WO2019029211A1 - 用作sirt6小分子别构激动剂的化合物及其药物组合物 - Google Patents

用作sirt6小分子别构激动剂的化合物及其药物组合物 Download PDF

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WO2019029211A1
WO2019029211A1 PCT/CN2018/086766 CN2018086766W WO2019029211A1 WO 2019029211 A1 WO2019029211 A1 WO 2019029211A1 CN 2018086766 W CN2018086766 W CN 2018086766W WO 2019029211 A1 WO2019029211 A1 WO 2019029211A1
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group
compound
nitro
sirt6
esi
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PCT/CN2018/086766
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French (fr)
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张健
陈颖毅
阮聪
杨秀岩
王承祥
张秋芬
商佳琳
徐新愿
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上海交通大学医学院
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Priority claimed from CN201710681498.6A external-priority patent/CN109384694B/zh
Priority claimed from CN201810126641.XA external-priority patent/CN110128375A/zh
Application filed by 上海交通大学医学院 filed Critical 上海交通大学医学院
Priority to US17/293,917 priority Critical patent/US20220220069A1/en
Publication of WO2019029211A1 publication Critical patent/WO2019029211A1/zh

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Definitions

  • the present invention relates to the field of medicinal chemotherapeutics, and in particular to a SIRT6 small molecule allosteric agonist and its use as a pharmaceutical compound for preventing or treating a related disease.
  • the mammalian Sirtuin family contains seven members (SIRT1-SIRT 7) and generally has Mono-ADP-ribosylation enzymatic activity or deacylation enzymatic activity, the latter mainly including deacetylation. (Deacetylation) enzymatic activity and demyristoylation enzyme activity, and the like. These members are widely involved in various life processes such as energy metabolism, cellular stress stress, genomic stability, aging, and tumors.
  • SIRT6 is one of the major members of the Sirtuin family, and its spatial structure has a large Rossmann folding domain and a small zinc ion domain, in which the enzyme cofactor NAD + and substrate polypeptide are bound to the Rossmann domain.
  • the zinc ion domain has a conserved zinc ion binding sequence.
  • SIRT6 can catalyze the deacetylation of substrate proteins or ribosylation of adenosine diphosphate by means of the cofactor NAD+.
  • H3K9, H3K56 histone H3
  • CtIP C-terminal binding protein interacting protein
  • PARP1 Poly (ADP-ribose) polymerase 1] is A single adenosine diphosphate ribosylation substrate is currently known.
  • SIRT6 regulates important transcription factors (such as NF- ⁇ B, HIF1 ⁇ , c-Myc) mainly through H3K9 and H3K56 deacetylation, and participates in genomic stability maintenance, DNA repair, inflammation, and glucose and lipid metabolism. It is closely related to many life processes and diseases such as tumor formation, heart disease, aging, diabetes and aging, which indicates that SIRT6 has very important biological functions.
  • important transcription factors such as NF- ⁇ B, HIF1 ⁇ , c-Myc
  • SIRT6 is differentially expressed in tumors, and nearly 35% of tumor cell lines showed different degrees of SIRT6 deletion, including digestive tract.
  • the expression level of SIRT6 in tumor cells was almost completely reduced. Therefore, up-regulation of SIRT6 activity is considered to be a new strategy for the treatment of various diseases.
  • SIRT6 small molecule agonists have become a hot spot for major pharmaceutical companies and research units, but there are no reports of related drugs.
  • the present invention is directed to solving the above problems, and an object of the present invention is to provide a compound which can be used as a small molecule allosteric agonist which can modulate SIRT6 deacetylation activity, and is a SIRT6 related chemical biology study. Explore the therapeutic role of SIRT6 in disease.
  • the present invention first provides a compound or a pharmacologically acceptable salt thereof, which is useful as a SIRT6 small molecule allosteric agonist.
  • the compound is represented by formula (I):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of H, halogen, hydroxy, nitro, amino, carboxy, acid ester a group consisting of sulfonamide, sulfhydryl, decyl, methoxy, ethoxy, benzyloxy, methyl and cyano;
  • R 11 is H, Cl, nitro, amino, benzyl alcohol, benzyl chloride, benzyl Amine, carboxyl, acid ester group,
  • R 12 and R 13 are independently C 1-8 substituted or unsubstituted alkyl; Represents a substituted or unsubstituted nitrogen-containing heterocycle.
  • the compound of the formula (I) has a symmetrical structure. That is, the selection of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 needs to satisfy the symmetry of the compound of the formula (I).
  • R 11 when R 11 is The compound has the structure represented by the formula (I-2) and the formula (I-3):
  • R 12 and R 13 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2- A group consisting of methylbutane and hexyl groups.
  • the nitrogen-containing heterocycle is aziridine, azetidine, pyrazole ring, morpholine ring, piperidine ring, piperazine ring, azepane or aza Cyclooctane.
  • At least one hydrogen atom of the nitrogen-containing heterocycle is selected from the group consisting of methyl, ethyl, carboxyl, acid ester, carboxyl, methanol, cyclopropyl, isopropyl, cyclobutyl Substituted by a substituent in the group consisting of a cyclohexyl group, a cyclohexyl group, an oxo-substituted alkyl group, and a propylene group.
  • the pharmacologically acceptable salt is a sodium salt, a hydrochloride salt, a sulfate salt, an oxalate salt, an acetate salt, a trifluoroacetate salt or a decanoate salt.
  • the present invention also provides a SIRT6 small molecule allosteric agonist comprising any one of the compounds described above or a pharmacologically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition comprising any one of the compounds described above or a pharmacologically acceptable salt thereof.
  • Figure 1 to Figure 8 are the deacetylation activity data of SIRT6 after treatment with SIRT6 small molecule allosteric agonist obtained by FDL experiment;
  • Figure 38 is a schematic representation of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of HEK-293T cells with different concentrations of Compound 177 for 12 hours, 24 hours, 48 hours or 60 hours;
  • Figure 39 is a schematic diagram of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after 48 hours of treatment of Bel7405 cells with different concentrations of Compound 183;
  • Figure 40 is a schematic diagram of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after 48 hours of treatment of PLC/PRF/5 cells with different concentrations of Compound 183;
  • Figure 41 is a schematic diagram of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after 48 hours of treatment of Bel7402 cells with different concentrations of Compound 183;
  • Figure 42 is a schematic diagram showing intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of HCT116 cells with 10 ⁇ mol/L of compound SOL-011 for 24 hours and 48 hours;
  • Figure 43 is a schematic diagram showing intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of HT29 cells with 10 ⁇ mol/L of Compound SOL-011 for 24 hours and 48 hours;
  • Figure 44 is a schematic diagram showing intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of SW480 cells with 10 ⁇ mol/L of compound SOL-011 for 24 hours and 48 hours;
  • Figure 45 is a schematic diagram of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of CT116 cells with different concentrations of compound SOL-011 for 48 hours;
  • Figure 46 is a schematic diagram of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of HT29 cells with different concentrations of compound SOL-011 for 48 hours;
  • Figure 47 is a schematic representation of intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac after treatment of SW480 cells with different concentrations of compound SOL-011 for 48 hours.
  • a compound of formula (I) or a pharmacologically acceptable salt thereof is first provided as a SIRT6 small molecule allosteric agonist.
  • the preparation method of the above compound specifically comprises the following steps:
  • a compound of formula (I) or a pharmacologically acceptable salt thereof is provided as a SIRT6 small molecule allosteric agonist.
  • the preparation method of the above compound specifically comprises the following steps:
  • the phosphorus oxychloride was slowly added at room temperature, and then refluxed under nitrogen for overnight. After the completion of the reaction, the solvent was distilled under reduced pressure, and then ethyl acetate and water were added; the organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate
  • the specific structure of the compound of formula (I) is described below in tabular form.
  • the compound for a SIRT6 small molecule allosteric agonist or a pharmacologically acceptable salt thereof according to the present invention has any one of the structures listed in Table 1 below.
  • a compound of the formula (I-2) or the formula (I-3) or a pharmacologically acceptable salt thereof is provided as a SIRT6 small molecule allosteric agonist.
  • the preparation method of the above compound specifically comprises the following steps:
  • the benzyl alcohol compound of the formula a5 was slowly added to the thionyl chloride in the reaction flask, and after the addition was completed, stirring was continued for an additional half hour in an ice bath and then the temperature was raised to room temperature.
  • the reaction system was heated to 75 ° C for 24 hours. After the reaction was completed, the reaction system was first moved to room temperature, and then the reaction liquid was slowly added to an aqueous solution of ice water. Stirring is continued until the solid is completely precipitated, followed by suction filtration, dried and recrystallized to give the benzyl chloride compound of formula a6.
  • the benzyl chloride compound of the formula a6 was dissolved in tetrahydrofuran in a reaction flask, and then 1.5 times equivalent of a fatty branched secondary amine having the same or different substitutions was added, followed by the addition of 2 equivalents of triethylamine.
  • the reaction was warmed to 60 ° C for 10 hours. After completion of the reaction, the mixture was transferred to room temperature, and then water was added and extracted with ethyl acetate three times. The organic phase was combined and washed three times with saturated brine and purified by column chromatography to afford compound of formula (I-2).
  • the benzyl chloride compound of the formula 6 was dissolved in tetrahydrofuran in a reaction flask at room temperature, and then 1.5 times equivalent of an aliphatic ring containing a secondary amine and various substituents thereof were added, followed by the addition of 2 equivalents of triethylamine.
  • the reaction was warmed to 60 ° C for 10 hours. After completion of the reaction, the mixture was transferred to room temperature, and then water was added and extracted with ethyl acetate three times. The organic phase was combined and washed three times with saturated brine and purified by column chromatography to afford compound of formula (I-3).
  • a compound of the formula (I-2) or the formula (I-3) or a pharmacologically acceptable salt thereof is provided as a SIRT6 small molecule allosteric agonist.
  • the preparation method of the above compound specifically comprises the following steps:
  • the compound a12 is dissolved in ethanol in a reaction flask, then an appropriate amount of saturated ammonium chloride solution is added, and after stirring, 5 times equivalent of reduced iron powder is added in portions; then, the reaction is heated to 70 ° C for 8 hours, and then hot filtered. After the filtrate was distilled under reduced pressure, ethyl acetate was added and the mixture was washed three times with brine, and the organic phase was dried over anhydrous sodium sulfate.
  • Step 5-2
  • Step 6-2
  • the specific structures of the compounds of the formulae (I-2) and (I-3) are described below in tabular form.
  • the compound for a SIRT6 small molecule allosteric agonist or a pharmacologically acceptable salt thereof according to the present invention has any one of the structures listed in Table 2 below.
  • SIRT6 small molecule allosteric agonist of the invention has the compounds listed in Table 1 as active ingredients.
  • a fluorescence quantification method is used to detect the deacetylation activity of SIRT6 by first fluorescein 7-amino-4-methylcoumarin on the C-terminal label of the acetylated polypeptide ( ⁇ -acetyl).
  • AMC AMC
  • trypsin cleavage was used to generate free AMC, and the reaction was subjected to fluorescence quantification.
  • the specific experimental method is as follows: 50 ⁇ L of the reaction solution is reacted at 37 ° C for 2 hours, and then the reaction is terminated by adding 40 mmol/L of nicotinamide; then 6 mg/mL trypsin is added to carry out color reaction at 25 ° C for 30 minutes; finally, the microplate reader is passed. (Synergy H4 Hybrid Reader, BioTek) Fluorescence quantitative detection of the reaction, excitation wavelength and emission wavelength were 360 nm and 460 nm, respectively.
  • the blank group reaction solution contained 2.5 mmol/L of NAD+, 75 ⁇ mol/L of RHKK-Ac-AMC, and 5 ⁇ mol/L of SIRT6, wherein the reaction buffer was 50 mmol/L of Tris-HCl, 137 mmol/L of NaCl, and 2.7 mM.
  • KCl was composed of 1 mmol/L of MgCl 2 and had a pH of 8.
  • the experimental group reaction solution further contained 100 ⁇ mol/L of an agonist in the blank group reaction solution, wherein the agonist was a DMSO solution of the compound of Table 1.
  • the present invention further determine SIRT6 small molecule allosteric agonist half maximal effective concentration (EC 50)
  • the SIRT6 small molecule allosteric agonist compound listed in Table 1 as an active ingredient.
  • the deacetylation activity of SIRT6 was determined by the method described in Experiment 1, and the data was finally determined by GraphPad Prism 6 software to determine the EC 50 of the agonist activation effect on SIRT6 under various concentration conditions, and the results are shown in Fig. 9 and Fig. 10. 9 and 10 illustrate that the agonist having Compound 177 and Compound 183 as active ingredients respectively activates SIRT6 deacetylation activity in a concentration-dependent manner.
  • the EC 50 of the SIRT6 small molecule allosteric agonist having the compounds listed in Table 2 as an active ingredient was further determined in the experiment, and the results are shown in Fig. 11 and Fig. 37. 11 to 37 illustrate that the agonists having the compounds listed in Table 2 as an active ingredient respectively activate SIRT6 deacetylation activity in a concentration-dependent manner.
  • SIRT6 small molecule allosteric agonists with the compounds listed in Table 1 and Table 2 as active ingredients on SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac were detected by Western blot.
  • HEK-293T cells Bel7405 cells, PLC/PRF/5 cells, Bel7402 cells, HCT116 cells, HT29 cells, SW480 cells, and HCT116 cells were selected as test subjects.
  • HEK-293T cells and PLC/PRF/5 cells were cultured in DMEM (HyClone, SH30022.01, UT, USA) medium containing 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 10% FBS; Bel7402 cells and Bel7405 cells were cultured in RPMI-1640 Medium (HyClone, SH30809.01, UT, USA) medium supplemented with mL penicillin, 100 ⁇ g/mL streptomycin and 10% FBS. All of the above cell lines were identified by Short Tandem Repeat (STR).
  • STR Short Tandem Repeat
  • the gradient concentration includes 0.5 ⁇ mol / L, 1 ⁇ mol / L, 5 ⁇ mol / L, 10 ⁇ mol / L, 25 ⁇ mol / L and 50 ⁇ mol / L;
  • the HT29 cells were treated with 10 ⁇ mol/L of Compound SOL-011 in Table 2 for 24 hours and 48 hours, and the intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac were detected by Western blot.
  • SOL-011 down-regulates H3K9Ac and H3K56Ac, so that the reaction compound SOL-011 can activate SIRT6 deacetylation activity in HT29 cells.
  • the intracellular SIRT6 deacetylation active substrates H3K9Ac and H3K56Ac were detected by Western blot.
  • the compound SOL-011 was down-regulated. H3K9Ac and H3K56Ac, and thus the reaction compound SOL-011 can be significantly concentration-dependent to histone 3 acetylation modification.

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Abstract

本发明公开了SIRT6小分子别构激动剂及其应用，提供一种含有式(1)所示的衍生物或其药理学上可接受的盐为有效成分的SIRT6小分子别构激动剂。本发明设计并合成高效低毒的SIRT6小分子别构激动剂，在体外实验中能够明显激动SIRT6的活性，对相关疾病药物的开发具有重要的意义。

Description

用作SIRT6小分子别构激动剂的化合物及其药物组合物 技术领域
本发明涉及药物化学治疗学领域，具体来说，涉及一种SIRT6小分子别构激动剂及其作为药物化合物预防或治疗相关疾病的应用。
背景技术
哺乳动物Sirtuin家族含有7个成员(SIRT1-SIRT 7)，一般具有单腺苷二磷酸核糖基化(Mono-ADP-ribosylation)酶活性或去酰基(Deacylation)酶活性，后者主要包括去乙酰化(Deacetylation)酶活性和去豆蔻酰化(Demyristoylation)酶活性等。这些成员广泛参与各种生命活动过程，例如能量代谢、细胞压力应激、基因组稳定性、衰老以及肿瘤等。
SIRT6是Sirtuin家族的主要成员之一，其空间结构上具有一个大的Rossmann折叠结构域以及一个小的锌离子结构域，其中酶的辅助因子NAD +和底物多肽都结合在Rossmann结构域，而锌离子结构域中具有保守的锌离子结合序列。SIRT6借助辅因子NAD+，可以催化底物蛋白进行去乙酰化或单腺苷二磷酸核糖基化。组蛋白H3的K9和K56位点(以下简称H3K9、H3K56)和CtIP(C-terminal binding protein interacting protein)是已报道的去乙酰化底物，而PARP1[Poly(ADP-ribose)polymerase 1]是目前已知的单腺苷二磷酸核糖基化底物。
在生物体中，SIRT6主要通过H3K9和H3K56去乙酰化来调控一些重要的转录因子(如NF-κB、HIF1α、c-Myc)，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等诸多生命过程，并与肿瘤生成、心脏病、衰老、糖尿病和衰老等疾病密切相关，这说明SIRT6具有非常重要的生物学功能。
通过对人类癌症数据库(Cancer cell line encyclopedia，CCLE)中1000多种肿瘤细胞系的SIRT6表达分析发现，SIRT6在肿瘤中差异表达，近35％的肿瘤细胞系出现不同程度的SIRT6缺失，其中消化道肿瘤细胞中SIRT6的表达量几乎全部降低。因此，SIRT6活性上调被认为是治疗多种疾病的新策略。
因此，SIRT6小分子激动剂的发现已成为各大制药公司和研究单位的热点，但目前还没有相关药物的报道。
发明内容
本发明旨在解决上述问题，并且，本发明的一个目标是提供一种化合物，该化合物可作为可调节SIRT6去乙酰化活性的小分子别构激动剂，为开展SIRT6相关的化学生物学研究并探索SIRT6在疾病中的治疗作用奠定基础。
为了实现上述目的，本发明首先提供一种化合物或其药理学上可接受的盐，可作为SIRT6小分子别构激动剂。所述化合物以式(I)所示：
Figure PCTCN2018086766-appb-000001
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10独立地选自由H、卤素、羟基、硝基、氨基、羧基、酸酯基、磺酰胺、巯基、甲氧基、乙氧基、苄氧基、甲基及氰基组成的群组；R 11为H、Cl、硝基、氨基、苄醇基、苄氯基、苄胺基、羧基、酸酯基、
Figure PCTCN2018086766-appb-000002
R 12和R 13独立地为C 1-8取代或未取代烷基；
Figure PCTCN2018086766-appb-000003
代表取代或未取代的含氮杂环。
需要说明的是，式(I)的化合物具有对称的结构。也就是说，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10的选择需要满足式(I)化合物的对称性。
在本发明一实施例中，当R 11为
Figure PCTCN2018086766-appb-000004
时，所述化合物具有式(I-2)和式(I-3)所示的结构：
Figure PCTCN2018086766-appb-000005
在本发明一实施例中，所述R 12和R 13独立地选自由甲基、乙基、丙基、 异丙基、正丁基、异丁基、叔丁基、正戊基、2-甲基丁烷及己基组成的群组。
在本发明一实施例中，所述含氮杂环为氮杂环丙烷、氮杂环丁烷、吡唑环、吗啉环、哌啶环、哌嗪环、氮杂环庚烷或氮杂环辛烷。
在本发明一实施例中，所述含氮杂环中的至少一个氢原子被选自由甲基、乙基、羧基、酸酯基、羧基、甲醇基、环丙基、异丙基、环丁基、环己基、环戊基、氧取代烷基及丙烯基组成的群组中的一个取代基取代。
在本发明一实施例中，所述药理学上可接受的盐为钠盐，盐酸盐，硫酸盐，草酸盐，醋酸盐，三氟乙酸盐或枸橼酸盐。
本发明还提供一种SIRT6小分子别构激动剂，含有上述任一种所述化合物或其药理学上可接受的盐。
本发明还提供一种药物组合物，含有上述任一种所述化合物或其药理学上可接受的盐。
附图说明
通过以下的详细描述和所附附图，本发明的上述及其他物体、特征和优点将是显而易见的，其中：
图1至图8为FDL实验获得的经SIRT6小分子别构激动剂处理后的SIRT6的去乙酰化活性数据；
图9至图37为根据本发明所述的SIRT6小分子别构激动剂的半数最大效应浓度曲线；
图38为以不同浓度的化合物177处理HEK-293T细胞12小时、24小时、48小时或60小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图39为以不同浓度的化合物183处理Bel7405细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图40为以不同浓度的化合物183处理PLC/PRF/5细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图41为以不同浓度的化合物183处理Bel7402细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图42为以10μmol/L的化合物SOL-011处理HCT116细胞24小时及48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图43为以10μmol/L的化合物SOL-011处理HT29细胞24小时及48小时后，细胞内 SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图44为以10μmol/L的化合物SOL-011处理SW480细胞24小时及48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图45为以不同浓度的化合物SOL-011处理CT116细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图46为以不同浓度的化合物SOL-011处理HT29细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图；
图47为以不同浓度的化合物SOL-011处理SW480细胞48小时后，细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的示意图。
具体实施方式
以下，将参考附图，对本发明的一些示例性实施例进行描述应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。在以下的描述中，不同附图中显示的相同元件将被标以相同的标号。此外，在以下本发明的描述中，当会造成本发明的主题不清楚时，将会省略对于本文所含的已知功能和构造的详细描述。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下列实施例中未注明具体条件的实验方法，通常参照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或参照制造厂商所建议的条件。
实施例1.合成式(I)化合物
在本实施例中，首先提供式(I)的化合物或其药理学上可接受的盐，可作为SIRT6小分子别构激动剂。
Figure PCTCN2018086766-appb-000006
上述化合物的合成路径为：
Figure PCTCN2018086766-appb-000007
上述化合物的制备方法具体包含以下步骤：
步骤1.
Figure PCTCN2018086766-appb-000008
取适当大小的圆底烧瓶，在室温条件下，将苯胺类化合物1溶解于适量的吡啶溶液中。然后，在同样的温度下加入1.2倍当量的化合物2，并室温搅拌10分钟。随后，将反应温度升高至75℃并反应8小时以上。TLC监测反应完全后，使反应体系冷却至室温，使用2摩尔/毫升的盐酸将反应体系的pH值调节至3-4，随后加入乙酸乙酯以萃取3次；合并有机 相并用饱和食盐水洗涤3次后，有机相用无水硫酸钠干燥。将乙酸乙酯溶液进行减压蒸馏后，所得到残留物质即为化合物3，可直接用于下一步反应；
步骤2.
Figure PCTCN2018086766-appb-000009
在室温下，将化合物3或不同取代的化合物用乙酸溶解；在室温条件下加入6倍当量的铁粉，以在室温条件下反应过夜。将溶剂进行减压蒸馏，随后加入乙酸乙酯并超声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化合物4；
步骤3.
Figure PCTCN2018086766-appb-000010
选取合适的圆底烧瓶，将化合物4用吡啶溶解，在室温条件下加入1.2倍当量的苯磺酰氯衍生物5，然后将反应温度升高到75℃反应8小时以上。TLC监测反应完全后，将反应体系冷却至室温，使用2摩尔/毫升的盐酸将反应体系的pH值调节至3-4，随后加入乙酸乙酯以萃取3次；合并有机相并用饱和食盐水洗涤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)化合物。
实施例2.合成式(I)化合物
在本实施例中，提供式(I)的化合物或其药理学上可接受的盐，可作为SIRT6小分子别构激动剂。
Figure PCTCN2018086766-appb-000011
上述化合物的合成路径为：
Figure PCTCN2018086766-appb-000012
上述化合物的制备方法具体包含以下步骤：
步骤1.
Figure PCTCN2018086766-appb-000013
选取合适的圆底烧瓶，将对氨基苯磺酸衍生物6加入适量的水，在室温条件下加入2.01倍当量的NaHCO 3，搅拌至溶液澄清后，将反应移至0℃，并在0℃下将溶解了Fmoc-Cl的 1，4-二氧六环溶液缓慢加入到圆底烧瓶中。待全部滴加完以后，在0℃下继续搅拌半小时，随后将反应体系移至室温，然后反应过夜。TLC监测反应完全后，在室温条件下使用2摩尔/毫升的盐酸将反应体系的pH值调节至2，然后在减压蒸馏下，将反应瓶中的溶剂全部蒸馏后，干燥待用，即得到化合物7。
步骤2.
Figure PCTCN2018086766-appb-000014
向干燥完的化合物7在室温条件下缓慢加入三氯氧磷，然后在氮气保护下回流反应过夜。待反应完成后，将溶剂全部减压蒸馏，随后加入乙酸乙酯和水；有机相再用饱和食盐水洗涤3次，并用无水硫酸钠干燥，然后柱层析得到化合物8。
步骤3.
Figure PCTCN2018086766-appb-000015
在室温条件下，将化合物8和苯胺类取代物1按1.2:1的质量比溶解于吡啶溶液中，然后将反应温度升高至75℃反应8小时以上。TLC监测反应完全后，将反应体系冷却至室温，使用2摩尔/毫升的盐酸将反应体系的pH值调节至3-4，然后加入乙酸乙酯萃取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。用柱层析分离纯化得到化合物4。
步骤4.
Figure PCTCN2018086766-appb-000016
选取合适的圆底烧瓶，将化合物4用吡啶溶解，在室温条件下加入1.2倍当量的苯磺酰氯衍生物5，然后将反应温度升高到75℃反应8小时以上。TLC监测反应完全后，将反应冷却至室温，使用2摩尔/毫升的盐酸将反应体系的pH值调节至3-4，然后加入乙酸乙酯萃取3次；合并有机相，并用饱和食盐水洗涤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)化合物。
实施例3.式(I)化合物具体结构
以下以表格形式描述式(I)化合物的具体结构。本发明所述的用于SIRT6小分子别构激动剂的化合物或其药理学上可接受的盐具有以下表1中所列的任意一种结构。
Figure PCTCN2018086766-appb-000017
表1.化合物(I)的具体结构
Figure PCTCN2018086766-appb-000018
Figure PCTCN2018086766-appb-000019
Figure PCTCN2018086766-appb-000020
Figure PCTCN2018086766-appb-000021
Figure PCTCN2018086766-appb-000022
实施例4.合成式(I-2)或式(I-3)化合物
在本实施例中，提供式(I-2)或式(I-3)的化合物或其药理学上可接受的盐，可作为SIRT6小分子别构激动剂。
上述化合物的合成路径为：
Figure PCTCN2018086766-appb-000023
上述化合物的制备方法具体包含以下步骤：
步骤1.
Figure PCTCN2018086766-appb-000024
在反应瓶中，将含有式a4的不同取代的化合物用无水四氢呋喃溶解后，在冰浴下，缓慢加入3倍当量的四氢铝锂的四氢呋喃溶液。待全部加入以后继续在冰浴条件下搅拌0.5至1小时。将反应体系移至室温，随后将反应升温至70℃反应4小时。待反应完成以后，先将反应体系移至室温，然后将反应液缓慢的加入0℃的pH值为2的稀盐酸中，继续搅拌直至待固体充分析出。将液体抽滤，得到白色固体并干燥，获得含有式a5的苄醇类化合物。粗产品无需纯化，直接用于下一步反应。
步骤2.
Figure PCTCN2018086766-appb-000025
冰浴下，将式a5的苄醇类化合物在反应瓶中缓慢地加入二氯亚砜，加入完毕后在冰浴下继续搅拌半小时然后升至室温。将反应体系升温至75℃反应24小时。待反应完成以后，先将反应体系移至室温，然后将反应液缓慢地加入冰水混合水溶液。继续搅拌至固体析出完全后抽滤，干燥并重结晶得到式a6的苄氯类化合物。
步骤3-1.
Figure PCTCN2018086766-appb-000026
温条件下，在反应瓶中将式a6的苄氯类化合物用四氢呋喃溶解后加入1.5倍当量的含有相同取代或不同取代的脂肪支链仲胺，然后加入2倍当量的三乙胺。将反应升温至60℃反应10小时。反应结束后移至室温，然后加入水并用乙酸乙酯萃取3次；合并有机相，再用饱和食盐水洗涤3次，经柱层析分离纯化得到式(I-2)的化合物。
步骤3-2
Figure PCTCN2018086766-appb-000027
室温条件下，在反应瓶中将式6的苄氯类化合物用四氢呋喃溶解后加入1.5倍当量的含有仲胺的脂肪环及其各种取代物，然后加入2倍当量的三乙胺。将反应升温至60℃反应10 小时。反应结束后移至室温，然后加入水并用乙酸乙酯萃取3次；合并有机相，再用饱和食盐水洗涤3次，经柱层析分离纯化得到式(I-3)的化合物。
实施例5.合成式(I-2)或式(I-3)化合物
在本实施例中，提供式(I-2)或式(I-3)的化合物或其药理学上可接受的盐，可作为SIRT6小分子别构激动剂。
上述化合物的合成路径为：
Figure PCTCN2018086766-appb-000028
上述化合物的制备方法具体包含以下步骤：
步骤1.
Figure PCTCN2018086766-appb-000029
取适当大小的圆底烧瓶，在室温条件下，将苯胺类化合物a1溶解于适量的吡啶溶液中。然后在同样的温度下加入1.2倍当量的化合物a9，待室温搅拌10分钟以后，将反应温度升高至75℃反应8小时以上。TLC监测反应完全后，将反应冷却至室温，使用2摩尔/毫升的盐酸将反应体系的pH值调节至3-4，然后加入乙酸乙酯萃取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。将乙酸乙酯溶液进行减压蒸馏后，所得到残留物质即化合物a10，直接用于下一步反应。
步骤2.
Figure PCTCN2018086766-appb-000030
在反应瓶中加入化合物a10和无水乙醇，冰浴下再加入氯化亚铈，然后分批缓慢加入硼氢化钠；待全部加完硼氢化钠后在相同温度下继续反应30分钟，转移至室温。然后加热至50℃反应4小时。待反应完毕后，将反应体系冷却至室温，然后在冰浴条件下缓慢加入3moL/L稀盐酸以调节pH值至3，溶液颜色由橙黄色变为紫色；减压浓缩出乙醇溶剂后用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后柱层析得到白色固体即化合物a11。
步骤3.
Figure PCTCN2018086766-appb-000031
在反应瓶中加入化合物a11，在冰浴下缓慢加入氯化亚砜后，将反应移至室温后加热至80℃回流。反应4小时后将反应体系移至室温。反应液用冰淬灭后，用乙酸乙酯萃取3次；有机相用饱和食盐水洗涤3次，用无水硫酸钠干燥，将有机全部移去，重结晶得白色固体，即为化合物a12。
步骤4.
Figure PCTCN2018086766-appb-000032
在反应瓶中用乙醇溶解化合物a12，然后加入适量饱和氯化铵溶液，搅拌均匀后分批加入5倍当量的还原铁粉；然后，将反应加热至70℃反应8小时后，趁热抽滤；滤液减压蒸馏后，加入乙酸乙酯，用饱和食盐水洗涤3次；有机相用无水硫酸钠干燥后，经柱层析得白色固体，即化合物a13。
步骤5-1.
Figure PCTCN2018086766-appb-000033
室温条件下，在反应瓶中化合物a13用四氢呋喃溶解后加入1.5倍当量的含有相同取代或者不同取代仲胺的脂肪支链；然后加入2倍当量的三乙胺。将反应升温至60℃反应10小时。反应结束后移至室温后加入水，用乙酸乙酯萃取3次；合并有机相，再用饱和食盐水洗涤3次，经柱层析分离纯化得到化合物a14。
步骤6-1.
Figure PCTCN2018086766-appb-000034
将化合物a14在室温下用吡啶溶解后，加入1.5倍当量的化合物5。常温搅拌4小时候后，将反应移至冰浴下，缓慢滴入2mol/L的稀盐酸以调节pH值至3；析出固体后抽滤，获得的固体用乙酸乙酯溶解后柱层析得到式(I-2)的化合物。
步骤5-2.
Figure PCTCN2018086766-appb-000035
室温条件下，在反应瓶中将化合物a13用四氢呋喃溶解后，加入1.5倍当量的含有仲胺的脂肪环及其各种取代物；然后加入2倍当量的三乙胺。将反应升温至60℃反应10小时。反应结束后移至室温后加入水，用乙酸乙酯萃取3次；合并有机相，再用饱和食盐水洗涤3次，经柱层析分离纯化得到化合物a15。
步骤6-2.
Figure PCTCN2018086766-appb-000036
将化合物a15在室温下用吡啶溶解后，加入1.5倍当量的化合物5。常温搅拌2小时后，将反应移至冰浴下，缓慢滴入2mol/L的稀盐酸以调节pH值至3；析出固体后抽滤，获得 的固体用乙酸乙酯溶解后柱层析得到式(I-3)的化合物。
实施例6.式(I-2)及(I-3)化合物具体结构
以下以表格形式描述式(I-2)及(I-3)化合物的具体结构。本发明所述的用于SIRT6小分子别构激动剂的化合物或其药理学上可接受的盐具有以下表2中所列的任意一种结构。
Figure PCTCN2018086766-appb-000037
表2.化合物(I-2)及(I-3)的具体结构
Figure PCTCN2018086766-appb-000038
Figure PCTCN2018086766-appb-000039
Figure PCTCN2018086766-appb-000040
实施例7.用于SIRT6小分子别构激动剂的具体化合物及验证数据
在本实施例中，详细列举根据本发明所述的用于SIRT6小分子别构激动剂的具体化合物及其验证数据。可以理解的是，下述所有化合物实例均为式(I)化合物的具体结构。本发明所述的式(I)化合物具有以下所有化合物实例的任意一种结构。
化合物实例1
2-氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),9.68(s,1H),8.12-8.10(m,1H),7.70-7.64 (m,2H),7.58-7.54(m,1H),7.47-7.45(d,J＝8Hz,2H),7.30-7.21(m,3H),7.09-7.05(m,1H),6.81-6.79(d,J＝8.0Hz,1H),1.78(s,3H)LCMS(ESI)m/z：471.0(M+H) +
化合物实例2
2-溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.68(s,1H),8.15-8.13(m,1H),7.85-7.83(m,2H),7.61-7.45(m,4H),7.30-7.20(m,3H),7.09-7.05(m,1H),6.82-6.80(d,J＝8.0Hz,1H),1.79(s,3H)LCMS(ESI)m/z：514.9(M+H) +
化合物实例3
2-氟-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),9.71(s,1H),7.92(s,1H),7.74(m,2H),7.48-7.08(m,9H),6.82(m,1H),1.82(s,3H)LCMS(ESI)m/z：455.0(M+H) +
化合物实例4
2-硝基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.67(s,1H),7.57-7.47(m,3H),7.28-7.07(m,5H),6.78-6.58(m,3H),7.30-7.26(m,3H),7.10-7.06(m,1H),6.83-6.81(d,J＝8.0Hz,1H),1.87(s,3H)LCMS(ESI)m/z：482.0(M+H) +
化合物实例5
2-氨基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.57(s,1H),7.57-7.47(m,3H),7.28-7.07(m,5H),6.78-6.58(m,3H),6.06(s,1H),1.88(s,3H)LCMS(ESI)m/z：452.0(M+H) +
化合物实例6
3-溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.73(s,1H),7.95-7.94(t,1H),7.91-7.88(m,1H),7.81-7.79(m,1H),7.57-7.49(m,3H),7.30-7.25(m,3H),7.11-7.07(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.81(s,3H)LCMS(ESI)m/z：514.9(M+H) +
化合物实例7
3-三氟甲基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.73(s,1H),8.10-8.08(m,3H),7.87-7.83(t,1H),7.51-7.48(d,J＝12Hz,2H),7.29-7.26(m,3H),7.08-7.04(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.77(s,3H)LCMS(ESI)m/z：505.0(M+H) +
化合物实例8
3-氟-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.73(s,1H),7.67-7.53(m,4H),7.51-7.48(d,J＝12Hz,2H),7.30-7.25(m,3H),7.10-7.06(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.81(s,3H)LCMS(ESI)m/z：455.0(M+H) +
化合物实例9
3-氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.73(s,1H),7.82-7.81(m,1H),7.78-7.75(m,2H),7.65-7.61(t,1H),7.51-7.49(d,J＝8Hz,2H),7.30-7.25(m,3H),7.10-7.06(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.81(s,3H)LCMS(ESI)m/z：471.0(M+H) +
化合物实例10
3-硝基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.74(s,1H),8.56-8.50(m,2H),8.23-8.21(d,J＝8.0Hz,2H),7.92-7.88(t,1H),7.51-7.49(d,J＝8Hz,2H),7.29-7.28(m,3H),7.10-7.06(t,1H),6.86-6.84(d,J＝8.0Hz,1H),1.76(s,3H)LCMS(ESI)m/z：482.0(M+H) +
化合物实例11
3-甲氧基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.71(s,1H),7.51-7.47(m,3H),7.38-7.36(d,J＝8.0Hz,2H),7.65-7.61(t,1H),7.51-7.49(d,J＝8.0Hz,2H),7.38-7.21(m,5H),7.09-7.05(t,1H),6.83-6.81(d,J＝8.0Hz,1H),3.79(s,3H),1.84(s,3H)LCMS(ESI)m/z：467.0(M+H) +
化合物实例12
3-氰基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.73(s,1H),8.27(s,1H),8.19-8.17(d,J＝8.0Hz,1H),8.11-8.09(d,J＝8.0Hz,1H),7.84-7.80(t,1H),7.50-7.48(d,J＝8.0Hz,2H),7.30-7.25(m,3H),7.11-7.07(t,1H),6.85-6.83(d,J＝8.0Hz,1H),1.78(s,3H)LCMS(ESI)m/z：462.0(M+H) +
化合物实例13
3-氨基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.75(s,1H),7.50-7.48(d,J＝8.0Hz,1H),7.30-7.06(m,5H),7.01(s,1H),6.88-6.86(d,J＝8.0Hz,1H),6.80-6.74(m,2H),5.66(s,2H),1.93(s,3H)LCMS(ESI)m/z：452.1(M+H) +
化合物实例14
4-氟-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.72(s,1H),7.90-7.86(m,2H),7.49-7.41(m,4H),7.30-7.23(m,3H),7.11-7.07(t,1H),6.86-6.84(d,J＝8.0Hz,1H),1.79(s,3H)LCMS(ESI)m/z：455.01(M+H) +
化合物实例15
4-氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.73(s,1H),7.90-7.86(m,2H),7.49-7.42(m,4H),7.31-7.24(m,3H),7.10-7.06(t,1H),6.86-6.84(d,J＝8.0Hz,1H),1.81(s,3H)LCMS(ESI)m/z：471.0(M+H) +
化合物实例16
4-溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.73(s,1H),7.80-7.74(m,4H),7.50-7.48(d,J＝8.0Hz,2H),7.27-7.25(m,3H),7.09-7.08(t,1H),6.88-6.86(d,J＝8.0Hz,1H),1.80(s,3H)LCMS(ESI)m/z：514.9(M+H) +
化合物实例17
4-甲氧基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.70(s,1H),7.76-7.74(d,J＝8.0Hz,2H),7.49-7.47(d,J＝8.0Hz,2H),7.30-7.23(m,3H),7.10-7.08(t,3H),6.85-6.83(d,J＝8.0Hz,1H),3.81(s,3H),1.83(s,3H)LCMS(ESI)m/z：467.0(M+H) +
化合物实例18
4-三氟甲基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.78(s,1H),8.22-8.10(m,6H),7.56-6.62(m,8H),1.77(s,3H)LCMS(ESI)m/z：505.0(M+H) +
化合物实例19
4-三氟甲氧基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),9.76(s,1H),8.10-8.00(m,6H),7.53-6.89(m,8H),1.76(s,3H)LCMS(ESI)m/z：521.0(M+H) +
化合物实例20
4-氰基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.73(s,1H),7.79-7.77(d,J＝8.0Hz,2H),7.52-7.50(d,J＝8.0Hz,2H),7.30-7.23(m,3H),7.10-7.08(t,3H),6.85-6.83(d,J＝8.0Hz,1H), 1.79(s,3H)LCMS(ESI)m/z：462.0(M+H) +
化合物实例21
2，3-二氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),9.70(s,1H),7.60-7.56(m,1H),7.48-7.46(d,J＝8.0Hz,2H),7.29-7.22(m,3H),7.10-7.06(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.74(s,3H)LCMS(ESI)m/z：506.9(M+H) +
化合物实例22
2，4-二氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),9.70(s,1H),8.11-8.09(d,J＝8.0Hz,1H),7.88-7.87(d,J＝4.0Hz,1H),7.48-7.46(d,J＝8.0Hz,2H),7.30-7.21(m,3H),7.10-7.06(t,1H),6.85-6.83(d,J＝8.0Hz,1H),1.73(s,3H)LCMS(ESI)m/z：506.9(M+H) +
化合物实例23
2-氯-4-氟-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),9.70(s,1H),8.20-8.16(m,1H),7.75-7.72(m,1H),7.47-7.42(m,3H),7.30-7.28(d,J＝8.0Hz,2H),7.23-7.20(d,J＝12.0Hz,2H),7.11-7.07(t,1H),6.85-6.83(d,J＝8.0Hz,1H),1.74(s,3H)LCMS(ESI)m/z：489.0(M+H) +
化合物实例24
3，6-二氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.71(s,1H),8.07(s,1H),7.80-7.69(m,2H),7.50-7.48(d,J＝8.0Hz,2H),7.30-7.24(m,3H),7.10-7.06(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.77(s,3H)LCMS(ESI)m/z：506.9(M+H) +
化合物实例25
2，6-二氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),9.70(s,1H),7.67-7.57(m,3H),7.51-7.49(d,J＝8.0Hz,2H),7.30-7.21(m,3H),7.10-7.06(t,1H),6.82-6.80(d,J＝8.0Hz,1H),1.79(s,3H)LCMS(ESI)m/z：506.9(M+H) +
化合物实例26
2，4-二甲氧基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),9.64(s,1H),7.77-7.75(d,J＝8.0Hz,2H),7.43-7.41(d,J＝8.0Hz,2H),7.29-7.27(d,J＝8.0Hz,1H),7.19-7.17(d,J＝8.0Hz,1H),7.09-7.05(t,1H),6.65-6.61(m,2H),3.82-3.81(d,J＝4.0Hz,6H),1.78(s,3H)LCMS(ESI)m/z：497.0 (M+H) +
化合物实例27
3-三氟甲基-4-氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.75(s,1H),8.18(s,1H),8.09-8.07(d,J＝8.0Hz,1H),7.99-7.97(d,J＝8.0Hz,1H),7.51-7.49(d,J＝8.0Hz,2H),7.29-7.27(m,3H),7.10-7.06(t,1H),6.89-6.87(d,J＝8.0Hz,1H),1.72(s,3H)LCMS(ESI)m/z：539.0(M+H) +
化合物实例28
4-甲氧基-3-氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.73(s,1H),7.82-7.74(m,2H),7.51-7.49(d,J＝8.0Hz,2H),7.32-7.25(m,4H),7.10-7.06(t,1H),6.87-6.85(d,J＝8.0Hz,1H),3.92(s,3H),1.72(s,3H)LCMS(ESI)m/z：501.0(M+H) +
化合物实例29
3，5-二氯-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.76(s,1H),7.99(s,1H),7.79(s,2H),7.53-7.51(d,J＝8.0Hz,2H),7.30-7.28(m,3H),7.11-7.07(t,1H),6.88-6.86(d,J＝8.0Hz,1H),1.79(s,3H).LCMS(ESI)m/z：506.9(M+H) +
化合物实例30
4-溴-3-氟-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.74(s,1H),8.00-7.96(t,1H),7.78-7.76(m,1H),7.58-7.48(m,3H),7.30-7.26(t,3H),7.11-7.07(t,1H),6.88-6.86(d,J＝8.0Hz,1H),1.74(s,3H).LCMS(ESI)m/z：532.9(M+H) +
化合物实例31
3，4-二甲氧基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.69(s,1H),7.49-7.47(d,J＝8.0Hz,2H),7.40-7.37(m,1H),7.32-7.25(m,4H),7.09-7.07(m,2H),6.83-6.81(d,J＝8.0Hz,1H),3.80-3.78(d,J＝4.0Hz,6H),1.82(s,3H)LCMS(ESI)m/z：497.0(M+H) +
化合物实例32
3-氯-4-甲氧基-氮-(4-(氮-(3-(三氟甲基)苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.79(s,1H),7.58-7.56(d,J＝8.0Hz,2H),7.35-7.13(m,10H),6.94-6.92(d,J＝8.0Hz,1H),4.61(s,3H),2.08(s,3H)LCMS(ESI)m/z：521.0(M+H) +
化合物实例33
氮-(4-(氮-(3-三氟甲基苯基)氨磺酰基)苯基)-3-溴-4-甲氧基苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),9.75(s,1H),8.42-8.40(d,J＝8.0Hz,2H),8.07-8.05(d,J＝8.0Hz,2H),7.51-7.49(d,J＝8.0Hz,2H),7.28-7.26(d,J＝8.0Hz,2H),7.12-7.08(t,1H),6.89-6.87(d,J＝8.0Hz,1H),1.75(s,3H).LCMS(ESI)m/z：565.0(M+H) +
化合物实例34
氮-(4-(氮-(3-氟苯基)氨磺酰基)苯基)-3-溴-4-甲氧基苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.17(s,1H),7.63-7.59(m,4H),7.32-7.28(t,1H),7.22-7.17(m,4H),7.02-6.99(m,3H),3.89(s,3H).LCMS(ESI)m/z：514.9(M+H) +
化合物实例35
氮-(4-(氮-(3-甲氧基苯基)氨磺酰基)苯基)-3-溴-4-甲氧基苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.32(s,1H),7.64-7.59(m,2H),7.48-7.46(d,J＝8.0Hz,2H),7.38-7.34(t,1H),7.24-7.21(d,J＝12.0Hz,2H),6.85-6.81(m,2H),6.72-6.70(d,J＝8.0Hz,2H),3.91(s,3H),2.19(s,3H),1.75(s,3H).LCMS(ESI)m/z：528.0(M+H) +
化合物实例36
3,5-二氯-氮-(4-(氮-(2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.34(s,1H),7.64-7.60(m,2H),7.33-7.22(m,5H),7.04-7.02(d,J＝8.0Hz,2H),3.89(s,3H).LCMS(ESI)m/z：471.0(M+H) +
化合物实例37
3,5-二氯-氮-(4-(氮-(3-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.34(s,1H),7.93(s,1H),7.79-7.76d,J＝12.0Hz,1H),7.64-7.62(d,J＝8.0Hz,2H),7.28-7.22(m,5H),7.04-7.02(d,J＝8.0Hz,2H),3.91(s,3H).LCMS(ESI)m/z：471.0(M+H) +
化合物实例38
3,5-二氯-氮-(4-(氮-(2-氯苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ8.53-8.50(d,J＝12.0Hz,2H),8.21-8.19(d,J＝8.0Hz,2H),8.01-7.99(d,J＝8.0Hz,1H),7.82-7.77(m,3H),7.48-7.38(m,3H),4.02(s,3H).LCMS(ESI)m/z：492.9(M+H) +
化合物实例39
3,5-二氯-氮-(4-(氮-(3-氯苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.32(s,1H),7.95-7.94(d,J＝4.0Hz,1H),7.81-7.79(m,1H),7.49-7.46(d,J＝12.0Hz,2H),7.29-7.22(m,3H),6.85-6.81(m,2H),6.72-6.70(d,J＝8.0Hz,1H),3.93(s,3H),2.19(s,3H),1.73(s,3H).LCMS(ESI)m/z：492.9(M+H) +
化合物实例40
3,5-二氯-氮-(4-(氮-(4-氯苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.11(s,1H),7.94(s,1H),7.79-7.77(m,1H),7.64-7.62(d,J＝8.0Hz,2H),7.24-7.21(m,3H),7.08-7.04(t,2H),6.83-6.81(m,3H),3.90(s,3H),2.16(s,3H).LCMS(ESI)m/z：492.9(M+H) +
化合物实例41
3,5-二氯-氮-(4-(氮-(2-溴苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.51(s,1H),7.93(s,1H),7.78-7.76(m,1H),7.69-7.67(d,J＝8.0Hz,2H),7.26-7.21(m,4H),6.86-6.82(m,3H),3.90(s,3H).LCMS(ESI)m/z：534.8(M+H) +
化合物实例42
3,5-二氯-氮-(4-(氮-(3-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.48(s,1H),8.03-8.02(m,1H),7.78-7.77(d,J＝4.0Hz,1H),7.53-7.51(d,J＝8.0Hz,2H),7.27-7.25(d,J＝8.0Hz,2H),7.09-7.06(m,3H),6.92-6.90(m,1H),1.77(s,3H).LCMS(ESI)m/z：534.8(M+H) +
化合物实例43
3,5-二氯-氮-(4-(氮-(2-氯苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.48(s,1H),8.03-8.02(m,1H),7.78-7.77(d,J＝4.0Hz,1H),7.53-7.51(d,J＝8.0Hz,2H),7.27-7.25(d,J＝8.0Hz,2H),7.09-7.06(m,3H),6.92-6.90(m,1H),1.77(s,3H).LCMS(ESI)m/z：487.0(M+H) +
化合物实例44
3,5-二氯-氮-(4-(氮-(3-三氟甲氧基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.50(s,1H),7.94-7.69(m,5H),7.30-7.06(m,6H),LCMS(ESI)m/z：541.0(M+H) +
化合物实例45
3,5-二氯-氮-(4-(氮-(4-溴苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.38(s,1H),7.94-7.93(m,1H),7.75-7.74(d,J＝4.0Hz,2H),7.68-7.66(d,J＝8.0Hz,2H),7.39-7.37(d,J＝8.0Hz,2H),7.28-7.26(d,J＝8.0Hz, 2H),6.99-6.97(d,J＝8.0Hz,2H)LCMS(ESI)m/z：534.9(M+H) +
化合物实例46
3,5-二氯-氮-(4-(氮-(2-甲氧基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.38(s,1H),8.00-7.99(t,1H),7.81-7.80(d,J＝4.0Hz,2H),7.57-7.55(d,J＝8.0Hz,2H),7.24-7.22(d,J＝8.0Hz,2H),7.17-7.09(m,2H),6.87-6.78(d,J＝8.0Hz,2H),3.24(s,3H)LCMS(ESI)m/z：487.0(M+H) +
化合物实例47
3,5-二氯-氮-(4-(氮-(3-三氟甲氧基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.62(s,1H),7.89(s,1H),7.75(s,2H),7.72-7.69(d,J＝8.0Hz,2H),7.40-7.27(m,3H),7.05-7.03(m,2H),6.98-6.96(d,J＝8.0Hz,2H),3.67(s,3H)LCMS(ESI)m/z：541.0(M+H) +
化合物实例48
2-溴-4-三氟甲基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),9.71(s,1H),8.31-8.30(d,J＝4.0Hz,1H),8.12-8.10(d,J＝8.0Hz,1H),7.98-7.96(m,1H),7.50-7.48(d,J＝8.0Hz,1H),7.28-7.24(t,3H),7.08-7.04(t,1H),6.85-6.83(d,J＝8.0Hz,1H),1.75(s,3H)LCMS(ESI)m/z：583.0(M+H) +
化合物实例49
3-氯-5-溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.76(s,1H),8.37(s,1H),8.25(s,1H),8.09(s,1H),7.53-7.51(d,J＝8.0Hz,1H),7.31-7.26(t,3H),7.09-7.05(t,1H),6.88-6.86(d,J＝8.0Hz,1H),1.75(s,3H)LCMS(ESI)m/z：549.0(M+H) +
化合物实例50
2,5-二溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.71(s,1H),8.19(s,1H),7.79(s,2H),7.51-7.49(d,J＝8.0Hz,1H),7.30-7.24(m,3H),7.10-7.06(t,1H),6.84-6.82(d,J＝8.0Hz,1H),1.79(s,3H)LCMS(ESI)m/z：592.9(M+H) +
化合物实例51
2,5-二三氟甲基-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),9.76(s,1H),8.39-8.29(m,3H),7.79(s,2H),7.53-7.51(d,J＝8.0Hz,1H),7.28-7.25(m,3H),7.06-7.02(t,1H),6.87-6.85(d,J＝8.0Hz,1H),1.78(s,3H).LCMS(ESI)m/z：572.9(M+H) +
化合物实例52
3,5-二溴-氮-(4-(氮-(3-氯-2-甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.76(s,1H),8.22(s,1H),7.95-7.93(d,J＝8.0Hz,1H),7.51-6.87(m,9H),1.80(s,3H).LCMS(ESI)m/z：592.9(M+H) +
化合物实例53
3,5-二氯-氮-(4-(氮-苯基氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.19(s,1H),7.95-7.94(t,1H),7.75-7.74(d,J＝8.0Hz,2H),7.67-6.65(d,J＝8.0Hz,2H),7.26-7.24(d,J＝8.0Hz,2H),7.21-7.17(m,2H),7.03-6.99(m,3H).LCMS(ESI)m/z：457.0(M+H) +
化合物实例54
3,5-二氯-氮-(4-(氮-(3-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.52(s,1H),7.88(s,1H),7.75-7.70(m,4H),7.29-7.19(m,3H),6.86-6.80(m,3H).LCMS(ESI)m/z：475.0(M+H) +
化合物实例55
3,5-二氯-氮-(4-(氮-(2-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.07(s,1H),7.98-7,97(t,1H),7.77(s,2H),7.63-7.60(d,J＝12.0Hz,2H),7.28-7.26(d,J＝8.0Hz,2H),7.20-7.15(m,2H),7.10-7.06(t,2H).LCMS(ESI)m/z：475.0(M+H) +
化合物实例56
3,5-二氯-氮-(4-(氮-(2-三氟甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.02(s,1H),7.99-7,33(m,10H),7.02(s,1H).LCMS(ESI)m/z：525.0(M+H) +
化合物实例57
3,5-二氯-氮-(4-(氮-(4-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.16(s,1H),7.90-7,89(t,1H),7.75-7.74(d,J＝4.0Hz,2H),7.64-7.62(d,J＝8.0Hz,2H),7.28-7.26(d,J＝8.0Hz,2H),7.04-7.02(d,J＝8.0Hz,4H).LCMS(ESI)m/z：475.0(M+H) +
化合物实例58
3,5-二氯-氮-(4-(氮-(2-甲基-3-氯苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),9.80(s,1H),7.99-7,88(m,5H),7.69-7.66(d,J＝12.0Hz,2H),7.32-7.30(d,J＝8.0Hz,1H),7.15-7.11(t,1H),6.93-6.91(t,1H),2.10(s,3H). LCMS(ESI)m/z：469.0(M+H) +
化合物实例59
3,5-二氯-氮-(4-(氮-(3-三氟甲基苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.68(s,1H),7.84(s,1H),7.74-7.70(m,4H),7.45-7.41(t,1H),7.34-7.29(m,5H).LCMS(ESI)m/z：525.0(M+H) +
化合物实例60
3,5-二氯-氮-(4-(氮-(2-溴-4-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.85(s,1H),7.99(s,1H),7.78(s,1H),7.56-7.54(d,J＝8.0Hz,2H),7.46-7.44(d,J＝8.0Hz,1H),7.29-7.20(m,4H).：LCMS(ESI)m/z：552.9(M+H) +
化合物实例61
3,5-二氯-氮-(4-(氮-(2-氯-4-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.93(s,1H),7.98(s,1H),7.78-7.77(d,J＝4.0Hz,1H),7.29-7.25(m,4H),7.19-7.14(m,1H).LCMS(ESI)m/z：：508.0(M+H) +
化合物实例62
3,5-二氯-氮-(4-(氮-(3-氯-5-溴苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),10.81(s,1H),7.88-7.75(m,5H),7.34-7.32(d,J＝8.0,2H),7.15(s,1H),7.01-6.70(t,1H),6.88-7.87(t,1H).LCMS(ESI)m/z：568.7(M+H) +
化合物实例63
3,5-二氯-氮-(4-(氮-(3-氟-5-溴苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.80(s,1H),7.75-7.70(m,5H),7.34-7.32(d,J＝8.0,2H),7.20(s,1H),7.15-7.14(t,1H),7.05-7.04(t,1H).LCMS(ESI)m/z：551.8(M+H) +
化合物实例64
3,5-二氯-氮-(4-(氮-(3-氯-4-氟苯基)氨磺酰基)苯基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.42(s,1H),7.87(s,1H),7.75-7.66(m,4H),7.30-7.22(m,3H),7.14-7.13(4,1H),7.02-7.00(m,1H).LCMS(ESI)m/z：509.0(M+H) +
化合物实例65
3,5-二氯-氮-(4-(氮-(2,3,6-三氟苯基)氨磺酰基)苯基)苯磺酰胺胺
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.34(s,1H),7.94-7.93(t,1H),7.77-7.76 (d,J＝4.0Hz,2H),7.48-7.41(m,1H),7.30-7.23(m,3H).LCMS(ESI)m/z：510.9(M+H) +
化合物实例66
3,5-二氯-氮-(4-(氮-(2-甲基-4-氟-6-溴苯基)氨磺酰基)苯基)苯磺酰胺
δ11.14(s,1H),9.71(s,1H),7.97-7.96(t,1H),7.79-7.78(d,J＝4.0Hz,2H),7.55-7.53(m,1H),7.31-7.29(d,J＝8.0Hz,2H)，7.14-7.10(m,2H),1.71(s,3H).LCMS(ESI)m/z：566.9(M+H) +
化合物实例67
3,5-二氯-氮-(4-(氮-(3-溴-4-甲基-苯基)氨磺酰基)苯基)苯磺酰胺
δ11.15(s,1H),10.32(s,1H),7.84-7.83(d,J＝4.0Hz,1H),7.76-7.75(d,J＝4.0Hz,2H),7.69-7.67(d,J＝8.0Hz,2H),7.30-7.28(d,J＝8.0Hz,2H)，7.20-7.19(d,J＝4.0Hz,2H),7.14-7.12(d,J＝8.0Hz,2H),6.97-6.94(m,1H),2.16(s,3H).LCMS(ESI)m/z：：549.0(M+H) +
化合物实例68
3,5-二氯-氮-(4-(氮-(2-甲基-4-氟-5-溴苯基)氨磺酰基)苯基)苯磺酰胺
δ11.13(s,1H),9.71(s,1H),8.01-8.00(t,1H),7.79-7.78(d,J＝4.0Hz,2H),7.54-7.52d,J＝8.0Hz,2H),7.31-7.28(d,J＝12.0Hz,2H)，7.14-7.11(m,2H),1.71(s,3H).LCMS(ESI)m/z：566.9(M+H) +
化合物实例69
3,5-二氯-氮-(4-(氮-(2-甲基-4-氟苯基)氨磺酰基)苯基)苯磺酰胺
δ11.09(s,1H),9.51(s,1H),8.00-7.99(t,1H),7.78-7.77(d,J＝4.0Hz,2H),7.53-7.50(d,J＝12.0Hz,2H),7.29-7.27(d,J＝8.0Hz,2H)，6.95-6.88(m,3H),1.75(s,3H).LCMS(ESI)m/z：566.9(M+H) +
化合物实例71
叔丁基4-(5-(3,5-二氯苯基磺酰胺)-2-(氮-(4-氟-2-甲基苯基)氨磺酰基)苯基)哌嗪δ11.10(s,1H),9.78(s,1H),8.06-8.05(t,1H),7.78-7.77(d,J＝4.0Hz,2H),7.62-7.61(d,J＝4.0Hz,1H),7.54-7.52(d,J＝8.0Hz,1H)，7.19-7.11(m,2H),6.97-6.95(d,J＝8.0Hz,1H),3.67(s,2H),3.34(s,4H),2.24(s,4H),1.77(s,3H),1.42(s,9H).LCMS(ESI)m/z：687.0(M+H) +
化合物实例71
4-(3,5-3,5-二氯苯基磺酰胺)-氮-(4-氟-2-甲基苯基)-2-(哌嗪-1-甲基)苯基磺酰胺
δ9.08(s,1H),7.63-7.62(d,J＝4.0Hz,2H),7.27-7.25(d,J＝8.0Hz,1H),7.19-7.17(m,2H)，7.01-6,99(d,J＝8.0Hz,1H),6.77-6.75(d,J＝8.0Hz,1H),3.63(s,2H),3.36(s,4H),3.09(s,4H),1.92-1.89(m,4H).LCMS(ESI)m/z：586.9(M+H) +
化合物实例81
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((2-氟苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺
1H-NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.79(s,1H),8.01(s,1H),7.78(d,J＝7.6Hz,1H),7.64–7.53(m,4H),7.51(d,J＝8.7Hz,1H),7.19(d,J＝9.6Hz,1H),7.03(d,J＝8.7Hz,1H),6.92(d,J＝6.7Hz,1H),3.90(d,J＝16.5Hz,1H),3.58(d,J＝15.3Hz,1H),3.39(d,J＝15.9Hz,2H),3.17–3.07(m,1H),2.45–2.36(m,1H),1.81(s,3H),0.79(d,J＝6.0Hz,3H)m/z(ESI)631.6(M+H) +
化合物实例82
(R)-氮-(5-溴-4-氟-2-甲苯基)-2-((3-甲基吗啉)甲基)-(4-(2-(三氟甲氧基)苯基)磺酰氨基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.79(s,1H),8.01(s,1H),7.79(s,1H),7.64–7.46(m,4H),7.18(s,1H),7.03(s,1H),6.92(s,1H),3.90(s,1H),3.59(s,2H),3.39(s,2H),3.12(s,1H),2.41(s,1H),1.81(s,3H),0.79(d,J＝6.2Hz,3H)m/z(ESI)697.6(M+H) +
化合物实例83
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((3-溴苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.79(s,1H),7.91(s,1H),7.88(d,J＝8.0Hz,1H),7.75(d,J＝8.1Hz,1H),7.67(s,1H),7.56–7.50(m,2H),7.18(d,J＝9.6Hz,1H),7.11–7.03(m,1H),6.95(d,J＝6.7Hz,1H),3.91(d,J＝16.7Hz,1H),3.63(td,J＝9.1,7.3,3.3Hz,2H),3.50–3.39(m,2H),3.16(dd,J＝11.2,8.2Hz,1H),1.79(s,3H),0.82(d,J＝6.2Hz,3H).m/z(ESI)692.6(M+H) +
化合物实例84
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((3-氯苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.86(s,1H),7.82–7.78(m,2H),7.72(s,1H)7.69(d,J＝2.2Hz,1H),7.64(d,J＝8.0Hz,1H),7.55(d,J＝8.6Hz,1H),7.21(d,J＝9.6Hz,1H),7.09(dd,J＝8.6,2.4Hz,1H),6.97(d,J＝6.7Hz,1H),3.93(d,J＝16.8Hz,1H),3.69–3.61(m,2H),3.47(d,J＝11.6Hz,2H),3.18(dd,J＝11.2,8.4Hz,1H),2.45(d,J＝7.7Hz,1H),1.80(s,3H),0.83(d,J＝6.2Hz,3H).m/z(ESI)648.0(M+H) +
化合物实例85
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((3,5-二溴苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.88(s,1H),8.29–8.22(m,1H),8.01(d,J＝1.6Hz,1H),7.91(d,J＝1.8Hz,2H),7.71(s,1H),7.56(d,J＝8.6Hz,1H),7.19(d,J＝9.5Hz,1H),7.11(dd,J＝8.6,2.3Hz,1H),7.01(d,J＝6.7Hz,1H),3.94(d,J＝16.8Hz,1H),3.67(dd,J＝8.3,5.4Hz,2H),3.49(s,2H),3.25–3.16(m,1H),2.46(s,1H),1.78(s,3H),0.84(d,J＝6.4Hz,3H).m/z(ESI)771.4(M+H) +
化合物实例86
(R)-氮-(5-溴-4-氟-2-甲苯基)-2-((3-甲基吗啉)甲基)-4-(苯磺酰氨基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.85(s,1H),7.83–7.78(m,2H),7.66(tq,J＝2.9,1.4Hz,2H),7.58(dd,J＝8.3,6.8Hz,2H),7.53(d,J＝8.6Hz,1H),7.22(d,J＝9.6Hz,1H),7.08(dd,J＝8.6,2.4Hz,1H),6.95(d,J＝6.7Hz,1H),3.93(d,J＝16.5Hz,1H),3.64(td,J＝11.6,3.3Hz,2H),3.49–3.40(m,2H),3.17(dd,J＝11.2,8.3Hz,1H),2.44(ddd,J＝9.0,6.6,3.0Hz,1H),1.84(s,3H),0.83(d,J＝6.3Hz,3H).m/z(ESI)613.5(M+H) +
化合物实例87
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((4-异丙基苯)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),9.81(s,1H),7.74(d,J＝8.5Hz,2H),7.67(d,J＝2.4Hz,1H),7.54(d,J＝8.6Hz,1H),7.46(d,J＝8.4Hz,2H),7.21(d,J＝9.6Hz,1H),7.07(dd,J＝8.6,2.4Hz,1H),6.97(d,J＝6.7Hz,1H),3.92(d,J＝16.6Hz,1H),3.68–3.58(m,2H),3.48–3.41(m,2H),3.16(dd,J＝11.2,8.3Hz,1H),2.96(h,J＝6.9Hz,1H),2.43(ddd,J＝9.0,6.3,3.0Hz,1H),1.85(s,3H),1.18(d,J＝6.9Hz,6H),0.81(d,J＝6.2Hz,3H).m/z(ESI)654.7(M+H) +
化合物实例88
(R)-氮-(5-溴-4-氟-2-甲苯基)-2-((3-甲基吗啉)甲基)-(4-(2-(三氟甲基)苯基)磺酰氨基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),9.82(s,1H),8.12–7.99(m,2H),7.83(t,J＝8.3Hz,1H),7.66(s,1H),7.53(d,J＝8.6Hz,1H),7.15(d,J＝9.6Hz,1H),7.09(d,J＝8.4Hz,1H),6.95(d,J＝6.7Hz,1H),3.89(d,J＝16.8Hz,1H),3.66–3.55(m,2H),3.41(d,J＝17.0Hz,2H),3.12(d,J＝20.1Hz,1H),2.41(s,1H),1.76(s,3H),0.78(d,J＝6.2Hz,3H).m/z(ESI)681.5(M+H) +
化合物实例89
(R)-氮-(5-溴-4-氟-2-甲苯基)4((4(叔丁基)苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),9.82(s,1H),7.75(d,J＝8.6Hz,2H),7.61(d,J＝8.6Hz,2H),7.54(d,J＝8.6Hz,1H),7.20(d,J＝9.5Hz,1H),7.07(dd,J＝8.7,2.4Hz,1H),6.98(d,J＝6.7Hz,1H),3.91(d,J＝16.6Hz,1H),3.69–3.57(m,2H),3.44(dd,J＝18.7,11.1Hz,2H),3.16(dd,J＝11.2,8.4Hz,1H),2.42(s,1H),2.00(s,3H),1.26(s,9H),0.79(d,J＝6.2Hz,3H).m/z(ESI)669.7(M+H) +
化合物实例90
(R)-氮-(5-溴-4-氟-2-甲苯基)-4-((2-氯苯基)磺酰氨基)－2－((3-甲基吗啉)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.79(s,1H),8.09-8.07(d,J＝8.0Hz,1H),7.66-7.64(d,J＝8.0Hz,2H),7.54(t,1H),7.49-7.47(d,J＝8.0Hz,1H),7.18-7.16(d,J＝12.0Hz,1H),7.04-7.02(d,J＝8.0Hz,1H),6.90-6.88(d,J＝8.0Hz,1H),3.89(s,1H),3.67-3.57(m,2H),3.41(d,J＝12.0Hz,2H),3.20-3.11(m,1H),2.41-2.39(d,J＝8.0Hz,1H),1.78(s,3H),0.79(s,3H).m/z(ESI)648.0(M+H) +
化合物实例91
甲基2-(氮-(5-溴-4-氟-2-甲基苯基)氨基磺酰基)-5-(3，5-二氯苯基磺酰氨基)苯甲酸甲酯 1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),9.46(s,1H),8.05(s,1H),7.81-7.80(d,J＝4.0Hz,2H),7.58-7.56(d,J＝8.0Hz,1H),7.42-7.39(d,J＝12.0Hz,1H),3.73(s,1H),1.80(s,3H).m/z(ESI)627.2(M+H) +
化合物实例92
(R)-氮-(5-溴-4-氟-2-甲基苯基)-4-(3，5-二氯苯基磺酰胺基)-2-((3-羟基吡咯烷-1-基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.78-7.77(d,J＝4.0Hz,2H),7.44-7.42(d,J＝8.0Hz,1H),7.36(s,1H),7.22-7.19(d,J＝12.0Hz,1H),7.10-7.07(m,1H),6.78-6.77(d,J＝8.0Hz,1H),4.96(s,1H),4.25(s,1H),4.07-3.95(m,2H),2.08-2.00(m,1H),1.93(s,1H),1.59(s,1H).m/z(ESI)668.3(M+H) +
化合物实例93
氮-(5-溴-4-氟-2-甲基苯基)-4-(3，5-二氯苯基磺酰胺)-2-((乙基(丙基)氨基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.73-7.72(d,J＝4.0Hz,2H),7.55-7.53(d,J ＝8.0Hz,2H),7.19-7.17(d,J＝8.0Hz,1H),7.08-7.06(m,1H),6.93-6.91(d,J＝8.0Hz,1H),4.75(s,2H),2.45-2.36(m,4H),1.98(s,1H),1.37-1.31(m,2H),0.95-0.93(m,4H),0.80-0.77(m,3H).m/z(ESI)668.3(M+H) +
化合物实例94
氮-(5-溴-4-氟-2-甲基苯基)-4(3，5-二氯苯基磺酰胺)-2((4-(2-乙氧基乙基)哌嗪-1-基)甲基)苯磺酰胺 1H NMR(400MHz,DMSO-d6)δ7.97-7.96(t,1H),7.75-7.74(d,J＝4.0Hz,2H),7.45-7.43(d,J＝8.0Hz,2H),7.21-7.19(d,J＝8.0Hz,1H),7.04-7.01(m,1H),6.86-6.84(d,J＝8.0Hz,1H),3.70(s,2H),3.54-3.52(t,2H),3.45-3.40(m,2H),2.71-2.43(m,8H),1.87(s,1H),1.12-1.08(t,3H).m/z(ESI)739.4(M+H) +
化合物实例95
氮-(5-溴-4-氟-2-甲基苯基)-2((4-环戊基哌嗪-1-基)甲基)-4-(3，5-二氯苯基磺酰胺基)苯磺酰胺
δ7.88(s,1H),7.71-7.70(d,J＝4.0Hz,2H),7.38-7.36(d,J＝8.0Hz,2H),7.32(s,1H),7.22-7.19(d,J＝8.0Hz,1H),6.94-6.91(m,1H),6.84-6.83(d,J＝4.0Hz,1H),3.67(s,2H),2.75-2.43(m,8H),1.91-1.84(m,5H),1.63-1.40(m,6H).m/z(ESI)739.4(M+H) +
化合物实例96
氮-(5-溴-4-氟-2-甲基苯基)-4-(3，5-二氯苯基磺酰氨基)-2-((4-(2-羟乙基)哌嗪-1-基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.72-7.71(t,1H),7.63-7.62(d,J＝4.0Hz,2H),7.25-7.18(m,2H),7.08-7.07(d,J＝4.0Hz,1H),6.75-6.72(m,1H),6.58-6.57(d,J＝4.0Hz,1H),4.45(s,1H),3.65(s,2H),3.48-3.47(m,8H),2.07(s,3H).m/z(ESI)711.4(M+H) +
化合物实例97
(S)-N-(3-溴-4-氟苯基)-4(3,5-二氯苯基磺酰胺)-2((2-甲基吡咯烷-1-基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.78(t,1H),7.66-7.65(d,J＝4.0Hz,2H),7.37-7.35(d,J＝8.0Hz,1H),7.21-7.19(d,J＝8.0Hz,2H),6.88-6.81(m,2H),4.30-4.26(d,J＝16.0Hz,1H),2.66(s,2H),2.17(s,1H),1.99(s,3H),1.67-1.54(m,2H),1.35(s,1H),1.11-1.09(m,3H).m/z(ESI)652.3(M+H) +
化合物实例98
氮-(3-溴-4-氟苯基)-2((4-环丙基哌嗪-1-基)甲基)-4-(3，5-二氯苯基磺酰胺基)苯磺酰胺 1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.69-7.68(d,J＝4.0Hz,2H),7.36-7.34 (d,J＝8.0Hz,1H),7.30(s,1H),7.22-7.19(d,J＝12.0Hz,1H),6.92-6.89(m,1H),6.83-6.81(d,J＝8.0Hz,1H),3.67(s,2H),2.70-2.43(m,1H),1.92(s,3H),0.87-0.86(m,1H),0.53-0.49(m,2H),0.15-0.14(m,2H).m/z(ESI)693.3(M+H) +
化合物实例99
氮-(3-溴-4-氟苯基)-4(3，5-二氯苯基磺酰胺)-2((4-异丙基哌嗪-1-基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.73-7.72(t,1H),7.64-7.63(d,J＝4.0Hz,2H),7.24-7.21(d,J＝12.0Hz,2H),7.09-7.08(d,J＝4.0Hz,1H),6.77-6.74(m,1H),6.67-6.65(d,J＝8.0Hz,1H),3.65(s,2H),2.70-2.64(m,1H),2.50-2.41(m,6H),2.04(s,3H),0.95-0.93(d,6H).m/z(ESI)695.4(M+H) +
化合物实例100
氮-(3-溴-4-氟苯基)-4(3，5-二氯苯基磺酰胺)-2((4-(氧乙基-3-基)哌嗪-1-基)甲基)苯磺酰胺
1H NMR(400MHz,DMSO-d6)δ7.73-7.72(t,1H),7.64-7.63(d,J＝4.0Hz,2H),7.24-7.18(t,2H),7.10-7.09(d,J＝4.0Hz,1H),6.74-6.72(m,1H),6.59-6.58(d,J＝4.0Hz,1H),4.51-4.48(t,2H),4.39-4.36(t,2H),3.66(s,2H),3.38-3.26(m,2H),2.39-2.05(m,10H).m/z(ESI)709.3(M+H) +
实施例8.验证实验
实验一、SIRT6小分子别构激动剂对于SIRT6的激动效应的验证实验
在本验证实验中，验证本发明所述的SIRT6小分子别构激动剂对于SIRT6去乙酰化活性的激动效应。本发明所述的SIRT6小分子别构激动剂以表1中所列化合物为有效成分。
在本实施例中，采用荧光定量的方法来检测SIRT6的去乙酰化活性，原理为：首先在乙酰化多肽(ε-acetyl)的C端标记上荧光素7-氨基-4-甲基香豆素(AMC)；随后，在使用SIRT6对ε-acetyl进行去乙酰化后，使用胰蛋白酶剪切以产生游离AMC，进而对反应进行荧光定量。
具体实验方法为：取50μL的反应液于37℃反应2小时后，加入40mmol/L烟酰胺终止反应；随后加入6mg/mL的胰蛋白酶于25℃进行显色反应30分钟；最后通过酶标仪(Synergy H4Hybrid Reader,BioTek)对反应进行荧光定量检测，激发波长和发射波长分别为360nm和460nm。空白组反应液包含2.5mmol/L的NAD+、75μmol/L的RHKK-Ac-AMC、5μmol/L的SIRT6，其中，反应缓冲液由50mmol/L的Tris-HCl、137mmol/L的NaCl、2.7mM KCl和1mmol/L的MgCl 2组成，并且pH值为8。实验组反应液为空白组反应液中进一步 包含100μmol/L的激动剂，其中所述激动剂为表1化合物的DMSO溶液。
对比空白组与实验组SIRT6去乙酰化活性，获得如图1至图8所示的实验结果，说明表1所列化合物对于SIRT6具有激动效应。
实验二、SIRT6小分子别构激动剂的半数最大效应浓度测定
在本实验中进一步测定本发明所述SIRT6小分子别构激动剂的半数最大效应浓度(EC 50)，所述SIRT6小分子别构激动剂以以表1中所列化合物为有效成分。
SIRT6的去乙酰化活性以实验一所述方法测定，测定数据最后通过GraphPad Prism 6软件求解激动剂在多种浓度条件下对SIRT6激活效应的EC 50，结果如图9和图10所示。图9和图10说明，以化合物177和化合物183为有效成分的激动剂分别浓度依赖性地激活SIRT6去乙酰化活性。
在本实验中还进一步测定以表2中所列化合物为有效成分的SIRT6小分子别构激动剂的EC 50，结果如图11和图37所示。图11至图37说明，以表2中所列化合物为有效成分的激动剂分别浓度依赖性地激活SIRT6去乙酰化活性。
实验三、细胞检测
以Western blot实验方法检测以表1和表2中所列化合物为有效成分的SIRT6小分子别构激动剂对于细胞细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac的影响。
(一)细胞培养
选取HEK-293T细胞、Bel7405细胞、PLC/PRF/5细胞、Bel7402细胞、HCT116细胞、HT29细胞、SW480细胞、HCT116细胞为测试对象。
在含有100U/mL青霉素、100μg/mL链霉素和10％FBS的DMEM(HyClone,SH30022.01,UT,USA)培养基中培养HEK-293T细胞和PLC/PRF/5细胞；在含有100U/mL青霉素、100μg/mL链霉素和10％FBS的RPMI-1640Medium(HyClone,SH30809.01,UT,USA)培养基中培养Bel7402细胞和Bel7405细胞。以上细胞系均经过Short Tandem Repeat(STR)鉴定分析。
(二)处理细胞
1)配置表1和表2中所列化合物母液(溶剂为DMSO)，梯度浓度包括0.5μmol/L、1μmol/L、5μmol/L、10μmol/L、25μmol/L及50μmol/L；
2)将生长于相应培养液中状态良好的细胞种入6孔板中，每孔3*10 5个(HEK-293T细胞)或5*10 5个(Bel7405、PLC/PRF/5和Bel7402细胞)，培养于37℃、5％CO 2条件下；
3)24小时后细胞状态良好的话，换用新鲜的培养液(2ml)，然后将以上配置的母液按照1:1000的比例加入实验组的细胞培养液中；对照组的细胞培养液中则加入相同体积的 DMSO(2ul)；
4)继续培养一定时间(12小时、24小时、48小时或60小时)。
(三)Western blot检测
1)对于培养结束的各组细胞，弃去各孔中的培养液，用1*PBS洗一次；
2)于每孔中分别加入含有溴酚蓝的SDS裂解液(150μl)，混匀后分别转移至1.5ml的EP管中；
3)先95℃放置5min，然后冰上放置5min，重复三次；
4)12000×g离心5min，取上清液用于western blot检测。本实验中所用抗体信息如表3所示。
表3.Western blot检测参数
Figure PCTCN2018086766-appb-000041
检测结果请见图38至图47。
以不同浓度的表1中化合物177处理HEK-293T细胞12小时、24小时、48小时或60小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图38所示，表明：化合物177可以浓度依赖性地下调H3K9Ac和H3K56Ac，从而反应化合物177可以在HEK-293T细胞内激活SIRT6去乙酰化活性。
以不同浓度的表1中化合物183处理Bel7405细胞48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图39所示，表明：化合物183可以浓度依赖性地下调H3K9Ac和H3K56Ac，从而反应化合物183可以在Bel7405细胞内激活SIRT6去乙酰化活性。
以不同浓度的表1中化合物183处理PLC/PRF/5细胞48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图40所示，表明：化合物183可以浓度依赖性地下调H3K9Ac和H3K56Ac，从而反应化合物183可以在PLC/PRF/5细胞内激活SIRT6去乙酰化活性。
以不同浓度的表1中化合物183处理Bel7402细胞48小时后，使用Western blot方法 检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图41所示，表明：化合物183可以浓度依赖性地下调H3K9Ac和H3K56Ac，从而反应化合物183可以在Bel7402细胞内激活SIRT6去乙酰化活性。
以10μmol/L的表2中化合物SOL-011处理HCT116细胞24小时及48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图42所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以在HCT116细胞内激活SIRT6去乙酰化活性。
以10μmol/L的表2中化合物SOL-011处理HT29细胞24小时及48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图43所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以在HT29细胞内激活SIRT6去乙酰化活性。
以10μmol/L的表2中化合物SOL-011处理SW480细胞24小时及48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图44所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以在SW480细胞内激活SIRT6去乙酰化活性。
以不同浓度的表2中化合物SOL-011处理CT116细胞48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图45所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以浓度依赖显著去组蛋白3乙酰化修饰。
以不同浓度的表2中化合物SOL-011处理HT29细胞48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图46所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以浓度依赖显著去组蛋白3乙酰化修饰。
以不同浓度的表2中化合物SOL-011处理SW480细胞48小时后，使用Western blot方法检测获得的细胞内SIRT6去乙酰化活性底物H3K9Ac和H3K56Ac如图47所示，表明：化合物SOL-011下调H3K9Ac和H3K56Ac，从而反应化合物SOL-011可以浓度依赖显著去组蛋白3乙酰化修饰。
尽管为了说明的目的而描述了本发明的一较佳实施例，本领域技术人员将理解的是，在不脱离如所附权利要求中公开的本发明的范围和精神下，多种修改、添加或替换是可行的。本发明的范围应在所附权利要求的基础上，以一种所述技术思路包含在与属于本发明的权利要求相当的范围内的方式进行解释。

Claims (8)

  1. 一种化合物，或其药理学上可接受的盐，以式(I)所示：
    Figure PCTCN2018086766-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10独立地选自由H、卤素、羟基、硝基、氨基、羧基、酸酯基、磺酰胺、巯基、甲氧基、乙氧基、苄氧基、甲基及氰基组成的群组；
    R 11为H、Cl、硝基、氨基、苄醇基、苄氯基、苄胺基、羧基、酸酯基、
    Figure PCTCN2018086766-appb-100002
    Figure PCTCN2018086766-appb-100003
    R 12和R 13独立地为C 1-8取代或未取代烷基；
    Figure PCTCN2018086766-appb-100004
    代表取代或未取代的含氮杂环。
  2. 如权利要求1所述的化合物，其中，所述含氮杂环为氮杂环丙烷、氮杂环丁烷、吡唑环、吗啉环、哌啶环、哌嗪环、氮杂环庚烷或氮杂环辛烷。
  3. 如权利要求1所述的化合物，其中，所述含氮杂环中的至少一个氢原子被选自由甲基、乙基、羧基、酸酯基、羧基、甲醇基、环丙基、异丙基、环丁基、环己基、环戊基、氧取代烷基及丙烯基组成的群组中的一个取代基取代。
  4. 如权利要求1所述的化合物，其中，
    Figure PCTCN2018086766-appb-100005
    为式(Rb-1)至(Rb-57)中的一个：
    Figure PCTCN2018086766-appb-100006
    Figure PCTCN2018086766-appb-100007
  5. 如权利要求1所述的化合物，其中，所述R 12和R 13独立地选自由甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-甲基丁烷及己基组成的群组。
  6. 如权利要求1所述的化合物，其中，所述药理学上可接受的盐为钠盐，盐酸盐，硫酸盐，草酸盐，醋酸盐，三氟乙酸盐或枸橼酸盐。
  7. 一种SIRT6小分子别构激动剂，含有权利要求1至5中任一项所述的化合物或其药理学上可接受的盐。
  8. 一种药物组合物，含有权利要求1至5中任一项所述的化合物或其药理学上可接受的盐。
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