(30mg，收率：13.9％)。 1H NMR(400MHz,DMSO-d6)δ11.33(br s,1H),8.02(s,1H),7.94(s,1H),7.81(s,2H),7.72(d,J＝8.6Hz,1H),7.44(d,J＝10.0Hz,2H),7.18(d,J＝9.7Hz,1H),7.10(d,J＝6.8Hz,1H),1.92(s,3H). ES-API:[M-H] -＝635.08。 Compound 19 (200 mg, 0.34 mmol), NH 4 Cl (92 mg, 1.70 mmol), NaN 3 (111 mg, 1.70 mmol) were added to 5 mL DMF. React at 100°C for 18 hours. The reaction solution was cooled to room temperature and poured into 30 mL of water, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine, and dried with anhydrous sodium sulfate. Concentrate under reduced pressure to obtain the crude product, Pre-HPLC (Ultimate XB-C18, 50*250mm, 10um; elution: A=H 2 O, B=MeCN, Rate=80mL/min, B/A=20%-90%in 40mins) separation and purification to obtain compound 20 (30mg, yield: 13.9%). 1 H NMR(400MHz,DMSO-d6)δ11.33(br s,1H), 8.02(s,1H), 7.94(s,1H), 7.81(s,2H), 7.72(d,J=8.6Hz, 1H),7.44(d,J＝10.0Hz,2H), 7.18(d,J＝9.7Hz,1H), 7.10(d,J＝6.8Hz,1H),1.92(s,3H). ES-API: [MH] - = 635.08.
实施例4：化合物21的合成Example 4: Synthesis of Compound 21
在本实施例中，提供上述具有化合物21所示结构的化合物。制备方法如下。In this embodiment, the above-mentioned compound having the structure shown in compound 21 is provided. The preparation method is as follows.
Figure PCTCN2020121732-appb-000016
Figure PCTCN2020121732-appb-000016
中间体21-I：2-氨基-N-(5-溴-4-氟-2-甲基苯基)-4-硝基苯磺酰胺Intermediate 21-I: 2-Amino-N-(5-bromo-4-fluoro-2-methylphenyl)-4-nitrobenzenesulfonamide
Figure PCTCN2020121732-appb-000017
Figure PCTCN2020121732-appb-000017
在冰浴下，将原料苯胺类化合物(1.0g，5.0mmol)溶解于5mL吡啶中，加入原料4-硝基-2-氨基苯磺酰氯(1.4g，6.0mmol)，室温反应2小时。TLC监测反应完全后，将反应冷却至室温，加入1N的盐酸，调pH至3-4，析出淡黄色沉淀，过滤、干燥即得中间体Int 21-I(1.5g，收率：75.0％)。可直接用于下一步反应。MS(ESI)m/z:403.9(M+H) +。 In an ice bath, the raw material aniline compound (1.0 g, 5.0 mmol) was dissolved in 5 mL of pyridine, the raw material 4-nitro-2-aminobenzenesulfonyl chloride (1.4 g, 6.0 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by TLC, the reaction was cooled to room temperature, 1N hydrochloric acid was added, the pH was adjusted to 3-4, a pale yellow precipitate was precipitated, filtered and dried to obtain the intermediate Int 21-I (1.5g, yield: 75.0%) . It can be used directly in the next reaction. MS (ESI) m/z: 403.9 (M+H) + .
中间体21-II：N-(5-溴-4-氟-2-甲基苯基)-4-硝基-2-(1H-吡咯-1-基)苯磺酰胺Intermediate 21-II: N-(5-bromo-4-fluoro-2-methylphenyl)-4-nitro-2-(1H-pyrrol-1-yl)benzenesulfonamide
Figure PCTCN2020121732-appb-000018
Figure PCTCN2020121732-appb-000018
在封管中，将中间体Int 21-I(0.45g，1.0mmol)、2,5-二甲氧基四氢呋喃(0.15g，1.2mmol)加入到2mL乙酸中，回流反应3小时。冷却至室温，加入水中，析出类白色固体，即为中间体Int 21-II(0.31g，收率：68.3％)。MS(ESI)m/z:453.9(M+H) +。 In the sealed tube, the intermediate Int 21-I (0.45 g, 1.0 mmol) and 2,5-dimethoxytetrahydrofuran (0.15 g, 1.2 mmol) were added to 2 mL of acetic acid, and the reaction was refluxed for 3 hours. After cooling to room temperature, adding water, an off-white solid precipitated out, which was the intermediate Int 21-II (0.31 g, yield: 68.3%). MS (ESI) m/z: 453.9 (M+H) + .
中间体21-III：4-氨基-N-(5-溴-4-氟-2-甲基苯基)-2-(1H-吡咯-1-基)苯磺酰胺Intermediate 21-III: 4-amino-N-(5-bromo-4-fluoro-2-methylphenyl)-2-(1H-pyrrol-1-yl)benzenesulfonamide
Figure PCTCN2020121732-appb-000019
Figure PCTCN2020121732-appb-000019
在室温下，将中间体Int 21-II(0.23g，0.5mmol)用5mL乙酸溶解，加入铁粉(0.23g,5mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤3次，再用饱和食盐水洗涤3次后，有机相用无水硫酸钠进行干燥，用柱层析分离纯化的油状物，即为中间体Int III(0.15g，收率：70.7％)。MS(ESI)m/z:424.9(M+H) +。 At room temperature, the intermediate Int 21-II (0.23 g, 0.5 mmol) was dissolved with 5 mL of acetic acid, iron powder (0.23 g, 5 mmol) was added, and then reacted at 50° C. for 3 hours. The solvent was distilled under reduced pressure, ethyl acetate was added, sonicated for 10 minutes and then filtered with suction. The filtrate was washed with saturated sodium bicarbonate 3 times and then with saturated brine for 3 times. The organic phase was dried with anhydrous sodium sulfate. The oily substance separated and purified by column chromatography is the intermediate Int III (0.15 g, yield: 70.7%). MS (ESI) m/z: 424.9 (M+H) + .
化合物21：N-(5-溴-4-氟-2-甲基苯基)-4-((3,5-二氯苯基)磺酰氨基)-2-(1H-吡咯-1-基)苯磺酰胺Compound 21: N-(5-Bromo-4-fluoro-2-methylphenyl)-4-((3,5-dichlorophenyl)sulfonamido)-2-(1H-pyrrol-1-yl )Benzenesulfonamide
Figure PCTCN2020121732-appb-000020
Figure PCTCN2020121732-appb-000020
室温下，中间体Int 21-III(0.15g,0.35mmol))溶解于3mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(0.10g,0.4mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3-4，析出固体，硅胶柱层析纯化得化合物21(0.14，收率：64.0％)。 1H NMR(400MHz,DMSO-d 6)δ11.38(s,1H),9.45(s,1H),8.03(s,1H),7.81(d,J＝2.0Hz,2H),7.59(d,J＝8.0Hz,1H),7.43(dd,J＝2.0Hz,J＝8Hz,1H),7.25(d,J＝2.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.20(d,J＝8.2Hz,2H),7.17(d,J＝8.0Hz,1H),6.57(d,J＝8.2Hz,2H),1.85(s,3H).MS(ESI)m/z:631.9(M+H) +。 At room temperature, the intermediate Int 21-III (0.15g, 0.35mmol)) was dissolved in 3mL of pyridine, and the raw material 3,5-dichlorobenzenesulfonyl chloride (0.10g, 0.4mmol)l) was added at 0°C, and reacted for 1 hour . Raise to room temperature and react for 6 hours. After the completion of the reaction monitored by TLC, at 0° C., 2N hydrochloric acid was added to adjust the pH to 3-4, and a solid was precipitated, which was purified by silica gel column chromatography to obtain compound 21 (0.14, yield: 64.0%). 1 H NMR(400MHz,DMSO-d 6 )δ11.38(s,1H), 9.45(s,1H), 8.03(s,1H), 7.81(d,J=2.0Hz,2H), 7.59(d, J = 8.0Hz, 1H), 7.43 (dd, J = 2.0 Hz, J = 8 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 ( d,J=8.2Hz,2H),7.17(d,J=8.0Hz,1H),6.57(d,J=8.2Hz,2H),1.85(s,3H).MS(ESI)m/z:631.9 (M+H) + .
实施例5：化合物22的合成Example 5: Synthesis of Compound 22
在本实施例中，提供上述具有化合物22所示结构的化合物。制备方法如下。In this embodiment, the above-mentioned compound having the structure shown in compound 22 is provided. The preparation method is as follows.
Figure PCTCN2020121732-appb-000021
Figure PCTCN2020121732-appb-000021
中间体22-I：N-(2-N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-硝基苯基)乙酰胺Intermediate 22-I: N-(2-N-(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-nitrophenyl)acetamide
Figure PCTCN2020121732-appb-000022
Figure PCTCN2020121732-appb-000022
将中间体2-氨基-N-(5-溴-4-氟-2-甲基苯基)-4-硝基苯磺酰胺(404mg，1.0mmol)溶解于5mL二氯甲烷中，加入三乙胺(303mg，3.0mmol)、DMAP(12mg，0.1mmol)。冰浴下，滴加乙酰氯(156mg，2.0mmol)，室温下继续反应3小时。反应液用1N盐酸洗涤、饱和碳酸氢钠洗涤，再用饱和食盐水洗涤，有机相用无水硫酸钠进行干燥，用柱层析分离纯化得中间体Int 22-I(220mg，收率：50.0％)。MS(ESI)m/z:445.9(M+H) +。 Intermediate 2-amino-N-(5-bromo-4-fluoro-2-methylphenyl)-4-nitrobenzenesulfonamide (404mg, 1.0mmol) was dissolved in 5mL of dichloromethane, and triethyl was added Amine (303 mg, 3.0 mmol), DMAP (12 mg, 0.1 mmol). Under ice bath, acetyl chloride (156mg, 2.0mmol) was added dropwise, and the reaction was continued for 3 hours at room temperature. The reaction solution was washed with 1N hydrochloric acid, saturated sodium bicarbonate, and then saturated brine. The organic phase was dried with anhydrous sodium sulfate and separated and purified by column chromatography to obtain intermediate Int 22-I (220 mg, yield: 50.0 %). MS (ESI) m/z: 445.9 (M+H) + .
中间体22-II：N-(5-氨基-2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)苯基)乙酰胺Intermediate 22-II: N-(5-amino-2-(N-(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl)phenyl)acetamide
Figure PCTCN2020121732-appb-000023
Figure PCTCN2020121732-appb-000023
在室温下，将中间体Int 21-II(0.22g，0.5mmol)用5mL乙酸溶解，加入铁粉(0.23g,5mmol)，然后在50℃反应3小时。将溶剂进行减压蒸馏，加入乙酸乙酯，超声10分钟后抽滤，滤液用饱和碳酸氢钠洗涤，再用饱和食盐水洗涤，有机相用无水硫酸钠进行干燥，用柱层析分离纯化得中间体22-Int II(0.13g，收率：62.5％)。MS(ESI)m/z:416.0(M+H) +。 At room temperature, the intermediate Int 21-II (0.22 g, 0.5 mmol) was dissolved in 5 mL of acetic acid, iron powder (0.23 g, 5 mmol) was added, and then reacted at 50° C. for 3 hours. The solvent was distilled under reduced pressure, ethyl acetate was added, ultrasonicated for 10 minutes, and then filtered with suction. The filtrate was washed with saturated sodium bicarbonate and then with saturated brine. The organic phase was dried with anhydrous sodium sulfate and separated and purified by column chromatography. The intermediate 22-Int II (0.13 g, yield: 62.5%) was obtained. MS (ESI) m/z: 416.0 (M+H) + .
化合物22：N-(2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯基)乙酰胺Compound 22: N-(2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzene Base) acetamide
Figure PCTCN2020121732-appb-000024
Figure PCTCN2020121732-appb-000024
室温下，中间体Int 22-II(125mg,0.3mmol))溶解于3mL吡啶中，0℃下加入原料3,5-二氯苯磺酰氯(88mg,0.36mmol)l)，反应1小时。升至室温反应6小时。TLC监测反应完全后，0℃下，加入2N的盐酸，调pH至3～4，析出固体，硅胶柱层析纯化得化合物22(103mg，收率：55.0％)。 1H NMR(400MHz,DMSO-d 6)δ11.32(s,1H),8.86(d,J＝6.3Hz,1H),8.80(s,1H),7.79(dt,J＝6.4,1.8Hz,1H),7.81(d,J＝1.8Hz,2H),7.43(dd,J＝8.7,1.7Hz,1H),7.32(dd,J＝8.6,2.4Hz,1H),7.25(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H),7.15(dd,J＝9.6,3.1Hz,1H),2.02(s,3H),1.88(s,3H).MS(ESI)m/z:623.9(M+H) +。 At room temperature, the intermediate Int 22-II (125 mg, 0.3 mmol)) was dissolved in 3 mL of pyridine, the raw material 3,5-dichlorobenzenesulfonyl chloride (88 mg, 0.36 mmol) 1) was added at 0°C, and the reaction was carried out for 1 hour. Raise to room temperature and react for 6 hours. After the completion of the reaction monitored by TLC, 2N hydrochloric acid was added at 0°C to adjust the pH to 3-4, and a solid precipitated, which was purified by silica gel column chromatography to obtain compound 22 (103 mg, yield: 55.0%). 1 H NMR(400MHz,DMSO-d 6 )δ11.32(s,1H),8.86(d,J=6.3Hz,1H),8.80(s,1H),7.79(dt,J=6.4,1.8Hz, 1H), 7.81 (d, J = 1.8 Hz, 2H), 7.43 (dd, J = 8.7, 1.7 Hz, 1H), 7.32 (dd, J = 8.6, 2.4 Hz, 1H), 7.25 (t, J = 2.4 Hz,1H),7.20(d,J=6.7Hz,1H),7.15(dd,J=9.6,3.1Hz,1H),2.02(s,3H),1.88(s,3H).MS(ESI)m /z:623.9(M+H) + .
实施例6：化合物23～27的合成Example 6: Synthesis of compounds 23-27
在本实施例中，提供上述具有化合物23～27所示结构的化合物。制备方法如下。化合物23～27采用如实施例1所述的反应路线合成。In this embodiment, the above-mentioned compounds having the structures shown in compounds 23-27 are provided. The preparation method is as follows. Compounds 23-27 were synthesized using the reaction route described in Example 1.
化合物23：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺Compound 23: 2-(N-(2,5-dibromo-4-fluorophenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.29(s,1H),8.85(s,1H),8.45(s,1H),7.98(t,J＝1.9Hz,1H),7.95(s,1H),7.79(d,J＝2.0Hz,2H),7.40(d,J＝8.6Hz,1H),7.28(t,J＝2.4Hz,1H),7.22(d,J＝6.8Hz,1H). 13C NMR(101MHz,DMSO)δ170.35,156.67(d,J＝244.5Hz),142.25,141.75,137.45,136.98(d,J＝7.8Hz),135.86,133.77,132.82(d,J＝3.2Hz),131.99,131.21,130.90,125.78,119.69,118.78,118.56(d,J＝23.0Hz),104.66(d,J＝22.4Hz).MS(ESI)m/z:673.8(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.29 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.95 (s, 1H), 7.79(d,J=2.0Hz,2H), 7.40(d,J=8.6Hz,1H), 7.28(t,J=2.4Hz,1H), 7.22(d,J=6.8Hz,1H) . 13 C NMR(101MHz,DMSO)δ170.35,156.67(d,J=244.5Hz),142.25,141.75,137.45,136.98(d,J=7.8Hz),135.86,133.77,132.82(d,J=3.2Hz) , 131.99, 131.21, 130.90, 125.78, 119.69, 118.78, 118.56 (d, J = 23.0 Hz), 104.66 (d, J = 22.4 Hz). MS (ESI) m/z: 673.8 (M+H) + .
化合物24：2-(N-(5-溴-2-氯-4-氟苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺Compound 24: 2-(N-(5-Bromo-2-chloro-4-fluorophenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.25(s,1H),8.75(s,1H),8.35(s,1H),7.96(t,J＝1.9Hz,1H),7.94(s,1H),7.77(d,J＝2.0Hz,2H),7.39(d,J＝8.6Hz,1H),7.25(t,J＝2.4Hz,1H),7.20(d,J＝6.7Hz,1H). 13C NMR(101MHz,DMSO)δ170.65,156.64(d,J＝244.3Hz),137.22,136.64,136.61,135.56,134.33(d,J＝4.0Hz),133.12,133.04,133.02,130.80,125.60,120.20,118.85,118.51(d,J＝22.6Hz),104.63(d,J＝22.3Hz).MS(ESI)m/z:629.8(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.25 (s, 1H), 8.75 (s, 1H), 8.35 (s, 1H), 7.96 (t, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 2.0 Hz, 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.25 (t, J = 2.4 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H) . 13 C NMR(101MHz,DMSO)δ170.65,156.64(d,J=244.3Hz),137.22,136.64,136.61,135.56,134.33(d,J=4.0Hz),133.12,133.04,133.02,130.80,125.60,120.20 , 118.85, 118.51 (d, J = 22.6 Hz), 104.63 (d, J = 22.3 Hz). MS (ESI) m/z: 629.8 (M+H) + .
化合物25：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二氟苯基)磺酰胺基)苯甲酰胺Compound 25: 2-(N-(2,5-dibromo-4-fluorophenyl)sulfamoyl)-5-((3,5-difluorophenyl)sulfonamido)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.30(s,1H),8.86(s,1H),8.45(s,1H),7.97(t,J＝1.9Hz,1H),7.98(s,1H),7.79(d,J＝2.0Hz,2H),7.41(d,J＝8.6Hz,1H),7.27(t,J＝2.4Hz,1H), 7.24(d,J＝6.8Hz,1H).MS(ESI)m/z:641.9(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.30 (s, 1H), 8.86 (s, 1H), 8.45 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J = 2.0 Hz, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 2.4 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H) .MS(ESI)m/z:641.9(M+H) + .
化合物26：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3,5-二溴苯基)磺酰胺基)苯甲酰胺Compound 26: 2-(N-(2,5-dibromo-4-fluorophenyl)sulfamoyl)-5-((3,5-dibromophenyl)sulfonamido)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.27(s,1H),8.85(s,1H),8.44(s,1H),7.97(t,J＝1.9Hz,1H),7.94(s,1H),7.79(d,J＝2.0Hz,2H),7.42(d,J＝8.6Hz,1H),7.29(t,J＝2.4Hz,1H),7.23(d,J＝6.8Hz,1H).MS(ESI)m/z:761.7(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.27 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J = 2.0 Hz, 2H), 7.42 (d, J = 8.6 Hz, 1H), 7.29 (t, J = 2.4 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H) .MS (ESI) m/z: 761.7 (M+H) + .
化合物27：2-(N-(2,5-二溴-4-氟苯基)氨磺酰基)-5-((3-溴-5-氟苯基)磺酰胺基)苯甲酰胺Compound 27: 2-(N-(2,5-Dibromo-4-fluorophenyl)sulfamoyl)-5-((3-bromo-5-fluorophenyl)sulfonamido)benzamide
1H NMR(400MHz,DMSO-d 6)δ11.28(s,1H),8.85(s,1H),8.44(s,1H),7.98(t,J＝1.9Hz,1H),7.94(s,1H),7.79(d,J＝2.0Hz,2H),7.41(d,J＝8.6Hz,1H),7.27(t,J＝2.4Hz,1H),7.21(d,J＝6.8Hz,1H).MS(ESI)m/z:701.8(M+H) +。 1 H NMR (400MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J = 2.0 Hz, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 2.4 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H) .MS(ESI)m/z:701.8(M+H) + .
实施例7：化合物28的合成Example 7: Synthesis of Compound 28
在本实施例中，提供上述具有化合物28所示结构的化合物。制备方法如下。In this embodiment, the above-mentioned compound having the structure shown in compound 28 is provided. The preparation method is as follows.
化合物28：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺二钠盐Compound 28: 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzamide Sodium salt
Figure PCTCN2020121732-appb-000025
Figure PCTCN2020121732-appb-000025
室温下，将化合物1(61mg,0.1mmol)溶解于2mL甲醇中，加入甲醇钠的甲醇溶液(0.02mL,5M)，搅拌30分钟，旋干后得白色固体化合物28(63mg，收率：96.0％)。MS(ESI)m/z:609.9(M+H) +。 At room temperature, compound 1 (61 mg, 0.1 mmol) was dissolved in 2 mL of methanol, sodium methoxide methanol solution (0.02 mL, 5M) was added, stirred for 30 minutes, and spin-dried to obtain a white solid compound 28 (63 mg, yield: 96.0 %). MS (ESI) m/z: 609.9 (M+H) + .
实施例8：化合物29的合成Example 8: Synthesis of compound 29
在本实施例中，提供上述具有化合物29所示结构的化合物。制备方法如下。In this embodiment, the above-mentioned compound having the structure shown in compound 29 is provided. The preparation method is as follows.
化合物29：2-(N-(5-溴-4-氟-2-甲基苯基)氨磺酰基)-5-((3,5-二氯苯基)磺酰胺基)苯甲酰胺二钾盐Compound 29: 2-(N-(5-Bromo-4-fluoro-2-methylphenyl)sulfamoyl)-5-((3,5-dichlorophenyl)sulfonamido)benzamide Potassium
Figure PCTCN2020121732-appb-000026
Figure PCTCN2020121732-appb-000026
室温下，将化合物1(61mg,0.1mmol)溶解于2mL甲醇中，加入叔丁醇钾的四氢呋喃(0.1mL,1M)，搅拌30分钟，旋干后得白色固体化合物29(66mg，收率：97.0％)。MS(ESI)m/z:609.9(M+H) +。 At room temperature, compound 1 (61 mg, 0.1 mmol) was dissolved in 2 mL of methanol, potassium tert-butoxide and tetrahydrofuran (0.1 mL, 1M) were added, stirred for 30 minutes, and spin-dried to obtain a white solid compound 29 (66 mg, yield: 97.0%). MS (ESI) m/z: 609.9 (M+H) + .
实施例9：荧光定量实验检测SIRT6去乙酰化活性及激动剂EC 50 Example 9: Fluorescence quantitative experiment to detect SIRT6 deacetylation activity and agonist EC 50
采用基于荧光定量的方法来检测SIRT6去乙酰化活性及激动剂EC  50。在乙酰化多肽acetyl-Arg-His-Lys-Lys(ε-acetyl)的C端标记上荧光基团AMC(香豆素)。SIRT6可以对这条多肽(RHKK-Ac-AMC)进行去乙酰化，然后它进一步被胰蛋白酶(Trypsin)剪切，产生游离的AMC，进而对反应进行荧光定量。在50μL的反应体系中含有2.5mM NAD+、75μM RHKK-Ac-AMC、5μM SIRT6、化合物或DMSO以及反应缓冲液(50m M Tris-HCl，pH 8,137mM NaCl,2.7mM KCl,1.0mM MgCl 2)。化合物溶解和稀释都使用DMSO。以上反应组分于37℃反应2小时后，加入40mM NAM(烟酰胺)终止去乙酰化反应，并加入6mg/mL的胰蛋白酶于25℃进行30分钟的显色反应。最后通过酶标仪对反应进行荧光定量检测，激发和发射波长分别为360nm和460nm。最后通过GrapHPad Prism 6软件求解三次独立实验中激动剂在多种浓度条件下对SIRT6激活效应的EC 50。结果参见图1-图2，说明化合物对于SIRT6具有显著的激动效应。 A method based on fluorescence quantification was used to detect SIRT6 deacetylation activity and agonist EC 50 . The C-terminal of the acetylated polypeptide acetyl-Arg-His-Lys-Lys (ε-acetyl) is labeled with the fluorescent group AMC (coumarin). SIRT6 can deacetylate this peptide (RHKK-Ac-AMC), and then it is further cleaved by trypsin (Trypsin) to produce free AMC, and then the reaction is fluorescently quantified. The 50 μL reaction system contains 2.5 mM NAD+, 75 μM RHKK-Ac-AMC, 5 μM SIRT6, compound or DMSO, and reaction buffer (50 mM Tris-HCl, pH 8, 137 mM NaCl, 2.7 mM KCl, 1.0 mM MgCl 2 ). DMSO was used for both dissolution and dilution of the compound. After the above reaction components were reacted at 37°C for 2 hours, 40mM NAM (nicotinamide) was added to terminate the deacetylation reaction, and 6mg/mL trypsin was added to perform a color reaction at 25°C for 30 minutes. Finally, the reaction was quantitatively detected by a microplate reader, and the excitation and emission wavelengths were 360nm and 460nm, respectively. Finally, the GrapHPad Prism 6 software was used to calculate the EC 50 of the agonist's activation effect on SIRT6 in three independent experiments at various concentrations. The results are shown in Figure 1 to Figure 2, indicating that the compound has a significant agonistic effect on SIRT6.
本申请已由上述相关实施例加以描述，然而上述实施例仅为实施本申请的范例。必需指出的是，已公开的实施例并未限制本申请的范围。相反地，包含于权利要求书的精神及范围的修改及均等设置均包括于本申请的范围内。This application has been described by the above-mentioned related embodiments, but the above-mentioned embodiments are only examples for implementing this application. It must be pointed out that the disclosed embodiments do not limit the scope of the application. On the contrary, modifications and equivalent arrangements included in the spirit and scope of the claims are all included in the scope of the present application.

Claims (10)

  1. 一种具有激动SIRT6乙酰化活性的化合物，或其药学上可接受的盐，具有式(I)所示的结构：A compound having the activity of agonizing SIRT6 acetylation, or a pharmaceutically acceptable salt thereof, has the structure shown in formula (I):
    Figure PCTCN2020121732-appb-100001
    Figure PCTCN2020121732-appb-100001
    其中，X 1、X 2、X 3、X 4分别独立地表示氢原子或卤素；Y表示氢原子、甲基或卤素；R表示甲酰胺基、氰基或含氮杂环。 Wherein, X 1 , X 2 , X 3 , and X 4 each independently represent a hydrogen atom or a halogen; Y represents a hydrogen atom, a methyl group or a halogen; and R represents a carboxamido group, a cyano group or a nitrogen-containing heterocyclic ring.
  2. 如权利要求1所述的化合物，其中，所述卤素为氟、氯、溴或碘。The compound of claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.
  3. 如权利要求1所述的化合物，其中，所述甲酰胺基为甲酰胺、甲酰脂肪胺或甲酰芳香胺。The compound of claim 1, wherein the formamide group is formamide, formyl fatty amine or formyl aromatic amine.
  4. 如权利要求1所述的化合物，其中，所述含氮杂环为三氮唑、四氮唑、咪唑、吡咯、吡唑、噁唑、异噁唑、噻唑或噻二唑。The compound of claim 1, wherein the nitrogen-containing heterocyclic ring is triazole, tetrazolium, imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole, or thiadiazole.
  5. 如权利要求1所述的化合物，其中，R表示
    Figure PCTCN2020121732-appb-100002
    The compound of claim 1, wherein R represents
    Figure PCTCN2020121732-appb-100002
  6. 如权利要求1所述的化合物，其中，式(I)所示化合物的药学上可接受的盐具有式(II)或式(III)所示的结构：The compound of claim 1, wherein the pharmaceutically acceptable salt of the compound represented by formula (I) has a structure represented by formula (II) or formula (III):
    Figure PCTCN2020121732-appb-100003
    Figure PCTCN2020121732-appb-100003
  7. 如权利要求1所述的化合物，其中，所述化合物具有式(化合物1)～(化合物29)所示的结构：The compound of claim 1, wherein the compound has a structure represented by the formula (Compound 1) to (Compound 29):
    Figure PCTCN2020121732-appb-100004
    Figure PCTCN2020121732-appb-100004
    Figure PCTCN2020121732-appb-100005
    Figure PCTCN2020121732-appb-100005
  8. 一种SIRT6激动剂，包含如权利要求1所述的化合物或其药学上可接受的盐。A SIRT6 agonist, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.
  9. 权利要求1所述的化合物在制备治疗SIRT6介导的相关疾病的药物中的应用。The use of the compound of claim 1 in the preparation of a medicament for the treatment of SIRT6-mediated related diseases.
  10. 权利要求7所述的SIRT6激动剂在制备治疗SIRT6介导的相关疾病的药物中的应用。The use of the SIRT6 agonist of claim 7 in the preparation of drugs for the treatment of related diseases mediated by SIRT6.
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