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WO2025228196A1 - Bifunctional aromatic alkylamine inhibitor for ferroptosis and/or sigma receptors, and preparation method therefor and use thereof - Google Patents

Bifunctional aromatic alkylamine inhibitor for ferroptosis and/or sigma receptors, and preparation method therefor and use thereof

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Publication number
WO2025228196A1
WO2025228196A1 PCT/CN2025/090581 CN2025090581W WO2025228196A1 WO 2025228196 A1 WO2025228196 A1 WO 2025228196A1 CN 2025090581 W CN2025090581 W CN 2025090581W WO 2025228196 A1 WO2025228196 A1 WO 2025228196A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
ferroptosis
chloroform
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/090581
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French (fr)
Chinese (zh)
Inventor
王勇
闫江坤
韩新宇
范雪静
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ocean University of China
Original Assignee
Ocean University of China
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Application filed by Ocean University of China filed Critical Ocean University of China
Publication of WO2025228196A1 publication Critical patent/WO2025228196A1/en
Pending legal-status Critical Current
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Definitions

  • This invention belongs to the field of pharmaceutical technology, specifically relating to an aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, its preparation method, and its application.
  • Cell death can be broadly classified into two categories: uncontrolled cell death caused by excessive cellular damage and regulated cell death dependent on tightly controlled molecular pathways.
  • Apoptosis is the most typical form of regulated cell death, initiating cell death through the activation of caspases.
  • Ferroptosis a novel cell death mechanism discovered in recent years, is an oxidative cell death induced by various factors, exhibiting iron ion dependence. Its occurrence stems from an imbalance between the generation and degradation of intracellular lipid reactive oxygen species (ROS).
  • ROS lipid reactive oxygen species
  • the mechanisms controlling ferroptosis primarily revolved around cysteine and glutathione metabolism, and the phospholipid peroxidase GPX4's prevention of lipid peroxidation accumulation.
  • Ferroptosis inducers act directly or indirectly on glutathione peroxidases (GPXs) through different pathways, leading to decreased cellular antioxidant capacity, ROS accumulation, and ultimately oxidative cell death.
  • GPXs glutathione peroxidases
  • the complex interactions between lipid, iron, and cysteine metabolism have become important regulatory factors in this cell death pathway.
  • Recently, the regulation of ferroptosis has become an attractive strategy for intervening in human diseases, including cancer, neurodegenerative diseases, and ischemic diseases.
  • Ferroplasm can be inhibited by iron chelators, lipophilic antioxidants, and/or ferrostatin-1 (fer-1).
  • Fer-1 is an aryl alkylamine with antioxidant properties and was one of the first feroplasm inhibitors identified.
  • Fer-1 intercepts and scavenges lipid free radicals through hydrogen atom transfer or direct reduction.
  • the Sigma ( ⁇ ) receptor is a complete membrane protein widely expressed in the central nervous system and peripheral tissues. Based on differences in tissue distribution and pharmacological characteristics, it can be divided into two subtypes, ⁇ 1 and ⁇ 2, although their names are similar, these two proteins are sequence-unrelated.
  • the ⁇ 1 receptor was cloned in 1996 and has no analogue in the human genome; its closest known functional homolog is the yeast ⁇ 8,7-sterol isomerase ERG2.
  • the structure of the ⁇ 2 receptor also known as TMEM97, was only confirmed in recent years; it is a resident membrane protein of the endoplasmic reticulum (ER)-regulated sterol transporter NPC1.
  • TMEM97 is predicted to be a four-helix bundle protein with both its N-terminus and C-terminus facing the cytoplasm.
  • the ⁇ 2 receptor is overexpressed in proliferating cells and many tumors, and labeled ⁇ 2 ligands have been proposed as tools for cancer diagnosis and treatment. Consistent with its high expression in the central nervous system (CNS), the ⁇ 2 receptor is also considered a therapeutic target for CNS diseases.
  • ⁇ 2 receptor ligands can alleviate alcohol withdrawal symptoms and have a neuroprotective effect in brain injury.
  • the present invention aims to provide an aromatic alkylamine bifunctional inhibitor of ferroptosis and/or Sigma receptors, its preparation method, and its applications.
  • the aromatic alkylamine compound exhibits strong anti-ferroptosis activity and can be used to prepare drugs for treating ferroptosis-related diseases; it also possesses Sigma receptor affinity, making it suitable for treating Sigma receptor-related diseases.
  • This type of compound combines the advantages of both and can be used to prepare drugs for treating diseases related to both.
  • the present invention employs the following technical solution:
  • This invention provides an aromatic alkylamine bifunctional inhibitor of ferroptosis and/or Sigma receptors, having the following structural formula:
  • R1 is selected from hydrogen, alkyl, aryl, C1 - C6 alkyl-aryl, C1 - C6 alkyl-phenolic or C3 - C10 cycloalkyl;
  • R2 is selected from C0 - C8 alkyl, C3 - C12 cycloalkyl, adamantyl or polyyne;
  • R3 , R4 , R5 , and R6 are selected from H, C1 - C6 alkyl, OH, OCH3 , OCH( CH3 ) 2 , OCH2CH (CH3) 2, OC(CH3)3 , O ( C1 -C6 alkyl), OCF3 , OCH2CH2OH , O( C1 - C6 alkyl)OH, F, Cl , Br, I, CF3 , CN, NO2 , NH2 , C1 - C6 heteroalkyl, C1 - C6 hydroxyalkyl, Ci - C6 alkoxy, C1 - C6 alkyl, aryl, aromatic heteroalkyl, C3 - C7 cycloalkyl, heterocyclic alkyl, alkylaryl , CO2Ra , C (O) Ra , NH( C1 - C4 alkyl), N( C1 -C6 alkyl)
  • X is selected from CH2 , O, S, NH, NH ( C1 - C4 alkyl), N ( C1 - C4 alkyl) 2 , NH ( C3 - C7 cycloalkyl), NHC(O)( C1 - C4 alkyl), NC(O) Ra , NS(O) 1/ 2Ra ;
  • n and n are the number of carbon atoms, which can be 0, 1, or 2.
  • Ra is selected from H, CH3 , CH2CH3 , C3 - C6 alkyl , C1-C6 haloalkyl or optionally substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocyclic alkyl, heteroaryl, C1 - C6 alkoxy, NH ( C1 -C4 alkyl) and N (C1-C4 alkyl)2 , wherein the optionally substituted group is selected from C1-C6 alkyl or C2 - C7 acrylate ;
  • the inhibitor is compounds I-1 to I-22, II-1 to II-17, whose structural formulas are as follows:
  • the present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:
  • Reagents and reaction conditions (a) Sodium borohydride, methanol; (b) Cyclohexylamine, potassium carbonate, DMSO, 150°C; (c) PCC, chloroform; (d) Acetone, sodium hydroxide; (e) Sodium borohydride, methanol; (f) Pd/C, hydrogen, methanol; (g) (Boc) 2O , triethylamine, tetrahydrofuran; (h) Carbon tetrabromide, triphenylphosphine, dichloromethane; (i) The corresponding amine, potassium carbonate, potassium iodide, DMF; (j) i: HCl/ CH3CH2OH ; ii: The corresponding aldehyde, sodium triacetoxyborohydride , dichloromethane.
  • the present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:
  • Reagents and reaction conditions (k) NBS, AIBN, chloroform, reflux; (l) 2-methylbut-3-yn-2-amine, potassium carbonate, tetrahydrofuran, 60°C; (m) 4-bromo-N-cyclohexyl-2- nitroaniline , Pd( PPh3 ) 2Cl2 , cuprous iodide, triethylamine, 40°C; (n) i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane; (o)
  • the present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:
  • Reagents and reaction conditions (p)i: thionyl chloride, dichloromethane, DMF; ii: tert-butyl (2-aminoethyl)carbamate, triethylamine, dichloromethane; (q) cyclohexylamine, potassium carbonate, DMF, 80°C; (r) trifluoroacetic acid, dichloromethane; (s) 1,2-bis(bromomethyl)benzene, potassium carbonate, tetrahydrofuran, 60°C; (t)i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane.
  • the present invention also provides the use of the described inhibitor in the preparation of ferroptosis inhibitors and/or Sigma receptor inhibitors.
  • the present invention also provides the use of the inhibitor in the preparation of medicaments for treating ferroptosis-related diseases and/or Sigma receptor-related diseases.
  • the present invention also provides the application of the aforementioned inhibitor in the preparation of neurological diseases related to A ⁇ amyloid aggregation.
  • iron death-related diseases include neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, liver and kidney failure, inflammation, and diabetic complications.
  • Sigma receptor-related diseases include neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), stroke, drug addiction, neuropathic pain, schizophrenia, and depression.
  • neurological diseases caused by A ⁇ amyloid aggregation include, but are not limited to, Alzheimer's disease and Parkinson's syndrome.
  • the drug also contains pharmaceutically acceptable salts, carriers, or adjuvants.
  • the use of the aromatic alkylamine compounds to treat ferroptosis is because these compounds can act as free radical scavengers to reduce intracellular reactive oxygen species and lipid peroxides, thereby rescuing ferroptosis caused by reactive oxygen species; wherein reactive oxygen species include, but are not limited to , H2O2 , t-BuOOH, O2 ⁇ , OH ⁇ , ONOO ⁇ , and ClO ⁇ .
  • ferroptosis inducers include, but are not limited to, RSL3 and its derivatives, Erastin and its derivatives, ML162 and its derivatives.
  • This invention obtains an arylalkylamine compound capable of simultaneously acting on ferroptosis and Sigma receptors through multiple synthetic methods, enriching the structure of ferroptosis and Sigma receptor inhibitors.
  • the arylalkylamine compound can inhibit ferroptosis induced by ferroptosis inducers and reduce the level of intracellular reactive oxygen species; experiments have also verified that the arylalkylamine compound can act as a Sigma receptor inhibitor, exhibiting a strong affinity for Sigma receptors; further experiments have verified that the arylalkylamine compound can inhibit the formation of polymers from monomeric amyloid A ⁇ 1-42 . Therefore, the arylalkylamine compound provided by this invention can exert significant application value in the treatment of neurological diseases related to ferroptosis and Sigma receptors through multiple actions.
  • Figure 1 shows the inhibitory effect of compound I-7 on A ⁇ 1-42 in this invention.
  • N-cyclohexyl-4-(3-(isoindolin-2-yl)-3-methylbut-1-yn-1-yl)-2-nitroaniline (0.04 g) was added to a reaction flask containing 20 mL of solvent, and palladium on carbon (0.012 g) was added. The reaction was carried out under H2 conditions. After the reaction was complete, the palladium on carbon was filtered off, and the mixture was separated by column chromatography to give a pale yellow solid (0.024 g, 64%).
  • GPX4 inhibitors such as RSL-3
  • RSL-3 can induce ferroptosis in cells.
  • This ferroptosis can be blocked by other small molecules, such as lipophilic antioxidants like Ferrostatin-1 (fer-1) and Liproxstatin. Therefore, the ability of ferroptosis inhibitors to block ferroptosis can be indicated by the reversal of ferroptosis induced by ferroptosis inducers.
  • Human neuroblastoma cells SH-SY5Y, human fibrosarcoma cells HT1080, and mouse hippocampal neurons were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.
  • the MTT assay was used, specifically as follows: Human renal cell carcinoma cell lines SH-SY5Y/HT1080/HT22 in logarithmic growth phase were digested, collected, and diluted. Approximately 4000-5000 cells per well were seeded into 96-well plates, with three replicates and 80 ⁇ L per well. The plates were incubated overnight at 37°C and 5% CO2 . The experiment included a DMSO control group and nine different concentrations of the compound treatment groups. Different concentrations of the compound were added to each treatment group, and a DMSO control group (diluted to the highest concentration compound) was set up.
  • Example 5 The compound can inhibit the polymerization of A ⁇ 1-42 monomers into polymers in vitro.
  • Alzheimer's disease is the most common neurodegenerative disease, and one of its main pathological features is the deposition of ⁇ -amyloid protein in extracellular senile plaques. Furthermore, numerous studies have shown that the levels of many metal ions (mainly Cu2+ , Zn2+ , and Fe2+ ) in the brains of AD patients are significantly higher than in normal individuals, and they accumulate in the senile plaques of AD patients, ultimately leading to an imbalance in metal ion homeostasis.
  • metal ions mainly Cu2+ , Zn2+ , and Fe2+
  • a ⁇ 1-42 monomer Preparation of A ⁇ 1-42 monomer: First, the A ⁇ 1-42 powder was removed from the -70°C freezer and thawed at room temperature for about 30 minutes. A certain amount of A ⁇ 1-42 was weighed and dissolved in hexafluoroisopropanol to a final concentration of 1 mg/mL. The solution was then allowed to stand at room temperature for 2 hours until it became clear. After that, it was sonicated in an ice bath for 30 minutes to remove any possible A ⁇ 1-42 aggregates. The sample was then frozen solid at -70°C for at least 4 hours, and then freeze-dried in a freeze dryer. After 24 hours, the sample was removed to obtain flocculent and fluffy A ⁇ 1-42 monomer, which was stored at -20°C for later use.
  • ThT fluorescence experiment Thioflavin T (ThT), as a fluorescent dye molecule, can specifically bind to the ⁇ -sheet structure in A ⁇ 1-42 fibers, thus exhibiting an absorption peak at 480 nm under 440 nm excitation light, which can be used to detect the aggregation of A ⁇ 1-42 .
  • a ⁇ 1-42 monomers were mixed with RTH in different proportions, always maintaining a final A ⁇ 1-42 concentration of 25 ⁇ M. The mixed samples were incubated in an air shaker (37°C).
  • ThT fluorescence intensity was measured in a fluorescence spectrophotometer.
  • the instrument parameters were as follows: excitation wavelength 440 nm, emission wavelength 480 nm, excitation bandwidth and emission bandwidth both 5 nm. Each experimental point was repeated three times, the average value was taken, and the standard deviation was calculated.

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Abstract

Disclosed in the present invention are a bifunctional aromatic alkylamine inhibitor for ferroptosis and/or Sigma receptors, and a preparation method therefor and the use thereof. The bifunctional inhibitor has the chemical structural formula of: (I). The bifunctional inhibitor is an arylalkylamine compound, can inhibit ferroptosis caused by a ferroptosis inducer, and can reduce the intracellular levels of reactive oxygen species. The arylalkylamine compound can also be used as a Sigma receptor inhibitor, showing relatively strong affinity for Sigma receptors. Moreover, it is verified by means of experiments that the arylalkylamine compound can inhibit monomeric amyloid Aβ1-42 from forming aggregates thereof. Therefore, the arylalkylamine compound provided in the present invention has great application value in the treatment, by means of multiple effects, of neurological diseases associated with ferroptosis and Sigma receptors.

Description

一种芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂及其制备方法和应用An aromatic alkylamine bifunctional inhibitor of ferroptosis and/or Sigma receptors, its preparation method and application 技术领域Technical Field

本发明属于医药技术领域，具体涉及一种芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂及其制备方法和应用。This invention belongs to the field of pharmaceutical technology, specifically relating to an aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, its preparation method, and its application.

背景技术Background Technology

细胞死亡大致可分为两大类：由过度细胞损伤引起的不受控制的细胞死亡以及依赖严格控制的分子通路的调控细胞死亡。凋亡是调节细胞死亡的最典型形式，通过激活caspases引发细胞死亡。铁死亡(ferroptosis)是近几年发现的一种新的细胞死亡方式，是在多种原因诱导下发生的氧化性细胞死亡，具有铁离子依赖性，其发生是细胞内脂质活性氧(reactive oxygen species,ROS)生成与降解的平衡失调所致。在发现铁死亡的最初几年中阐明的控制铁死亡机制主要围绕半胱氨酸和谷胱甘肽代谢，以及磷脂过氧化物酶GPX4防止过氧化脂质积累。铁死亡诱导剂通过不同的通路直接或间接作用于谷胱甘肽过氧化物酶(glutathione peroxidase,GPXs)，导致细胞抗氧化能力降低、ROS堆积、最终引起细胞氧化性死亡。脂质、铁和半胱氨酸代谢之间复杂的相互作用已成为这一细胞死亡途径的重要调节因素。最近，对铁死亡的调控已成为一种有吸引力的策略，用于干预人类疾病，包括癌症、神经退行性疾病和缺血性疾病。Cell death can be broadly classified into two categories: uncontrolled cell death caused by excessive cellular damage and regulated cell death dependent on tightly controlled molecular pathways. Apoptosis is the most typical form of regulated cell death, initiating cell death through the activation of caspases. Ferroptosis, a novel cell death mechanism discovered in recent years, is an oxidative cell death induced by various factors, exhibiting iron ion dependence. Its occurrence stems from an imbalance between the generation and degradation of intracellular lipid reactive oxygen species (ROS). In the early years after its discovery, the mechanisms controlling ferroptosis primarily revolved around cysteine and glutathione metabolism, and the phospholipid peroxidase GPX4's prevention of lipid peroxidation accumulation. Ferroptosis inducers act directly or indirectly on glutathione peroxidases (GPXs) through different pathways, leading to decreased cellular antioxidant capacity, ROS accumulation, and ultimately oxidative cell death. The complex interactions between lipid, iron, and cysteine metabolism have become important regulatory factors in this cell death pathway. Recently, the regulation of ferroptosis has become an attractive strategy for intervening in human diseases, including cancer, neurodegenerative diseases, and ischemic diseases.

铁死亡能被铁螯合剂、亲脂抗氧化剂和/或ferrostatin-1(fer-1)所抑制。Fer-1是一种具有抗氧化性能的芳基烷基胺，是最早被鉴定为铁死亡抑制剂之一。Fer-1作为脂质过氧化还原剂，通过氢原子转移或直接还原拦截和清除脂质自由基。Ferroplasm can be inhibited by iron chelators, lipophilic antioxidants, and/or ferrostatin-1 (fer-1). Fer-1 is an aryl alkylamine with antioxidant properties and was one of the first feroplasm inhibitors identified. As a lipid peroxidation agent, Fer-1 intercepts and scavenges lipid free radicals through hydrogen atom transfer or direct reduction.

Sigma(σ)受体是一种完整的膜蛋白，广泛表达于中枢神经系统和外周组织中。根据组织分布和药理特征的差异，可分为σ1和σ2两种亚型，尽管它们的名称很相似，但是这两种蛋白质在序列上是不相关的。σ1受体于1996年被克隆，在人类基因组中没有类似物；其已知功能最接近的同源物是酵母Δ8,7甾醇异构酶ERG2。而σ2受体结构在近几年才被证实，也叫TMEM97,一种内质网(ER)-调节甾醇转运体NPC1的常驻膜蛋白。TMEM97被预测为一个四螺旋束蛋白，其氨基端和羧基端都面向细胞质。σ2受体在增殖细胞和许多肿瘤中过表达，而标记的σ2配体已被提出作为癌症诊断和治疗的工具。与它在中枢神经系统(CNS)中的高表达相一致，σ2受体也被认为是中枢神经系统疾病治疗的一个靶点。σ2受体配体可减轻酒精戒断症状，在脑损伤中具有神经保护作用。The Sigma (σ) receptor is a complete membrane protein widely expressed in the central nervous system and peripheral tissues. Based on differences in tissue distribution and pharmacological characteristics, it can be divided into two subtypes, σ1 and σ2, although their names are similar, these two proteins are sequence-unrelated. The σ1 receptor was cloned in 1996 and has no analogue in the human genome; its closest known functional homolog is the yeast Δ8,7-sterol isomerase ERG2. The structure of the σ2 receptor, also known as TMEM97, was only confirmed in recent years; it is a resident membrane protein of the endoplasmic reticulum (ER)-regulated sterol transporter NPC1. TMEM97 is predicted to be a four-helix bundle protein with both its N-terminus and C-terminus facing the cytoplasm. The σ2 receptor is overexpressed in proliferating cells and many tumors, and labeled σ2 ligands have been proposed as tools for cancer diagnosis and treatment. Consistent with its high expression in the central nervous system (CNS), the σ2 receptor is also considered a therapeutic target for CNS diseases. σ2 receptor ligands can alleviate alcohol withdrawal symptoms and have a neuroprotective effect in brain injury.

发明内容Summary of the Invention

针对现有技术的不足，本发明的目的是提供了一种芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂及其制备方法和应用。所述芳香烷胺类化合物抗铁死亡活性强，能够用于制备治疗铁死亡相关疾病的药物；且具有Sigma受体亲和力，适用于Sigma受体相关疾病的治疗，此类化合物兼具两者的优势可用于制备治疗两者相关疾病的药物。为了实现上述发明目的，本发明采用如下技术方案实现：To address the shortcomings of existing technologies, the present invention aims to provide an aromatic alkylamine bifunctional inhibitor of ferroptosis and/or Sigma receptors, its preparation method, and its applications. The aromatic alkylamine compound exhibits strong anti-ferroptosis activity and can be used to prepare drugs for treating ferroptosis-related diseases; it also possesses Sigma receptor affinity, making it suitable for treating Sigma receptor-related diseases. This type of compound combines the advantages of both and can be used to prepare drugs for treating diseases related to both. To achieve the above-mentioned objective, the present invention employs the following technical solution:

本发明提供了一种芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂，其具有如下所示的结构式：
This invention provides an aromatic alkylamine bifunctional inhibitor of ferroptosis and/or Sigma receptors, having the following structural formula:

式中，R1选自氢、烷基、芳基、C1-C6烷基-芳基、C1-C6烷基-酚基或C3～C10环烷基；R2选自C0～C8烷基、C3～C12环烷基、金刚烷基或多炔基；In the formula, R1 is selected from hydrogen, alkyl, aryl, C1 - C6 alkyl-aryl, C1 - C6 alkyl-phenolic or C3 - C10 cycloalkyl; R2 is selected from C0 - C8 alkyl, C3 - C12 cycloalkyl, adamantyl or polyyne;

Linker选自直接键、C1-C6烷基或含1-3个独立取代基的C1-C6烷基、C2-C6烯基或含1-3个独立取代基的C2-C6烯基、(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基)、(C0-C6烷基)-Z-(C0-C6烷基)或含1-3个独立取代基的(C0-C6烷基)-Z-(C0-C6烷基)；其中，Z选自N(Ra)、-SO2-、OC(＝O)或者C(＝O)O；Linker is selected from direct bond, C1 - C6 alkyl or C1-C6 alkyl containing 1-3 independent substituents, C2 - C6 alkenyl or C2 - C6 alkenyl containing 1-3 independent substituents, ( C0 - C6 alkyl )-( C3 - C6 cycloalkyl)-( C0 - C6 alkyl) or (C0-C6 alkyl ) -( C3 - C6 cycloalkyl)-( C0 - C6 alkyl) containing 1-3 independent substituents, ( C0 - C6 alkyl)-Z-( C0 - C6 alkyl) or (C0-C6 alkyl ) -Z-( C0 - C6 alkyl) containing 1-3 independent substituents; wherein Z is selected from N( Ra ), -SO2- , OC(=O) or C(=O)O;

当A环存在为芳香环时，R3，R4，R5和R6选自H、C1-C6烷基、OH、OCH3、OCH(CH3)2、OCH2CH(CH3)2、OC(CH3)3、O(C1-C6烷基)、OCF3、OCH2CH2OH、O(C1-C6烷基)OH,F、Cl、Br、I、CF3、CN、NO2、NH2、C1-C6杂烷基、C1-C6羟基烷基、Ci-C6烷氧基、C1-C6烷基、芳基、芳杂基、C3-C7环烷基、杂环烷基、烷基芳基、CO2Ra、C(O)Ra、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(C3-C7环烷基)、NHC(O)(C1-C4烷基)、CONRa,NC(O)Ra、NS(O)1/2Ra、S(O)1/2NRa、S(O)1/2R、C(O)O(C1-C4烷基)、OC(O)N(Ra)2、C(O)(C1-C4烷基)、C(O)NH(C1-C4烷基)；其中R3，R4，R5和R6可单独为上述取代基，或R3，R4，R5，R6中其中两个、三个或四个同时为上述取代基；When ring A is an aromatic ring, R3 , R4 , R5 , and R6 are selected from H, C1 - C6 alkyl, OH, OCH3 , OCH( CH3 ) 2 , OCH2CH (CH3) 2, OC(CH3)3 , O ( C1 -C6 alkyl), OCF3 , OCH2CH2OH , O( C1 - C6 alkyl)OH, F, Cl , Br, I, CF3 , CN, NO2 , NH2 , C1 - C6 heteroalkyl, C1 - C6 hydroxyalkyl, Ci - C6 alkoxy, C1 - C6 alkyl, aryl, aromatic heteroalkyl, C3 - C7 cycloalkyl, heterocyclic alkyl, alkylaryl , CO2Ra , C (O) Ra , NH( C1 - C4 alkyl), N( C1 -C6 alkyl) 4 -alkyl) 2 , NH ( C3 - C7 cycloalkyl), NHC(O) ( C1 - C4 alkyl), CONR a , NC(O) Ra , NS(O) 1/2 Ra , S(O) 1/2 NR a , S(O) 1/2 R, C(O)O (C1-C4 alkyl), OC(O)N(Ra) 2, C(O) (C1 - C4 alkyl ) , C(O)NH ( C1 - C4 alkyl); wherein R3 , R4 , R5 and R6 may be the above substituents individually, or two, three or four of R3 , R4 , R5 and R6 may be the above substituents simultaneously;

当A环不存在时，X选自CH2、O、S、NH、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(C3-C7环烷基)、NHC(O)(C1-C4烷基)、NC(O)Ra、NS(O)1/2Ra；When ring A is absent, X is selected from CH2 , O, S, NH, NH ( C1 - C4 alkyl), N ( C1 - C4 alkyl) 2 , NH ( C3 - C7 cycloalkyl), NHC(O)( C1 - C4 alkyl), NC(O) Ra , NS(O) 1/ 2Ra ;

m，n为碳原子的个数，可为0，1，2；m and n are the number of carbon atoms, which can be 0, 1, or 2.

Ra选自H、CH3、CH2CH3、C3-C6烷基、C1-C6卤代烷基或任选取代的芳基、烷芳基、哌嗪基、哌啶基、吗啉基、杂环烷基、杂芳基、C1-C6烷氧基、NH(C1-C4烷基)和N(C1-C4烷基)2，其中任选取代的基团选自C1-C6烷基或C2-C7丙烯酸基； Ra is selected from H, CH3 , CH2CH3 , C3 - C6 alkyl , C1-C6 haloalkyl or optionally substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocyclic alkyl, heteroaryl, C1 - C6 alkoxy, NH ( C1 -C4 alkyl) and N (C1-C4 alkyl)2 , wherein the optionally substituted group is selected from C1-C6 alkyl or C2 - C7 acrylate ;

其中，C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烷氧基、苯基、苄基、萘基、C5-C10芳香性杂环基、C3-C7饱和杂环基、C3～C12环烷基、多炔基、芳基、C1-C6烷基-芳基、C1-C6烷基-酚基或C3～C10环烷基能够被一个或多个原子或基团取代。Among them, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 ynyl, C3- C8 cycloalkyl, C3 - C8 cycloalkoxy, phenyl, benzyl, naphthyl, C5 - C10 aromatic heterocyclic, C3 - C7 saturated heterocyclic, C3 - C12 cycloalkyl, polyynyl, aryl, C1-C6 alkyl - aryl, C1 - C6 alkyl-phenolic, or C3 - C10 cycloalkyl can be substituted by one or more atoms or groups.

进一步的，所述抑制剂为化合物I-1～I-22、II-1～II-17，其结构式具体如下：

Furthermore, the inhibitor is compounds I-1 to I-22, II-1 to II-17, whose structural formulas are as follows:

本发明还提供了所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，所述制备方法包括以下步骤：The present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:

所述化合物I-1～I-22的合成如下：以4-氯-3-硝基苯甲醛为原料，经硼氢化钠还原得到其羟基化合物2，随后和相应的胺发生取代反应得到化合物3；化合物3经PCC氧化得到醛基化合物4，其和丙酮在碱性条件下发生羟醛缩合反应得到化合物5；经硼氢化钠还原化合物5的双键及羰基得到化合物6，氢气还原硝基得到关键中间体7；通过(Boc)2O保护氨基得的相应的化合物8；其和CBr4在PPh3存在下发生卤代反应得到卤代化合物9；化合物10由化合物9和相应的芳香胺或脂肪胺经取代反应得到，随后脱掉Boc保护基可得到化合物I-1～I-22；
The synthesis of compounds I-1 to I-22 is as follows: 4-chloro-3-nitrobenzaldehyde is used as a starting material, reduced with sodium borohydride to obtain its hydroxy compound 2, which then undergoes a substitution reaction with the corresponding amine to obtain compound 3; compound 3 is oxidized with PCC to obtain aldehyde compound 4, which undergoes an aldol condensation reaction with acetone under alkaline conditions to obtain compound 5; the double bond and carbonyl group of compound 5 are reduced with sodium borohydride to obtain compound 6, and the nitro group is reduced with hydrogen to obtain the key intermediate 7; the amino group is protected by (Boc) ₂O to obtain the corresponding compound 8; it undergoes a halogenation reaction with CBr₄ in the presence of PPh₃ to obtain halogenated compound 9; compound 10 is obtained by substitution reaction of compound 9 with the corresponding aromatic amine or aliphatic amine, followed by removal of the Boc protecting group to obtain compounds I-1 to I-22.

试剂及反应条件：(a)硼氢化钠，甲醇；(b)环己胺，碳酸钾，DMSO，150℃；(c)PCC,氯仿；(d)丙酮，氢氧化钠；(e)硼氢化钠，甲醇；(f)Pd/C,氢气，甲醇；(g)(Boc)2O,三乙胺，四氢呋喃；(h)四溴化碳，三苯基膦，二氯甲烷；(i)相应的胺，碳酸钾，碘化钾，DMF；(j)i：HCl/CH3CH2OH；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷。Reagents and reaction conditions: (a) Sodium borohydride, methanol; (b) Cyclohexylamine, potassium carbonate, DMSO, 150℃; (c) PCC, chloroform; (d) Acetone, sodium hydroxide; (e) Sodium borohydride, methanol; (f) Pd/C, hydrogen, methanol; (g) (Boc) ₂O , triethylamine, tetrahydrofuran; (h) Carbon tetrabromide, triphenylphosphine, dichloromethane; (i) The corresponding amine, potassium carbonate, potassium iodide, DMF; (j) i: HCl/ CH₃CH₂OH ; ii: The corresponding aldehyde, sodium triacetoxyborohydride , dichloromethane.

本发明还提供了所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，所述制备方法包括以下步骤：The present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:

所述化合物II-1～II-5，II-16和II-17的合成如下：化合物11在AIBN催化下，和NBS发生自由基取代反应得到化合物12，之后和2-甲基丁-3-炔-2-胺发生亲和取代反应得到关键中间体13；化合物13和相应的化合物，如4-溴-N-环己基-2-硝基苯胺，在Pd(PPh3)2Cl2和CuI催化下发生偶联反应得到关键中间体化合物14；化合物II-16/17是由化合物14经锌粉还原得到。而化合物II-1～II-5则需要再氢气条件下进一步还原得到；
The synthesis of compounds II-1 to II-5, II-16, and II-17 is as follows: Compound 11 undergoes a radical substitution reaction with NBS under AIBN catalysis to give compound 12, which then undergoes an affinity substitution reaction with 2-methylbut-3-yn-2-amine to give key intermediate 13; Compound 13 and a corresponding compound, such as 4-bromo-N-cyclohexyl-2-nitroaniline, undergo a coupling reaction under Pd( PPh3 ) 2Cl2 and CuI catalysis to give key intermediate compound 14; Compounds II-16/17 are obtained by reducing compound 14 with zinc powder . Compounds II-1 to II-5 require further reduction under hydrogen conditions.

试剂及反应条件：(k)NBS,AIBN,氯仿，回流；(l)2-甲基丁-3-炔-2-胺，碳酸钾，四氢呋喃，60℃；(m)4-溴-N-环己基-2-硝基苯胺，Pd(PPh3)2Cl2，碘化亚铜，三乙胺，40℃；(n)i:锌粉，盐酸，甲醇；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷；(o)Reagents and reaction conditions: (k) NBS, AIBN, chloroform, reflux; (l) 2-methylbut-3-yn-2-amine, potassium carbonate, tetrahydrofuran, 60℃; (m) 4-bromo-N-cyclohexyl-2- nitroaniline , Pd( PPh3 ) 2Cl2 , cuprous iodide, triethylamine, 40℃; (n) i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane; (o)

Pd/C，氢气，甲醇。Pd/C, hydrogen, methanol.

本发明还提供了所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，所述制备方法包括以下步骤：The present invention also provides a method for preparing the aforementioned aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, the preparation method comprising the following steps:

所述化合物II-4～II-15的合成如下：以4-氯-3-硝基苯甲酸为起始原料，和相应的胺基片段发生缩合反应得到化合物16，之后和胺基衍生物进行亲核取代反应得到化合物17，脱掉Boc保护基后得到中间体18。化合物18和相应的溴代化合物发生亲核取代得到关键中间体19，进一步经锌粉还原得到目标化合物II-4～II-15。
The synthesis of compounds II-4 to II-15 is as follows: Starting with 4-chloro-3-nitrobenzoic acid, a condensation reaction with the corresponding amino fragment yields compound 16, followed by a nucleophilic substitution reaction with an amino derivative to give compound 17. After removing the Boc protecting group, intermediate 18 is obtained. Compound 18 undergoes nucleophilic substitution with the corresponding brominated compound to give key intermediate 19, which is further reduced with zinc powder to obtain the target compounds II-4 to II-15.

试剂及反应条件：(p)i：氯化亚砜，二氯甲烷，DMF；ii：(2-氨基乙基)氨基甲酸叔丁酯，三乙胺，二氯甲烷；(q)环己胺，碳酸钾，DMF，80℃；(r)三氟乙酸，二氯甲烷；(s)1,2-双(溴甲基)苯，碳酸钾，四氢呋喃，60℃；(t)i:锌粉，盐酸，甲醇；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷。Reagents and reaction conditions: (p)i: thionyl chloride, dichloromethane, DMF; ii: tert-butyl (2-aminoethyl)carbamate, triethylamine, dichloromethane; (q) cyclohexylamine, potassium carbonate, DMF, 80℃; (r) trifluoroacetic acid, dichloromethane; (s) 1,2-bis(bromomethyl)benzene, potassium carbonate, tetrahydrofuran, 60℃; (t)i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane.

本发明还提供了所述的抑制剂在制备铁死亡抑制剂和/或Sigma受体抑制剂中的应用。The present invention also provides the use of the described inhibitor in the preparation of ferroptosis inhibitors and/or Sigma receptor inhibitors.

本发明还提供了所述的抑制剂在制备治疗铁死亡相关疾病和/或Sigma受体相关疾病的药物中的应用。The present invention also provides the use of the inhibitor in the preparation of medicaments for treating ferroptosis-related diseases and/or Sigma receptor-related diseases.

本发明还提供了所述的抑制剂在制备Aβ淀粉样蛋白聚集引起的相关神经性疾病中的应用。The present invention also provides the application of the aforementioned inhibitor in the preparation of neurological diseases related to Aβ amyloid aggregation.

进一步的，所述铁死亡相关疾病包括神经退行性、组织缺血再灌注损伤、脑卒中、心血管、肝肾衰竭、炎症、糖尿病并发症。Furthermore, the iron death-related diseases include neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, liver and kidney failure, inflammation, and diabetic complications.

进一步的，所述Sigma受体相关疾病包括神经退行性(阿尔茨海默病、帕金森病)、脑卒中、药物成瘾、神经性疼痛、精神分裂和抑郁症。Furthermore, the Sigma receptor-related diseases include neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), stroke, drug addiction, neuropathic pain, schizophrenia, and depression.

进一步的，Aβ淀粉样蛋白聚集引起的相关神经性疾病包括但不限于阿尔兹海默症、帕金森综合征等。Furthermore, neurological diseases caused by Aβ amyloid aggregation include, but are not limited to, Alzheimer's disease and Parkinson's syndrome.

进一步的，所述药物中还添加有药物学上可接受的盐、载体或助剂。Furthermore, the drug also contains pharmaceutically acceptable salts, carriers, or adjuvants.

进一步的，用所述芳香烷胺类化合物治疗铁死亡是该类化合物可以作为自由基清除剂降低细胞内的活性氧，脂质过氧化物，进而挽救因活性氧导致的铁死亡；其中活性氧包括但不限于H2O2，t-BuOOH,O2-，OH·，ONOO-，ClO-。Furthermore, the use of the aromatic alkylamine compounds to treat ferroptosis is because these compounds can act as free radical scavengers to reduce intracellular reactive oxygen species and lipid peroxides, thereby rescuing ferroptosis caused by reactive oxygen species; wherein reactive oxygen species include, but are not limited to , H₂O₂ , t-BuOOH, O₂⁻ , OH·, ONOO⁻ , and ClO⁻ .

进一步的，用所述芳香烷胺类化合物治疗铁死亡是该类化合物可以作为自由基清除剂挽救因铁死亡诱导剂导致的铁死亡；其中铁死亡诱导剂包括但不限于RSL3及其衍生物，Erastin及其衍生物，ML162及其衍生物。Furthermore, the use of the aromatic alkylamine compounds to treat ferroptosis is because these compounds can act as free radical scavengers to rescue ferroptosis caused by ferroptosis inducers; wherein ferroptosis inducers include, but are not limited to, RSL3 and its derivatives, Erastin and its derivatives, ML162 and its derivatives.

进一步的，用所述芳香烷胺类化合物治疗Sigma受体相关疾病是该类化合物可以作为Sigma受体抑制剂抑制因Sigma表达错误或异常引起的相关疾病。Furthermore, the use of the aromatic alkylamine compounds to treat Sigma receptor-related diseases means that these compounds can act as Sigma receptor inhibitors to suppress related diseases caused by erroneous or abnormal Sigma expression.

与现有技术相比，本发明具有的优点和有益效果是：本发明通过多种合成手段获得了一种能够同时作用于铁死亡和Sigma受体的芳基烷胺类化合物，丰富了铁死亡与Sigma受体抑制剂的结构。本发明经过实验验证，所述的芳基烷胺类化合物能够抑制有铁死亡诱导剂引起的铁死亡，可降低细胞内活性氧的水平；经过实验验证，所述的芳基烷胺类化合物能够作为Sigma受体抑制剂，表现出和Sigma受体较强的亲和力；还经实验验证所述的芳基烷胺类化合物可抑制单体淀粉样蛋白Aβ1-42形成其多聚合物。因此，本发明提供的所述芳基烷胺类化合物可通过多重作用对与铁死亡及Sigma受体相关性神经性疾病的治疗发挥很好的应用价值。Compared with existing technologies, the advantages and beneficial effects of this invention are as follows: This invention obtains an arylalkylamine compound capable of simultaneously acting on ferroptosis and Sigma receptors through multiple synthetic methods, enriching the structure of ferroptosis and Sigma receptor inhibitors. Experiments have verified that the arylalkylamine compound can inhibit ferroptosis induced by ferroptosis inducers and reduce the level of intracellular reactive oxygen species; experiments have also verified that the arylalkylamine compound can act as a Sigma receptor inhibitor, exhibiting a strong affinity for Sigma receptors; further experiments have verified that the arylalkylamine compound can inhibit the formation of polymers from monomeric amyloid Aβ1-42 . Therefore, the arylalkylamine compound provided by this invention can exert significant application value in the treatment of neurological diseases related to ferroptosis and Sigma receptors through multiple actions.

附图说明Attached Figure Description

图1表明本发明中化合物I-7对Aβ1-42的抑制作用。Figure 1 shows the inhibitory effect of compound I-7 on Aβ1-42 in this invention.

具体实施方式Detailed Implementation

下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

实施例1Example 1

1、(4-氯-3-硝基苯基)甲醇(化合物2)1. (4-Chloro-3-nitrophenyl)methanol (compound 2)

将4-氯-3-硝基苯甲醛(2.19g,11.8mmol)加入含有40mL甲醇的茄形瓶中，室温条件下分批加入NaBH4(0.22g,5.9mmol)，TLC检测至反应结束。用1N的盐酸淬灭NaBH4，将溶剂蒸出，乙酸乙酯萃取残余的混合物，合并有机层，饱和食盐水萃取有机层并用无水Na2SO4干燥有机层，真空条件下浓缩有机层即得到化合物2，为淡黄色固体(2g,90％)。1H NMR(400MHz,Chloroform-d)δ7.88(d,J＝8.5Hz,1H),7.51(d,J＝8.7Hz,2H),4.76(s,2H)。4-Chloro-3-nitrobenzaldehyde (2.19 g, 11.8 mmol) was added to a round-bottom flask containing 40 mL of methanol. NaBH₄ (0.22 g, 5.9 mmol) was added in portions at room temperature, and the reaction was monitored by TLC until completion. NaBH₄ was quenched with 1 N hydrochloric acid, the solvent was evaporated, and the residual mixture was extracted with ethyl acetate. The organic layers were combined, extracted with saturated brine, and dried with anhydrous Na₂SO₄ . The organic layer was concentrated under vacuum to obtain compound 2, a pale yellow solid (2 g, 90%). ¹H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 4.76 (s, 2H).

2、(4-(环己胺基)-3-硝基苯基)甲醇(化合物3)2. (4-(cyclohexylamino)-3-nitrophenyl)methanol (compound 3)

将(4-氯-3-硝基苯基)甲醇(2g,10.6mmol)，环己胺(2.1g,21.2mmol)和K2CO3(2.9g,21.2mmol)加入茄形瓶中，加入DMSO(5mL)作溶剂，150℃反应过夜。将反应液倒入50mL水中，DCM萃取水层(50mL×3)，合并有机层并浓缩。混合物用柱层析分离(PE:EA＝10:1)，得到黄色固状化合物3(2.1g,78％)。1H NMR(400MHz,Chloroform-d)δ8.14(s,2H),7.45(dd,J＝6.5,2.2Hz,1H),6.92–6.82(m,1H),4.57(d,J＝5.7Hz,2H),3.57–3.42(m,1H),2.09–1.98(m,2H),1.79(s,2H),1.73–1.61(m,3H),1.45–1.37(m,3H)。(4-chloro-3-nitrophenyl)methanol (2 g, 10.6 mmol), cyclohexylamine (2.1 g, 21.2 mmol), and K₂CO₃ (2.9 g, 21.2 mmol) were added to a round-bottom flask, and DMSO (5 mL) was added as a solvent. The mixture was reacted overnight at 150 °C. The reaction solution was poured into 50 mL of water, and the aqueous layer was extracted with DCM (50 mL × 3). The organic layers were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 10:1) to give a yellow solid compound 3 (2.1 g, 78%). 1 H NMR(400MHz,Chloroform-d)δ8.14(s,2H),7.45(dd,J＝6.5,2.2Hz,1H),6.92–6.82(m,1H),4.57(d,J＝ 5.7Hz,2H),3.57–3.42(m,1H),2.09–1.98(m,2H),1.79(s,2H),1.73–1.61(m,3H),1.45–1.37(m,3H).

3、4-(环己胺基)-3-硝基苯甲醛(化合物4)3,4-(cyclohexylamino)-3-nitrobenzaldehyde (compound 4)

将(4-(环己胺基)-3-硝基苯基)甲醇(3g,11.98mmol)和PCC(7.7g,35.94mmol)加入到装有50mL的茄形瓶中，室温搅拌至反应结束。反应液经硅藻土过滤，滤液经过干燥，浓缩，混合物经柱层析分离得到化合物4，为黄色固体，产率为80.1％。(4-(cyclohexylamino)-3-nitrophenyl)methanol (3 g, 11.98 mmol) and PCC (7.7 g, 35.94 mmol) were added to a 50 mL round-bottom flask and stirred at room temperature until the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filtrate was dried, concentrated, and the mixture was separated by column chromatography to give compound 4 as a yellow solid, with a yield of 80.1%.

4、4-(4-(环己胺基)-3-硝基苯基)丁-3-烯-2-酮(化合物5)4. 4-(4-(cyclohexylamino)-3-nitrophenyl)but-3-en-2-one (compound 5)

将4-(环己胺基)-3-硝基苯甲醛(0.4g,1.6mmol)加到丙酮/乙醇混合溶液中(1.6mL/0.2mL),在室温搅拌条件下加入10％的氢氧化钠水溶液7mL，TLC检测直至反应结束。将有机溶剂在真空条件蒸出，残余的水用DCM萃取，干燥有机层并浓缩，混合物经柱层析分离得到目标化合物5，为深红色固体，产率为79.3％。1H NMR(400MHz,Chloroform-d)δ8.38(d,J＝7.1Hz,1H),8.33(s,1H),7.61(d,J＝9.0Hz,1H),7.40(d,J＝16.2Hz,1H),6.90(d,J＝9.0Hz,1H),6.57(d,J＝16.2Hz,1H),3.61–3.49(m,1H),2.35(s,3H),2.05(dd,J＝9.3,3.5Hz,2H),1.75(dd,J＝58.5,12.6Hz,3H),1.48–1.28(m,5H)。0.4 g (1.6 mmol) of 4-(cyclohexylamino)-3-nitrobenzaldehyde was added to an acetone/ethanol mixture (1.6 mL/0.2 mL). 7 mL of a 10% sodium hydroxide aqueous solution was added under stirring at room temperature. The reaction was monitored by TLC until completion. The organic solvent was evaporated under vacuum, and the residual water was extracted with DCM. The organic layer was dried and concentrated. The mixture was separated by column chromatography to give the target compound 5 as a deep red solid in 79.3% yield. 1 H NMR(400MHz,Chloroform-d)δ8.38(d,J＝7.1Hz,1H),8.33(s,1H),7.61(d,J＝9.0Hz,1H),7.40(d,J＝16.2Hz,1H),6.90(d,J＝9.0Hz,1H), 6.57(d,J＝16.2Hz,1H),3.61–3.49(m,1H),2.35(s,3H),2.05(dd,J＝9.3,3.5Hz,2H),1.75(dd,J＝58.5,12.6Hz,3H),1.48–1.28(m,5H).

5、4-(4-(环己胺基)-3-硝基苯基)丁-3-烯-2-醇(化合物6)5. 4-(4-(cyclohexylamino)-3-nitrophenyl)but-3-en-2-ol (compound 6)

合成方法同化合物2，产率为83％。1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝6.7Hz,1H),8.12(s,1H),7.48(d,J＝9.0Hz,1H),6.84(d,J＝8.7Hz,1H),6.43(d,J＝15.8Hz,1H),6.16–6.05(m,1H),4.47(p,J＝6.6Hz,1H),3.56–3.46(m,1H),2.07–2.01(m,2H),1.84–1.76(m,2H),1.66(dd,J＝12.9,2.8Hz,1H),1.46–1.32(m,8H)。The synthesis method was the same as that for compound 2, with a yield of 83%. ¹H NMR (400MHz, Chloroform-d) δ 8.19 (d, J = 6.7 Hz, 1H), 8.12 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 6.16–6.05 (m, 1H), 4.47 (p, J = 6.6 Hz, 1H), 3.56–3.46 (m, 1H), 2.07–2.01 (m, 2H), 1.84–1.76 (m, 2H), 1.66 (dd, J = 12.9, 2.8 Hz, 1H), 1.46–1.32 (m, 8H).

6、4-(3-氨基-4-(环己基氨基)苯基)丁-2-醇(化合物7)6. 4-(3-amino-4-(cyclohexylamino)phenyl)but-2-ol (compound 7)

将化合物6(0.3g,1.0mmol)加入到装有甲醇溶液的反应瓶中，加入Pd/C(0.03g)，在氢气条件下反应至结束。Pd/C经滤纸过滤，将溶剂浓缩得到化合物7，为淡黄色固体(0.24g,90％)。1H NMR(400MHz,Chloroform-d)δ6.59(dd,J＝11.9,4.2Hz,3H),3.81(dt,J＝12.1,6.0Hz,1H),3.22–3.09(m,1H),2.66–2.49(m,2H),2.05(d,J＝4.6Hz,2H),1.79–1.62(m,5H),1.29(dd,J＝22.0,4.9Hz,3H),1.22–1.18(m,5H)。Compound 6 (0.3 g, 1.0 mmol) was added to a reaction flask containing methanol solution, followed by Pd/C (0.03 g). The reaction was carried out under hydrogen atmosphere until completion. The Pd/C was filtered through filter paper, and the solvent was concentrated to obtain compound 7, a pale yellow solid (0.24 g, 90%). ¹H NMR (400 MHz, Chloroform-d) δ 6.59 (dd, J = 11.9, 4.2 Hz, 3H), 3.81 (dt, J = 12.1, 6.0 Hz, 1H), 3.22–3.09 (m, 1H), 2.66–2.49 (m, 2H), 2.05 (d, J = 4.6 Hz, 2H), 1.79–1.62 (m, 5H), 1.29 (dd, J = 22.0, 4.9 Hz, 3H), 1.22–1.18 (m, 5H).

7、(2-(环己基氨基)-5-(3-羟基丁基)苯基)氨基甲酸叔丁酯(化合物8)7. (2-(cyclohexylamino)-5-(3-hydroxybutyl)phenyl) tert-butyl carbamate (compound 8)

将化合物7(1g,3.8mmol)溶于30mL THF中，加入三乙胺(0.46g,4.56mmol)，之后在冰浴条件下缓慢滴加(Boc)2O,滴加完毕后，在室温条件下反应至原料消失。将反应液浓缩，混合物经柱层析分离得到化合物8，为黄色固体，产率为90％。1H NMR(400MHz,Chloroform-d)δ7.31(s,1H),6.86(t,J＝8.0Hz,1H),6.70(t,J＝7.0Hz,1H),3.88–3.74(m,1H),3.17–3.02(m,1H),2.60(qd,J＝15.9,15.1,9.1Hz,2H),2.05–1.92(m,2H),1.81–1.57(m,7H),1.51(d,J＝9.0Hz,9H),1.34(dd,J＝12.4,6.9Hz,2H),1.23–1.18(m,4H)。Compound 7 (1 g, 3.8 mmol) was dissolved in 30 mL of THF, and triethylamine (0.46 g, 4.56 mmol) was added. Then, (Boc) ₂O was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature until the starting material disappeared. The reaction solution was concentrated, and the mixture was separated by column chromatography to give compound 8 as a yellow solid in 90% yield. 1 H NMR(400MHz,Chloroform-d)δ7.31(s,1H),6.86(t,J＝8.0Hz,1H),6.70(t,J＝7.0Hz,1H),3.88–3.74(m,1H),3.17–3.02(m,1H),2.60(qd, J＝15.9,15.1,9.1Hz,2H),2.05–1.92(m,2H),1.81–1.57(m,7H),1.51(d,J＝9.0Hz,9H),1.34(dd,J＝12.4,6.9Hz,2H),1.23–1.18(m,4H).

8、叔丁基(5-(3-溴丁基)-2-(环己胺基)苯基)氨基甲酸酯(化合物9)8. Tert-butyl (5-(3-bromobutyl)-2-(cyclohexylamino)phenyl)carbamate (compound 9)

将化合物8(1g,2.7mmol)加入装有40mL的茄形瓶中，之后加入PPh3(0.8g,3.3mmol)和CBr4(1.1g,3.3mmol),室温反应1h。将反应液浓缩，混合物经柱层析分离得到化合物9(0.7g,60％)，为黄色油状物。1H NMR(400MHz,Chloroform-d)δ7.27(s,1H),6.86(d,J＝8.1Hz,1H),6.72–6.66(m,1H),6.31(s,1H),4.07(dq,J＝12.2,7.1Hz,1H),3.18–3.07(m,1H),2.77–2.58(m,2H),2.05–1.94(m,4H),1.77(d,J＝6.5Hz,2H),1.70(d,J＝6.6Hz,3H),1.50(s,9H),1.33(d,J＝11.0Hz,2H),1.25–1.13(m,4H)。Compound 8 (1 g, 2.7 mmol) was added to a 40 mL round-bottom flask, followed by PPh 3 (0.8 g, 3.3 mmol) and CBr 4 (1.1 g, 3.3 mmol), and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated, and the mixture was separated by column chromatography to obtain compound 9 (0.7 g, 60%), which was a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.27(s,1H),6.86(d,J＝8.1Hz,1H),6.72–6.66(m,1H),6.31(s,1H),4.07(dq,J＝12.2,7.1Hz,1H),3.18–3.07(m,1 H),2.77–2.58(m,2H),2.05–1.94(m,4H),1.77(d,J＝6.5Hz,2H),1.70(d ,J＝6.6Hz,3H),1.50(s,9H),1.33(d,J＝11.0Hz,2H),1.25–1.13(m,4H).

9、叔丁基(2-(环己胺基)-5-(3-((4-(三氟甲基)苄基)氨基)丁基)苯基)氨基甲酸酯(化合物10)9. Tert-butyl(2-(cyclohexylamino)-5-(3-((4-(trifluoromethyl)benzyl)amino)butyl)phenyl)carbamate (Compound 10)

将化合物9(0.07g,0.165mmol)、(4-(三氟甲基)苯基)甲胺(0.045g,0.25mmol)和K2CO3(0.035g,0.25mmol)加入反应瓶中，1mL DMF作溶剂，60℃反应过夜。反应结束后，将反应液倒入15mL水中，DCM萃取水层(50mL×3)，合并有机层并浓缩。混合物用柱层析分离(PE:EA＝4:1)，得到淡黄色油状状化合物10(0.06g,70％)。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),7.29(s,1H),6.80(d,J＝7.1Hz,1H),6.66(d,J＝8.2Hz,1H),3.89–3.75(m,2H),3.16–3.05(m,1H),2.69(p,J＝6.2Hz,1H),2.55(q,J＝8.5Hz,2H),2.05–1.94(m,2H),1.81–1.70(m,3H),1.68–1.60(m,3H),1.50(s,9H),1.38–1.12(m,7H),1.11(d,J＝6.2Hz,3H)。Compound 9 (0.07 g, 0.165 mmol), (4-(trifluoromethyl)phenyl)methylamine (0.045 g, 0.25 mmol), and K₂CO₃ (0.035 g, 0.25 mmol) were added to a reaction flask, with 1 mL of DMF as solvent, and reacted overnight at 60 °C. After the reaction was complete, the reaction solution was poured into 15 mL of water, and the aqueous layer was extracted with DCM (50 mL × 3). The organic layers were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 4:1) to give compound 10 (0.06 g, 70%), a pale yellow oil. NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),7.29(s ,1H),6.80(d,J＝7.1Hz,1H),6.66(d,J＝8.2Hz,1H),3.89–3.75(m,2H),3.16–3.05( m,1H),2.69(p,J＝6.2Hz,1H),2.55(q,J＝8.5Hz,2H),2.05–1.94(m,2H),1.81–1.70 (m,3H),1.68–1.60(m,3H),1.50(s,9H),1.38–1.12(m,7H),1.11(d,J＝6.2Hz,3H).

10、N1-环己基-4-(3-((4-(三氟甲基)苄基)氨基)丁基)苯-1,2-二胺(化合物I-1)10. N 1 -Cyclohexyl-4-(3-((4-(trifluoromethyl)benzyl)amino)butyl)phenyl-1,2-diamine (Compound I-1)

将上一步得到的化合物10加入反应瓶中，加入2N的盐酸，反应5h。将溶剂蒸出，用K2CO3调节PH至10，EA萃取水层，之后干燥有机层并浓缩，得到黄色油状物I-1(0.04g,83.3％)。1H NMR(400MHz,Methanol-d4)δ7.65(q,J＝8.4Hz,4H),7.55(d,J＝8.5Hz,2H),7.21(d,J＝8.4Hz,1H),4.26(d,J＝6.1Hz,2H),2.95(dt,J＝9.3,5.0Hz,1H),2.81–2.74(m,1H),2.30–2.21(m,1H),2.15(d,J＝12.7Hz,2H),1.89(dq,J＝32.3,16.2Hz,8H),1.59(q,J＝14.4,12.7Hz,3H),1.46(d,J＝6.5Hz,3H).13C NMR(101MHz,Methanol-d4)δ136.57,134.77,130.21,125.54,123.46,118.11,110.59,55.45,53.47,35.57,35.12,32.78,31.17,25.31,25.03,15.26。Compound 10 obtained in the previous step was added to a reaction flask, and 2N hydrochloric acid was added. The reaction was carried out for 5 hours. The solvent was evaporated, the pH was adjusted to 10 with K2CO3 , the aqueous layer was extracted with EA, and then the organic layer was dried and concentrated to obtain a yellow oily substance I-1 (0.04 g, 83.3%). 1 H NMR (400MHz, Methanol-d 4 )δ7.65(q,J＝8.4Hz,4H),7.55(d,J＝8.5Hz,2H),7.21(d,J＝8.4Hz,1H),4.26(d,J＝6.1Hz,2H),2.95(dt,J＝9.3,5.0Hz,1H),2.81–2.74( m,1H),2.30–2.21(m,1H),2.15(d,J＝12.7Hz,2H),1.89(dq,J＝32.3,16.2Hz,8H),1.59(q,J＝14.4,12.7Hz,3H),1.46(d,J＝6.5Hz,3H). 13 C NMR (101MHz, Methanol-d 4 )δ136.57,134.77,130.21,125.54,123.46,118.11,110.59,55.45,53.47,35.57,35.12,32.78,31.17,25.31,25.03,15.26.

11、4-(3-(苄氨基)丁基)-N1-环己基苯-1,2-二胺(化合物I-2)11. 4-(3-(benzylamino)butyl)-N- 1 -cyclohexylphenyl-1,2-diamine (Compound I-2)

合成方法同I-1，黄色油状物，产率79％。1H NMR(400MHz,Chloroform-d)δ7.35–7.26(m,5H),6.60(s,2H),6.53(s,1H),3.85–3.72(m,2H),3.18(td,J＝10.0,5.0Hz,1H),2.76–2.71(m,1H),2.52(tt,J＝10.5,5.2Hz,2H),2.09–2.03(m,2H),1.81–1.74(m,3H),1.64(ddd,J＝14.1,10.3,7.2Hz,2H),1.41–1.33(m,2H),1.24–1.16(m,3H),1.14(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ140.72,134.99,134.39,132.74,128.44,126.89,120.00,116.83,113.63,52.16,51.27,38.87,33.78,31.60,26.12,25.10,20.35。The synthesis method is the same as I-1, producing a yellow oily substance with a yield of 79%. 1 H NMR(400MHz,Chloroform-d)δ7.35–7.26(m,5H),6.60(s,2H),6.53(s,1H),3 .85–3.72(m,2H),3.18(td,J＝10.0,5.0Hz,1H),2.76–2.71(m,1H),2.52(tt,J ＝10.5,5.2Hz,2H),2.09–2.03(m,2H),1.81–1.74(m,3H),1.64(ddd,J＝14.1,1 0.3,7.2Hz,2H),1.41–1.33(m,2H),1.24–1.16(m,3H),1.14(d,J＝6.3Hz,3H). 13C NMR(101MHz,Chloroform-d)δ140.72,134.99,134.39,132.74,128.44,126.89,1 20.00,116.83,113.63,52.16,51.27,38.87,33.78,31.60,26.12,25.10,20.35.

12、N1-环己基-4-(3-((4-甲基苄基)氨基)丁基)苯-1,2-二胺(化合物I-3)12. N 1 -Cyclohexyl-4-(3-((4-methylbenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-3)

合成方法同I-1，黄色油状物，产率81％。1H NMR(400MHz,Chloroform-d)δ7.20–7.17(m,2H),7.12(d,J＝7.0Hz,2H),6.58(s,2H),6.52(s,1H),3.80–3.66(m,2H),3.17(dq,J＝10.1,4.8,4.2Hz,1H),2.74–2.69(m,1H),2.53–2.47(m,2H),2.33(s,3H),2.05(d,J＝11.2Hz,2H),1.76(dt,J＝13.6,4.4Hz,3H),1.68–1.59(m,2H),1.42–1.30(m,3H),1.18(d,J＝12.1Hz,2H),1.12(dd,J＝6.3,1.8Hz,3H).13C NMR(101MHz,Chloroform-d)δ137.65,136.50,134.99,134.44,132.48,129.18,128.30,120.06,116.88,113.59,52.20,52.04,51.02,38.92,33.82,31.64,29.82,26.16,25.16,21.22,20.36。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 81%. ¹H NMR (400 MHz, Chloroform-d) δ 7.20–7.17 (m, 2H), 7.12 (d, J = 7.0 Hz, 2H), 6.58 (s, 2H), 6.52 (s, 1H), 3.80–3.66 (m, 2H), 3.17 (dq, J = 10.1, 4.8, 4.2 Hz, 1H), 2.74–2.69 (m, 1H), 2. 53–2.47(m,2H),2.33(s,3H),2.05(d,J＝11.2Hz,2H),1.76(dt,J＝13.6,4.4Hz,3H),1.6 8–1.59(m,2H),1.42–1.30(m,3H),1.18(d,J＝12.1Hz,2H),1.12(dd,J＝6.3,1.8Hz,3H). 13C NMR(101MHz,Chloroform-d)δ137.65,136.50,134.99,134.44,132.48,129.18,128.30,120.06 ,116.88,113.59,52.20,52.04,51.02,38.92,33.82,31.64,29.82,26.16,25.16,21.22,20.36.

13、N1-环己基-4-(3-((4-氟苄基)氨基)丁基)苯-1,2-二胺(化合物I-4)13. N 1 -Cyclohexyl-4-(3-((4-fluorobenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-4)

合成方法同I-1，黄色油状物，产率82％。1H NMR(400MHz,Chloroform-d)δ7.26–7.21(m,2H),6.98(ddd,J＝8.7,6.8,3.5Hz,2H),6.58(d,J＝3.5Hz,2H),6.52(d,J＝2.9Hz,1H),3.81–3.64(m,2H),3.19–3.12(m,1H),2.70(dt,J＝11.8,5.7Hz,1H),2.58–2.44(m,2H),2.04(d,J＝12.1Hz,2H),1.82–1.71(m,3H),1.69–1.57(m,2H),1.42–1.33(m,3H),1.14–1.09(m,3H).13C NMR(101MHz,Chloroform-d)δ160.72,135.00,134.48,132.63,129.83,120.05,116.84,115.33,115.12,113.58,52.20,52.11,50.53,38.81,33.82,31.66,29.82,26.16,25.15,20.38。The synthesis method is the same as I-1, producing a yellow oily substance with a yield of 82%. 1 H NMR(400MHz,Chloroform-d)δ7.26–7.21(m,2H),6.98(ddd,J=8.7,6.8,3.5Hz, 2H),6.58(d,J＝3.5Hz,2H),6.52(d,J＝2.9Hz,1H),3.81–3.64(m,2H),3.19–3.1 2(m,1H),2.70(dt,J＝11.8,5.7Hz,1H),2.58–2.44(m,2H),2.04(d,J＝12.1Hz,2 H),1.82–1.71(m,3H),1.69–1.57(m,2H),1.42–1.33(m,3H),1.14–1.09(m,3H). 13C NMR(101MHz,Chloroform-d)δ160.72,135.00,134.48,132.63,129.83,120.05,116.84,115 .33,115.12,113.58,52.20,52.11,50.53,38.81,33.82,31.66,29.82,26.16,25.15,20.38.

14、N1-环己基-4-(3-((4-氯苄基)氨基)丁基)苯-1,2-二胺(化合物I-5)14. N 1 -Cyclohexyl-4-(3-((4-chlorobenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-5)

合成方法同I-1，黄色油状物，产率78％。1H NMR(400MHz,Chloroform-d)δ7.27–7.18(m,4H),6.57(d,J＝2.1Hz,2H),6.50(s,1H),3.80–3.64(m,2H),3.16(tt,J＝10.0,5.6Hz,1H),2.67(p,J＝6.2Hz,1H),2.57–2.43(m,2H),2.08–1.99(m,2H),1.75(ddt,J＝9.7,6.7,3.9Hz,3H),1.67–1.56(m,2H),1.44–1.26(m,5H),1.11(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ139.28,134.99,134.48,132.61,129.69,128.56,120.05,116.83,113.55,52.19,52.02,50.55,38.86,33.82,31.64,26.16,25.16,20.42。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 78%. ¹H NMR (400MHz, Chloroform-d) δ 7.27–7.18 (m, 4H), 6.57 (d, J = 2.1Hz, 2H), 6.50 (s, 1H), 3.80–3.64 (m, 2H), 3.16 (tt, J = 10.0, 5.6Hz, 1H), 2.67 (p, J = 6.2Hz, 1H), 2.57–2.43 (m, 2H), 2.08–1.99 (m, 2H), 1.75 (ddt, J = 9.7, 6.7, 3.9Hz, 3H), 1.67–1.56 (m, 2H), 1.44–1.26 (m, 5H), 1.11 (d, J = 6.3Hz, 3H). 13 C NMR(101MHz,Chloroform-d)δ139.28,134.99,134.48,132.61,129.69,128.56,120. 05,116.83,113.55,52.19,52.02,50.55,38.86,33.82,31.64,26.16,25.16,20.42.

15、N1-环己基-4-(3-((4-异丙基苄基)氨基)丁基)苯-1,2-二胺(化合物I-6)15. N 1 -Cyclohexyl-4-(3-((4-isopropylbenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-6)

合成方法同I-1，黄色油状物，产率83％。1H NMR(400MHz,Chloroform-d)δ7.26–7.24(m,2H),7.21–7.17(m,2H),6.59(s,2H),6.54(s,1H),3.83–3.68(m,2H),3.17(tt,J＝10.1,3.6Hz,1H),2.90(p,J＝6.9Hz,1H),2.75(p,J＝6.2Hz,1H),2.60–2.45(m,2H),2.09–2.02(m,2H),1.77(dt,J＝12.0,3.8Hz,3H),1.70–1.59(m,2H),1.42–1.31(m,3H),1.27–1.23(m,9H),1.15(d,J＝6.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ147.69,135.01,134.47,132.68,128.45,126.58,120.08,116.88,113.56,52.20,50.91,38.72,33.91,31.61,26.18,25.17,24.18,20.22。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 83%. ¹H NMR (400 MHz, Chloroform-d) δ 7.26–7.24 (m, 2H), 7.21–7.17 (m, 2H), 6.59 (s, 2H), 6.54 (s, 1H), 3.83–3.68 (m, 2H), 3.17 (tt, J = 10.1, 3.6 Hz, 1H), 2.90 (p, J = 6.9 Hz, 1H), 2. 75(p,J＝6.2Hz,1H),2.60–2.45(m,2H),2.09–2.02(m,2H),1.77(dt,J＝12.0,3.8Hz, 3H),1.70–1.59(m,2H),1.42–1.31(m,3H),1.27–1.23(m,9H),1.15(d,J＝6.2Hz,3H). 13C NMR(101MHz,Chloroform-d)δ147.69,135.01,134.47,132.68,128.45,126.58,120. 08,116.88,113.56,52.20,50.91,38.72,33.91,31.61,26.18,25.17,24.18,20.22.

16、4-(3-((4-(叔丁基)苄基)氨基)丁基)-N1-环己基苯-1,2-二胺(化合物I-7)16. 4-(3-((4-(tert-butyl)benzyl)amino)butyl)-N- 1 -cyclohexylphenyl-1,2-diamine (Compound I-7)

合成方法同I-1，黄色油状物，产率73％。1H NMR(400MHz,Chloroform-d)δ7.36–7.32(m,2H),7.25(s,2H),6.58(d,J＝1.1Hz,2H),6.54(s,1H),3.83–3.65(m,2H),3.17(tt,J＝10.1,3.7Hz,1H),2.73(p,J＝6.2Hz,1H),2.60–2.44(m,2H),2.05(dd,J＝12.6,2.9Hz,2H),1.77(ddd,J＝9.5,7.7,3.8Hz,3H),1.63(dtt,J＝13.6,6.8,3.5Hz,2H),1.40–1.33(m,2H),1.31(d,J＝2.9Hz,9H),1.20(ddd,J＝17.1,9.2,3.0Hz,3H),1.13(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ149.85,134.99,134.45,132.78,128.07,125.42,120.08,116.88,113.56,52.25,50.94,38.89,34.56,33.83,31.63,31.50,26.17,25.16,20.37。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 73%. ¹H NMR (400 MHz, Chloroform-d) δ 7.36–7.32 (m, 2H), 7.25 (s, 2H), 6.58 (d, J = 1.1 Hz, 2H), 6.54 (s, 1H), 3.83–3.65 (m, 2H), 3.17 (tt, J = 10.1, 3.7 Hz, 1H), 2.73 (p, J = 6.2 Hz, 1H), 2.60–2.44 (m, 2H), 2.05 ( dd,J＝12.6,2.9Hz,2H),1.77(ddd,J＝9.5,7.7,3.8Hz,3H),1.63(dtt,J＝13.6,6.8,3.5Hz,2H),1. 40–1.33(m,2H),1.31(d,J＝2.9Hz,9H),1.20(ddd,J＝17.1,9.2,3.0Hz,3H),1.13(d,J＝6.3Hz,3H). 13C NMR(101MHz,Chloroform-d)δ149.85,134.99,134.45,132.78,128.07,125.42,120.08, 116.88,113.56,52.25,50.94,38.89,34.56,33.83,31.63,31.50,26.17,25.16,20.37.

17、N1-环己基-4-(3-((2-(三氟甲基)苄基)氨基)丁基)苯-1,2-二胺(化合物I-8)17. N 1 -Cyclohexyl-4-(3-((2-(trifluoromethyl)benzyl)amino)butyl)phenyl-1,2-diamine (Compound I-8)

合成方法同I-1，黄色油状物，产率71％。1H NMR(400MHz,Chloroform-d)δ7.61(t,J＝8.0Hz,2H),7.49(t,J＝7.5Hz,1H),7.32(t,J＝7.6Hz,1H),6.58(s,2H),6.55(s,1H),3.92(q,J＝13.9Hz,2H),3.16(ddd,J＝13.7,8.3,3.7Hz,1H),2.75(h,J＝6.2Hz,1H),2.52(dt,J＝9.2,6.1Hz,2H),2.08–2.00(m,2H),1.76(dt,J＝12.9,3.5Hz,3H),1.63(ddd,J＝13.6,9.3,6.7Hz,2H),1.40–1.30(m,3H),1.24–1.17(m,2H),1.13(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ135.01,134.46,132.70,132.01,130.82,126.89,120.04,116.84,113.61,52.65,52.08,47.34,38.98,33.81,31.65,26.16,25.15,20.47。The synthesis method was the same as I-1. A yellow oily substance was obtained in 71% yield. ¹H NMR (400MHz, Chloroform-d) δ 7.61 (t, J = 8.0Hz, 2H), 7.49 (t, J = 7.5Hz, 1H), 7.32 (t, J = 7.6Hz, 1H), 6.58 (s, 2H), 6.55 (s, 1H), 3.92 (q, J = 13.9Hz, 2H), 3.16 (ddd, J = 13.7, 8.3, 3.7Hz, 1H), 2.75 ( h,J＝6.2Hz,1H),2.52(dt,J＝9.2,6.1Hz,2H),2.08–2.00(m,2H),1.76(dt,J＝12.9,3.5Hz,3H),1 .63(ddd,J＝13.6,9.3,6.7Hz,2H),1.40–1.30(m,3H),1.24–1.17(m,2H),1.13(d,J＝6.3Hz,3H). 13C NMR(101MHz,Chloroform-d)δ135.01,134.46,132.70,132.01,130.82,126.89,120. 04,116.84,113.61,52.65,52.08,47.34,38.98,33.81,31.65,26.16,25.15,20.47.

18、N1-环己基-4-(3-((吡啶-4-基甲基)氨基)丁基)苯-1,2-二胺(化合物I-9)18. N 1 -Cyclohexyl-4-(3-((pyridin-4-ylmethyl)amino)butyl)phenyl-1,2-diamine (Compound I-9)

合成方法同I-1，黄色油状物，产率82％。1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.47(d,J＝4.8Hz,1H),7.65–7.59(m,1H),7.24–7.19(m,1H),6.57(s,2H),6.51(s,1H),3.83–3.68(m,2H),3.19–3.11(m,1H),2.69(h,J＝6.0Hz,1H),2.49(dp,J＝14.0,6.9Hz,2H),2.03(d,J＝11.6Hz,2H),1.80–1.68(m,3H),1.68–1.57(m,2H),1.35(q,J＝12.1Hz,2H),1.23–1.15(m,3H),1.11(dd,J＝6.3,1.8Hz,3H).13C NMR(101MHz,Chloroform-d)δ149.79,148.42,136.30,135.99,135.03,134.48,132.58,123.48,120.00,116.80,113.57,52.27,52.18,48.65,38.94,33.80,31.66,26.15,25.15,20.50。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 82%. ¹H NMR (400 MHz, Chloroform-d) δ 8.53 (s, ¹H), 8.47 (d, J = 4.8 Hz, ¹H), 7.65–7.59 (m, ¹H), 7.24–7.19 (m, ¹H), 6.57 (s, 2H), 6.51 (s, ¹H), 3.83–3.68 (m, 2H), 3.19–3.11 (m, ¹H), 2.69 (h, J＝6.0Hz,1H),2.49(dp,J＝14.0,6.9Hz,2H),2.03(d,J＝11.6Hz,2H),1.80–1.68(m,3H),1 .68–1.57(m,2H),1.35(q,J＝12.1Hz,2H),1.23–1.15(m,3H),1.11(dd,J＝6.3,1.8Hz,3H). 13C NMR(101MHz,Chloroform-d)δ149.79,148.42,136.30,135.99,135.03,134.48,132.58,123. 48,120.00,116.80,113.57,52.27,52.18,48.65,38.94,33.80,31.66,26.15,25.15,20.50.

19、N1-环己基-4-(3-(苯氨基)丁基)苯-1,2-二胺(化合物I-10)19. N 1 -Cyclohexyl-4-(3-(phenylamino)butyl)phenyl-1,2-diamine (Compound I-10)

合成方法同I-1，黄色油状物，产率84％。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),7.29(s,1H),6.80(d,J＝7.1Hz,1H),6.66(d,J＝8.2Hz,1H),3.89–3.75(m,2H),3.16–3.05(m,1H),2.69(p,J＝6.2Hz,1H),2.55(q,J＝8.5Hz,2H),2.05–1.94(m,2H),1.81–1.70(m,3H),1.68–1.60(m,3H),1.50(s,9H),1.38–1.12(m,7H),1.11(d,J＝6.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ147.65,129.24,120.01,116.99,116.78,113.15,47.87,39.01,33.53,31.69,29.70,26.01,25.03,20.85。The synthesis method is the same as I-1; the product is a yellow oily substance with a yield of 84%. 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,2H),7.29(s ,1H),6.80(d,J＝7.1Hz,1H),6.66(d,J＝8.2Hz,1H),3.89–3.75(m,2H),3.16–3.05( m,1H),2.69(p,J＝6.2Hz,1H),2.55(q,J＝8.5Hz,2H),2.05–1.94(m,2H),1.81–1.70 (m,3H),1.68–1.60(m,3H),1.50(s,9H),1.38–1.12(m,7H),1.11(d,J＝6.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ 147.65, 129.24, 120.01, 116.99, 116.78, 113.15, 47.87, 39.01, 33.53, 31.69, 29.70, 26.01, 25.03, 20.85.

20、N1-环己基-4-(3-(环己基氨基)丁基)苯-1,2-二胺(化合物I-11)20. N 1 -Cyclohexyl-4-(3-(cyclohexylamino)butyl)phenyl-1,2-diamine (Compound I-11)

合成方法同I-1，黄色油状物，产率74％。1H NMR(400MHz,Chloroform-d)δ7.64(ddd,J＝12.0,8.2,1.3Hz,1H),7.56–7.41(m,2H),3.17–3.09(m,1H),3.08–2.97(m,1H),2.80–2.71(m,1H),2.57(ddd,J＝14.6,9.5,5.4Hz,1H),2.43–2.33(m,1H),2.01(d,J＝10.9Hz,4H),1.69(tdt,J＝34.4,17.8,9.6Hz,9H),1.36–1.28(m,4H),1.25(d,J＝6.4Hz,3H),1.18–1.12(m,5H).13C NMR(101MHz,Chloroform-d)δ134.64,132.21,128.68,120.02,116.76,113.48,53.79,52.12,36.04,33.74,31.37,31.09,30.64,26.13,25.41,25.12,24.99。The synthesis method is the same as I-1, producing a yellow oily substance with a yield of 74%. 1 H NMR(400MHz,Chloroform-d)δ7.64(ddd,J＝12.0,8.2,1.3Hz,1H),7.56–7.41(m ,2H),3.17–3.09(m,1H),3.08–2.97(m,1H),2.80–2.71(m,1H),2.57(ddd,J＝14. 6,9.5,5.4Hz,1H),2.43–2.33(m,1H),2.01(d,J＝10.9Hz,4H),1.69(tdt,J＝34.4 ,17.8,9.6Hz,9H),1.36–1.28(m,4H),1.25(d,J=6.4Hz,3H),1.18–1.12(m,5H). 13C NMR(101MHz,Chloroform-d)δ134.64,132.21,128.68,120.02,116.76,113.48 ,53.79,52.12,36.04,33.74,31.37,31.09,30.64,26.13,25.41,25.12,24.99.

21、N1-环己基-4-(3-(哌啶-1-基)丁基)苯-1,2-二胺(化合物I-12)21. N 1 -Cyclohexyl-4-(3-(piperidin-1-yl)butyl)phenyl-1,2-diamine (Compound I-12)

合成方法同I-1，黄色油状物，产率75％。1H NMR(400MHz,Methanol-d4)δ6.64–6.62(m,1H),6.60–6.53(m,2H),3.30(dt,J＝3.2,1.5Hz,1H),2.72–2.59(m,1H),2.49–2.39(m,1H),2.15–1.99(m,4H),1.89–1.73(m,9H),1.70–1.58(m,4H),1.37(dd,J＝15.8,4.6Hz,5H),1.25–1.15(m,3H).13C NMR(101MHz,Methanol-d4)δ135.42,134.07,129.99,119.14,116.27,113.64,61.85,52.31,49.08,33.07,32.57,31.18,25.81,24.95,23.21,21.72,12.43。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 75%. ¹H NMR (400MHz, methanol- d4 ) δ 6.64–6.62 (m, 1H), 6.60–6.53 (m, 2H), 3.30 (dt, J = 3.2, 1.5Hz, 1H), 2.72–2.59 (m, 1H), 2.49–2.39 (m, 1H), 2.15–1.99 (m, 4H), 1.89–1.73 (m, 9H), 1.70–1.58 (m, 4H), 1.37 (dd, J = 15.8, 4.6Hz, 5H), 1.25–1.15 (m, 3H). ¹³C NMR (101MHz, methanol-d4 ) )δ135.42,134.07,129.99,119.14,116.27,113.64,61.85,52.31,49.08,33.07,32.57,31.18,25.81,24.95,23.21,21.72,12.43.

22、N1-环己基-4-(3-((萘-1-基甲基)氨基)丁基)苯-1,2-二胺(化合物I-13)22. N 1 -Cyclohexyl-4-(3-((naphthyl-1-ylmethyl)amino)butyl)phenyl-1,2-diamine (Compound I-13)

合成方法同I-1，黄色油状物，产率85％。1H NMR(400MHz,Chloroform-d)δ8.09(d,J＝8.4Hz,1H),7.81(d,J＝8.2Hz,1H),7.76(d,J＝8.3Hz,1H),7.68–7.60(m,1H),7.57–7.51(m,1H),7.51–7.37(m,3H),6.50–6.41(m,2H),4.36(q,J＝13.3Hz,2H),2.97–2.87(m,1H),2.46(ddd,J＝59.1,15.1,8.2Hz,2H),2.14–1.96(m,3H),1.85(dd,J＝12.7,8.8Hz,1H),1.73(d,J＝12.4Hz,2H),1.63(d,J＝12.8Hz,1H),1.29–1.08(m,9H).13C NMR(101MHz,Chloroform-d)δ132.74,131.11,131.01,130.58,127.96,127.81,127.56,127.44,125.78,124.97,124.45,122.28,118.93,115.71,51.71,51.51,32.54,30.12,28.68,25.00,24.01。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 85%. ¹H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.68–7.60 (m, 1H), 7.57–7.51 (m, 1H), 7.51–7.37 (m, 3H), 6.50–6.41 (m, 2H), 4.36 (q, J = 8.4 Hz, 1H). 13.3Hz,2H),2.97–2.87(m,1H),2.46(ddd,J＝59.1,15.1,8.2Hz,2H),2.14–1.96(m,3H),1.8 5(dd,J＝12.7,8.8Hz,1H),1.73(d,J＝12.4Hz,2H),1.63(d,J＝12.8Hz,1H),1.29–1.08(m,9H). 13C NMR(101MHz,Chloroform-d)δ132.74,131.11,131.01,130.58,127.96,127.81,127.56,127.44,1 25.78,124.97,124.45,122.28,118.93,115.71,51.71,51.51,32.54,30.12,28.68,25.00,24.01.

23、N1-环己基-4-(3-(6,7-二甲氧基-3,4-二氢喹啉-1(2H)-基)丁基)苯-1,2-二胺(化合物I-14)23. N 1 -cyclohexyl-4-(3-(6,7-dimethoxy-3,4-dihydroquinoline-1(2H)-yl)butyl)phenyl-1,2-diamine (compound I-14)

合成方法同I-1，黄色油状物，产率84％。1H NMR(400MHz,Chloroform-d)δ6.59(dd,J＝9.6,3.9Hz,4H),6.52(s,1H),3.86–3.77(m,7H),3.72–3.57(m,2H),3.19–3.13(m,1H),2.78(d,J＝9.7Hz,4H),2.68(q,J＝7.8,6.4Hz,1H),2.54(tq,J＝13.9,8.3,7.9Hz,2H),2.04(d,J＝11.8Hz,2H),1.96–1.86(m,1H),1.80–1.70(m,2H),1.68–1.57(m,2H),1.39–1.30(m,2H),1.23–1.14(m,3H),1.08(d,J＝5.7Hz,3H).13C NMR(101MHz,Chloroform-d)δ147.10,135.01,134.38,133.12,127.72,126.80,120.09,116.98,113.61,111.50,109.65,58.18,56.01,52.22,50.92,45.95,35.87,33.83,32.44,29.71,26.17,25.17,14.01。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 84%. ¹H NMR (400 MHz, Chloroform-d) δ 6.59 (dd, J = 9.6, 3.9 Hz, 4H), 6.52 (s, 1H), 3.86–3.77 (m, 7H), 3.72–3.57 (m, 2H), 3.19–3.13 (m, 1H), 2.78 (d, J = 9.7 Hz, 4H), 2.68 (q, J = 7.8, 6.4 Hz, 1H) ,2.54(tq,J＝13.9,8.3,7.9Hz,2H),2.04(d,J＝11.8Hz,2H),1.96–1.86(m,1H),1.80–1.7 0(m,2H),1.68–1.57(m,2H),1.39–1.30(m,2H),1.23–1.14(m,3H),1.08(d,J＝5.7Hz,3H). 13C NMR(101MHz,Chloroform-d)δ147.10,135.01,134.38,133.12,127.72,126.80,120.09,116.98,113.61 ,111.50,109.65,58.18,56.01,52.22,50.92,45.95,35.87,33.83,32.44,29.71,26.17,25.17,14.01.

24、N1-环己基-4-(3-((3,5-二氟苄基)氨基)丁基)苯-1,2-二胺(化合物I-15)24. N 1 -Cyclohexyl-4-(3-((3,5-difluorobenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-15)

合成方法同I-1，黄色油状物，产率86％。1H NMR(400MHz,Chloroform-d)δ7.00(d,J＝6.1Hz,2H),6.69(t,J＝8.8Hz,1H),6.54(dd,J＝12.2,7.4Hz,3H),3.87(d,J＝26.9Hz,2H),3.12(dq,J＝21.9,6.9Hz,2H),2.81(dt,J＝12.3,6.3Hz,1H),2.59(ddd,J＝14.0,9.0,6.0Hz,1H),2.42(dt,J＝14.3,7.9Hz,1H),1.98(dd,J＝20.8,8.7Hz,3H),1.76(td,J＝11.7,9.2,5.0Hz,3H),1.69–1.60(m,1H),1.39–1.31(m,5H),1.26(d,J＝4.5Hz,3H).13C NMR(101MHz,Chloroform-d)δ164.37,161.76,135.20,131.32,120.02,116.75,113.64,112.28,112.03,52.31,52.06,48.50,45.88,36.54,33.64,31.13,29.76,26.10,25.12。The synthesis method was the same as I-1. The product was a yellow oily substance with a yield of 86%. ¹H NMR (400MHz, Chloroform-d) δ 7.00 (d, J = 6.1Hz, 2H), 6.69 (t, J = 8.8Hz, 1H), 6.54 (dd, J = 12.2, 7.4Hz, 3H), 3.87 (d, J = 26.9Hz, 2H), 3.12 (dq, J = 21.9, 6.9Hz, 2H), 2.81 (dt, J = 12.3, 6.3Hz, 1H), 2 .59(ddd,J＝14.0,9.0,6.0Hz,1H),2.42(dt,J＝14.3,7.9Hz,1H),1.98(dd,J＝20.8,8.7Hz,3H), 1.76(td,J＝11.7,9.2,5.0Hz,3H),1.69–1.60(m,1H),1.39–1.31(m,5H),1.26(d,J＝4.5Hz,3H). 13C NMR(101MHz,Chloroform-d)δ164.37,161.76,135.20,131.32,120.02,116.75,113.64, 112.28,112.03,52.31,52.06,48.50,45.88,36.54,33.64,31.13,29.76,26.10,25.12.

25、N1-环己基-4-(3-((3,5-二氯苄基)氨基)丁基)苯-1,2-二胺(化合物I-16)25. N 1 -Cyclohexyl-4-(3-((3,5-dichlorobenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-16)

合成方法同I-1，黄色油状物，产率83％。1H NMR(400MHz,Chloroform-d)δ7.22(s,3H),6.58(d,J＝1.6Hz,2H),6.53(s,1H),3.80–3.64(m,2H),3.15(ddt,J＝10.1,7.5,3.7Hz,1H),2.69(q,J＝6.3Hz,1H),2.59–2.45(m,2H),2.03(dd,J＝9.1,3.4Hz,2H),1.79–1.72(m,3H),1.68–1.60(m,2H),1.34(ddd,J＝15.1,12.5,3.2Hz,3H),1.21–1.15(m,3H),1.12(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ135.04,134.89,134.50,127.18,126.78,120.02,116.79,113.59,52.19,50.09,38.60,33.79,31.58,29.82,26.16,25.16,20.23。The synthesis method is the same as I-1. It is a yellow oily substance with a yield of 83%. 1 H NMR(400MHz,Chloroform-d)δ7.22(s,3H),6.58(d,J＝1.6Hz,2H),6.53(s,1H),3 .80–3.64(m,2H),3.15(ddt,J＝10.1,7.5,3.7Hz,1H),2.69(q,J＝6.3Hz,1H),2.5 9–2.45(m,2H),2.03(dd,J＝9.1,3.4Hz,2H),1.79–1.72(m,3H),1.68–1.60(m,2H ),1.34(ddd,J＝15.1,12.5,3.2Hz,3H),1.21–1.15(m,3H),1.12(d,J＝6.3Hz,3H). 13C NMR(101MHz,Chloroform-d)δ135.04,134.89,134.50,127.18,126.78,120.02, 116.79,113.59,52.19,50.09,38.60,33.79,31.58,29.82,26.16,25.16,20.23.

26、4-(3-((3,5-双(三氟甲基)苄基)氨基)丁基)-N1-环己基苯-1,2-二胺(化合物I-17)26. 4-(3-((3,5-bis(trifluoromethyl)benzyl)amino)butyl)-N- 1 -cyclohexylphenyl-1,2-diamine (Compound I-17)

合成方法同I-1，黄色油状物，产率81％。1H NMR(400MHz,Chloroform-d)δ7.78(d,J＝29.7Hz,2H),6.62–6.51(m,4H),3.97–3.75(m,2H),3.16(tq,J＝10.2,3.6Hz,1H),2.75–2.68(m,1H),2.60–2.48(m,3H),2.06–2.00(m,2H),1.80–1.69(m,5H),1.69–1.59(m,3H),1.14(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ135.05,134.33,131.66,131.33,128.30,119.99,119.87,116.84,116.67,113.64,67.66,52.60,52.19,50.08,41.08,33.68,31.52,29.71,26.06,25.04,23.57。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 81%. ¹H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 29.7 Hz, 2H), 6.62–6.51 (m, 4H), 3.97–3.75 (m, 2H), 3.16 (tq, J = 10.2, 3.6 Hz, 1H), 2.75–2.68 (m, 1H), 2.60–2.48 (m, 3H), 2.06–2.00 (m, 2H), 1.80–1.69 (m, 5H), 1.69–1.59 (m, 3H), 1.14 (d, J = 6.3 Hz, 3H). 13 C NMR(101MHz,Chloroform-d)δ135.05,134.33,131.66,131.33,128.30,119.99,119.87,116.84 ,116.67,113.64,67.66,52.60,52.19,50.08,41.08,33.68,31.52,29.71,26.06,25.04,23.57.

27、N1-环己基-4-(3-((3，5-二甲氧基苄基)氨基)丁基)苯-1,2-二胺(化合物I-18)27. N 1 -Cyclohexyl-4-(3-((3,5-dimethoxybenzyl)amino)butyl)phenyl-1,2-diamine (Compound I-18)

合成方法同I-1，黄色油状物，产率80％。1H NMR(400MHz,Chloroform-d)δ6.56(s,2H),6.53–6.46(m,3H),6.35(t,J＝2.2Hz,1H),3.77(s,8H),3.19–3.11(m,1H),2.75(q,J＝6.2Hz,1H),2.49(dddd,J＝23.8,17.5,11.9,6.5Hz,2H),2.07–1.97(m,2H),1.80–1.71(m,3H),1.68–1.60(m,2H),1.40–1.31(m,2H),1.13(d,J＝6.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.93,135.00,134.49,132.37,128.68,120.03,116.84,113.54,106.36,99.30,55.44,52.17,52.00,50.86,38.32,33.80,31.53,29.81,26.15,25.15,19.73。Synthesized using the same method as I-1, the substance was a yellow oil with a yield of 80%. ¹H NMR (400MHz, Chloroform-d) δ 6.56 (s, 2H), 6.53–6.46 (m, 3H), 6.35 (t, J = 2.2Hz, 1H), 3.77 (s, 8H), 3.19–3.11 (m, 1H), 2.75 (q, J = 6.2Hz, 1H), 2.49 (dddd, J = 23.8, 17.5, 11.9, 6.5Hz, 2H), 2.07–1.97 (m, 2H), 1.80–1.71 (m, 3H), 1.68–1.60 (m, 2H), 1.40–1.31 (m, 2H), 1.13 (d, J = 6.3Hz, 3H). ¹³C NMR(101MHz,Chloroform-d)δ160.93,135.00,134.49,132.37,128.68,120.03,116.84,113.54 ,106.36,99.30,55.44,52.17,52.00,50.86,38.32,33.80,31.53,29.81,26.15,25.15,19.73.

28、N1-环己基-4-(3-(苯乙基氨基)丁基)苯-1,2-二胺(化合物I-19)28. N 1 -Cyclohexyl-4-(3-(phenethylamino)butyl)phenyl-1,2-diamine (Compound I-19)

合成方法同I-1，黄色油状物，产率86％。1H NMR(400MHz,Chloroform-d)δ7.30–7.27(m,1H),7.20(ddd,J＝10.0,6.7,3.9Hz,4H),6.56–6.47(m,3H),3.14(ddd,J＝9.7,7.7,3.3Hz,2H),2.97–2.90(m,5H),2.90–2.82(m,3H),2.53(tt,J＝9.3,4.6Hz,1H),2.46–2.34(m,1H),2.02(dd,J＝13.7,4.1Hz,2H),1.96–1.89(m,1H),1.78–1.68(m,3H),1.64(dd,J＝10.3,5.8Hz,1H),1.22(dd,J＝9.8,5.2Hz,5H).13C NMR(101MHz,Chloroform-d)δ138.71,135.02,134.58,131.35,128.76,128.61,126.52,119.95,116.67,113.51,53.04,51.94,47.30,36.72,33.70,31.22,26.06,25.04,18.36。Synthesized using the same method as I-1, the substance is a yellow oil with a yield of 86%. ¹H NMR (400 MHz, Chloroform-d) δ 7.30–7.27 (m, 1H), 7.20 (ddd, J = 10.0, 6.7, 3.9 Hz, 4H), 6.56–6.47 (m, 3H), 3.14 (ddd, J = 9.7, 7.7, 3.3 Hz, 2H), 2.97–2.90 (m, 5H), 2.90–2.82 (m, 3H) ,2.53(tt,J＝9.3,4.6Hz,1H),2.46–2.34(m,1H),2.02(dd,J＝13.7,4.1Hz,2H),1.96–1. 89(m,1H),1.78–1.68(m,3H),1.64(dd,J＝10.3,5.8Hz,1H),1.22(dd,J＝9.8,5.2Hz,5H). 13C NMR(101MHz,Chloroform-d)δ138.71,135.02,134.58,131.35,128.76,128.61,126.52, 119.95,116.67,113.51,53.04,51.94,47.30,36.72,33.70,31.22,26.06,25.04,18.36.

29、N1-环己基-4-(3-吗啉代丁基)苯-1,2-二胺(化合物I-20)29. N 1 -Cyclohexyl-4-(3-morpholinobutyl)benzene-1,2-diamine (Compound I-20)

合成方法同I-1，黄色油状物，产率83％。1H NMR(400MHz,Chloroform-d)δ6.58(s,2H),6.55(s,1H),3.73(s,4H),3.19–3.12(m,1H),2.61–2.44(m,8H),2.03(dd,J＝8.5,3.8Hz,2H),1.79–1.70(m,2H),1.68–1.60(m,1H),1.57–1.47(m,1H),1.39–1.29(m,2H),1.23–1.12(m,3H),1.03(d,J＝5.9Hz,3H).13C NMR(101MHz,Chloroform-d)δ135.03,134.33,132.57,119.98,116.81,113.66,67.03,58.91,52.18,48.62,34.98,33.71,32.01,26.07,25.05,13.94。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 83%. ¹H NMR (400 MHz, Chloroform-d) δ 6.58 (s, 2H), 6.55 (s, 1H), 3.73 (s, 4H), 3.19–3.12 (m, 1H), 2.61–2.44 (m, 8H), 2.03 (dd, J = 8.5, 3.8 Hz, 2H), 1.79–1.70 (m, 2H), 1.68–1.60 (m, 1H), 1.57–1.47 (m, 1H), 1.39–1.29 (m, 2H), 1.23–1.12 (m, 3H), 1.03 (d, J = 5.9 Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ135.03,134.33,132.57,119.98,116.81,113.66,67.03,58.91,52.18,48.62,34.98,33.71,32.01,26.07,25.05,13.94.

30、N1-环己基-4-(3-((3-(三氟甲基)苄基)氨基)丁基)苯-1,2-二胺(化合物I-21)30. N 1 -Cyclohexyl-4-(3-((3-(trifluoromethyl)benzyl)amino)butyl)phenyl-1,2-diamine (Compound I-21)

合成方法同I-1，黄色油状物，产率81％。1H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.55–7.45(m,2H),7.45–7.38(m,1H),6.55(dd,J＝16.0,3.6Hz,3H),3.91–3.72(m,2H),3.21–3.10(m,1H),2.78–2.65(m,1H),2.59–2.42(m,2H),2.07–1.97(m,2H),1.84–1.68(m,3H),1.70–1.56(m,2H),1.42–1.24(m,5H),1.16–1.12(m,3H)。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 81%. ¹H NMR (400 MHz, Chloroform-d) δ 7.60 (s, ¹H), 7.55–7.45 (m, 2H), 7.45–7.38 (m, ¹H), 6.55 (dd, J = 16.0, 3.6 Hz, 3H), 3.91–3.72 (m, 2H), 3.21–3.10 (m, ¹H), 2.78–2.65 (m, 1H), 2.59–2.42 (m, 2H), 2.07–1.97 (m, 2H), 1.84–1.68 (m, 3H), 1.70–1.56 (m, 2H), 1.42–1.24 (m, 5H), 1.16–1.12 (m, 3H).

31、N1-环己基-4-(3-((1,2,3,4-四氢萘-1-基)氨基)丁基)苯-1,2-二胺(化合物I-22)31. N 1 -Cyclohexyl-4-(3-((1,2,3,4-tetrahydronaphth-1-yl)amino)butyl)phenyl-1,2-diamine (Compound I-22)

合成方法同I-1，黄色油状物，产率71％。1H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,1H),7.12(dd,J＝5.4,2.8Hz,2H),7.08–7.04(m,1H),6.57(d,J＝5.3Hz,3H),3.95–3.81(m,1H),3.21–3.11(m,1H),2.96–2.76(m,1H),2.74–2.64(m,1H),2.59–2.49(m,2H),2.08–1.91(m,4H),1.87–1.59(m,10H),1.22–1.16(m,6H)。Synthesized using the same method as I-1, the product is a yellow oily substance with a yield of 71%. ¹H NMR (400MHz, Chloroform-d) δ 7.32–7.28 (m, 1H), 7.12 (dd, J = 5.4, 2.8Hz, 2H), 7.08–7.04 (m, 1H), 6.57 (d, J = 5.3Hz, 3H), 3.95–3.81 (m, 1H), 3.21–3.11 (m, 1H), 2.96–2.76 (m, 1H), 2.74–2.64 (m, 1H), 2.59–2.49 (m, 2H), 2.08–1.91 (m, 4H), 1.87–1.59 (m, 10H), 1.22–1.16 (m, 6H).

实施例2Example 2

1、1,2-双(溴甲基)苯(化合物12)1. 1,2-Bis(bromomethyl)benzene (compound 12)

将邻二甲苯(0.5g,4.7mmol)、NBS(1.84g,10.36mmol)和AIBN(0.08g,0.47mmol)加入含有40mL氯仿的茄形瓶中，N2保护下，回流反应至TLC检测反应结束。混合物用柱层析分离，得到白色固体(1.02g,82％)。1H NMR(400MHz,Chloroform-d)δ7.38–7.34(m,2H),7.32–7.29(m,2H),4.66(s,4H)。o-Xylene (0.5 g, 4.7 mmol), NBS (1.84 g, 10.36 mmol), and AIBN (0.08 g, 0.47 mmol) were added to a round-bottom flask containing 40 mL of chloroform. The mixture was refluxed under N2 protection until the reaction was complete as detected by TLC. The mixture was separated by column chromatography to give a white solid (1.02 g, 82%). ¹H NMR (400 MHz, Chloroform-d) δ 7.38–7.34 (m, 2H), 7.32–7.29 (m, 2H), 4.66 (s, 4H).

2、2-(2-甲基丁-3-炔-2-基)异吲哚啉-4-羧酸甲酯(化合物13)2. Methyl 2-(2-methylbut-3-yn-2-yl)isoindoline-4-carboxylic acid (Compound 13)

将2,3-双(溴甲基)苯甲酸甲酯(0.25g,0.76mmol),2-甲基丁-3-炔-2-胺(0.06g,0.72mmol)和K2CO3(0.29g,2.2mmol)加入茄形瓶中，加入THF(25mL)作溶剂，60℃反应18h。将反应液倒入50mL水中，EA萃取水层(50mL×3)，合并有机层并浓缩。混合物用柱层析分离(PE:EA＝10:1)，得到白色固状化合物13(0.04g,21％)。1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,1H),7.98(d,J＝7.5Hz,1H),7.54(t,J＝7.6Hz,1H),4.92(s,2H),3.96(d,J＝8.1Hz,5H),2.52(s,1H),1.89(s,6H)。Methyl 2,3-bis(bromomethyl)benzoate (0.25 g, 0.76 mmol), 2-methylbut-3-yn-2-amine (0.06 g, 0.72 mmol), and K₂CO₃ (0.29 g, 2.2 mmol) were added to a round-bottom flask, and THF (25 mL) was added as a solvent. The mixture was reacted at 60 ° C for 18 h. The reaction solution was poured into 50 mL of water, and the aqueous layer was extracted with EA (50 mL × 3). The organic layers were combined and concentrated. The mixture was separated by column chromatography (PE:EA = 10:1) to give a white solid compound 13 (0.04 g, 21%). 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,1H),7.98(d,J＝7.5Hz,1H),7.54 (t,J=7.6Hz,1H),4.92(s,2H),3.96(d,J=8.1Hz,5H),2.52(s,1H),1.89(s,6H).

3、N-环己基-4-(3-(异吲哚啉-2-基)-3-甲基丁-1-炔-1-基)-2-硝基苯胺(化合物14)3. N-cyclohexyl-4-(3-(isoindoline-2-yl)-3-methylbut-1-yn-1-yl)-2-nitroaniline (compound 14)

将2-(2-甲基丁-3-炔-2-基)异吲哚啉(0.03g,0.16mmol)、4-溴-N-环己基-2-硝基苯胺(0.06g,0.19mmol)、Pd(PPh3)2Cl2(0.034g,0.0046mmol)和CuI(0.015g,0.008mmol)加入反应瓶中，三乙胺(5mL)作溶剂，N2保护，40℃反应过夜，得到黄色固体(0.04g。61％)。1H NMR(400MHz,Chloroform-d)δ8.10(d,J＝8.8Hz,1H),7.81(d,J＝7.4Hz,1H),7.52(dd,J＝7.6,1.0Hz,1H),7.45(t,J＝8.0Hz,2H),6.89(d,J＝1.5Hz,1H),6.62(dd,J＝8.9,1.6Hz,1H),4.65(s,2H),3.52(m,1H),2.06–2.00(m,2H),1.97(s,6H),1.83–1.76(m,2H),1.47–1.31(m,6H)。2-(2-methylbut-3-yn-2-yl)isoindoline (0.03 g, 0.16 mmol), 4-bromo-N-cyclohexyl-2-nitroaniline (0.06 g, 0.19 mmol), Pd( PPh3 ) 2Cl2 ( 0.034 g, 0.0046 mmol), and CuI (0.015 g, 0.008 mmol) were added to a reaction flask. Triethylamine (5 mL) was used as the solvent, and the reaction was carried out overnight at 40 °C under N2 protection to give a yellow solid (0.04 g, 61%). 1 H NMR (400MHz, Chloroform-d) δ8.10(d,J＝8.8Hz,1H),7.81(d,J＝7.4Hz,1H),7.52(dd,J＝7.6,1.0Hz,1H),7.45(t,J＝8.0Hz,2H),6.89(d,J＝ 1.5Hz,1H),6.62(dd,J=8.9,1.6Hz,1H),4.65(s,2H),3.52(m,1H),2.06–2.00(m,2H),1.97(s,6H),1.83–1.76(m,2H),1.47–1.31(m,6H).

4、N1-环己基-4-(3-(异吲哚啉-2-基)-3-甲基丁基)苯-1，2-二胺(化合物II-1)4. N 1 -Cyclohexyl-4-(3-(isoindoline-2-yl)-3-methylbutyl)benzene-1,2-diamine (Compound II-1)

将N-环己基-4-(3-(异吲哚啉-2-基)-3-甲基丁-1-炔-1-基)-2-硝基苯胺(0.04g)加入到含有20mL的反应瓶中，加入钯碳(0.012g)，H2条件下反应。反应结束后，过滤钯碳，混合物经柱层析分离，得到淡黄色固体(0.024g，64％)。1H NMR(400MHz,Methanol-d4)δ7.72(d,J＝7.6Hz,1H),7.57(d,J＝7.3Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(t,J＝7.5Hz,1H),6.60(d,J＝7.7Hz,1H),6.46(s,1H),6.39(d,J＝7.8Hz,1H),4.59(s,2H),3.18(s,1H),2.46–2.40(m,2H),2.31(dd,J＝11.1,5.6Hz,2H),2.02(d,J＝12.9Hz,2H),1.77(d,J＝13.8Hz,3H),1.67(d,J＝12.1Hz,1H),1.57(s,6H),1.44–1.32(m,4H).13C NMR(101MHz,Methanol-d4)δ141.63,135.90,133.88,133.43,131.15,127.55,122.51,122.22,117.78,116.80,113.45,57.23,52.02,49.44,41.38,33.04,30.35,25.80,25.48,24.88。N-cyclohexyl-4-(3-(isoindolin-2-yl)-3-methylbut-1-yn-1-yl)-2-nitroaniline (0.04 g) was added to a reaction flask containing 20 mL of solvent, and palladium on carbon (0.012 g) was added. The reaction was carried out under H₂ conditions. After the reaction was complete, the palladium on carbon was filtered off, and the mixture was separated by column chromatography to give a pale yellow solid (0.024 g, 64%). ¹H NMR (400 MHz, methanol- d4) )δ7.72(d,J＝7.6Hz,1H),7.57(d,J＝7.3Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(t,J＝7 .5Hz,1H),6.60(d,J＝7.7Hz,1H),6.46(s,1H),6.39(d,J＝7.8Hz,1H),4.59(s,2H), 3.18(s,1H),2.46–2.40(m,2H),2.31(dd,J＝11.1,5.6Hz,2H),2.02(d,J＝12.9Hz,2 H),1.77(d,J＝13.8Hz,3H),1.67(d,J＝12.1Hz,1H),1.57(s,6H),1.44–1.32(m,4H). 13 C NMR (101MHz, Methanol-d 4 )δ141.63,135.90,133.88,133.43,131.15,127.55,122.51,122.22,117.78,1 16.80,113.45,57.23,52.02,49.44,41.38,33.04,30.35,25.80,25.48,24.88.

5、2-(4-(3-氨基-4-(环己基氨基)苯基)-2-甲基丁-2-基)异吲哚啉-4-羧酸甲酯(化合物II-2)合成方法同II-1。1H NMR(400MHz,Chloroform-d)δ8.15(dd,J＝7.7,1.1Hz,1H),7.98(dd,J＝7.6,1.0Hz,1H),7.69–7.59(m,1H),7.53(t,J＝7.7Hz,1H),7.24–7.15(m,1H),7.09(d,J＝4.7Hz,1H),4.79(s,2H),4.20–4.10(m,1H),3.95(s,3H),2.76–2.68(m,2H),2.48–2.39(m,2H),2.21–2.15(m,2H),1.95(d,J＝13.5Hz,2H),1.83–1.70(m,4H),1.64(s,6H),1.55–1.47(m,2H).13C NMR(101MHz,Chloroform-d)δ166.63,141.66,135.84,134.52,131.43,127.25,126.72,123.72,122.06,56.23,51.21,49.61,40.99,32.36,30.36,28.68,25.71,24.68,24.40。5. Methyl 2-(4-(3-amino-4-(cyclohexylamino)phenyl)-2-methylbut-2-yl)isoindoline-4-carboxylic acid (compound II-2) was synthesized using the same method as II-1. ¹H NMR (400MHz, Chloroform-d) δ 8.15 (dd, J = 7.7, 1.1Hz, 1H), 7.98 (dd, J = 7.6, 1.0Hz, 1H), 7.69–7.59 (m, 1H), 7.53 (t, J = 7.7Hz, 1H), 7.24–7.15 (m, 1H), 7.09 (d, J = 4.7Hz, 1H), 4.7 9(s,2H),4.20–4.10(m,1H),3.95(s,3H),2.76–2.68(m,2H),2.48–2.39(m,2H),2.21–2 .15(m,2H),1.95(d,J＝13.5Hz,2H),1.83–1.70(m,4H),1.64(s,6H),1.55–1.47(m,2H). 13C NMR(101MHz,Chloroform-d)δ166.63,141.66,135.84,134.52,131.43,127.25,126.72, 123.72,122.06,56.23,51.21,49.61,40.99,32.36,30.36,28.68,25.71,24.68,24.40.

6、N1-环己基-4-(3-甲基-3-(5-(甲磺酰基)异吲哚啉-2-基)丁基)苯-1,2-二胺(化合物II-3)合成方法同II-1。1H NMR(400MHz,Chloroform-d)δ7.80(d,J＝8.5Hz,2H),7.39(d,J＝7.8Hz,1H),6.66(d,J＝7.6Hz,1H),6.48(d,J＝7.2Hz,2H),4.17(s,4H),3.23(m,1H),3.03(s,3H),2.63–2.56(m,2H),2.09–2.01(m,2H),1.83–1.72(m,5H),1.70–1.58(m,2H),1.39(q,J＝12.8,12.0Hz,3H),1.22(s,6H).13C NMR(101MHz,Chloroform-d)δ139.26,137.12,131.83,126.33,122.93,121.70,117.24,51.69,51.46,33.61,30.20,29.70,26.02,25.00。6. The synthesis method of N 1 -cyclohexyl-4-(3-methyl-3-(5-(methanesulfonyl)isoindoline-2-yl)butyl)phenyl-1,2-diamine (compound II-3) is the same as that of II-1. 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J＝8.5Hz,2H),7.39(d,J＝7.8Hz,1H),6.66(d,J＝7.6Hz,1H),6.48(d,J＝7.2Hz,2H),4.17(s,4H),3.23( m,1H),3.03(s,3H),2.63–2.56(m,2H),2.09–2.01(m,2H),1.83–1.72(m,5H),1.70–1.58(m,2H),1.39(q,J＝12.8,12.0Hz,3H),1.22(s,6H). 13C NMR(101MHz,Chloroform-d)δ139.26,137.12,131.83,126.33,122.93,121.70,117.24,51.69,51.46,33.61,30.20,29.70,26.02,25.00.

7、3-氨基-4-(环己基氨基)-N-(2-(异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-4)7. 3-Amino-4-(cyclohexylamino)-N-(2-(isoindoline-2-yl)ethyl)benzamide (compound II-4)

合成方法同II-1。1H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.0Hz,1H),7.56–7.51(m,1H),7.48–7.42(m,2H),7.18(d,J＝1.8Hz,1H),7.09(dd,J＝7.8,1.7Hz,2H),6.67(dd,J＝8.0,0.6Hz,1H),4.50(s,2H),3.92–3.87(m,2H),3.73(q,J＝5.4Hz,2H),3.35–3.25(m,1H),2.10–2.01(m,2H),1.76(m,2H),1.66(m,1H),1.47–1.35(m,3H),1.21–1.12(m,2H).13C NMR(101MHz,Chloroform-d)δ167.98,141.41,140.57,132.49,132.29,131.54,128.07,123.59,122.87,122.19,120.66,116.30,110.02,51.41,50.86,42.28,39.73,33.30,25.88,24.94。The synthesis method is the same as II-1. 1 H NMR(400MHz,Chloroform-d)δ7.82(d,J＝8.0Hz,1H),7.56–7.51(m,1H),7.48–7.4 2(m,2H),7.18(d,J＝1.8Hz,1H),7.09(dd,J＝7.8,1.7Hz,2H),6.67(dd,J＝8.0,0.6H z,1H),4.50(s,2H),3.92–3.87(m,2H),3.73(q,J＝5.4Hz,2H),3.35–3.25(m,1H),2 .10–2.01(m,2H),1.76(m,2H),1.66(m,1H),1.47–1.35(m,3H),1.21–1.12(m,2H). 13C NMR(101MHz,Chloroform-d)δ167.98,141.41,140.57,132.49,132.29,131.54,128.07,123.5 9,122.87,122.19,120.66,116.30,110.02,51.41,50.86,42.28,39.73,33.30,25.88,24.94.

8、2-(2-(3-氨基-4-(环己基氨基)苯甲酰胺基)乙基)异吲哚啉-4-羧酸甲酯(化合物II-5)合成方法同II-1。1H NMR(400MHz,Chloroform-d)δ8.57(d,J＝2.1Hz,1H),8.30(d,J＝7.4Hz,1H),7.93–7.85(m,2H),7.39(d,J＝7.4Hz,1H),7.29(t,J＝7.6Hz,1H),6.87(d,J＝9.1Hz,1H),6.77(t,J＝4.3Hz,1H),4.33(s,2H),4.02(s,2H),3.89(d,J＝0.9Hz,3H),3.64(m,2H),3.53(m,1H),3.01(t,J＝5.8Hz,2H),2.03(d,J＝9.8Hz,2H),1.79(m,2H),1.69–1.62(m,1H),1.47–1.32(m,5H).13C NMR(101MHz,Chloroform-d)δ167.80,166.72,140.57,132.57,128.77,127.33,126.70,125.15,122.77,120.55,116.42,110.03,60.02,58.34,54.79,53.43,52.04,51.43,38.07,33.28,29.71,25.89,24.93。8. Methyl 2-(2-(3-amino-4-(cyclohexylamino)benzamido)ethyl)isoindoline-4-carboxylic acid (compound II-5) was synthesized using the same method as II-1. ¹H NMR (400MHz, Chloroform-d) δ 8.57 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H), 7.93–7.85 (m, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 9.1 Hz, 1H), 6.77 (t, J = 4.3 Hz). z,1H),4.33(s,2H),4.02(s,2H),3.89(d,J＝0.9Hz,3H),3.64(m,2H),3.53(m,1H),3.01(t ,J＝5.8Hz,2H),2.03(d,J＝9.8Hz,2H),1.79(m,2H),1.69–1.62(m,1H),1.47–1.32(m,5H). 13C NMR(101MHz,Chloroform-d)δ167.80,166.72,140.57,132.57,128.77,127.33,126.70,125.15,122.77 ,120.55,116.42,110.03,60.02,58.34,54.79,53.43,52.04,51.43,38.07,33.28,29.71,25.89,24.93.

9、3-氨基-4-(环己基氨基)-N-(2-(5-(甲磺酰基)异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-6)9. 3-Amino-4-(cyclohexylamino)-N-(2-(5-(methanesulfonyl)isoindoline-2-yl)ethyl)benzamide (compound II-6)

合成方法同II-1。1H NMR(400MHz,Chloroform-d)δ7.84–7.75(m,2H),7.39(d,J＝7.9Hz,1H),7.21(s,1H),6.72–6.66(m,1H),6.55(d,J＝8.0Hz,1H),4.10(s,4H),3.62(t,J＝5.3Hz,2H),3.31–3.21(m,1H),3.04(d,J＝5.7Hz,5H),2.03(m,2H),1.80–1.71(m,2H),1.65(m,1H),1.41–1.26(m,3H),1.19(d,J＝12.4Hz,2H).13C NMR(101MHz,Methanol-d4)δ169.71,144.77,140.21,140.06,132.90,126.68,123.17,121.33,119.82,114.93,109.18,58.38,58.20,54.80,51.32,43.07,37.65,32.82,25.69,25.30,24.85。Synthetic method as in II-1. ¹H NMR (400MHz, Chloroform-d): δ 7.84–7.75 (m, 2H), 7.39 (d, J = 7.9Hz, 1H), 7.21 (s, 1H), 6.72–6.66 (m, 1H), 6.55 (d, J = 8.0Hz, 1H), 4.10 (s, 4H), 3.62 (t, J = 5.3Hz, 2H), 3.31–3.21 (m, 1H), 3.04 (d, J = 5.7Hz, 5H), 2.03 (m, 2H), 1.80–1.71 (m, 2H), 1.65 (m, 1H), 1.41–1.26 (m, 3H), 1.19 (d, J = 12.4Hz, 2H). ¹³C NMR (101MHz, Methanol- d4) )δ169.71,144.77,140.21,140.06,132.90,126.68,123.17,121.33,119.82,114. 93,109.18,58.38,58.20,54.80,51.32,43.07,37.65,32.82,25.69,25.30,24.85.

10、3-氨基-4-(环己基氨基)-N-(2-(5-氟异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-7)10. 3-Amino-4-(cyclohexylamino)-N-(2-(5-fluoroisoindoline-2-yl)ethyl)benzamide (Compound II-7)

将化合物4-(环己基氨基)-N-(2-(5-氟异吲哚啉-2-基)乙基)-3-硝基苯甲酰胺(0.1g,0.23mmol)、锌粉(0.045g,0.69mmol)和催化量的盐酸加入装有20mL的甲醇茄形瓶中，室温反应至结束。将混合物用硅藻土过滤，溶液浓缩得到的混合物经柱层析分离得到淡黄色化合物(0.73g,79％)。1H NMR(400MHz,Chloroform-d)δ8.64(s,1H),8.26(d,J＝6.8Hz,1H),7.82(d,J＝9.1Hz,1H),7.54(s,1H),7.44–7.36(m,1H),7.22–7.09(m,1H),6.83(d,J＝9.0Hz,1H),4.49(d,J＝4.1Hz,2H),3.88(d,J＝4.6Hz,2H),3.74(s,2H),3.54–3.48(m,1H),2.06–1.96(m,2H),1.83–1.74(m,2H),1.69–1.59(m,1H),1.37(m,5H).13C NMR(101MHz,Methanol-d4)δ169.78,163.90,139.98,132.92,123.70,121.02,119.86,114.92,114.08,109.55,109.32,109.14,58.57,58.06,54.89,51.31,37.39,32.82,25.69,24.8。Compound 4-(cyclohexylamino)-N-(2-(5-fluoroisoindoline-2-yl)ethyl)-3-nitrobenzamide (0.1 g, 0.23 mmol), zinc powder (0.045 g, 0.69 mmol), and a catalytic amount of hydrochloric acid were added to a 20 mL methanol-filled round-bottom flask, and the reaction was carried out at room temperature until completion. The mixture was filtered through diatomaceous earth, and the solution was concentrated. The resulting mixture was separated by column chromatography to give a pale yellow compound (0.73 g, 79%). 1 H NMR(400MHz,Chloroform-d)δ8.64(s,1H),8.26(d,J＝6.8Hz,1H),7.82(d,J＝9 .1Hz,1H),7.54(s,1H),7.44–7.36(m,1H),7.22–7.09(m,1H),6.83(d,J＝9.0H z,1H),4.49(d,J＝4.1Hz,2H),3.88(d,J＝4.6Hz,2H),3.74(s,2H),3.54–3.48( m,1H),2.06–1.96(m,2H),1.83–1.74(m,2H),1.69–1.59(m,1H),1.37(m,5H). 13C NMR(101MHz, Methanol-d 4 )δ169.78,163.90,139.98,132.92,123.70,121.02,119.86,114.92,114.08,1 09.55,109.32,109.14,58.57,58.06,54.89,51.31,37.39,32.82,25.69,24.8.

11、3-氨基-N-(2-(4-溴异吲哚啉-2-基)乙基)-4-(环己基氨基)苯甲酰胺(化合物II-8)11. 3-Amino-N-(2-(4-bromoisoindoline-2-yl)ethyl)-4-(cyclohexylamino)benzamide (Compound II-8)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.31(d,J＝7.6Hz,1H),7.24(dd,J＝4.4,1.1Hz,1H),7.07(dt,J＝15.1,7.4Hz,2H),6.74(t,J＝4.5Hz,1H),6.54(d,J＝8.1Hz,1H),4.02(m,4H),3.57(q,J＝5.6Hz,2H),3.25(m,1H),2.93(t,J＝5.9Hz,2H),2.05–1.98(m,2H),1.74(m,2H),1.67–1.60(m,1H),1.40–1.30(m,2H),1.18(m,3H).13C NMR(101MHz,Chloroform-d)δ167.85,140.51,140.36,132.69,129.96,128.80,122.70,121.19,120.44,117.28,116.29,109.96,59.96,59.75,54.55,51.43,38.23,33.31,25.91,24.96。Synthesis method as in II-7. ¹H NMR (400MHz, Chloroform-d) δ 7.31 (d, J = 7.6Hz, 1H), 7.24 (dd, J = 4.4, 1.1Hz, 1H), 7.07 (dt, J = 15.1, 7.4Hz, 2H), 6.74 (t, J = 4.5Hz, 1H), 6.54 (d, J = 8.1Hz, 1H), 4.02 (m, 4H), 3.57 (q, J = 5.6Hz, 2H), 3.25 (m, 1H), 2.93 (t, J = 5.9Hz, 2H), 2.05–1.98 (m, 2H), 1.74 (m, 2H), 1.67–1.60 (m, 1H), 1.40–1.30 (m, 2H), 1.18 (m, 3H). 13 C NMR(101MHz,Chloroform-d)δ167.85,140.51,140.36,132.69,129.96,128.80,122.70,121. 19,120.44,117.28,116.29,109.96,59.96,59.75,54.55,51.43,38.23,33.31,25.91,24.96.

12、3-氨基-4-(环己基氨基)-N-(2-(4-氟异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-9)12. 3-Amino-4-(cyclohexylamino)-N-(2-(4-fluoroisoindoline-2-yl)ethyl)benzamide (Compound II-9)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.24–7.21(m,2H),7.18(dt,J＝8.0,3.7Hz,1H),6.98(d,J＝7.4Hz,1H),6.89(t,J＝8.6Hz,1H),6.73(s,1H),6.58–6.54(m,1H),4.05(d,J＝16.1Hz,4H),3.60(q,J＝5.5Hz,2H),3.26(dm,1H),2.98(t,J＝5.8Hz,2H),2.07–2.00(m,2H),1.75(m,2H),1.65(m,1H),1.41–1.31(m,2H),1.19(m,3H).13C NMR(101MHz,Chloroform-d)δ167.81,158.90,140.58,132.60,129.06,122.70,120.46,118.06,116.38,113.82,113.62,109.99,58.93,55.45,54.61,51.43,38.14,33.31,29.70,25.89,24.93。The synthesis method is the same as II-7. 1 H NMR(400MHz,Chloroform-d)δ7.24–7.21(m,2H),7.18(dt,J＝8.0,3.7Hz,1H),6 .98(d,J＝7.4Hz,1H),6.89(t,J＝8.6Hz,1H),6.73(s,1H),6.58–6.54(m,1H),4. 05(d,J＝16.1Hz,4H),3.60(q,J＝5.5Hz,2H),3.26(dm,1H),2.98(t,J＝5.8Hz,2H ),2.07–2.00(m,2H),1.75(m,2H),1.65(m,1H),1.41–1.31(m,2H),1.19(m,3H). 13C NMR(101MHz,Chloroform-d)δ167.81,158.90,140.58,132.60,129.06,122.70,120.46,118.06, 116.38,113.82,113.62,109.99,58.93,55.45,54.61,51.43,38.14,33.31,29.70,25.89,24.93.

13、3-氨基-N-(2-(5-氯异吲哚啉-2-基)乙基)-4-(环己基氨基)苯甲酰胺(化合物II-10)合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.23(d,J＝5.4Hz,2H),7.16(d,J＝6.7Hz,2H),7.08(dd,J＝6.4,1.8Hz,1H),6.72(d,J＝5.2Hz,1H),6.56(d,J＝8.8Hz,1H),4.06(s,4H),3.60(q,J＝5.7Hz,2H),3.27(m,1H),2.98(t,J＝5.9Hz,2H),2.10–1.96(m,2H),1.75(m,2H),1.64(m,1H),1.43–1.23(m,4H).13C NMR(101MHz,Chloroform-d)δ167.79,141.57,140.56,138.03,132.61,128.77,128.65,127.07,122.74,120.62,120.47,116.37,110.00,59.49,58.14,54.61,51.42,38.12,33.31,25.88,24.93。13. The synthesis method of 3-amino-N-(2-(5-chloroisoindoline-2-yl)ethyl)-4-(cyclohexylamino)benzamide (compound II-10) is the same as that of II-7. 1 H NMR(400MHz,Chloroform-d)δ7.23(d,J＝5.4Hz,2H),7.16(d,J＝6.7Hz,2H),7.08(dd,J＝6.4,1.8Hz,1H),6.72(d,J＝5.2Hz,1H),6.56(d,J＝8.8H z,1H),4.06(s,4H),3.60(q,J＝5.7Hz,2H),3.27(m,1H),2.98(t,J＝5.9H z,2H),2.10–1.96(m,2H),1.75(m,2H),1.64(m,1H),1.43–1.23(m,4H). 13C NMR(101MHz,Chloroform-d)δ167.79,141.57,140.56,138.03,132.61,128.77,128.65,127.07,1 22.74,120.62,120.47,116.37,110.00,59.49,58.14,54.61,51.42,38.12,33.31,25.88,24.93.

14、3-氨基-4-(环己基氨基)-N-(3-(异吲哚啉-2-基)丙基)苯甲酰胺(化合物II-11)14. 3-Amino-4-(cyclohexylamino)-N-(3-(isoindoline-2-yl)propyl)benzamide (Compound II-11)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.85(d,J＝7.5Hz,1H),7.54(t,J＝7.4Hz,2H),7.45(q,J＝8.2Hz,3H),7.35(s,1H),6.67(d,J＝8.3Hz,1H),4.40(s,2H),3.77–3.70(m,2H),3.37(q,J＝5.9Hz,2H),3.30(dd,J＝8.5,5.1Hz,1H),2.10–2.01(m,2H),1.88(p,J＝6.4Hz,2H),1.77(m,2H),1.66(m,1H),1.44–1.30(m,2H),1.20(m,3H).13C NMR(101MHz,Chloroform-d)δ169.67,141.22,132.36,131.56,128.21,123.71,122.87,120.59,116.63,51.93,50.15,39.48,35.64,33.13,29.70,27.74,25.87,24.96。The synthesis method is the same as II-7. 1 H NMR(400MHz,Chloroform-d)δ7.85(d,J＝7.5Hz,1H),7.54(t,J＝7.4Hz,2H),7.4 5(q,J＝8.2Hz,3H),7.35(s,1H),6.67(d,J＝8.3Hz,1H),4.40(s,2H),3.77–3.70( m,2H),3.37(q,J＝5.9Hz,2H),3.30(dd,J＝8.5,5.1Hz,1H),2.10–2.01(m,2H),1 .88(p,J＝6.4Hz,2H),1.77(m,2H),1.66(m,1H),1.44–1.30(m,2H),1.20(m,3H). 13C NMR(101MHz,Chloroform-d)δ169.67,141.22,132.36,131.56,128.21,123.71,122. 87,120.59,116.63,51.93,50.15,39.48,35.64,33.13,29.70,27.74,25.87,24.96.

15、3-氨基-4-(环己基氨基)-N-(4-(异吲哚啉-2-基)丁基)苯甲酰胺(化合物II-12)15. 3-Amino-4-(cyclohexylamino)-N-(4-(isoindoline-2-yl)butyl)benzamide (Compound II-12)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.85–7.80(m,1H),7.52(t,J＝7.4Hz,1H),7.44(t,J＝8.7Hz,2H),7.23(d,J＝8.7Hz,1H),6.61(d,J＝8.4Hz,1H),6.41(d,J＝5.5Hz,1H),4.37(s,2H),3.66(t,J＝7.1Hz,2H),3.47(q,J＝6.4Hz,2H),3.34–3.24(m,1H),2.04(d,J＝12.5Hz,2H),1.76(q,J＝6.1Hz,4H),1.65(q,J＝6.7Hz,3H),1.44–1.24(m,5H).13C NMR(101MHz,Chloroform-d)δ168.82,141.16,132.81,131.28,128.04,123.61,122.75,50.01,42.06,39.52,32.88,26.67,26.09,25.77,24.91。The synthesis method is the same as II-7. 1 H NMR(400MHz,Chloroform-d)δ7.85–7.80(m,1H),7.52(t,J＝7.4Hz,1H),7.44(t,J ＝8.7Hz,2H),7.23(d,J＝8.7Hz,1H),6.61(d,J＝8.4Hz,1H),6.41(d,J＝5.5Hz,1H),4 .37(s,2H),3.66(t,J＝7.1Hz,2H),3.47(q,J＝6.4Hz,2H),3.34–3.24(m,1H),2.04( d,J＝12.5Hz,2H),1.76(q,J＝6.1Hz,4H),1.65(q,J＝6.7Hz,3H),1.44–1.24(m,5H). 13 C NMR (101MHz, Chloroform-d) δ 168.82, 141.16, 132.81, 131.28, 128.04, 123.61, 122.75, 50.01, 42.06, 39.52, 32.88, 26.67, 26.09, 25.77, 24.91.

16、3-氨基-4-(环戊氨基)-N-(2-(异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-13)16. 3-Amino-4-(cyclopentanamino)-N-(2-(isoindoline-2-yl)ethyl)benzamide (Compound II-13)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.22(d,J＝4.6Hz,5H),6.84(s,1H),6.58(d,J＝8.2Hz,1H),4.05(s,4H),3.82–3.76(m,1H),3.65–3.59(m,2H),3.02(t,J＝5.8Hz,2H),2.03(m,2H),1.77–1.69(m,2H),1.66–1.57(m,2H),1.54–1.44(m,2H).13C NMR(101MHz,Chloroform-d)δ141.12,132.88,126.99,123.06,122.35,120.35,115.89,58.89,54.70,54.39,38.16,33.58,24.24。Synthesis method as in II-7. ¹H NMR (400MHz, Chloroform-d) δ 7.22 (d, J = 4.6Hz, 5H), 6.84 (s, 1H), 6.58 (d, J = 8.2Hz, 1H), 4.05 (s, 4H), 3.82–3.76 (m, 1H), 3.65–3.59 (m, 2H), 3.02 (t, J = 5.8Hz, 2H), 2.03 (m, 2H), 1.77–1.69 (m, 2H), 1.66–1.57 (m, 2H), 1.54–1.44 (m, 2H). 13 C NMR (101MHz, Chloroform-d) δ141.12,132.88,126.99,123.06,122.35,120.35,115.89,58.89,54.70,54.39,38.16,33.58,24.24.

17、3-氨基-4-(环庚氨基)-N-(2-(异吲哚啉-2-基)乙基)苯甲酰胺(化合物II-14)17. 3-Amino-4-(cycloheptaneamino)-N-(2-(isoindoline-2-yl)ethyl)benzamide (Compound II-14)

合成方法同II-7。1H NMR(500MHz,Chloroform-d)δ7.26–7.24(m,2H),7.21(s,3H),6.88(t,J＝5.1Hz,1H),6.47(d,J＝8.2Hz,1H),4.02(s,4H),3.64–3.59(m,2H),3.44(m,J＝8.5,6.3,3.7Hz,1H),2.99(t,J＝5.9Hz,2H),2.01–1.94(m,2H),1.71–1.46(m,11H).13C NMR(101MHz,Chloroform-d)δ166.23,139.46,137.84,130.53,125.10,121.67,121.34,119.49,115.20,109.14,59.69,54.33,52.41,36.65,33.24,27.26,23.99。Synthesis method as in II-7. ¹H NMR (500MHz, Chloroform-d) δ 7.26–7.24 (m, 2H), 7.21 (s, 3H), 6.88 (t, J = 5.1 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 4.02 (s, 4H), 3.64–3.59 (m, 2H), 3.44 (m, J = 8.5, 6.3, 3.7 Hz, 1H), 2.99 (t, J = 5.9 Hz, 2H), 2.01–1.94 (m, 2H), 1.71–1.46 (m, 11H). ¹³C NMR(101MHz,Chloroform-d)δ166.23,139.46,137.84,130.53,125.10,121.67,1 21.34,119.49,115.20,109.14,59.69,54.33,52.41,36.65,33.24,27.26,23.99.

18、3-氨基-N-(2-(异吲哚啉-2-基)乙基)-4-((四氢2H-吡喃-4-基)氨基)苯甲酰胺(化合物II-15)18. 3-Amino-N-(2-(isoindoline-2-yl)ethyl)-4-((tetrahydro-2H-pyran-4-yl)amino)benzamide (Compound II-15)

合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.23(d,J＝10.2Hz,5H),6.85(t,J＝4.1Hz,1H),6.57(d,J＝8.9Hz,1H),4.04(s,4H),3.99(m,2H),3.65–3.59(m,2H),3.51(m,3H),3.01(t,J＝5.8Hz,2H),2.07–1.97(m,2H),1.51(m,2H).13C NMR(101MHz,Chloroform-d)δ167.70,139.87,138.67,132.99,127.29,123.46,122.44,120.58,116.55,110.36,66.72,58.96,54.91,48.82,37.88,33.42。Synthesis method as in II-7. ¹H NMR (400MHz, Chloroform-d) δ 7.23 (d, J = 10.2 Hz, 5H), 6.85 (t, J = 4.1 Hz, 1H), 6.57 (d, J = 8.9 Hz, 1H), 4.04 (s, 4H), 3.99 (m, 2H), 3.65–3.59 (m, 2H), 3.51 (m, 3H), 3.01 (t, J = 5.8 Hz, 2H), 2.07–1.97 (m, 2H), 1.51 (m, 2H). 13 C NMR(101MHz,Chloroform-d)δ167.70,139.87,138.67,132.99,127.29,123.4 6,122.44,120.58,116.55,110.36,66.72,58.96,54.91,48.82,37.88,33.42.

19、N1-环己基-4-(3-(异吲哚啉-2-基)-3-甲基丁-1-炔-1-基)苯-1,2-二胺(化合物II-16)合成方法同II-7。1H NMR(400MHz,Chloroform-d)δ7.20(q,J＝5.0Hz,4H),6.71(dd,J＝7.9,1.9Hz,1H),6.65(s,1H),6.56(d,J＝7.9Hz,1H),4.20(s,4H),3.18(m,1H),2.06–1.97(m,2H),1.80–1.62(m,4H),1.59(s,6H),1.37(d,J＝12.5Hz,2H),1.25(d,J＝11.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ139.76,136.02,135.14,126.64,122.81,122.37,116.08,114.44,87.77,87.32,54.58,54.23,51.66,33.59,29.54,25.97,24.95。19. The synthesis method of N 1 -cyclohexyl-4-(3-(isoindoline-2-yl)-3-methylbut-1-yn-1-yl)phenyl-1,2-diamine (compound II-16) is the same as that of II-7. 1 H NMR(400MHz,Chloroform-d)δ7.20(q,J＝5.0Hz,4H),6.71(dd,J＝7.9,1.9Hz,1H),6.65(s,1H),6.56(d,J＝7.9Hz,1H),4.2 0(s,4H),3.18(m,1H),2.06–1.97(m,2H),1.80–1.62(m,4H),1.59(s,6H),1.37(d,J＝12.5Hz,2H),1.25(d,J＝11.1Hz,2H). 13C NMR(101MHz,Chloroform-d)δ139.76,136.02,135.14,126.64,122.81,122.37, 116.08,114.44,87.77,87.32,54.58,54.23,51.66,33.59,29.54,25.97,24.95.

实施例3：化合物的铁死亡抑制活性测试Example 3: Test of the compound's ferroptosis inhibitory activity

GPX4抑制剂如RSL-3能够诱导细胞发生铁死亡，这种铁死亡也可以被其他小分子物质阻断，如亲脂性抗氧化剂，如Ferrostatin-1(fer-1)、Liproxstatin等。因此，铁死亡抑制剂阻断铁死亡的能力可以通过对铁死亡诱导剂诱发的细胞铁死亡的逆转情况进行指示。GPX4 inhibitors, such as RSL-3, can induce ferroptosis in cells. This ferroptosis can be blocked by other small molecules, such as lipophilic antioxidants like Ferrostatin-1 (fer-1) and Liproxstatin. Therefore, the ability of ferroptosis inhibitors to block ferroptosis can be indicated by the reversal of ferroptosis induced by ferroptosis inducers.

细胞株：人神经母细胞瘤细胞SH-SY5Y，人纤维肉瘤细胞HT1080和小鼠海马神经元细胞购自中国科学院上海细胞库。Cell lines: Human neuroblastoma cells SH-SY5Y, human fibrosarcoma cells HT1080, and mouse hippocampal neurons were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

方法：MTT法，具体如下：取对数生长期的人肾癌细胞株SH-SY5Y/HT1080/HT22，消化收集并稀释，以每孔约为4000-5000个细胞种于96孔板，实验设3个复孔，每孔80μL。置于37℃、5％CO2培养箱中培养过夜。实验分别设DMSO对照组和九个不同浓度的化合物给药组。给药组加入不同浓度的化合物，并设置DMSO对照组(与最高浓度化合物的稀释倍数相同)，置5％CO2、37℃的培养箱中继续孵育1h后，每个化合物浓度均加入浓度为5μM/100nM/100nM RSL3诱导铁死亡，并设置RSL3对照组和DMSO对照组，置5％CO2、37℃的培养箱中继续孵育48h。每孔加入5mg/mL的20μL MTT溶液，继续于37℃培养箱中培养细胞2h，每孔加入100μL DMSO，平稳振荡10min，混匀。置于酶联免疫法检测仪上，在570nm波长下检测每孔光密度值(OD值)，实验重复3次。按照下列公式计算：存活率％＝实验组OD值/DMSO对照组OD值×100％。Methods: The MTT assay was used, specifically as follows: Human renal cell carcinoma cell lines SH-SY5Y/HT1080/HT22 in logarithmic growth phase were digested, collected, and diluted. Approximately 4000-5000 cells per well were seeded into 96-well plates, with three replicates and 80 μL per well. The plates were incubated overnight at 37°C and 5% CO2 . The experiment included a DMSO control group and nine different concentrations of the compound treatment groups. Different concentrations of the compound were added to each treatment group, and a DMSO control group (diluted to the highest concentration compound) was set up. After incubation for 1 hour at 37 °C and 5% CO2, ferroptosis was induced by adding 5 μM/100 nM/100 nM RSL3 to each compound concentration. RSL3 and DMSO control groups were also set up. The plates were incubated for another 48 hours at 37°C and 5% CO2 . Add 20 μL of 5 mg/mL MTT solution to each well and incubate the cells at 37°C for 2 hours. Then add 100 μL of DMSO to each well, shake gently for 10 minutes, and mix thoroughly. Measure the optical density (OD value) of each well at 570 nm using an ELISA reader. Repeat the experiment three times. Calculate the survival rate (%) using the following formula: Survival rate % = (OD value of experimental group / OD value of DMSO control group) × 100%.

结果参见表1，说明本发明的多种化合物能够明显抑制铁死亡，具有良好的铁死亡抑制活性。The results are shown in Table 1, indicating that the various compounds of the present invention can significantly inhibit ferroptosis and have good ferroptosis inhibitory activity.

表1化合物对RSL3诱导的SH-SY5Y细胞铁死亡的抑制活性
Table 1. Inhibitory activity of compounds against RSL3-induced ferroptosis in SH-SY5Y cells.

表中：“A”指示IC50≤0.1μM，“B”指示IC50>0.1μM且≤0.5μM。In the table: "A" indicates IC 50 ≤ 0.1μM, and "B" indicates IC 50 > 0.1μM and ≤ 0.5μM.

表2化合物对RSL3诱导的HT1080细胞铁死亡的抑制活性
Table 2. Inhibitory activity of compounds against RSL3-induced ferroptosis in HT1080 cells.

表3化合物对RSL3诱导的HT22细胞铁死亡的抑制活性
Table 3. Inhibitory activity of compounds against RSL3-induced ferroptosis in HT22 cells.

实施例4：化合物的Sigma受体亲和力测试Example 4: Sigma receptor affinity test of the compound

研究表示，Sigma受体抑制剂通常可以和Sigma受体表现出较强的亲和力，进而发挥相应的药理作用。放射性竞争实验由上海药明康德新药开发有限公司测试，具体步骤如下：(1)将1μl稀释的参考化合物和测试化合物转移到检测板中。加1μl非特异性结合化合物转移到检测板中作为对照。另外将1μl的二甲基亚砜转移到检测板中，以检测总结合力。(2)将100μL的膜原液加入到检测板中。(3)加入100μL放射配体。(4)密封平板，在规定条件下以300rpm的转速摇动平板。(5)在室温下，用0.3％的PEI浸泡Unifilter-96GF/C过滤板至少0.5小时。(6)完成结合测定后，使用Perkin Elmer Filtermate Harvester将混合物过滤到GF/B板中，然后用冷的洗涤缓冲液洗涤6次。(7)将过滤板在50℃下干燥1小时。(8)干燥后，用背封胶带密封滤板孔底。加入50μl Perkin Elmer Microscint 20cocktail，并用密封膜密封滤板顶部。(9)使用Perkin Elmer MicroBeta2读数仪对过滤器上截留的[3H]DTG进行计数。(10)计算化合物的亲和力。Studies have shown that Sigma receptor inhibitors typically exhibit strong affinity for Sigma receptors, thereby exerting corresponding pharmacological effects. The radioactivity competition experiment was conducted by Shanghai WuXi AppTec New Drug Development Co., Ltd., and the specific steps are as follows: (1) Transfer 1 μl of diluted reference compound and test compound to the detection plate. Add 1 μl of non-specific binding compound to the detection plate as a control. In addition, transfer 1 μl of dimethyl sulfoxide to the detection plate to detect the total binding force. (2) Add 100 μL of membrane stock solution to the detection plate. (3) Add 100 μL of radioligand. (4) Seal the plate and shake it at 300 rpm under specified conditions. (5) Soak the Unifilter-96GF/C filter plate in 0.3% PEI for at least 0.5 hours at room temperature. (6) After completing the binding assay, filter the mixture into the GF/B plate using a Perkin Elmer Filtermate Harvester and then wash it 6 times with cold washing buffer. (7) Dry the filter plate at 50°C for 1 hour. (8) After drying, seal the bottom of the filter plate pores with back sealing tape. Add 50 μl of Perkin Elmer Microscint 20 cocktail and seal the top of the filter plate with a sealing film. (9) Count the [ 3H ]DTG retained on the filter using a Perkin Elmer MicroBeta2 reader. (10) Calculate the affinity of the compound.

表4化合物对Sigma1/2(σ1/2)的亲和力

Table 4. Affinity of compounds to Sigma1/2 (σ1 /2 ).

表中：“A”指示IC50≤0.1μM，“B”指示IC50>0.1μM且≤0.5μM，“C”指示IC50>0.5μM且≤2μM，“D”指示IC50>2μM。In the table: "A" indicates IC 50 ≤ 0.1μM, "B" indicates IC 50 > 0.1μM and ≤ 0.5μM, "C" indicates IC 50 > 0.5μM and ≤ 2μM, and "D" indicates IC 50 > 2μM.

实施例5：化合物能抑制体外的Aβ1-42单体聚合成多聚体Example 5: The compound can inhibit the polymerization of Aβ1-42 monomers into polymers in vitro.

阿尔兹海默症是最普遍的神经退行性疾病，主要病理学特征之一是细胞外老年斑中β-淀粉样蛋白的沉积。。此外大量研究表明，许多金属离子(主要是Cu2+，Zn2+以及Fe2+)的水平在AD患者的脑中远高于正常人，并且富集在AD患者老年斑中，最终导致金属离子稳态失衡。Alzheimer's disease is the most common neurodegenerative disease, and one of its main pathological features is the deposition of β-amyloid protein in extracellular senile plaques. Furthermore, numerous studies have shown that the levels of many metal ions (mainly Cu²⁺ , Zn²⁺ , and Fe²⁺ ) in the brains of AD patients are significantly higher than in normal individuals, and they accumulate in the senile plaques of AD patients, ultimately leading to an imbalance in metal ion homeostasis.

Aβ1-42单体的制备：首先将Aβ1-42粉末从-70℃冰箱中拿出，并在室温下放置约30min解冻。称取一定量的Aβ1-42并溶解于六氟异丙醇中，终浓度为1mg/mL，再将该溶液在室温下静置2h，待溶液澄清后，冰浴条件下超声30min，以除去可能存在的Aβ1-42聚集体。然后将样品在-70℃冰箱中冷冻4h以上冻实，再将样品在冷冻干燥机中冻干，24h后取出，得到絮状蓬松的Aβ1-42单体，并将其保存于-20℃冰箱中保存备用。Preparation of Aβ 1-42 monomer: First, the Aβ 1-42 powder was removed from the -70℃ freezer and thawed at room temperature for about 30 minutes. A certain amount of Aβ 1-42 was weighed and dissolved in hexafluoroisopropanol to a final concentration of 1 mg/mL. The solution was then allowed to stand at room temperature for 2 hours until it became clear. After that, it was sonicated in an ice bath for 30 minutes to remove any possible Aβ 1-42 aggregates. The sample was then frozen solid at -70℃ for at least 4 hours, and then freeze-dried in a freeze dryer. After 24 hours, the sample was removed to obtain flocculent and fluffy Aβ 1-42 monomer, which was stored at -20℃ for later use.

ThT荧光实验：硫黄素T(Thioflavin T，ThT)作为荧光染料分子能与Aβ1-42纤维中的β-折叠结构特异性结合，进而在440nm激发光波作用下，在480nm出现吸收峰，可用于检测Aβ1-42的聚集情况。实验前，将Aβ1-42单体与RTH在不同比例下混合，始终保持Aβ1-42终浓度为25μM。混合后的样品在空气摇床中培养(37℃)。培养24h后，吸取200μl样品，加入到2mL ThT溶液(25μM ThT，20mM HEPES，pH 7.4)中，充分混合后在荧光分光光度计中测定ThT荧光强度。仪器参数如下：激发波长440nm，发射波长480nm，激发带宽和发射带宽均为5nm。每个实验点重复三次取平均值，并计算标准方差。ThT fluorescence experiment: Thioflavin T (ThT), as a fluorescent dye molecule, can specifically bind to the β-sheet structure in Aβ 1-42 fibers, thus exhibiting an absorption peak at 480 nm under 440 nm excitation light, which can be used to detect the aggregation of Aβ 1-42 . Before the experiment, Aβ 1-42 monomers were mixed with RTH in different proportions, always maintaining a final Aβ 1-42 concentration of 25 μM. The mixed samples were incubated in an air shaker (37℃). After 24 h of incubation, 200 μl of sample was added to 2 mL of ThT solution (25 μM ThT, 20 mM HEPES, pH 7.4), thoroughly mixed, and the ThT fluorescence intensity was measured in a fluorescence spectrophotometer. The instrument parameters were as follows: excitation wavelength 440 nm, emission wavelength 480 nm, excitation bandwidth and emission bandwidth both 5 nm. Each experimental point was repeated three times, the average value was taken, and the standard deviation was calculated.

以上实施例仅用于说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions claimed by the present invention.

Claims (10)

一种芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂，其特征在于，所述芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂具有如下所示的结构式：
An aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor, characterized in that the aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor has the following structural formula:
式中，R1选自氢、烷基、芳基、C1到C6烷基-芳基、C1到C6烷基-酚基或C3～C10环烷基；In the formula, R1 is selected from hydrogen, alkyl, aryl, C1 to C6 alkyl-aryl, C1 to C6 alkyl-phenolic or C3 to C10 cycloalkyl; R2选自C0～C8烷基、C3～C12环烷基、金刚烷基或多炔基； R2 is selected from C0 - C8 alkyl, C3 - C12 cycloalkyl, adamantyl, or polyynyl; Linker选自直接键、C1-C6烷基或含1-3个独立取代基的C1-C6烷基、C2-C6烯基或含1-3个独立取代基的C2-C6烯基、C0到C6烷基-C3到C6环烷基-C0到C6烷基或含1-3个独立取代基的C0到C6烷基-C3到C6环烷基-C0到C6烷基、C0到C6烷基-Z-C0到C6烷基或含1-3个独立取代基的C0到C6烷基-Z-C0到C6烷基；其中，Z选自N、NRa、-SO2-、OC、OC＝O、CO或C＝OO；Linker is selected from direct bond, C1 - C6 alkyl or C1-C6 alkyl containing 1-3 independent substituents, C2 - C6 alkenyl or C2 - C6 alkenyl containing 1-3 independent substituents, C0 to C6 alkyl - C3 to C6 cycloalkyl- C0 to C6 alkyl or C0 to C6 alkyl- C3 to C6 cycloalkyl- C0 to C6 alkyl containing 1-3 independent substituents, C0 to C6 alkyl-ZC0 to C6 alkyl or C0 to C6 alkyl- ZC0 to C6 alkyl containing 1-3 independent substituents; wherein Z is selected from N, NRa , -SO2- , OC, OC=O, CO or C = OO; 当A环存在为芳香环时，R3，R4，R5和R6均选自H、C1-C6烷基、OH、OCH3、OCH(CH3)2、OCH2CH(CH3)2、OC(CH3)3、O(C1-C6烷基)、OCF3、OCH2CH2OH、O(C1-C6烷基)OH、F、Cl、Br、I、CF3、CN、NO2、NH2、C1-C6杂烷基、C1-C6羟基烷基、Ci-C6烷氧基、C1-C6烷基、芳基、芳杂基、C3-C7环烷基、杂环烷基、烷基芳基、CO2Ra、C(O)Ra、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(C3-C7环烷基)、NHC(O)(C1-C4烷基)、CONRa,NC(O)Ra、NS(O)1/2Ra、S(O)1/2NRa、S(O)1/2R、C(O)O(C1-C4烷基)、OC(O)N(Ra)2、C(O)(C1-C4烷基)或C(O)NH(C1-C4烷基)；其中R3，R4，R5和R6为上述取代基之一，或R3，R4，R5，R6中其中两个、三个或四个同时选自上述取代基；When ring A is an aromatic ring, R3 , R4 , R5 , and R6 are all selected from H , C1 - C6 alkyl, OH, OCH3 , OCH( CH3 ) 2 , OCH2CH (CH3) 2 , OC( CH3 ) 3 , O (C1-C6 alkyl), OCF3 , OCH2CH2OH , O( C1 - C6 alkyl)OH, F, Cl, Br, I, CF3 , CN, NO2 , NH2 , C1 - C6 heteroalkyl, C1 - C6 hydroxyalkyl, Ci - C6 alkoxy, C1 - C6 alkyl, aryl, aromatic heteroalkyl, C3 - C7 cycloalkyl, heterocyclic alkyl, alkylaryl , CO2Ra , C(O) Ra , NH ( C1 - C4 alkyl), N( C1 -C6 alkyl) 4 -alkyl) 2 , NH ( C3 - C7 cycloalkyl), NHC(O) ( C1 - C4 alkyl), CONR a , NC(O) Ra , NS(O) 1/2 Ra , S(O) 1/2 NR a , S(O) 1/2 R, C(O)O ( C1 - C4 alkyl), OC(O)N( Ra ) 2 , C(O) ( C1 - C4 alkyl) or C(O)NH ( C1 - C4 alkyl); wherein R3 , R4 , R5 and R6 are one of the above substituents, or two, three or four of R3 , R4 , R5 and R6 are simultaneously selected from the above substituents; 当A环不存在时，X选自CH2、O、S、NH、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(C3-C7环烷基)、NHC(O)(C1-C4烷基)、NC(O)Ra、NS(O)1/2Ra；When ring A is absent, X is selected from CH2 , O, S, NH, NH ( C1 - C4 alkyl), N ( C1 - C4 alkyl) 2 , NH ( C3 - C7 cycloalkyl), NHC(O)( C1 - C4 alkyl), NC(O) Ra , NS(O) 1/ 2Ra ; m，n为碳原子的个数，为0，1或2；m and n are the number of carbon atoms, which can be 0, 1, or 2; Ra选自H、CH3、CH2CH3、C3-C6烷基、C1-C6卤代烷基或任选取代的芳基、烷芳基、哌嗪基、哌啶基、吗啉基、杂环烷基、杂芳基、C1-C6烷氧基、NH(C1-C4烷基)和N(C1-C4烷基)2，其中任选取代的基团选自C1-C6烷基或C2-C7丙烯酸基； Ra is selected from H, CH3 , CH2CH3 , C3 - C6 alkyl , C1-C6 haloalkyl or optionally substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocyclic alkyl, heteroaryl, C1 - C6 alkoxy, NH ( C1 -C4 alkyl) and N (C1-C4 alkyl)2 , wherein the optionally substituted group is selected from C1-C6 alkyl or C2 - C7 acrylate ; 其中，C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烷氧基、苯基、苄基、萘基、C5-C10芳香性杂环基、C3-C7饱和杂环基、C3～C12环烷基、多炔基、芳基、C1-C6烷基-芳基、C1-C6烷基-酚基或C3～C10环烷基能够被一个或多个原子或基团取代。Among them, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 ynyl, C3- C8 cycloalkyl, C3 - C8 cycloalkoxy, phenyl, benzyl, naphthyl, C5 - C10 aromatic heterocyclic, C3 - C7 saturated heterocyclic, C3 - C12 cycloalkyl, polyynyl, aryl, C1-C6 alkyl - aryl, C1 - C6 alkyl-phenolic, or C3 - C10 cycloalkyl can be substituted by one or more atoms or groups. 根据权利要求1所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂，其特征在于，所述抑制剂为化合物I-1～I-22、II-1～II-17，其结构式具体如下：


According to claim 1, the aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor is characterized in that the inhibitor is compounds I-1 to I-22, II-1 to II-17, whose structural formulas are as follows:


权利要求2所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，其特征在于，所述制备方法包括以下步骤：The method for preparing the aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor according to claim 2 is characterized in that the preparation method comprises the following steps: 所述化合物I-1～I-22的合成如下：以4-氯-3-硝基苯甲醛为原料，经硼氢化钠还原得到化合物2，随后和相应的胺发生取代反应得到化合物3；化合物3经PCC氧化得到化合物4，其和丙酮在碱性条件下发生羟醛缩合反应得到化合物5；经硼氢化钠还原化合物5的双键及羰基得到化合物6，之后经氢气还原硝基得到关键中间体7；通过(Boc)2O保护氨基得到相应的化合物8；其和CBr4在PPh3存在下发生卤代反应得到化合物9；化合物10由化合物9和相应的芳香胺或脂肪胺经取代反应得到，随后脱掉Boc保护基可得到化合物I-1～I-22；
The synthesis of compounds I-1 to I-22 is as follows: 4-chloro-3-nitrobenzaldehyde was used as a starting material, reduced with sodium borohydride to obtain compound 2, which then underwent a substitution reaction with the corresponding amine to obtain compound 3; compound 3 was oxidized with PCC to obtain compound 4, which underwent an aldol condensation reaction with acetone under alkaline conditions to obtain compound 5; the double bond and carbonyl group of compound 5 were reduced with sodium borohydride to obtain compound 6, followed by hydrogen reduction of the nitro group to obtain the key intermediate 7; the amino group was protected by (Boc) ₂O to obtain the corresponding compound 8; it underwent a halogenation reaction with CBr₄ in the presence of PPh₃ to obtain compound 9; compound 10 was obtained by substitution reaction of compound 9 with the corresponding aromatic or aliphatic amine, followed by removal of the Boc protecting group to obtain compounds I-1 to I-22.
试剂及反应条件：(a)硼氢化钠，甲醇；(b)环己胺，碳酸钾，DMSO；(c)PCC,氯仿；(d)丙酮，氢氧化钠；(e)硼氢化钠，甲醇；(f)Pd/C,氢气，甲醇；(g)(Boc)2O,三乙胺，四氢呋喃；(h)四溴化碳，三苯基膦，二氯甲烷；(i)相应的胺，碳酸钾，碘化钾，DMF；(j)i：HCl/CH3CH2OH；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷。Reagents and reaction conditions: (a) Sodium borohydride, methanol; (b) Cyclohexylamine, potassium carbonate, DMSO; (c) PCC, chloroform; (d) Acetone, sodium hydroxide; (e) Sodium borohydride, methanol; (f) Pd/C, hydrogen, methanol; (g) (Boc) ₂O , triethylamine, tetrahydrofuran; (h) Carbon tetrabromide, triphenylphosphine, dichloromethane; (i) The corresponding amine, potassium carbonate, potassium iodide, DMF; (j) i: HCl/ CH₃CH₂OH ; ii: The corresponding aldehyde, sodium triacetoxyborohydride , dichloromethane. 权利要求2所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，其特征在于，所述制备方法包括以下步骤：The method for preparing the aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor according to claim 2 is characterized in that the preparation method comprises the following steps: 所述化合物II-1～II-5，II-16和II-17的合成如下：化合物11在AIBN催化下，和NBS发生自由基取代反应得到化合物12，之后和2-甲基丁-3-炔-2-胺发生亲和取代反应得到关键中间体13；化合物13和相应的芳基卤代化合物在Pd(PPh3)2Cl2和CuI催化下发生偶联反应得到关键中间体化合物14；化合物II-16/17是由化合物14经锌粉还原得到，而化合物II-1～II-5则需要再氢气条件下进一步还原得到；
The synthesis of compounds II-1 to II-5, II-16, and II-17 is as follows: Compound 11 undergoes a radical substitution reaction with NBS under AIBN catalysis to give compound 12, which then undergoes an affinity substitution reaction with 2-methylbut-3-yn-2-amine to give key intermediate 13; Compound 13 and the corresponding aryl halide undergo a coupling reaction under Pd( PPh3 ) 2Cl2 and CuI catalysis to give key intermediate compound 14; Compounds II-16/17 are obtained by reducing compound 14 with zinc powder, while compounds II-1 to II-5 require further reduction under hydrogen conditions;
试剂及反应条件：(k)NBS,AIBN,氯仿，回流；(l)2-甲基丁-3-炔-2-胺，碳酸钾，四氢呋喃，60℃；(m)4-溴-N-环己基-2-硝基苯胺，Pd(PPh3)2Cl2，碘化亚铜，三乙胺；(n)i:锌粉，盐酸，甲醇；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷；(o)Pd/C，氢气，甲醇。Reagents and reaction conditions: (k) NBS, AIBN, chloroform, reflux; (l) 2-methylbut-3-yn-2-amine, potassium carbonate, tetrahydrofuran, 60℃; (m) 4-bromo-N-cyclohexyl-2- nitroaniline , Pd( PPh3 ) 2Cl2 , cuprous iodide, triethylamine; (n) i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane; (o) Pd/C, hydrogen, methanol. 权利要求2所述的芳香烷胺类铁死亡和/或Sigma受体双功能抑制剂的制备方法，其特征在于，所述制备方法包括以下步骤：The method for preparing the aromatic alkylamine ferroptosis and/or Sigma receptor bifunctional inhibitor according to claim 2 is characterized in that the preparation method comprises the following steps: 所述化合物II-4～II-15的合成如下：以4-氯-3-硝基苯甲酸为起始原料，和相应的胺基片段发生缩合反应得到化合物16，之后和胺基衍生物进行亲核取代反应得到化合物17，脱掉Boc保护基后得到中间体18，化合物18和相应的溴代化合物发生亲核取代得到关键中间体19，进一步经锌粉还原得到目标化合物II-4～II-15；
The synthesis of compounds II-4 to II-15 is as follows: 4-chloro-3-nitrobenzoic acid is used as the starting material, and a condensation reaction is carried out with the corresponding amino fragment to obtain compound 16. Then, a nucleophilic substitution reaction is carried out with the amino derivative to obtain compound 17. After removing the Boc protecting group, intermediate 18 is obtained. Compound 18 undergoes nucleophilic substitution with the corresponding brominated compound to obtain key intermediate 19. Further reduction with zinc powder yields the target compounds II-4 to II-15.
试剂及反应条件：(p)i：氯化亚砜，二氯甲烷，DMF；ii：(2-氨基乙基)氨基甲酸叔丁酯，三乙胺，二氯甲烷；(q)环己胺，碳酸钾，DMF；(r)三氟乙酸，二氯甲烷；(s)1,2-双(溴甲基)苯，碳酸钾，四氢呋喃；(t)i:锌粉，盐酸，甲醇；ii：相应的醛，三乙酰氧基硼氢化钠，二氯甲烷。Reagents and reaction conditions: (p)i: thionyl chloride, dichloromethane, DMF; ii: tert-butyl (2-aminoethyl)carbamate, triethylamine, dichloromethane; (q) cyclohexylamine, potassium carbonate, DMF; (r) trifluoroacetic acid, dichloromethane; (s) 1,2-bis(bromomethyl)benzene, potassium carbonate, tetrahydrofuran; (t)i: zinc powder, hydrochloric acid, methanol; ii: the corresponding aldehyde, sodium triacetoxyborohydride, dichloromethane. 权利要求1或2所述的抑制剂在制备铁死亡抑制剂和/或Sigma受体抑制剂中的应用。The use of the inhibitor according to claim 1 or 2 in the preparation of ferroptosis inhibitors and/or Sigma receptor inhibitors. 权利要求1或2所述的抑制剂在制备治疗铁死亡相关疾病和/或Sigma受体相关疾病的药物中的应用。The use of the inhibitor according to claim 1 or 2 in the preparation of a medicament for treating ferroptosis-related diseases and/or Sigma receptor-related diseases. 根据权利要求7所述的应用，其特征在于，所述铁死亡相关疾病包括神经退行性、组织缺血再灌注损伤、脑卒中、心血管、肝肾衰竭、炎症、糖尿病并发症。According to the application of claim 7, the iron death-related diseases include neurodegeneration, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, liver and kidney failure, inflammation, and diabetic complications. 根据权利要求7所述的应用，其特征在于，所述Sigma受体相关疾病包括阿尔茨海默病、帕金森病、脑卒中、药物成瘾、神经性疼痛、精神分裂和抑郁症。According to the application of claim 7, the Sigma receptor-related diseases include Alzheimer's disease, Parkinson's disease, stroke, drug addiction, neuropathic pain, schizophrenia, and depression. 一种用于治疗铁死亡和/或Sigma受体相关疾病的药物，其特征在于，所述药物含有权利要求1或2所述的化合物和药物学上可接受的盐、载体或助剂。A medicament for treating ferroptosis and/or Sigma receptor-related diseases, characterized in that the medicament contains the compound of claim 1 or 2 and a pharmaceutically acceptable salt, carrier, or adjuvant.
PCT/CN2025/090581 2024-04-28 2025-04-23 Bifunctional aromatic alkylamine inhibitor for ferroptosis and/or sigma receptors, and preparation method therefor and use thereof Pending WO2025228196A1 (en)

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