CN110256305B - 一种萘磺酰胺类化合物、制备方法和应用 - Google Patents

一种萘磺酰胺类化合物、制备方法和应用 Download PDF

Info

Publication number
CN110256305B
CN110256305B CN201910673326.3A CN201910673326A CN110256305B CN 110256305 B CN110256305 B CN 110256305B CN 201910673326 A CN201910673326 A CN 201910673326A CN 110256305 B CN110256305 B CN 110256305B
Authority
CN
China
Prior art keywords
compound
synthesis
ddo
amino
esi
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.)
Active
Application number
CN201910673326.3A
Other languages
English (en)
Other versions
CN110256305A (zh
Inventor
尤启冬
姜正羽
刘雨亭
陆朦辰
邵红丽
赵静
徐晓莉
郭小可
王磊
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.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201910673326.3A priority Critical patent/CN110256305B/zh
Publication of CN110256305A publication Critical patent/CN110256305A/zh
Priority to KR1020227001409A priority patent/KR20220027958A/ko
Priority to EP20843918.2A priority patent/EP3978471B1/en
Priority to AU2020317159A priority patent/AU2020317159B2/en
Priority to PCT/CN2020/084460 priority patent/WO2021012721A1/zh
Priority to US17/626,505 priority patent/US11773057B2/en
Priority to CA3147319A priority patent/CA3147319C/en
Priority to JP2022502268A priority patent/JP7301433B2/ja
Application granted granted Critical
Publication of CN110256305B publication Critical patent/CN110256305B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Vascular Medicine (AREA)
  • Psychology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种萘磺酰胺类化合物、制备方法和应用。本发明提供的萘磺酰胺类化合物可以干扰Keap1‑Nrf2结合，激活Nrf2，从而减轻炎性损伤，改善炎症微环境，具有潜在的抗炎活性，可用于制备成抗炎药物用于众多炎症相关疾病的炎性损伤，这些疾病包括慢性阻塞性肺疾病(COPD)、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病(CKD)、糖尿病、肠部炎症、类风湿性关节炎等。

Description

一种萘磺酰胺类化合物、制备方法和应用
技术领域
本发明属于药物化学领域，具体涉及一种萘磺酰胺类化合物、制备方法和应用。
背景技术
氧气(O2)对细胞能量代谢和生命系统至关重要，但在这些代谢过程会产生活性氧(ROS)，ROS在癌症、炎性疾病和神经退行性疾病的发生和发展中起主要作用。由解毒酶和抗氧化酶组成的抗氧化防御系统可以减弱ROS的破坏作用，如超氧化物歧化酶(SOD)、谷胱甘肽过氧化氢酶(GPx)、硫氧还蛋白、HO-1、铁蛋白、谷胱甘肽还原酶、NAD(P)H脱氢酶(NQO1)和谷胱甘肽S转移酶(GST)。抗氧化酶通过抗氧化反应元件(ARE)调节，核因子E2相关因子2(Nrf2)是主要的ARE结合转录因子之一。先前的研究已经证实了Nrf2对氧化应激的保护作用，这使得上调Nrf2活性成为一种有前景的治疗策略，特别是针对炎症和中枢神经系统(CNS)疾病。在非应激条件下，Nrf2的细胞浓度很低，其受底物调节蛋白Kelch样环氧氯丙烷相关蛋白1(Keap1)的负调控，后者与胞质中的Nrf2结合并靶向运送至蛋白酶体中进行泛素化降解。在氧化应激状态下，Keap1充当氧化还原传感器和调节剂，活性氧化剂修饰特定Keap1半胱氨酸残基上的巯基(即Cys151、Cys257、Cys273、Cys288和Cys297)，Keap1的构象发生改变，扰乱Keap1-Nrf2蛋白-蛋白相互作用(PPI)从而阻断Nrf2泛素化的过程。进而Nrf2积聚并转移到细胞核中形成转录因子复合物，结合ARE启动子区域并诱导抗氧化酶的基因表达。因此，Keap1-Nrf2 PPI抑制剂可作为在氧化应激状态下提高抗氧化能力的一种治疗手段。
通过大量文献调研发现，Keap1-Nrf2 PPI抑制剂激活Nrf2从而对抗炎症、神经退行性疾病、呼吸系统疾病等具有巨大的治疗潜力。前期对共价修饰Keap1的抑制剂研究成果较多，并已有药物上市(富马酸二甲酯)，但该类药物缺乏选择性，且具有潜在毒性。与之相比，Keap1-Nrf2 PPI抑制剂由于具有靶向明确、不易脱靶且竞争性结合可逆等优点，现已成为该领域的研究热点。在Keap1-Nrf2 PPI抑制剂中，小分子PPI抑制剂具有成本较低、化学性稳定、生物利用度好等成药性优势，目前已成为研究主流方向。
作为Keap1-Nrf2 PPI小分子抑制剂，本课题组前期研究得到化合物DDO-1002(化学结构如下)为活性最优化合物，其对Keap1亲和力较高，但双羧基的存在导致分子极性较大，不利于透膜，导致其细胞活性较差。本课题组采取破除其对称结构、去除一侧磺酰胺结构等一系列降低分子极性表面积的策略设计合成了一系列含β氨基酸结构的萘磺酰胺类Keap1-Nrf2PPI小分子抑制剂，其中DDO-1146(化学结构如下)活性较优，但其与DDO-1002仍存在很大差距，同时，由于双羧基的存在，分子极性仍较大。因此，本课题以DDO-1146为先导化合物，采用基于结构的药物设计策略和系统的构效关系研究，设计合成具有高活性、理化性质改善的Keap1-Nrf2 PPI抑制剂，丰富Keap1-Nrf2 PPI抑制剂的结构类型，为靶向Keap1-Nrf2PPI提供更多选择。
Figure BDA0002142422810000011
为此，特提出本发明。
发明内容
本发明的目的在于克服现有技术的不足，提供一种萘磺酰胺类化合物、制备方法和应用。
本发明上述目的通过如下技术方案实现：
一种萘磺酰胺类化合物，化学结构如通式Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ或Ⅵ所示：
Figure BDA0002142422810000021
其中，通式Ⅰ或Ⅱ中，取代基R为：
Figure BDA0002142422810000022
我们采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物DDO-1160～DDO-1179进行靶标活性测试，结果如下表所示：
Figure BDA0002142422810000023
Figure BDA0002142422810000024
其中，通式Ⅲ或Ⅳ中，取代基R为：
Figure BDA0002142422810000025
Figure BDA0002142422810000031
我们采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物DDO-1186～DDO-1209进行靶标活性测试，结果如下表所示：
Figure BDA0002142422810000032
Figure BDA0002142422810000033
其中，通式Ⅴ或Ⅵ中，取代基R为：
Figure BDA0002142422810000034
我们采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物DDO-1210～DDO-1223进行靶标活性测试，结果如下表所示：
Figure BDA0002142422810000041
一种制备通式Ⅰ或Ⅱ所示化合物的方法，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯盐酸盐经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与溴化苄在K2CO3和NaI作用下反应得到中间体23；中间体23用三氟乙酸脱Boc后得到中间体24，中间体24与4-甲氧基苯磺酰氯反应得到关键中间体25；中间体25K2CO3作用下与溴乙酸甲酯反应得到化合物26，化合物26在LiOH的作用下脱甲酯得到通式Ⅱ双酸化合物，或中间体25在LiOH的作用下脱甲酯得到通式Ⅰ单酸化合物；合成路线如下：
Figure BDA0002142422810000042
合成路线中反应参数：(a)tBu-COOH,KOH,DMSO/H2O,r.t.4h；(b)Tf2O,Et3N,DCM,r.t.2h；(c)Pd2(dba)3,BINAP,Cs2CO3,DIPEA,dioxane,100℃,20h；(d)H2,Pd/C,THF,r.t.4-6h；(e)Boc2O,EtOH,8h；(f)K2CO3,,NaI,DMF,100℃,24h；(g)CF3COOH,DCM,r.t.2h；(h)Py,THF,70℃,4h；(i)K2CO3,DMF,r.t.2h；(j)LiOH,MeOH/H2O,r.t.10h.
一种制备通式Ⅲ或Ⅳ所示化合物的方法，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯盐酸盐经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与溴丙炔在K2CO3和NaI作用下反应得到中间体35；中间体35用三氟乙酸脱Boc后得到中间体36，中间体36与不同取代基的苯磺酰氯反应得到关键中间体37；中间体37K2CO3作用下与溴乙酸甲酯反应得到化合物38，化合物38在LiOH的作用下脱甲酯得到通式Ⅳ双酸化合物，或中间体37在LiOH的作用下脱甲酯得到通式Ⅲ单酸化合物；合成路线如下：
Figure BDA0002142422810000051
合成路线中反应参数：(a)tBu-COOH,KOH,DMSO/H2O,r.t.4h；(b)Tf2O,Et3N,DCM,r.t.2h；(c)Pd2(dba)3,BINAP,Cs2CO3,DIPEA,dioxane,100℃,20h；(d)H2,Pd/C,THF,r.t.4-6h；(e)Boc2O,EtOH,8h；(f)K2CO3,,NaI,DMF,100℃,24h；(g)CF3COOH,DCM,r.t.2h；(h)Py,THF,70℃,4h；(i)K2CO3,DMF,r.t.2h；(j)LiOH,MeOH/H2O,r.t.10h.
一种制备通式Ⅴ或Ⅵ所示化合物的方法，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯盐酸盐经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与溴丙炔在K2CO3和NaI作用下反应得到中间体35；中间体35用三氟乙酸脱Boc后得到中间体36，中间体36与不同取代基的4-甲氧基苯磺酰氯反应得到关键中间体39；中间体39K2CO3作用下与溴乙酸甲酯反应得到化合物40，化合物40在LiOH的作用下脱甲酯得到通式Ⅵ双酸化合物，或中间体39在LiOH的作用下脱甲酯得到通式Ⅴ单酸化合物；合成路线如下：
Figure BDA0002142422810000052
合成路线中反应参数：(a)tBu-COOH,KOH,DMSO/H2O,r.t.4h；(b)Tf2O,Et3N,DCM,r.t.2h；(c)Pd2(dba)3,BINAP,Cs2CO3,DIPEA,dioxane,100℃,20h；(d)H2,Pd/C,THF,r.t.4-6h；(e)Boc2O,EtOH,8h；(f)K2CO3,,NaI,DMF,100℃,24h；(g)CF3COOH,DCM,r.t.2h；(h)Py,THF,70℃,4h；(i)K2CO3,DMF,r.t.2h；(j)LiOH,MeOH/H2O,r.t.10h.
上述萘磺酰胺类化合物的药学上可以接受的盐。
上述萘磺酰胺类化合物及其药学上可以接受的盐用于制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂的用途。
上述萘磺酰胺类化合物及其药学上可以接受的盐用于制备氧化应激状态下提高抗氧化能力的药物的用途。
上述萘磺酰胺类化合物及其药学上可以接受的盐用于制备治疗或缓解疾病的炎症的药物的用途。
进一步地，所述疾病为炎性疾病或神经退行性疾病，包括慢性阻塞性肺疾病、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病、糖尿病、肠部炎症、类风湿性关节炎。
有益效果：
本发明提供的萘磺酰胺类化合物可以干扰Keap1-Nrf2结合，激活Nrf2，从而减轻炎性损伤，改善炎症微环境，具有潜在的抗炎活性，可用于制备成抗炎药物用于众多炎症相关疾病的炎性损伤，这些疾病包括慢性阻塞性肺疾病(COPD)、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病(CKD)、糖尿病、肠部炎症、类风湿性关节炎等。
附图说明
图1为选定化合物的ARE荧光素酶报告基因活性(诱导倍数)。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
实施例1：化合物的合成和结构确证
一、实验通则
本论文所用的化学试剂均为市售的化学纯或者分析纯。熔点使用M.P.50 MeltingPointSystem进行测定(温度计未经校正)。1H-NMR、13C-NMR核磁共振图谱由Bruker AV300型(300MHz)核磁共振仪测定(TMS为内标物，质谱由Agilent 1946A-MSD型质谱仪(ESI-MS)、Water Q-Tof型质谱仪(HRMS)测定，纯度由HPLC测定，色谱柱为Agilent C18(4.6×150mm,3.5μM)型反相柱，流动相采用甲醇：水：三氟乙酸＝85：15：0.1。
溶剂的浓缩使用的是EYELA仪器有限公司生产的N-1100旋转蒸发仪(在40℃下进行)，柱层析用硅胶为200-300目硅胶(青岛海洋化工厂分厂)，洗脱剂为石油醚(沸程60-90℃)和乙酸乙酯。采用0.25×0.75mm规格的GF254薄层层析硅胶板(烟台德信)监测反应，紫外吸收在ZF-1型三用紫外分析仪(杭州大卫科教仪器有限公司)下照射检测。
二、中间体的制备
4-硝基-1-萘酚(41)的合成
Figure BDA0002142422810000061
将1-硝基萘(8.50g,49.10mmol)溶于20.00mL DMSO(二甲基亚砜)中，随后将氢氧化钾(11.00g,196.30mmol)溶于10.00mL水中，冰浴下滴加入反应体系，最后将溶有过氧叔丁醇(9.80mL,98.20mmol)的10.00mL DMSO溶液滴入反应体系。滴加完毕后搅拌约10min，撤去冰浴，于室温下反应。反应4h，加入Na2S2O3(1.50g,9.30mmol)搅拌1h，后加200.00mL水，用稀盐酸调节pH至4析出大量黄色固体，抽滤留滤饼，然后滤饼用2M氢氧化钠调节pH至9～10，再用稀盐酸溶液调节水层pH至4，有黄色固体析出，抽滤，烘干，得亮黄色固体415.20g，产率为72.5％；m.p.156-159℃；1H-NMR(300MHz,DMSO-d6)δ:6.98(d,1H,J＝8.70Hz),7.61-7.66(m,1H),7.78-7.83(m,1H),8.33(d,1H,J＝8.34Hz),8.42(d,1H,J＝8.70Hz),8.68(d,1H,J＝8.79Hz),11.98(br,1H)；ESI-MS m/z:190.0[M+H]+.
4-硝基萘-1-基三氟甲磺酸酯(42)的合成
Figure BDA0002142422810000071
将4-硝基-1-萘酚41(2.00g,10.60mmol)溶于20.00mL DCM中，于冰浴条件下先后加入Et3N(4.40mL,31.90mmol)和Tf2O(2.70mL,16.30mmol)，加料完毕后将反应体系置于室温搅拌2h至TLC监测反应完全。反应液用饱和NaHCO3(20.00mL)中和，有机相用水(20.00mL)洗涤两次，再用饱和NaCl(20.00mL)洗涤两次。最后用无水Na2SO4干燥，旋干有机溶剂直接制沙，经柱层析得淡黄色固体42 2.00g，产率为56％,m.p.59-61℃；ESI-MSm/z:321.99[M+H]+.
(S)-3-((4-硝基萘-1-基)氨基)丁酸甲酯(43)的合成
Figure BDA0002142422810000072
在反应瓶中加入化合物42(2g,6.22mmol)和(S)-氨基丁酸甲酯盐酸盐(1.14g,7.46mmol)，随后快速加入Cs2CO3(4.00g,12.44mmol)、(±)-BINAP(0.58g,0.94mmol)和Pd2(dba)3(0.28g,0.32mmol),最后及时加入DIPEA(2.20mL,12.44mmol)和toluene(20.00mL)，氮气保护下加热100℃反应20h。冷却至室温，反应液经硅藻土助滤，旋干滤液直接制沙，经柱层析的黄色油状液体43 1.10g，产率为61％；1H NMR(300MHz,Chloroform-d)δ9.06(d,J＝8.8Hz,1H),8.51(d,J＝8.9Hz,1H),7.89(d,J＝8.5Hz,1H),7.74(t,J＝7.9Hz,1H),7.58(t,J＝7.7Hz,1H),6.58(d,J＝8.9Hz,1H),6.08(d,J＝8.2Hz,1H),4.35–4.20(m,1H),3.79(s,3H),2.78(t,J＝4.2Hz,2H),1.31(d,J＝8.4Hz,3H)；ESI-MS m/z:289.1[M+H]+.
(S)-3-((4-氨基萘-1-基)氨基)丁酸甲酯(44)的合成
Figure BDA0002142422810000073
在反应瓶中加入化合物43(1.10g,3.81mmol)溶于20.00mL乙酸乙酯中，加入氯化亚锡二水合物(3.45g,15.26mmol)，78℃反应4h后，TLC监测反应完全后冷却至室温，加入饱和NaHCO3调节pH至弱碱性7～8，反应液经砂芯漏斗过滤，乙酸乙酯洗涤滤饼至无紫外吸收，滤液分层，弃去水层，有机层用饱和NaCl溶液洗涤两次，无水硫酸钠干燥，减压浓缩后得到棕色油状液体44 0.83g，产率85％，直接投下一步；
(S)-3-((4((叔丁氧基羰基)氨基)萘-1-基)氨基)丁酸甲酯(45)的合成
Figure BDA0002142422810000074
在反应瓶中加入化合物44(0.83g,3.22mmol)溶于10.00mL乙醇中，加入二碳酸二叔丁酯(0.77g,3.54mmol)，室温下搅拌4h后，TLC监测反应完全后，旋干有机溶剂直接制沙，经柱层析得深蓝色油状液体45 0.96g，产率87％；1H NMR(300MHz,Chloroform-d)δ7.93–7.81(m,2H),7.55–7.44(m,3H),6.65(d,J＝8.2Hz,1H),6.43(s,1H),4.67(s,1H),4.12(q,J＝6.3Hz,1H),3.72(s,3H),2.78(dd,J＝15.2,4.9Hz,1H),2.64–2.56(m,1H),1.55(s,9H),1.41(d,J＝6.3Hz,3H)；ESI-MS m/z:359.2[M+H]+.
三、苄基取代系列化合物的合成
(S)-3-(苄基(4-(叔丁氧羰基)氨基)萘-1基)氨基)丁酸甲酯(46)的合成
Figure BDA0002142422810000081
在反应瓶中加入化合物45(0.50g,1.40mmol)，溶于5.00mL DMSO中，加入溴化苄(0.71g,4.20mmol),K2CO3(1.16g,8.40mmol),NaI(1.26g,8.40mmol)，氮气保护后100℃反应24h，TLC监测反应完全后，冷却至室温，加入10.00mL水，用EA(30.00mL)萃取三次，合并有机相，再用饱和NaCl水溶液(30.00mL)洗涤有机相两次，然后有机相用无水Na2SO4干燥，制沙，经柱层析得黄色油状液体46 0.31g，产率49％；1H NMR(300MHz,Chloroform-d)δ8.48–8.38(m,1H),7.84(dd,J＝7.6,2.2Hz,1H),7.54(td,J＝7.5,1.6Hz,2H),7.37(dd,J＝12.6,2.2Hz,2H),7.23–7.06(m,5H),6.66(s,1H),4.42(d,J＝2.7Hz,2H),3.92(dt,J＝9.0,6.2Hz,1H),3.62(s,3H),2.87(dd,J＝14.4,5.3Hz,1H),2.52(dd,J＝14.5,8.8Hz,1H),1.53(s,9H),1.41(s,3H)；ESI-MS m/z:449.2[M+H]+.
(S)-3-((4-氨基萘-1-基(苄基)氨基)丁酸甲酯(47)的合成
Figure BDA0002142422810000082
在反应瓶中加入化合物46(0.31g,0.69mmol)，溶于5.00mL DCM中，加入三氟乙酸(0.51mL,6.90mmol)，室温下搅拌2h，TLC监测反应完全后减压旋干溶剂，加入乙酸乙酯(30.00mL)溶解，用饱和NaHCO3调节pH至弱碱性(约为8)，分液，弃去水层，有机相再用饱和NaCl水溶液(10.00mL)洗涤有机相两次，然后有机相用无水Na2SO4干燥，有机相减压旋干得棕色油状液体47 0.20g，产率82％。
(S)-3-((4-((4甲氧基苯基)磺酰胺基)萘-1-基)(苄基)氨基)丁酸甲酯(48)的合成
Figure BDA0002142422810000083
在反应瓶中加入化合物47(0.20g,0.57mmol)，溶于10.00mL THF中，加入4-甲氧基苯磺酰氯(0.14g,0.69mmol)，吡啶(0.14g,1.72mmol)，氮气保护后70℃反应8h，TLC监测反应完全后，减压旋干溶剂，加入乙酸乙酯(30.00mL)溶解，用1M HCl(10.00mL)洗涤有机相两次，再用饱和NaCl水溶液(10.00mL)洗涤有机相两次，然后有机相用无水Na2SO4干燥，有机相旋干制沙，经柱层析得淡黄色油状液体480.21g，产率71％；1H NMR(300MHz,Chloroform-d)δ8.33(d,J＝8.4Hz,1H),7.76(d,J＝8.4Hz,1H),7.58–7.44(m,3H),7.44–7.34(m,1H),7.32–7.29(m,1H),7.27(s,1H),7.20–6.99(m,5H),6.79–6.70(m,2H),6.64(s,1H),4.41(s,2H),4.03–3.92(m,1H),3.79(s,3H),3.59(s,3H),2.83(dd,J＝14.6,5.6Hz,1H),2.51(dd,J＝14.5,8.5Hz,1H),1.37(d,J＝6.5Hz,3H)；ESI-MS m/z:519.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(苄基)氨基)丁酸甲酯(49)的合成
Figure BDA0002142422810000091
将化合物48(0.10g,0.19mol)溶于5.00mL DMF中，加入碳酸钾(78.66mg,0.57mmol)，最后加入溴乙酸甲酯(35.19mg,0.23mmol)于室温下搅拌。反应2h，向溶液中加入水至固体析出，用EA(30.00mL)萃取三次，合并有机相，再用饱和NaCl水溶液(10.00mL)洗三次，然后有机相用无水Na2SO4干燥，有机相旋干得淡黄色油状液体49 90.65mg，产率为81％；ESI-MS m/z:591.2[M+H]+.
(S)-3-((4-((4甲氧基苯基)磺酰胺基)萘-1-基)(苄基)氨基)丁酸(DDO-1160)的合成
Figure BDA0002142422810000092
将化合物48(0.10g,0.19mmol)溶解在5.00mL甲醇中，加入2M LiOH水溶液(0.95mL,1.90mmol)于室温下搅拌过夜。次日TLC监测反应完全后减压旋干溶剂，用水溶解后，滤去不溶物，再用1M稀盐酸溶液调节pH至4-5，溶液逐渐析出白色沉淀，过滤得白色固体DDO-1160 63.20mg,产率为66％；1H NMR(300MHz,DMSO-d6)δ12.19(s,1H),9.73(s,1H),8.30(d,J＝8.2Hz,1H),7.96(d,J＝8.2Hz,1H),7.55–7.35(m,4H),7.31(d,J＝6.8Hz,2H),7.19(d,J＝7.5Hz,1H),7.14–7.00(m,3H),6.98–6.90(m,2H),6.84(d,J＝7.8Hz,1H),4.35(s,2H),3.83–3.72(m,3H),3.67(s,1H),2.70(dd,2H),1.25(s,3H)；13C NMR(75MHz,DMSO-d6)δ173.52,144.90,139.99,131.33,129.22,128.42,128.18,126.78,126.07,124.20,123.43,119.36,114.48,56.96,56.02,48.04,17.03；HRMS(ESI):found 505.1789(C28H28N2O5S,[M+H]+,requires505.1791)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.44min,96.3％.
(S)-3-(苄基(4-((N-(羧甲基)-4甲氧基苯基)磺酰胺基)萘-1-基)(苄基)氨基)丁酸(DDO-1161)的合成
Figure BDA0002142422810000093
与化合物DDO-1160的合成方法相同，以化合物49(90.65mg,0.15mmol)，2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1161 50.56mg,产率为60％；1HNMR(300MHz,DMSO-d6)δ8.33(d,J＝8.2Hz,1H),8.06(d,J＝6.5Hz,1H),7.57–7.27(m,6H),7.14(dq,J＝16.4,8.3,6.9Hz,4H),7.01–6.88(m,3H),4.32(dd,J＝31.5,13.5Hz,4H),3.84(d,J＝3.3Hz,3H),3.77(s,1H),2.73(s,2H),1.28(s,3H)；13C NMR(75MHz,DMSO-d6)δ173.49,170.47,163.09,146.96,140.00,133.38,131.30,130.20,128.42,128.27,127.33,126.85,126.37,126.13,125.07,124.19,118.84,114.45,57.06,56.12,53.50,47.75,38.78,17.05；HRMS(ESI):found 563.1844(C30H30N2O7S,[M+H]+,requires 563.1846)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.38min,100.00％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(4-甲基苄基)氨基)丁酸甲酯(50)的合成
Figure BDA0002142422810000101
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、4-甲基溴化苄(0.56g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体50 0.35g，产率76％；1H NMR(300MHz,Chloroform-d)δ8.42(d,J＝8.5Hz,1H),7.83(d,J＝7.7Hz,1H),7.65(d,J＝8.0Hz,1H),7.53(dq,J＝12.6,6.8Hz,2H),7.18(d,J＝9.4Hz,3H),6.95(d,J＝7.7Hz,2H),6.65(s,1H),4.38(s,2H),3.90(dt,J＝8.6,6.1Hz,1H),3.61(s,3H),2.94–2.79(m,1H),2.51(dd,J＝14.5,8.9Hz,1H),2.21(s,3H),1.55(s,9H),1.33(d,J＝6.3Hz,3H)；ESI-MS m/z:463.3[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(4-甲基苄基)氨基)丁酸甲酯(51)的合成
Figure BDA0002142422810000102
与化合物48合成方法相同，化合物50(0.35g,0.76mmol)脱Boc后与4-甲氧基苯磺酰氯(0.19g,0.91mmol)、吡啶(0.18g,2.28mmol)反应得到白色固体51 0.25g，产率为62％；1H NMR(300MHz,Chloroform-d)δ8.32(d,J＝8.4Hz,1H),7.75(d,J＝8.4Hz,1H),7.57–7.51(m,2H),7.48(d,J＝7.9Hz,1H),7.40(d,J＝8.0Hz,1H),7.21–7.10(m,3H),7.03(d,J＝8.1Hz,1H),6.95(d,J＝7.7Hz,2H),6.75(d,J＝9.0Hz,2H),6.56(s,1H),4.37(s,2H),4.00–3.90(m,1H),3.80(s,3H),3.58(s,3H),2.82(dd,J＝14.3,5.8Hz,1H),2.57–2.45(m,1H),2.22(s,3H),1.30(d,J＝8.3Hz,3H)；ESI-MS m/z:533.2[M+H]+.
(S)-3-(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(4-甲基苄基)氨基)丁酸甲酯(52)的合成
Figure BDA0002142422810000103
与化合物49的合成方法相同，以化合物51(0.10g,0.18mmol)、溴乙酸甲酯(34.51mg,0.22mmol)和K2CO3(74.52mg,0.54mmol)为原料反应得到淡黄色固体52 80.36mg，产率为74％；ESI-MS m/z:605.2[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(4-甲基苄基)氨基)丁酸(DDO-1162)的合成
Figure BDA0002142422810000111
与化合物DDO-1160的合成方法相同，以化合物51(0.10g,0.18mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1162 65.00mg，产率为70％；1HNMR(300MHz,DMSO-d6)δ12.25(s,1H),9.78(s,1H),8.28(d,J＝8.4Hz,1H),7.96(d,J＝8.4Hz,1H),7.55–7.44(m,3H),7.40(t,J＝7.6Hz,1H),7.18(dd,J＝7.9,4.5Hz,3H),7.02–6.87(m,4H),6.82(d,J＝8.0Hz,1H),4.28(d,J＝5.8Hz,2H),3.79(s,3H),3.64(s,1H),2.69(s,1H),2.51(d,J＝1.9Hz,1H),2.12(s,3H),1.24(s,3H)；HRMS(ESI):found 519.1953(C29H30N2O5S,[M+H]+,requires 519.1875)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.47min,100.00％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(4-甲基苄基)氨基)丁酸(DDO-1163)的合成
Figure BDA0002142422810000112
与化合物DDO-1161的合成方法相同，以化合物52(80.36mg,0.13mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1163 50.30mg，产率为67％；1HNMR(300MHz,DMSO-d6)δ12.39(s,2H),8.30(d,J＝8.3Hz,1H),8.10–8.00(m,1H),7.61–7.34(m,4H),7.20(dd,J＝13.3,7.8Hz,3H),6.95(t,J＝7.2Hz,5H),4.44–4.19(m,4H),3.89–3.78(m,3H),3.73(s,1H),2.73(s,1H),2.58(s,1H),2.14(s,3H),1.25(d,J＝11.5Hz,3H)；HRMS(ESI):found 577.2008(C31H32N2O7S,[M+H]+,requires 577.1930)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.36min,96.50％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(4-氯苄基)氨基)丁酸甲酯(53)的合成
Figure BDA0002142422810000113
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、4-氯溴化苄(0.61g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体530.33g，产率68％；ESI-MS m/z:483.2[M+H]+.
(S)-3-((4-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(54)的合成
Figure BDA0002142422810000121
与化合物48合成方法相同，化合物53(0.33g,0.68mmol)脱Boc后与4-甲氧基苯磺酰氯(0.17g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体54 0.23g，产率为61％；1H NMR(300MHz,Chloroform-d)δ8.28(d,J＝8.5Hz,1H),7.79(d,J＝8.5Hz,1H),7.57–7.44(m,3H),7.38(s,1H),7.30–7.05(m,6H),6.85(s,1H),6.78–6.68(m,2H),4.35(d,J＝4.2Hz,2H),3.93(p,J＝6.7Hz,1H),3.78(d,J＝3.6Hz,3H),3.59(s,3H),2.79(s,1H),2.51(s,1H),1.32(dd,J＝13.4,7.1Hz,3H)；ESI-MS m/z:553.1[M+H]+.
(S)-3-((4-氯苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(55)的合成
Figure BDA0002142422810000122
与化合物49的合成方法相同，以化合物54(0.10g,0.18mmol)、溴乙酸甲酯(34.51mg,0.22mmol)和K2CO3(74.52mg,0.54mmol)为原料反应得到淡黄色固体55 74.16mg，产率为65％；ESI-MS m/z:625.2[M+H]+.
(S)-3-((4-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1164)的合成
Figure BDA0002142422810000123
与化合物DDO-1160的合成方法相同，以化合物54(0.10g,0.18mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1164 63.00mg，产率为65％；1HNMR(300MHz,DMSO-d6)δ9.77(s,1H),8.30(d,J＝8.5Hz,1H),7.99(d,J＝8.5Hz,1H),7.57–7.46(m,3H),7.42(t,J＝7.7Hz,1H),7.34(d,J＝8.1Hz,2H),7.26–7.13(m,3H),7.00–6.91(m,2H),6.87(d,J＝8.0Hz,1H),4.43–4.27(m,2H),3.81(d,J＝2.0Hz,3H),3.68(s,1H),2.72(s,2H),1.26(s,3H)；HRMS(ESI):found 539.1408(C28H27ClN2O5S,[M+H]+,requires539.1329)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.92min,97.55％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(4-氯苄基)氨基)丁酸(DDO-1165)的合成
Figure BDA0002142422810000124
与化合物DDO-1161的合成方法相同，以化合物55(74.16mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1165 52.30mg，产率为73％；1HNMR(300MHz,DMSO-d6)δ12.47(s,2H),8.32(s,1H),8.10(s,1H),7.40(d,J＝8.8Hz,5H),7.22(s,3H),6.98(s,3H),4.36(d,J＝19.5Hz,4H),3.86(t,J＝5.5Hz,3H),3.84(s,1H),2.76(s,2H),1.28(s,3H)；HRMS(ESI):found 597.1459(C30H29ClN2O7S,[M+H]+,requires597.1384)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.50min,95.71％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(4-氟苄基)氨基)丁酸甲酯(56)的合成
Figure BDA0002142422810000131
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、4-氟溴化苄(0.57g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体560.36g，产率77％；1H NMR(300MHz,Chloroform-d)δ8.31–8.22(m,1H),7.72(dq,J＝7.1,2.7Hz,1H),7.56(d,J＝8.1Hz,1H),7.42(ddt,J＝7.3,4.7,2.2Hz,2H),7.17(tq,J＝5.6,2.5Hz,2H),7.06(dt,J＝8.1,2.5Hz,1H),6.70(tt,J＝8.7,2.5Hz,2H),6.56(s,1H),4.26(s,2H),3.84–3.71(m,1H),3.51(s,3H),2.79–2.67(m,1H),2.47–2.34(m,1H),1.48–1.38(s,9H),1.19(dq,J＝8.7,3.1,2.3Hz,3H)；ESI-MS m/z:467.2[M+H]+.
(S)-3-((4-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(57)的合成
Figure BDA0002142422810000132
与化合物48合成方法相同，化合物56(0.36g,0.77mmol)脱Boc后与4-甲氧基苯磺酰氯(0.19g,0.92mmol)、吡啶(0.18g,2.31mmol)反应得到白色固体57 0.26g，产率为63％；1H NMR(300MHz,Chloroform-d)δ8.28(d,J＝8.4Hz,1H),7.75(d,J＝8.3Hz,1H),7.59–7.43(m,3H),7.38(s,1H),7.25–7.13(m,3H),7.02(dd,J＝8.1,2.8Hz,1H),6.86–6.65(m,5H),4.36(s,2H),3.99–3.87(m,1H),3.79(d,J＝2.9Hz,3H),3.59(d,J＝2.7Hz,3H),2.81(dd,J＝14.8,5.5Hz,1H),2.49(dd,J＝14.4,8.2Hz,1H),1.30–1.25(m,3H)；ESI-MS m/z:537.2[M+H]+.
(S)-3-((4-氟苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(58)的合成
Figure BDA0002142422810000133
与化合物49的合成方法相同，以化合物57(0.10g,0.18mmol)、溴乙酸甲酯(34.51mg,0.22mmol)和K2CO3(74.52mg,0.54mmol)为原料反应得到淡黄色固体58 75.36mg，产率为68％。ESI-MS m/z:609.2[M+H]+.
(S)-3-((4-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1166)的合成
Figure BDA0002142422810000141
与化合物DDO-1160的合成方法相同，以化合物57(0.10g,0.18mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1166 60.00mg，产率为65％；1HNMR(300MHz,DMSO-d6)δ12.20(s,1H),9.78(d,J＝6.9Hz,1H),8.30(s,1H),7.97(d,J＝10.9Hz,1H),7.51(s,4H),7.36(s,2H),7.22(d,J＝7.0Hz,1H),7.05–6.74(m,5H),4.35(s,2H),3.79(d,J＝4.4Hz,3H),3.68(s,1H),2.74(dd,2H),1.26(s,3H)；HRMS(ESI):found523.1703(C28H27FN2O5S,[M+H]+,requires 523.1625)；HPLC(85:15methanol:water with1‰TFA):tR＝11.89min,95.74％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(4-氟苄基)氨基)丁酸(DDO-1167)的合成
Figure BDA0002142422810000142
与化合物DDO-1161的合成方法相同，以化合物58(75.36mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1167 53.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ12.47(s,2H),8.33(s,1H),8.09(s,1H),7.44(d,J＝21.9Hz,6H),7.22(s,1H),6.99(s,5H),4.38(s,4H),3.90–3.80(m,3H),3.78(s,1H),2.68(d,J＝48.8Hz,2H),1.28(s,3H)；HRMS(ESI):found 581.1755(C30H29FN2O7S,[M+H]+,requires 581.1680)；HPLC(85:15methanol:water with 1‰TFA):tR＝11.37min,95.89％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(3-甲基苄基)氨基)丁酸甲酯(59)的合成
Figure BDA0002142422810000143
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、3-甲基溴化苄(0.56g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体59 0.32g，产率69％；1H NMR(300MHz,Chloroform-d)δ8.47–8.39(m,1H),7.83(dd,J＝7.7,1.9Hz,1H),7.65(d,J＝7.9Hz,1H),7.59–7.48(m,2H),7.14(t,J＝8.5Hz,3H),7.02(t,J＝7.6Hz,1H),6.88(d,J＝7.5Hz,1H),6.64(s,1H),4.37(d,J＝3.2Hz,2H),3.90(dt,J＝8.9,6.1Hz,1H),3.61(s,3H),2.88–2.80(m,1H),2.50(dd,J＝14.5,8.9Hz,1H),2.22(s,3H),1.57(s,9H),1.34(d,J＝7.8Hz,3H)；ESI-MS m/z:463.3[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(3-甲基苄基)氨基)丁酸甲酯(60)的合成
Figure BDA0002142422810000151
与化合物48合成方法相同，化合物59(0.33g,0.69mmol)脱Boc后与4-甲氧基苯磺酰氯(0.17g,0.83mmol)、吡啶(0.16g,2.07mmol)反应得到白色固体60 0.25g，产率为68％；1H NMR(300MHz,Chloroform-d)δ8.32(d,J＝8.5Hz,1H),7.74(d,J＝8.4Hz,1H),7.51(t,J＝10.1Hz,3H),7.39(d,J＝14.9Hz,1H),7.14–6.98(m,5H),6.90(d,J＝7.4Hz,1H),6.75(d,J＝8.7Hz,2H),6.53(s,1H),4.36(s,2H),3.95(q,J＝6.8Hz,1H),3.80(s,3H),3.58(s,3H),2.82(dd,J＝14.5,5.7Hz,1H),2.49(dd,J＝14.5,8.5Hz,1H),2.22(s,3H),1.29(d,J＝8.5Hz,3H)；ESI-MS m/z:533.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(3-甲基苄基)氨基)丁酸甲酯(61)的合成
Figure BDA0002142422810000152
与化合物49的合成方法相同，以化合物60(0.10g,0.19mmol)、溴乙酸甲酯(34.51mg,0.26mmol)和K2CO3(77.81mg,0.56mmol)为原料反应得到淡黄色固体61 65.16mg，产率为57％；ESI-MS m/z:605.2[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(3-甲基苄基)氨基)丁酸(DDO-1168)的合成
Figure BDA0002142422810000153
与化合物DDO-1160的合成方法相同，以化合物60(0.10g,0.19mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1168 60.40mg，产率为61％；1HNMR(300MHz,DMSO-d6)δ12.25(s,1H),9.79(d,J＝6.8Hz,1H),8.29(d,J＝8.3Hz,1H),8.05–7.88(m,1H),7.51(s,4H),7.13(s,3H),6.99–6.77(m,5H),4.40–4.22(m,2H),3.80(s,3H),3.66(s,1H),2.71(s,2H),2.12(t,J＝7.3Hz,3H),1.26(s,3H)；HRMS(ESI):found 519.1952(C29H30N2O5S,[M+H]+,requires 519.1875)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.49min,96.45％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(3-甲基苄基)氨基)丁酸(DDO-1169)的合成
Figure BDA0002142422810000154
与化合物DDO-1161的合成方法相同，以化合物61(65.16mg,0.11mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1169 45.30mg，产率为71％；1HNMR(300MHz,DMSO-d6)δ12.48(s,2H),8.32(s,1H),8.07(s,1H),7.52–7.39(m,4H),7.18(s,3H),7.04–6.92(m,5H),4.32(d,J＝18.0Hz,4H),3.84(d,J＝4.1Hz,3H),3.36(s,1H),2.73(d,2H),2.17(d,J＝4.7Hz,3H),1.27(s,3H)；HRMS(ESI):found 577.2011(C31H32N2O7S,[M+H]+,requires 577.1930)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.32min,96.00％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(2-甲基苄基)氨基)丁酸甲酯(62)的合成
Figure BDA0002142422810000161
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、2-甲基溴化苄(0.56g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体62 0.34g，产率74％；1H NMR(300MHz,Chloroform-d)δ8.44–8.37(m,1H),7.87–7.80(m,1H),7.67(d,J＝8.1Hz,1H),7.56–7.49(m,2H),7.38(q,J＝3.0Hz,1H),7.27(d,J＝2.4Hz,2H),7.02(d,J＝2.4Hz,1H),6.92(t,J＝7.4Hz,1H),6.66(s,1H),4.38(s,2H),3.94(dt,J＝9.0,6.2Hz,1H),3.59(s,3H),2.86(dd,J＝14.4,5.0Hz,1H),2.58–2.48(m,1H),2.44(s,3H),1.55(s,9H),1.38–1.34(m,3H)；ESI-MS m/z:463.3[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(2-甲基苄基)氨基)丁酸甲酯(63)的合成
Figure BDA0002142422810000162
与化合物48合成方法相同，化合物62(0.34g,0.74mmol)脱Boc后与4-甲氧基苯磺酰氯(0.18g,0.88mmol)、吡啶(0.18g,2.22mmol)反应得到白色固体63 0.26g，产率为65％；1H NMR(300MHz,Chloroform-d)δ8.33(d,J＝8.4Hz,1H),7.82(d,J＝8.4Hz,1H),7.55(d,J＝8.7Hz,2H),7.50–7.43(m,1H),7.39(d,J＝7.3Hz,1H),7.24(s,1H),7.17(d,J＝8.1Hz,1H),7.09–6.97(m,4H),6.92(td,J＝7.2,1.9Hz,1H),6.74(d,J＝8.6Hz,2H),4.38(s,2H),4.05–3.95(m,1H),3.77(s,3H),3.57(s,3H),2.85(dd,J＝14.6,5.5Hz,1H),2.52(dd,J＝14.6,8.7Hz,1H),2.43(s,3H),1.37(d,J＝6.5Hz,3H)；ESI-MS m/z:533.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(2-甲基苄基)氨基)丁酸甲酯(64)的合成
Figure BDA0002142422810000163
与化合物49的合成方法相同，以化合物63(0.10g,0.19mmol)、溴乙酸甲酯(34.51mg,0.26mmol)和K2CO3(77.81mg,0.56mmol)为原料反应得到淡黄色固体64 64.16mg，产率为57％。ESI-MS m/z:605.2[M+H]+.
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)萘-1-基)(2-甲基苄基)氨基)丁酸(DDO-1170)的合成
Figure BDA0002142422810000171
与化合物DDO-1160的合成方法相同，以化合物63(0.10g,0.19mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1170 61.40mg，产率为62％；1HNMR(300MHz,DMSO-d6)δ12.24(s,1H),8.28(d,J＝8.7Hz,1H),7.97(d,J＝8.6Hz,1H),7.70–7.33(m,4H),7.22(t,J＝8.3Hz,2H),7.16–6.73(m,6H),4.34(s,2H),3.83(s,3H),3.68(s,1H),2.70(s,2H),2.53–2.36(m,3H),1.33(d,J＝16.7Hz,3H)；HRMS(ESI):found 519.1948(C29H30N2O5S,[M+H]+,requires 519.1875)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.30min,96.65％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(2-甲基苄基)氨基)丁酸(DDO-1171)的合成
Figure BDA0002142422810000172
与化合物DDO-1161的合成方法相同，以化合物64(64.16mg,0.11mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1171 43.30mg，产率为68％；1HNMR(300MHz,DMSO-d6)δ12.48(s,2H),8.30(d,J＝8.4Hz,1H),8.10(t,J＝7.6Hz,1H),7.58–7.39(m,4H),7.23(dd,J＝18.2,7.7Hz,2H),7.06–6.87(m,6H),4.43–4.25(m,4H),3.83(t,J＝2.1Hz,3H),3.77(s,1H),2.74(d,J＝14.8Hz,1H),2.59(s,1H),2.41(s,3H),1.37–1.26(m,3H)；HRMS(ESI):found 577.2009(C31H32N2O7S,[M+H]+,requires 577.1930)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.91min,96.44％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(3-氯苄基)氨基)丁酸甲酯(65)的合成
Figure BDA0002142422810000173
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、3-氯溴化苄(0.61g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体650.35g，产率72％；1H NMR(300MHz,Chloroform-d)δ8.29(d,J＝8.2Hz,1H),7.78–7.70(m,1H),7.50–7.36(m,2H),7.21(d,J＝15.6Hz,2H),7.13–7.05(m,2H),6.98–6.91(m,2H),6.58(s,1H),4.28(s,2H),3.85–3.76(m,1H),3.52(s,3H),2.71(s,1H),2.41(dd,J＝14.5,8.8Hz,1H),1.44(d,J＝3.3Hz,9H),1.26–1.20(m,3H)；ESI-MS m/z:483.2[M+H]+.
(S)-3-((3-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(66)的合成
Figure BDA0002142422810000181
与化合物48合成方法相同，化合物65(0.35g,0.72mmol)脱Boc后与4-甲氧基苯磺酰氯(0.18g,0.86mmol)、吡啶(0.17g,2.16mmol)反应得到白色固体66 0.26g，产率为65％；1H NMR(300MHz,Chloroform-d)δ8.29(s,1H),7.74(s,1H),7.50(q,J＝7.7Hz,3H),7.39(d,J＝7.9Hz,1H),7.27(d,J＝5.9Hz,1H),7.19–6.98(m,5H),6.79–6.71(m,2H),6.62(s,1H),4.37(d,J＝6.6Hz,2H),3.94(s,1H),3.82–3.71(m,3H),3.59(d,J＝6.7Hz,3H),2.79(s,1H),2.49(t,J＝7.7Hz,1H),1.29–1.19(m,3H)；ESI-MS m/z:553.1[M+H]+.
(S)-3-((3-氯苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(67)的合成
Figure BDA0002142422810000182
与化合物49的合成方法相同，以化合物66(0.10g,0.18mmol)、溴乙酸甲酯(34.51mg,0.22mmol)和K2CO3(74.52mg,0.54mmol)为原料反应得到淡黄色固体67 63.50mg，产率为57％；ESI-MS m/z:625.2[M+H]+.
(S)-3-((3-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1172)的合成
Figure BDA0002142422810000183
与化合物DDO-1160的合成方法相同，以化合物66(0.10g,0.18mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1172 56.40mg，产率为58％；1HNMR(300MHz,DMSO-d6)δ9.79(s,1H),8.30(d,J＝8.5Hz,1H),7.97(d,J＝8.5Hz,1H),7.49(d,J＝8.7Hz,3H),7.44–7.32(m,2H),7.28(d,J＝7.3Hz,1H),7.22(d,J＝8.2Hz,1H),7.17–7.09(m,2H),6.94(d,J＝8.4Hz,2H),6.84(d,J＝8.0Hz,1H),4.34(t,J＝10.4Hz,2H),3.78(s,3H),3.65(s,1H),2.71(s,1H),2.57(s,0H),1.22(s,3H)；HRMS(ESI):found 539.1408(C28H27ClN2O5S,[M+H]+,requires 539.1329)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.96min,96.21％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(3-氯苄基)氨基)丁酸(DDO-1173)的合成
Figure BDA0002142422810000184
与化合物DDO-1161的合成方法相同，以化合物67(63.50mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1173 47.30mg，产率为78％；1HNMR(300MHz,DMSO-d6)δ12.51(s,2H),8.32(d,J＝8.4Hz,1H),8.10(dd,J＝8.5,4.3Hz,1H),7.59–7.47(m,2H),7.45–7.37(m,3H),7.32(d,J＝7.4Hz,1H),7.22(dd,J＝7.9,5.0Hz,1H),7.18–7.10(m,2H),7.03–6.87(m,3H),4.49–4.29(m,4H),3.88–3.79(m,3H),3.74(s,1H),2.74(s,1H),2.58(s,1H),1.25(s,3H)；HRMS(ESI):found 597.1458(C30H29ClN2O7S,[M+H]+,requires 597.1384)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.80min,98.83％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(2-氯苄基)氨基)丁酸甲酯(68)的合成
Figure BDA0002142422810000191
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、2-氯溴化苄(0.61g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体680.36g，产率75％；1H NMR(300MHz,Chloroform-d)δ8.43(dd,J＝8.1,1.7Hz,1H),7.90–7.82(m,1H),7.67(d,J＝8.1Hz,1H),7.58–7.48(m,2H),7.36(dd,J＝7.6,1.9Hz,1H),7.23(t,J＝7.4Hz,2H),7.05–6.92(m,2H),6.67(s,1H),4.52(s,2H),3.95(q,J＝6.8Hz,1H),3.61(s,3H),2.87(dt,J＝12.9,6.4Hz,1H),2.56(dd,J＝14.7,9.1Hz,1H),1.55(s,9H),1.36(d,J＝6.6Hz,3H)；ESI-MS m/z:483.2[M+H]+.
(S)-3-((2-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(69)的合成
Figure BDA0002142422810000192
与化合物48合成方法相同，化合物68(0.36g,0.75mmol)脱Boc后与4-甲氧基苯磺酰氯(0.19g,0.90mmol)、吡啶(0.18g,2.25mmol)反应得到白色固体69 0.26g，产率为63％；1H NMR(300MHz,Chloroform-d)δ8.34(d,J＝10.2Hz,1H),7.83(t,J＝8.3Hz,1H),7.63–7.49(m,3H),7.42(d,J＝7.9Hz,1H),7.28(t,J＝7.6Hz,2H),7.05(dt,J＝22.4,8.1Hz,4H),6.76(dt,J＝14.8,7.1Hz,3H),4.51(d,J＝6.8Hz,2H),4.06–3.96(m,1H),3.81(d,J＝6.5Hz,3H),3.59(d,J＝6.6Hz,3H),2.86(s,1H),2.57(s,1H),1.30(t,J＝10.7Hz,3H)；ESI-MS m/z:553.1[M+H]+.
(S)-3-((2-氯苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(70)的合成
Figure BDA0002142422810000193
与化合物49的合成方法相同，以化合物69(0.10g,0.18mmol)、溴乙酸甲酯(34.51mg,0.22mmol)和K2CO3(74.52mg,0.54mmol)为原料反应得到淡黄色固体70 63.20mg，产率为56％；ESI-MS m/z:625.2[M+H]+.
(S)-3-((2-氯苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1174)的合成
Figure BDA0002142422810000201
与化合物DDO-1160的合成方法相同，以化合物69(0.10g,0.18mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1174 53.60mg，产率为55％；1HNMR(300MHz,DMSO-d6)δ9.81(s,1H),8.31(d,J＝8.5Hz,1H),7.97(d,J＝8.6Hz,1H),7.57–7.45(m,3H),7.42–7.34(m,2H),7.28(d,J＝7.8Hz,1H),7.22–7.16(m,1H),7.04(s,2H),6.96–6.79(m,3H),4.44(d,J＝7.0Hz,2H),3.77(d,J＝4.1Hz,3H),3.68(s,1H),2.74(s,1H),2.58(s,1H),1.23(d,J＝15.9Hz,3H)；HRMS(ESI):found 539.1404(C28H27ClN2O5S,[M+H]+,requires 539.1329)；HPLC(85:15methanol:water with 1‰TFA):tR＝13.21min,97.20％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(2-氯苄基)氨基)丁酸(DDO-1175)的合成
Figure BDA0002142422810000202
与化合物DDO-1161的合成方法相同，以化合物70(63.20mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1175 45.60mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ12.53(s,2H),8.34(d,J＝8.5Hz,1H),8.12(t,J＝7.5Hz,1H),7.52(d,J＝11.3Hz,2H),7.41(qd,J＝7.1,4.6,3.4Hz,3H),7.32(d,J＝6.7Hz,1H),7.17(dd,J＝8.9,3.3Hz,1H),7.11(dd,J＝9.9,4.4Hz,2H),6.96(td,J＝10.1,9.2,4.0Hz,3H),4.54–4.44(m,2H),4.33(d,J＝8.9Hz,2H),3.87–3.81(m,3H),3.77(s,1H),2.78(s,1H),2.61(d,J＝12.2Hz,1H),1.29(s,3H)；HRMS(ESI):found 597.1459(C30H29ClN2O7S,[M+H]+,requires597.1384)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.67min,95.45％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(3-氟苄基)氨基)丁酸甲酯(71)的合成
Figure BDA0002142422810000203
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、3-氟溴化苄(0.57g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体710.33g，产率71％；1H NMR(300MHz,Chloroform-d)δ8.30(d,J＝8.1Hz,1H),7.78–7.70(m,1H),7.57(d,J＝8.2Hz,1H),7.48–7.41(m,2H),7.08(d,J＝8.3Hz,1H),7.01–6.94(m,3H),6.71–6.62(m,1H),6.57(s,1H),4.31(s,2H),3.84–3.76(m,1H),3.52(s,3H),2.74(d,J＝13.4Hz,1H),2.41(dd,J＝14.5,8.9Hz,1H),1.47(s,9H),1.19(s,3H)；ESI-MS m/z:467.2[M+H]+.
(S)-3-((3-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(72)的合成
Figure BDA0002142422810000211
与化合物48合成方法相同，化合物71(0.33g,0.71mmol)脱Boc后与4-甲氧基苯磺酰氯(0.17g,0.85mmol)、吡啶(0.16g,2.03mmol)反应得到白色固体72 0.23g，产率为61％；1H NMR(300MHz,Chloroform-d)δ8.29(d,J＝8.4Hz,1H),7.74(d,J＝8.4Hz,1H),7.56–7.44(m,3H),7.42–7.37(m,1H),7.27(s,1H),7.19–7.08(m,2H),7.08–6.95(m,3H),6.82–6.70(m,3H),6.64(s,1H),4.40(s,2H),3.95(q,J＝6.6Hz,1H),3.78(s,3H),3.58(s,3H),2.79(t,J＝7.3Hz,1H),2.50(dd,J＝14.5,8.2Hz,1H),1.29(d,J＝8.7Hz,3H)；ESI-MS m/z:537.2[M+H]+.
(S)-3-((3-氟苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(73)的合成
Figure BDA0002142422810000212
与化合物49的合成方法相同，以化合物72(0.10g,0.19mmol)、溴乙酸甲酯(34.51mg,0.26mmol)和K2CO3(77.81mg,0.56mmol)为原料反应得到淡黄色固体73 53.30mg，产率为46％；ESI-MS m/z:609.2[M+H]+.
(S)-3-((3-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1176)的合成
Figure BDA0002142422810000213
与化合物DDO-1160的合成方法相同，以化合物72(0.10g,0.19mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1176 53.00mg，产率为54％；1HNMR(300MHz,DMSO-d6)δ9.78(d,J＝3.6Hz,1H),8.31(d,J＝8.5Hz,1H),7.97(d,J＝8.4Hz,1H),7.47(ddd,J＝16.5,10.8,6.6Hz,4H),7.23–7.03(m,4H),6.97–6.75(m,4H),4.45–4.28(m,2H),3.77(d,J＝3.4Hz,3H),3.69–3.62(m,1H),2.70(dd,2H),1.22(s,3H)；HRMS(ESI):found 523.1702(C28H27FN2O5S,[M+H]+,requires 523.1625)；HPLC(85:15methanol:waterwith 1‰TFA):tR＝11.99min,96.23％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(3-氟苄基)氨基)丁酸(DDO-1177)的合成
Figure BDA0002142422810000221
与化合物DDO-1161的合成方法相同，以化合物73(53.30mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1177 44.30mg，产率为76％；1HNMR(300MHz,DMSO-d6)δ12.50(s,2H),8.33(d,J＝8.4Hz,1H),8.15–8.05(m,1H),7.58–7.37(m,4H),7.24–7.12(m,4H),7.00–6.85(m,4H),4.43–4.26(m,4H),3.86–3.79(m,3H),3.76(s,1H),2.73(s,1H),2.58(s,1H),1.25(s,3H)；HRMS(ESI):found 581.1752(C30H29FN2O7S,[M+H]+,requires 581.1680)；HPLC(85:15methanol:water with 1‰TFA):tR＝11.64min,95.96％.
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(2-氟苄基)氨基)丁酸甲酯(74)的合成
Figure BDA0002142422810000222
与化合物46的合成方法相同，以化合物45(0.36g,1.00mmol)、2-氟溴化苄(0.57g,3.00mmol)、K2CO3(0.83g,6.00mmol)及NaI(0.90g,6.00mmol)为原料反应得到淡黄色液体740.34g，产率73％；1H NMR(300MHz,Chloroform-d)δ8.29(s,1H),7.73(s,1H),7.58(s,1H),7.47–7.36(m,2H),7.22–7.16(m,2H),6.93(s,1H),6.74(d,J＝7.7Hz,2H),6.56(s,1H),4.35(s,2H),3.80(d,J＝9.3Hz,1H),3.51(d,J＝5.2Hz,3H),2.73(d,J＝6.8Hz,1H),2.49–2.40(m,1H),1.44(s,J＝5.6Hz,9H),1.24–1.21(m,3H)；ESI-MS m/z:467.2[M+H]+.
(S)-3-((2-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(75)的合成
Figure BDA0002142422810000223
与化合物48合成方法相同，化合物74(0.34g,0.73mmol)脱Boc后与4-甲氧基苯磺酰氯(0.18g,0.88mmol)、吡啶(0.17g,2.19mmol)反应得到白色固体75 0.24g，产率为62％；1H NMR(300MHz,Chloroform-d)δ8.34–8.26(m,1H),7.79(d,J＝8.3Hz,1H),7.58–7.51(m,2H),7.49–7.43(m,1H),7.42–7.36(m,1H),7.27–7.21(m,1H),7.10(dq,J＝14.8,7.6,7.0Hz,3H),6.95–6.87(m,1H),6.85–6.80(m,1H),6.75(d,J＝9.1Hz,3H),4.43(s,2H),3.93(m,J＝10.5,4.4Hz,1H),3.79(s,3H),3.59(s,3H),2.89–2.78(m,1H),2.52(dd,J＝14.6,8.5Hz,1H),1.35(d,J＝6.6Hz,3H)；ESI-MS m/z:537.2[M+H]+.
(S)-3-((2-氟苄基)(4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(76)的合成
Figure BDA0002142422810000231
与化合物49的合成方法相同，以化合物75(0.10g,0.19mmol)、溴乙酸甲酯(34.51mg,0.26mmol)和K2CO3(77.81mg,0.56mmol)为原料反应得到淡黄色固体76 64.20mg，产率为56％；ESI-MS m/z:609.2[M+H]+.
(S)-3-((2-氟苄基)(4-((4-甲氧基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1178)的合成
Figure BDA0002142422810000232
与化合物DDO-1160的合成方法相同，以化合物75(0.10g,0.19mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1178 53.80mg，产率为54％；1HNMR(300MHz,DMSO-d6)δ9.77(s,1H),8.24(d,J＝8.3Hz,1H),7.95(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,3H),7.38(t,J＝7.5Hz,1H),7.31(s,1H),7.23(d,J＝8.0Hz,1H),7.09(d,J＝7.1Hz,1H),7.01(d,J＝9.4Hz,1H),6.91(dd,J＝12.6,8.1Hz,4H),4.38(d,J＝9.4Hz,2H),3.78(s,3H),3.64(s,1H),2.71(s,1H),2.60(s,1H),1.26(s,3H)；HRMS(ESI):found523.1708(C28H27FN2O5S,[M+H]+,requires 523.1625)；HPLC(85:15methanol:water with1‰TFA):tR＝14.60min,97.52％.
(S)-3-(4-((N-(羧甲基)-4-甲氧基苯基)磺酰胺基)萘-1-基)(2-氟苄基)氨基)丁酸(DDO-1179)的合成
Figure BDA0002142422810000233
与化合物DDO-1161的合成方法相同，以化合物76(64.20mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1179 42.10mg，产率为72％；1HNMR(300MHz,DMSO-d6)δ8.27(d,J＝8.3Hz,1H),8.09(t,J＝7.1Hz,1H),7.61–7.30(m,5H),7.23(d,J＝8.1Hz,1H),7.13(d,J＝6.8Hz,1H),7.10–7.03(m,1H),6.98(dq,J＝9.7,5.3,4.0Hz,4H),4.38(dd,J＝26.3,10.6Hz,4H),3.84(d,J＝1.9Hz,3H),3.73(s,1H),2.74(s,1H),2.60(d,J＝11.4Hz,1H),1.29(s,3H)；HRMS(ESI):found 581.1758(C30H29FN2O7S,[M+H]+,requires 581.1680)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.20min,100.00％.
四、苯环电子等排体取代化合物的合成
(S)-3-((4-((叔丁氧基羰基)氨基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(77)的合成
Figure BDA0002142422810000234
与化合物46的合成方法相同，以化合物45(0.72g,2.00mmol)、3-溴丙炔(0.71g,6.00mmol)、K2CO3(1.66g,12.00mmol)及NaI(1.80g,12.00mmol)为原料反应得到淡黄色液体77 0.43g，产率53％；1H NMR(300MHz,Chloroform-d)δ8.37–8.26(m,1H),7.92–7.75(m,2H),7.59–7.47(m,3H),6.81(s,1H),4.14–3.97(m,2H),3.89(s,1H),3.61(d,J＝1.9Hz,3H),2.69(dd,J＝14.8,4.6Hz,1H),2.39(dd,J＝14.9,9.0Hz,1H),2.26–2.16(m,1H),1.57(s,9H),1.36–1.30(s,3H)；ESI-MS m/z:397.2[M+H]+.
五、丙炔基取代衍生物的合成
(S)-3-((4-(苯基磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(86)的合成
Figure BDA0002142422810000241
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与苯磺酰氯(0.15g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体86 0.22g，产率为71％；1HNMR(300MHz,Chloroform-d)δ8.23(d,J＝8.3Hz,1H),7.77(t,J＝8.5Hz,3H),7.53–7.44(m,2H),7.39(q,J＝8.2,6.8Hz,4H),7.33(s,1H),6.78(s,1H),4.07–4.00(m,1H),3.97–3.81(m,2H),3.60(s,3H),2.67(dd,J＝14.9,4.8Hz,1H),2.41(dd,J＝14.9,8.5Hz,1H),2.21(d,J＝2.4Hz,1H),1.34–1.26(m,3H)；ESI-MS m/z:437.1[M+H]+.
(S)-3-((4-(N-(2-甲氧基-2-氧代乙基)苯磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(87)的合成
Figure BDA0002142422810000242
与化合物49的合成方法相同，以化合物86(0.10g,0.23mmol)、溴乙酸甲酯(42.23mg,0.27mmol)和K2CO3(95.22mg,0.69mmol)为原料反应得到淡黄色固体87 72.40mg，产率为59％；ESI-MS m/z:509.2[M+H]+.
(S)-3-((4-(苯基磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1186)的合成
Figure BDA0002142422810000243
与化合物DDO-1160的合成方法相同，以化合物86(0.10g,0.23mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1186 53.60mg，产率为55％；1HNMR(300MHz,DMSO-d6)δ12.23(s,1H),10.11(s,1H),8.14(d,J＝8.3Hz,1H),7.97(d,J＝8.3Hz,1H),7.75–7.63(m,2H),7.58(d,J＝7.1Hz,1H),7.46(dt,J＝20.6,7.5Hz,4H),7.27(d,J＝8.1Hz,1H),7.03(d,J＝8.0Hz,1H),4.03–3.82(m,2H),3.69(s,1H),2.97(t,J＝2.2Hz,1H),2.57(s,1H),2.40–2.31(m,1H),1.17(d,J＝6.4Hz,3H)；HRMS(ESI):found423.1379(C23H22N2O4S,[M+H]+,requires 423.1300)；HPLC(85:15methanol:water with1‰TFA):tR＝9.70min,95.72％.
(S)-3-((4-(N-(羧甲基)苯磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1187)的合成
Figure BDA0002142422810000251
与化合物DDO-1161的合成方法相同，以化合物87(72.40mg,0.14mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1187 47.30mg，产率为74％；1HNMR(300MHz,DMSO-d6)δ12.64(s,2H),8.23(d,J＝7.9Hz,1H),8.11(d,J＝7.7Hz,1H),7.70(d,J＝3.5Hz,5H),7.58(s,2H),7.35(d,J＝8.1Hz,1H),7.26(d,J＝7.9Hz,1H),4.63(d,J＝17.9Hz,1H),4.42(dd,J＝17.5,3.3Hz,1H),4.04(s,2H),3.82(s,1H),3.09(d,J＝3.9Hz,1H),2.65(d,1H),2.48(d,J＝4.0Hz,1H),1.31–1.24(m,3H)；HRMS(ESI):found 481.1436(C25H24N2O6S,[M+H]+,requires 481.1355)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.55min,100.00％.
(S)-3-((4-((4-乙酰胺基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(88)的合成
Figure BDA0002142422810000252
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与4-乙酰胺基苯磺酰氯(0.20g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体88 0.25g，产率为71％；1H NMR(300MHz,Chloroform-d)δ8.24(d,J＝8.2Hz,1H),7.88(d,J＝8.0Hz,1H),7.69–7.61(m,3H),7.55(d,J＝8.6Hz,3H),7.47(s,1H),7.45–7.37(m,2H),6.94(s,1H),4.04(s,1H),4.01–3.83(m,2H),3.63(s,4H),2.68(dd,J＝14.9,4.7Hz,1H),2.50–2.39(m,1H),2.29–2.24(m,1H),2.20(s,3H),1.36(d,J＝6.9Hz,3H)；ESI-MS m/z:494.2[M+H]+.
(S)-3-((4-((4-乙酰胺基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(89)的合成
Figure BDA0002142422810000253
与化合物49的合成方法相同，以化合物88(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体89 70.20mg，产率为62％；ESI-MS m/z:566.2[M+H]+.
(S)-3-((4-((4-乙酰胺基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1188)的合成
Figure BDA0002142422810000254
与化合物DDO-1160的合成方法相同，以化合物88(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1188 58.60mg，产率为60％；1HNMR(300MHz,DMSO-d6)δ10.32(s,1H),9.99(s,1H),8.09(dd,J＝37.2,7.9Hz,2H),7.65(d,J＝15.3Hz,3H),7.48(d,J＝9.4Hz,2H),7.28(d,J＝8.7Hz,1H),7.04(s,1H),3.93(s,2H),3.71(s,1H),2.96(s,1H),2.59(s,1H),2.37(d,J＝11.1Hz,1H),2.19–1.94(m,3H),1.17(d,J＝6.2Hz,3H)；HRMS(ESI):found 480.1591(C25H25N3O5S,[M+H]+,requires 480.1515)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.44min,96.3％.
(S)-3-((4-((4-乙酰胺基-N-(羧甲基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1189)的合成
Figure BDA0002142422810000261
与化合物DDO-1161的合成方法相同，以化合物89(70.20mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1189 46.60mg，产率为72％；1HNMR(300MHz,DMSO-d6)δ10.39(s,1H),8.16(s,2H),7.82–7.66(m,2H),7.66–7.46(m,3H),7.28(d,J＝8.0Hz,1H),7.13(s,1H),4.44(d,J＝17.8Hz,1H),4.32(d,J＝15.8Hz,1H),3.98(s,2H),3.77(s,1H),2.99(s,1H),2.58(s,1H),2.47–2.37(m,1H),2.11(s,3H),1.20(s,3H)；HRMS(ESI):found 538.1642(C27H27N3O7S,[M+H]+,requires 538.1570)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.38min,100.00％.
(S)-3-((4-((4-氟苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(90)的合成
Figure BDA0002142422810000262
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与4-氯苯磺酰氯(0.14g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体90 0.22g，产率为70％；1HNMR(300MHz,Chloroform-d)δ8.28–8.23(m,1H),7.76(tt,J＝6.9,2.7Hz,3H),7.54–7.45(m,2H),7.41(s,1H),7.34(d,J＝8.1Hz,1H),7.06(td,J＝9.2,8.6,2.5Hz,2H),6.79(s,1H),4.09–4.03(m,1H),3.99–3.86(m,2H),3.62(s,3H),2.68(dd,J＝14.9,4.8Hz,1H),2.50–2.40(m,1H),2.22(t,J＝2.3Hz,1H),1.36(d,J＝6.4Hz,3H).ESI-MS m/z:454.2[M+H]+.
(S)-3-((4-((4-氟-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(91)的合成
Figure BDA0002142422810000263
与化合物49的合成方法相同，以化合物90(0.10g,0.22mmol)、溴乙酸甲酯(39.78mg,0.26mmol)和K2CO3(91.08mg,0.66mmol)为原料反应得到淡黄色固体91 74.10mg，产率为64％；ESI-MS m/z:526.2[M+H]+.
(S)-3-((4-((4-氟苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1190)的合成
Figure BDA0002142422810000271
与化合物DDO-1160的合成方法相同，以化合物90(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1190 56.20mg，产率为59％；1HNMR(300MHz,DMSO-d6)δ8.28(dd,J＝7.5,1.4Hz,1H),8.01–7.94(m,2H),7.70–7.60(m,2H),7.52(td,J＝7.4,1.7Hz,1H),7.38–7.30(m,2H),6.99(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,1H),6.29(s,1H),4.29(dd,J＝12.4,3.0Hz,1H),4.01–3.89(m,2H),2.91(dd,J＝12.4,7.0Hz,1H),2.65(t,J＝2.9Hz,1H),2.52(dd,J＝12.4,7.0Hz,1H),1.35(d,J＝6.8Hz,3H).HRMS(ESI):found 441.1276(C23H21FN2O4S,[M+H]+,requires 441.1206)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.17min,98.41％.
(S)-3-((4-((N-(羧甲基)-4-氟苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1191)的合成
Figure BDA0002142422810000272
与化合物DDO-1161的合成方法相同，以化合物91(64.20mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1191 46.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ8.25(dd,J＝7.4,1.6Hz,1H),7.88(tt,J＝8.2,2.0Hz,3H),7.68(td,J＝7.5,1.5Hz,1H),7.53(td,J＝7.5,1.6Hz,1H),7.20–7.12(m,2H),7.03(d,J＝7.4Hz,1H),6.59(d,J＝7.5Hz,1H),4.44(d,J＝17.8Hz,1H),4.32(d,J＝15.8Hz,1H),4.05(dd,J＝12.5,3.1Hz,1H),3.83(dd,J＝12.5,2.9Hz,1H),3.75(h,J＝6.9Hz,1H),3.10(dd,J＝12.3,6.9Hz,1H),2.85–2.76(m,2H),1.35(d,J＝6.8Hz,3H).HRMS(ESI):found 499.1333(C25H23FN2O6S,[M+H]+,requires 499.1359)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.01min,100.00％.
(S)-3-((4-((4-氯苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(92)的合成
Figure BDA0002142422810000273
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与4-氯苯磺酰氯(0.18g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体92 0.23g，产率为69％；1HNMR(300MHz,Chloroform-d)δ8.14(d,J＝8.2Hz,1H),7.68(d,J＝8.1Hz,1H),7.60–7.53(m,2H),7.44–7.31(m,3H),7.25(s,1H),7.20(d,J＝8.5Hz,2H),6.70(s,1H),3.94(d,J＝9.3Hz,1H),3.89–3.74(m,2H),3.51(s,3H),2.63–2.53(m,1H),2.38–2.29(m,1H),2.12(t,J＝2.1Hz,1H),1.25(d,J＝6.3Hz,3H)；ESI-MS m/z:471.1[M+H]+.
(S)-3-((4-((4-氯-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(93)的合成
Figure BDA0002142422810000281
与化合物49的合成方法相同，以化合物92(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体93 64.20mg，产率为56％；ESI-MS m/z:543.1[M+H]+.
(S)-3-((4-((4-氯苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1192)的合成
Figure BDA0002142422810000282
与化合物DDO-1160的合成方法相同，以化合物92(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1192 56.20mg，产率为59％；1HNMR(300MHz,DMSO-d6)δ10.31(s,1H),8.20(d,J＝8.5Hz,1H),8.02(d,J＝8.2Hz,1H),7.81–7.60(m,3H),7.52(s,2H),7.33(s,1H),7.08(s,1H),3.98(s,2H),3.75(s,1H),3.03(s,1H),2.56(s,1H),2.41(s,1H),1.33–1.12(m,3H)；HRMS(ESI):found 457.0988(C23H21ClN2O4S,[M+H]+,requires 457.0911)；HPLC(85:15methanol:water with 1‰TFA):tR＝10.79min,97.06％.
(S)-3-((4-((N-(羧甲基)-4-氯苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1193)的合成
Figure BDA0002142422810000283
与化合物DDO-1161的合成方法相同，以化合物93(64.20mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1193 46.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ12.58(s,2H),8.16(d,J＝8.1Hz,1H),8.05(d,J＝8.0Hz,1H),7.67(d,J＝17.4Hz,3H),7.54(dd,J＝15.0,7.7Hz,3H),7.27(d,J＝7.9Hz,1H),7.14(d,J＝8.0Hz,1H),4.53(d,J＝17.9Hz,1H),4.36(d,J＝18.1Hz,1H),3.98(s,2H),3.75(s,1H),3.02(s,1H),2.59(s,1H),2.41(s,1H),1.20(s,3H)；HRMS(ESI):found 515.1044(C25H23ClN2O6S,[M+H]+,requires 515.0965)；HPLC(85:15methanol:water with 1‰TFA):tR＝10.64min,95.08％.
(S)-3-(4-((4-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(94)的合成
Figure BDA0002142422810000284
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与4-甲基苯磺酰氯(0.13g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体94 0.24g，产率为75％；1HNMR(300MHz,Chloroform-d)δ8.27–8.16(m,1H),7.82(d,J＝8.3Hz,1H),7.62(dd,J＝8.4,2.3Hz,2H),7.48–7.33(m,3H),7.31(m,1H),7.16(dd,J＝8.3,2.4Hz,2H),6.87–6.79(m,1H),4.00(d,J＝8.6Hz,1H),3.95–3.81(m,2H),3.58(d,J＝2.3Hz,3H),2.71–2.59(m,1H),2.40(dd,J＝8.7,2.3Hz,1H),2.35(d,J＝2.3Hz,3H),2.18(q,J＝2.3Hz,1H),1.31(dd,J＝6.5,2.3Hz,3H)；ESI-MS m/z:451.2[M+H]+.
(S)-3-((4-((N-(2-甲氧基-2-氧代乙基)-4-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(95)的合成
Figure BDA0002142422810000291
与化合物49的合成方法相同，以化合物94(0.10g,0.22mmol)、溴乙酸甲酯(40.39mg,0.26mmol)和K2CO3(91.08mg,0.66mmol)为原料反应得到淡黄色固体95 60.16mg，产率为52％；ESI-MS m/z:523.2[M+H]+.
(S)-3-((4-((4-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1194)的合成
Figure BDA0002142422810000292
与化合物DDO-1160的合成方法相同，以化合物94(0.10g,0.22mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1194 50.30mg，产率为53％；1HNMR(300MHz,DMSO-d6)δ12.21(s,1H),10.04(s,1H),8.14(d,J＝8.2Hz,1H),8.01(d,J＝8.2Hz,1H),7.57(d,J＝7.9Hz,2H),7.47(q,J＝8.7,7.9Hz,2H),7.28(t,J＝9.9Hz,3H),7.02(d,J＝7.9Hz,1H),3.91(d,J＝9.2Hz,2H),3.68(s,1H),2.96(s,1H),2.56(s,1H),2.37(s,1H),2.33(s,3H),1.17(d,J＝6.4Hz,3H)；HRMS(ESI):found 437.1533(C24H24N2O4S,[M+H]+,requires437.1457)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.21min,100.00％.
(S)-3-((4-((N-(羧甲基)-4-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1195)的合成
Figure BDA0002142422810000293
与化合物DDO-1161的合成方法相同，以化合物95(60.16mg,0.11mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1195 42.30mg，产率为77％；1HNMR(300MHz,DMSO-d6)δ12.52(s,2H),8.14(dd,J＝15.6,7.8Hz,2H),7.52(m,J＝8.2Hz,4H),7.36(d,J＝8.0Hz,2H),7.26(d,J＝8.1Hz,1H),7.12(d,J＝8.0Hz,1H),4.47(d,J＝17.8Hz,1H),4.34(d,J＝18.0Hz,1H),3.97(s,2H),3.75(s,1H),3.01(s,1H),2.59(s,1H),2.44(s,1H),2.40(s,3H),1.20(s,3H)；HRMS(ESI):found 495.1587(C26H26N2O6S,[M+H]+,requires495.1512)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.11min,100.00％.
(S)-3-((4-((4-异丙基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(96)的合成
Figure BDA0002142422810000301
与化合物48合成方法相同，化合物77(0.28g,0.71mmol)脱Boc后与4-异丙基苯磺酰氯(0.19g,0.85mmol)、吡啶(0.17g,2.13mmol)反应得到白色固体96 0.24g，产率为70％；1H NMR(300MHz,Chloroform-d)δ8.20(d,J＝8.4Hz,1H),7.72(d,J＝8.3Hz,1H),7.62(d,J＝8.4Hz,2H),7.46–7.31(m,4H),7.22–7.14(m,2H),6.82(s,1H),4.00(t,J＝6.4Hz,1H),3.93–3.78(m,2H),3.58(s,3H),2.89(p,J＝7.0Hz,1H),2.64(dd,J＝14.9,4.7Hz,1H),2.44–2.34(m,1H),2.18(d,J＝2.5Hz,1H),1.31(d,J＝6.4Hz,3H),1.19(d,J＝6.9Hz,6H)；ESI-MS m/z:479.2[M+H]+.
(S)-3-((4-((4-异丙基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(97)的合成
Figure BDA0002142422810000302
与化合物49的合成方法相同，以化合物96(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体97 60.40mg，产率为52％；ESI-MS m/z:551.2[M+H]+.
(S)-3-((4-((4-异丙基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1196)的合成
Figure BDA0002142422810000303
与化合物DDO-1160的合成方法相同，以化合物96(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1196 52.80mg，产率为54％；1HNMR(300MHz,DMSO-d6)δ12.23(s,1H),10.03(s,1H),8.14(d,J＝8.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.57(d,J＝8.0Hz,2H),7.45(d,J＝7.9Hz,1H),7.36(dd,J＝11.9,7.9Hz,3H),7.28(d,J＝8.0Hz,1H),7.08(d,J＝8.0Hz,1H),4.01–3.84(m,2H),3.69(s,1H),2.95(d,J＝8.6Hz,1H),2.90(d,J＝6.9Hz,1H),2.57(d,J＝4.0Hz,1H),2.37–2.29(m,1H),1.16(d,J＝6.8Hz,9H)；HRMS(ESI):found 465.1846(C26H28N2O4S,[M+H]+,requires 465.1770)；HPLC(85:15methanol:water with 1‰TFA):tR＝10.02min,100.00％.
(S)-3-((4-((N-(羧甲基)-4-异丙基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1197)的合成
Figure BDA0002142422810000304
与化合物DDO-1161的合成方法相同，以化合物97(60.40mg,0.11mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1197 46.30mg，产率为80％；1HNMR(300MHz,DMSO-d6)δ8.05(s,1H),7.93(s,1H),7.47(s,2H),7.44–7.20(m,4H),7.13(d,J＝8.8Hz,2H),4.23(d,J＝13.8Hz,1H),3.99(d,J＝16.0Hz,1H),3.85(s,2H),3.65(s,1H),2.88(s,1H),2.77(s,1H),2.61(s,1H),2.30(d,J＝13.6Hz,1H),1.22–0.87(m,9H)；HRMS(ESI):found 523.1903(C28H30N2O6S,[M+H]+,requires 523.1825)；HPLC(85:15methanol:water with1‰TFA):tR＝9.91min,99.49％.
((S)-3-((4-((2-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(98)的合成
Figure BDA0002142422810000311
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2-甲氧基苯磺酰氯(0.17g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体98 0.22g，产率为69％；1H NMR(300MHz,Chloroform-d)δ8.19(d,J＝8.3Hz,1H,2H),7.81(s,1H),7.52(t,J＝8.5Hz,3H),7.19(m,J＝8.2,6.8Hz,4H),7.02(s,2H),4.10(m,1H),4.03(s,3H),3.97–3.81(m,2H),3.56(s,3H),2.61(s,1H),2.37(dd,J＝14.9,8.5Hz,1H),2.17(d,J＝2.4Hz,1H),1.30(s,3H)；ESI-MS m/z:467.2[M+H]+.
(S)-3-((4-((2-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(99)的合成
Figure BDA0002142422810000312
与化合物49的合成方法相同，以化合物98(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体99 70.26mg，产率为62％；ESI-MS m/z:539.2[M+H]+.
(S)-3-((4-((4-乙酰胺基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1198)的合成
Figure BDA0002142422810000313
与化合物DDO-1160的合成方法相同，以化合物98(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1198 60.20mg，产率为63％；1HNMR(300MHz,DMSO-d6)δ9.87(d,J＝3.4Hz,1H),8.12(d,J＝8.4Hz,2H),7.63–7.43(m,4H),7.27(d,J＝8.4Hz,1H),7.14(s,2H),6.94(d,J＝8.7Hz,1H),3.91(d,J＝9.8Hz,2H),3.75(d,J＝3.4Hz,3H),3.68(s,1H),2.95(s,1H),2.51(s,1H),2.33(t,J＝12.1Hz,1H),1.16(d,J＝6.3Hz,3H)；HRMS(ESI):found 453.1486(C24H24N2O5S,[M+H]+,requires 453.1406)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.67min,96.78％.
(S)-3-((4-((N-(羧甲基)-2-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1199)的合成
Figure BDA0002142422810000321
与化合物DDO-1161的合成方法相同，以化合物99(70.26mg,0.13mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1199 50.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ8.12(d,J＝8.0Hz,1H),8.01(dd,J＝8.6,4.7Hz,1H),7.57(t,J＝7.9Hz,1H),7.46–7.38(m,3H),7.26(d,J＝6.6Hz,2H),6.89(t,J＝7.6Hz,1H),4.67(d,J＝18.4Hz,1H),4.40(dd,J＝18.0,7.5Hz,1H),4.05–3.94(m,2H),3.90(d,J＝9.8Hz,3H),3.73(s,1H),2.95(s,1H),2.57(s,1H),2.43–2.32(m,1H),1.16(dt,J＝7.0,3.6Hz,3H)；HRMS(ESI):found 511.1534(C26H26N2O7S,[M+H]+,requires 511.1561)；HPLC(85:15methanol:water with1‰TFA):tR＝8.59min,100.00％.
((S)-3-((4-((3-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(100)的合成
Figure BDA0002142422810000322
化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与3-甲氧基苯磺酰氯(0.17g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体100 0.22g，产率为69％；1HNMR(300MHz,Chloroform-d)δ8.25(d,J＝8.3Hz,1H),7.82(d,J＝8.2Hz,1H),7.49(d,J＝7.8Hz,1H),7.41(dd,J＝8.0,3.4Hz,3H),7.35–7.28(m,3H),7.15(d,J＝4.0Hz,1H),7.07–7.03(m,1H),6.91(s,1H),4.05(q,J＝5.6,4.8Hz,1H),3.99–3.89(m,1H),3.68(s,1H),3.64(s,3H),3.62(s,3H),2.67(dd,J＝15.0,4.7Hz,1H),2.42(dd,J＝15.0,8.6Hz,1H),2.22(s,1H),1.30(d,J＝9.2Hz,3H)；ESI-MS m/z:466.2[M+H]+.
(S)-3-((4-((3-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(101)的合成
Figure BDA0002142422810000323
与化合物49的合成方法相同，以化合物100(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体10170.26mg，产率为62％；ESI-MS m/z:539.2[M+H]+.
(S)-3-((4-((3-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1200)的合成
Figure BDA0002142422810000331
与化合物DDO-1160的合成方法相同，以化合物100(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1200 60.20mg，产率为63％；1HNMR(300MHz,DMSO-d6)δ9.87(d,J＝3.4Hz,1H),8.12(d,J＝8.4Hz,2H),7.63–7.43(m,4H),7.27(d,J＝8.4Hz,1H),7.14(s,2H),6.94(d,J＝8.7Hz,1H),3.91(d,J＝9.8Hz,2H),3.75(d,J＝3.4Hz,3H),3.68(s,1H),2.95(s,1H),2.51(s,1H),2.33(t,J＝12.1Hz,1H),1.16(d,J＝6.3Hz,3H)；HRMS(ESI):found 453.1486(C24H24N2O5S,[M+H]+,requires 453.1406)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.63min,95.03％.
(S)-3-((4-((N-(羧甲基)-3-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1201)的合成
Figure BDA0002142422810000332
与化合物DDO-1161的合成方法相同，以化合物101(70.26mg,0.13mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1201 50.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ8.38(dd,J＝7.5,1.5Hz,1H),8.04(dd,J＝7.4,1.6Hz,1H),7.66(ddd,J＝8.5,5.2,1.7Hz,2H),7.57–7.46(m,3H),7.13(dt,J＝7.5,2.0Hz,1H),6.86(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,1H),4.52(d,J＝12.3Hz,1H),4.35(d,J＝12.5Hz,1H),4.14(dd,J＝12.4,3.0Hz,1H),4.07(dd,J＝12.4,3.0Hz,1H),3.81(s,3H),3.68(s,1H),2.95(dd,J＝12.5,6.9Hz,1H),2.83(t,J＝3.0Hz,1H),2.74(dd,J＝12.4,7.0Hz,1H),1.23(d,J＝6.8Hz,3H).HRMS(ESI):found 511.1534(C26H26N2O7S,[M+H]+,requires 511.1461)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.84min,99.04％.
(S)-3-((4-((2-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(102)的合成
Figure BDA0002142422810000333
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2-甲基苯磺酰氯(0.15g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体102 0.21g，产率为68％；1HNMR(300MHz,Chloroform-d)δ8.27–8.21(m,1H),7.93(dd,J＝8.2,1.5Hz,2H),7.49(ddd,J＝7.0,4.3,1.7Hz,2H),7.42(dd,J＝7.5,1.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.24(d,J＝6.5Hz,2H),7.16–7.10(m,1H),6.95(d,J＝5.9Hz,1H),4.00(dt,J＝7.5,3.8Hz,1H),3.96–3.86(m,2H),3.59(s,3H),2.63(s,1H),2.58(s,3H),2.45–2.37(m,1H),2.18(t,J＝2.4Hz,1H),1.33–1.30(m,3H)；ESI-MS m/z:451.2[M+H]+.
(S)-3-((4-((N-(2-甲氧基-2-氧代乙基)-2-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基甲基)丁酸甲酯(103)的合成
Figure BDA0002142422810000341
与化合物49的合成方法相同，以化合物102(0.10g,0.22mmol)、溴乙酸甲酯(40.80mg,0.26mmol)和K2CO3(91.08mg,0.66mmol)为原料反应得到淡黄色固体10372.26mg，产率为63％；ESI-MS m/z:523.2[M+H]+.
(S)-3-((4-((2-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1202)的合成
Figure BDA0002142422810000342
与化合物DDO-1160的合成方法相同，以化合物102(0.10g,0.22mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1202 61.30mg，产率为64％；1HNMR(300MHz,DMSO-d6)δ10.07(s,1H),8.15(d,J＝8.4Hz,1H),8.04–7.99(m,1H),7.71(d,J＝7.9Hz,1H),7.46(tt,J＝11.3,6.2Hz,3H),7.32(d,J＝8.1Hz,1H),7.27(d,J＝7.0Hz,1H),6.99(d,J＝8.0Hz,1H),3.99–3.83(m,2H),3.72–3.67(m,1H),2.93(s,1H),2.54(dd,J＝13.8,3.4Hz,1H),2.45(s,3H),2.33(dd,J＝15.0,9.4Hz,1H),1.13(dd,J＝16.2,6.5Hz,3H)；HRMS(ESI):found 437.1536(C24H24N2O4S,[M+H]+,requires 437.1457)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.99min,97.94％.
(S)-3-((4-((N-(羧甲基)-2-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1203)的合成
Figure BDA0002142422810000343
与化合物DDO-1161的合成方法相同，以化合物103(72.26mg,0.14mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1203 52.80mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ8.20–8.10(m,1H),7.97(dd,J＝22.9,8.3Hz,1H),7.81(t,J＝6.5Hz,1H),7.47(dt,J＝14.0,7.6Hz,3H),7.41–7.33(m,1H),7.24(dd,J＝9.5,3.9Hz,2H),7.04(d,J＝8.1Hz,1H),4.53(d,J＝17.9Hz,1H),4.35(d,J＝18.1Hz,1H),4.06–3.84(m,2H),3.75(s,1H),2.71(s,1H),2.58(dd,J＝15.0,5.0Hz,1H),2.40(td,J＝9.9,9.5,5.0Hz,1H),2.03(d,J＝8.0Hz,1H),1.95(d,J＝8.4Hz,2H),1.26–1.14(m,3H)；HRMS(ESI):found495.1594(C26H26N2O6S,[M+H]+,requires 495.1512)；HPLC(85:15methanol:water with1‰TFA):tR＝9.22min,100.00％.
(S)-3-((4-((2,4-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(104)的合成
Figure BDA0002142422810000351
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2，4-二甲基苯磺酰氯(0.17g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体104 0.22g，产率为69％；1H NMR(300MHz,Chloroform-d)δ8.26–8.22(m,1H),7.96(d,J＝2.6Hz,1H),7.80(d,J＝4.2Hz,1H),7.50(dd,J＝6.8,2.8Hz,2H),7.33(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),7.07(s,2H),6.82(s,1H),3.99(s,1H),3.92(dd,J＝14.3,7.3Hz,2H),3.59(s,3H),2.66(dd,J＝10.3,4.6Hz,1H),2.56(d,J＝4.1Hz,3H),2.44–2.40(m,1H),2.36(s,3H),2.19(s,1H),1.31(s,3H)；ESI-MS m/z:465.2[M+H]+.
(S)-3-((4-((N-(2-甲氧基-2-氧代乙基)-2,4-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(105)的合成
Figure BDA0002142422810000352
与化合物49的合成方法相同，以化合物104(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体10574.06mg，产率为66％；ESI-MS m/z:537.2[M+H]+.
(S)-3-((4-((2,4-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1204)的合成
Figure BDA0002142422810000353
与化合物DDO-1160的合成方法相同，以化合物104(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1204 59.80mg，产率为63％；1HNMR(300MHz,DMSO-d6)δ10.00(s,1H),8.19–8.13(m,1H),8.05(dd,J＝5.9,3.2Hz,1H),7.63–7.58(m,1H),7.49–7.43(m,2H),7.25(d,J＝8.1Hz,1H),7.15(s,1H),7.09(d,J＝7.5Hz,1H),6.99(d,J＝7.8Hz,1H),3.99–3.84(m,2H),3.71(d,J＝8.6Hz,1H),2.93(s,1H),2.58–2.51(m,1H),2.44(d,J＝8.3Hz,3H),2.36(d,J＝9.4Hz,1H),2.29(s,3H),1.16(d,J＝6.5Hz,3H)；HRMS(ESI):found 451.1690(C25H26N2O4S,[M+H]+,requires 451.1613)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.55min,100.00％.
(S)-3-((4-((N-(羧甲基)-2,4-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1205)的合成
Figure BDA0002142422810000361
与化合物DDO-1161的合成方法相同，以化合物105(74.06mg,0.14mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1205 50.20mg，产率为70％；1HNMR(300MHz,DMSO-d6)δ12.49(s,2H),8.19–8.14(m,1H),8.07(d,J＝8.2Hz,1H),7.70(d,J＝8.1Hz,1H),7.48(p,J＝7.1Hz,2H),7.28(d,J＝8.1Hz,1H),7.20(dd,J＝10.5,6.4Hz,2H),7.06(d,J＝4.5Hz,1H),4.55–4.33(m,2H),3.97(s,2H),3.75(s,1H),2.97(s,1H),2.57(d,J＝15.2Hz,1H),2.45–2.36(m,1H),2.32(s,3H),1.94(dd,J＝21.6,8.0Hz,3H),1.21(d,J＝10.7Hz,3H)；HRMS(ESI):found 509.1744(C27H28N2O6S,[M+H]+,requires 509.1668)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.48min,97.95％.
(S)-3-(丙-2-炔-1-基)(4-((2,4,6-三甲基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(106)的合成
Figure BDA0002142422810000362
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2，4，6-三甲基苯磺酰氯(0.18g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体106 0.23g，产率为70％；1H NMR(300MHz,Chloroform-d)δ8.27–8.22(m,1H),8.01(q,J＝4.8,2.9Hz,1H),7.49(dt,J＝8.5,5.1Hz,3H),6.98(d,J＝7.8Hz,1H),6.92(s,2H),6.73(s,1H),4.00(s,1H),3.91(d,J＝14.2Hz,2H),3.60(s,3H),2.68–2.62(m,1H),2.49(s,6H),2.44–2.37(m,1H),2.31(s,3H),2.17(d,J＝2.4Hz,1H),1.31(d,J＝1.6Hz,3H)；ESI-MS m/z:479.2[M+H]+.
(S)-3-((4-((N-(2-甲氧基-2-氧代乙基)-2,4,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-甲基)基)氨基)丁酸甲酯(107)的合成
Figure BDA0002142422810000363
与化合物49的合成方法相同，以化合物106(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体10770.20mg，产率为61％；ESI-MS m/z:551.2[M+H]+.
(S)-3-(丙-2-炔-1-基(4-((2,4,6-三甲基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1206)的合成
Figure BDA0002142422810000364
与化合物DDO-1160的合成方法相同，以化合物106(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1206 60.20mg，产率为64％；1HNMR(300MHz,DMSO-d6)δ12.20(s,1H),9.86(s,1H),8.14(t,J＝6.9Hz,1H),8.03–7.95(m,1H),7.45(td,J＝8.3,4.0Hz,2H),7.24(d,J＝8.0Hz,1H),6.93(d,J＝1.9Hz,3H),4.04–3.85(m,2H),3.69(s,1H),2.92(d,J＝2.4Hz,1H),2.56(d,J＝4.3Hz,1H),2.47–2.37(m,1H),2.31(s,6H),2.22(s,3H),1.16(d,J＝6.5Hz,3H)；13C NMR(75MHz,DMSO-d6)δ172.82,144.89,141.53,138.53,131.48,128.39,125.82,125.75,124.07,123.74,123.59,119.54,80.93,74.49,54.48,38.67,38.49,37.33,22.55,20.35,17.00；HRMS(ESI):found465.1848(C26H28N2O4S,[M+H]+,requires 465.1770)；HPLC(85:15methanol:water with1‰TFA):tR＝11.81min,100.00％.
(S)-3-((4-((N-(羧甲基)-2,4,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1207)的合成
Figure BDA0002142422810000371
与化合物DDO-1161的合成方法相同，以化合物107(70.20mg,0.13mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1207 50.10mg，产率为73％；1HNMR(300MHz,DMSO-d6)δ8.13(t,J＝7.6Hz,1H),7.86(d,J＝8.6Hz,1H),7.52–7.41(m,2H),7.38–7.25(m,2H),6.85(d,J＝6.3Hz,2H),4.70(d,J＝17.7Hz,1H),4.38(d,J＝17.4Hz,1H),3.95(s,2H),3.72(s,1H),2.95(s,1H),2.57(dd,J＝15.3,4.4Hz,1H),2.42–2.32(m,1H),2.17(s,3H),2.14(d,J＝4.0Hz,6H),1.25–1.13(m,3H)；13C NMR(75MHz,DMSO-d6)δ172.77,170.22,146.84,142.07,139.23,132.29,131.57,130.78,129.29,126.02,125.73,123.72,123.64,119.29,119.15,74.57,54.75,54.61,52.89,38.66,38.10,36.99,36.82,22.82,20.31,17.15,16.67；HRMS(ESI):found 523.1897(C28H30N2O6S,[M+H]+,requires523.1825)；HPLC(85:15methanol:water with 1‰TFA):tR＝10.15min,99.20％.
(S)-3-(丙-2-炔-1-基)(4-((2,3,5,6-四甲基苯基)磺酰胺基)萘-1-基)氨基)丁酸甲酯(108)的合成
Figure BDA0002142422810000372
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2，3，5，6-四甲基苯磺酰氯(0.19g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体108 0.22g，产率为65％；1HNMR(300MHz,Chloroform-d)δ8.28–8.24(m,1H),8.14–8.08(m,1H),7.56–7.51(m,2H),7.33(s,1H),7.17(s,1H),6.99(d,J＝8.0Hz,1H),6.71(s,1H),4.02(s,1H),3.93(d,J＝14.4Hz,2H),3.61(s,3H),2.63(d,J＝4.4Hz,1H),2.44(s,6H),2.38(d,J＝9.1Hz,1H),2.27(s,6H),2.19(d,J＝2.4Hz,1H),1.33(s,3H)；ESI-MS m/z:493.2[M+H]+.
(S)-3-((4-((N-(2-甲氧基-2-氧代乙基)-2,3,5,6-四甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-甲基)基)氨基)丁酸甲酯(109)的合成
Figure BDA0002142422810000373
与化合物49的合成方法相同，以化合物108(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体10968.20mg，产率为61％；ESI-MS m/z:565.2[M+H]+.
(S)-3-(丙-2-炔-1-基(4-((2,3,5,6-四甲基苯基)磺酰胺基)萘-1-基)氨基)丁酸(DDO-1208)的合成
Figure BDA0002142422810000381
与化合物DDO-1160的合成方法相同，以化合物108(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1208 60.10mg，产率为63％；1HNMR(300MHz,DMSO-d6)δ9.90(s,1H),8.18–8.08(m,2H),7.48(td,J＝6.1,5.3,2.5Hz,2H),7.25(d,J＝8.0Hz,1H),7.17(s,1H),6.97(d,J＝8.0Hz,1H),4.00–3.85(m,2H),3.69(s,1H),2.92(s,1H),2.54(d,J＝3.9Hz,1H),2.38–2.30(m,1H),2.23(s,6H),2.15(s,6H),1.14(dd,J＝16.5,6.5Hz,3H)；HRMS(ESI):found 479.1996(C27H30N2O4S,[M+H]+,requires479.1999)；HPLC(85:15methanol:water with 1‰TFA):tR＝12.68min,96.84％.
(S)-3-((4-((N-(羧甲基)-2,3,5,6-四甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1209)的合成
Figure BDA0002142422810000382
与化合物DDO-1161的合成方法相同，以化合物109(68.20mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1209 48.30mg，产率为75％；1HNMR(300MHz,DMSO-d6)δ12.52(s,2H),8.16–8.02(m,1H),7.89(dd,J＝11.9,8.4Hz,1H),7.58(t,J＝7.9Hz,1H),7.44(t,J＝7.5Hz,1H),7.34(dd,J＝8.2,5.0Hz,2H),7.12(d,J＝3.8Hz,1H),4.73(ddd,J＝17.7,5.0,2.5Hz,1H),4.47(d,J＝17.4Hz,1H),4.07–3.83(m,2H),3.76–3.66(m,1H),2.96(dd,J＝5.0,2.5Hz,1H),2.62–2.53(m,1H),2.40–2.31(m,1H),2.07(dd,J＝6.8,3.3Hz,12H),1.28–1.21(m,3H)；HRMS(ESI):found 537.2051(C29H32N2O6S,[M+H]+,requires 537.2053)；HPLC(85:15methanol:water with 1‰TFA):tR＝10.67min,100.00％.
(S)-3-((4-((3,4-二甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(110)的合成
Figure BDA0002142422810000383
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与3,4-二甲氧基苯磺酰氯(0.20g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体110 0.23g，产率为68％；1H NMR(300MHz,Chloroform-d)δ8.31–8.23(m,1H),7.84(d,J＝7.6Hz,1H),7.47–7.41(m,4H),7.38(d,J＝4.1Hz,1H),7.08(d,J＝2.2Hz,1H),6.92(s,1H),6.85(d,J＝5.8Hz,1H),4.09–3.99(m,2H),3.96(d,J＝2.4Hz,1H),3.91(s,3H),3.65(s,3H),3.62(s,3H),2.72–2.65(m,1H),2.42(dd,J＝14.9,8.6Hz,1H),2.21(t,J＝2.3Hz,1H),1.33(d,J＝5.0Hz,3H)；ESI-MS m/z:496.2[M+H]+.
(S)-3-((4-((3,4-二甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(prop-2-yn-1)基)氨基)丁酸甲酯(111)的合成
Figure BDA0002142422810000391
与化合物49的合成方法相同，以化合物110(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体11160.20mg，产率为53％；ESI-MS m/z:541.2[M+H]+.
(S)-3-((4-((3,4-二甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1210)的合成
Figure BDA0002142422810000392
与化合物DDO-1160的合成方法相同，以化合物110(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1210 60.80mg，产率为62％；1HNMR(300MHz,DMSO-d6)δ12.19(s,1H),9.89(s,1H),8.16(d,J＝8.3Hz,1H),7.98(d,J＝8.3Hz,1H),7.51–7.38(m,2H),7.35–7.27(m,2H),7.11–7.03(m,2H),6.98(d,J＝2.2Hz,1H),4.02–3.84(m,2H),3.81(s,3H),3.70(t,J＝9.9Hz,1H),3.54(s,3H),2.94(d,J＝2.2Hz,1H),2.59–2.53(m,1H),2.41–2.31(m,1H),1.18(d,J＝6.4Hz,3H)；HRMS(ESI):found483.1583(C25H26N2O6S,[M+H]+,requires 483.1584)；HPLC(85:15methanol:water with1‰TFA):tR＝8.62min,98.71％.
(S)-3-((4-((N-(羧甲基)-3,4-二甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1211)的合成
Figure BDA0002142422810000393
与化合物DDO-1161的合成方法相同，以化合物111(60.20mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1211 40.30mg，产率为74％；1HNMR(300MHz,DMSO-d6)δ12.47(s,2H),8.22–8.08(m,2H),7.58–7.47(m,2H),7.31(d,J＝8.1Hz,2H),7.13(td,J＝8.2,2.8Hz,2H),6.94(dd,J＝4.6,2.2Hz,1H),4.50–4.32(m,2H),4.07–3.88(m,2H),3.85(s,3H),3.77(d,J＝7.5Hz,1H),3.69–3.58(m,3H),2.98(d,J＝2.3Hz,1H),2.62–2.54(m,1H),2.44–2.34(m,1H),1.26–1.18(m,3H)；HRMS(ESI):found541.1637(C27H28N2O8S,[M+H]+,requires 541.1639)；HPLC(85:15methanol:water with1‰TFA):tR＝8.13min,99.27％.
(S)-3-((4-((3-氟-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(112)的合成
Figure BDA0002142422810000401
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与3-氟-4-甲氧基苯磺酰氯(0.18g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体112 0.21g，产率为64％；1H NMR(300MHz,Chloroform-d)δ8.26(dd,J＝7.8,1.9Hz,1H),7.85(dd,J＝8.7,6.9Hz,1H),7.49(tdd,J＝7.3,5.3,1.9Hz,4H),7.42(d,J＝7.9Hz,1H),7.37–7.30(m,1H),6.95(d,J＝9.8Hz,1H),6.92–6.87(m,1H),4.03(d,J＝3.0Hz,1H),4.01–3.92(m,2H),3.91(s,3H),3.61(d,J＝5.6Hz,3H),2.70(dt,J＝14.9,5.8Hz,1H),2.51–2.40(m,1H),2.22(t,J＝2.3Hz,1H),1.35(d,J＝6.5Hz,3H)；ESI-MS m/z:485.1[M+H]+.
(S)-3-((4-((3-氟-4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(prop-2-yn-1)基)氨基)丁酸甲酯(113)的合成
Figure BDA0002142422810000402
与化合物49的合成方法相同，以化合物112(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体11364.80mg，产率为58％；ESI-MS m/z:557.2[M+H]+.
(S)-3-((4-((3-氟-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1212)的合成
Figure BDA0002142422810000403
与化合物DDO-1160的合成方法相同，以化合物112(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1212 56.80mg，产率为60％；1HNMR(300MHz,DMSO-d6)δ8.25–7.90(m,2H),7.44(s,6H),7.03(s,1H),3.89(d,J＝16.3Hz,5H),3.70(s,1H),2.92(s,1H),2.68(s,1H),2.33(s,1H),1.18(d,J＝14.8Hz,3H)；HRMS(ESI):found 471.1382(C24H23FN2O5S,[M+H]+,requires 471.1384)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.33min,96.08％.
(S)-3-((4-((N-(羧甲基)-3-氟-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1213)的合成
Figure BDA0002142422810000404
与化合物DDO-1161的合成方法相同，以化合物113(64.80mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1213 46.30mg，产率为73％；1HNMR(300MHz,DMSO-d6)δ8.21–8.13(m,1H),8.11–8.05(m,1H),7.54–7.45(m,3H),7.40(d,J＝8.6Hz,1H),7.28(dd,J＝7.6,3.6Hz,2H),7.17(d,J＝8.0Hz,1H),4.52(d,J＝17.8Hz,1H),4.41–4.32(m,1H),3.97(d,J＝3.5Hz,1H),3.91(s,3H),3.75(s,2H),2.96(d,J＝2.5Hz,1H),2.59(dd,J＝15.2,4.9Hz,1H),2.38(dq,J＝11.9,4.6,2.7Hz,1H),1.22–1.12(m,3H)；HRMS(ESI):found 529.1436(C26H25FN2O7S,[M+H]+,requires 529.1439)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.22min,95.96％.
(S)-3-((4-((3-氯-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(114)的合成
Figure BDA0002142422810000411
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与3-氯-4-甲氧基苯磺酰氯(0.20g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体114 0.24g，产率为70％；1H NMR(300MHz,Chloroform-d)δ8.29–8.16(m,1H),7.91–7.83(m,1H),7.81–7.74(m,1H),7.65–7.58(m,1H),7.55–7.40(m,3H),7.31(d,J＝8.8Hz,1H),6.92–6.82(m,2H),4.05(d,J＝9.4Hz,2H),3.97(s,1H),3.93(s,3H),3.61(d,J＝5.7Hz,3H),2.84(s,1H),2.69(dd,J＝14.8,4.8Hz,1H),2.49–2.38(m,1H),1.33(d,J＝5.9Hz,3H)；ESI-MS m/z:501.1[M+H]+.
(S)-3-((4-((3-氯-4-甲氧基-N-(2-甲氧基-2-氧代乙基)苯基)磺酰胺基)萘-1-基)(prop-2-yn-1)基)氨基)丁酸甲酯(115)的合成
Figure BDA0002142422810000412
与化合物49的合成方法相同，以化合物114(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体11560.26mg，产率为52％；ESI-MS m/z:573.1[M+H]+.
(S)-3-((4-((3-氯-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1214)的合成
Figure BDA0002142422810000413
与化合物DDO-1160的合成方法相同，以化合物114(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1214 58.00mg，产率为59％；1HNMR(300MHz,DMSO-d6)δ10.07(s,1H),8.16(d,J＝8.2Hz,1H),8.00(t,J＝7.7Hz,1H),7.61(dd,J＝6.1,2.3Hz,2H),7.47(p,J＝7.1Hz,2H),7.26(dd,J＝16.9,8.6Hz,2H),7.02(d,J＝8.1Hz,1H),3.97(d,J＝18.2Hz,2H),3.90(s,3H),3.71(s,1H),2.94(s,1H),2.59–2.51(m,1H),2.35(dd,J＝15.1,9.3Hz,1H),1.19(t,J＝9.2Hz,3H)；HRMS(ESI):found 487.1078(C24H23ClN2O5S,[M+H]+,requires 487.1089)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.98min,96.16％.
(S)-3-((4-((N-(羧甲基)-3-氯-4-甲氧基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1215)的合成
Figure BDA0002142422810000421
与化合物DDO-1161的合成方法相同，以化合物115(60.26mg,0.10mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1215 44.30mg，产率为81％；1HNMR(300MHz,DMSO-d6)δ8.14(ddd,J＝13.9,7.7,2.9Hz,2H),7.63–7.55(m,2H),7.49(tt,J＝9.2,3.9Hz,2H),7.30–7.22(m,2H),7.15(d,J＝7.9Hz,1H),4.51(d,J＝17.7Hz,1H),4.39–4.29(m,1H),3.97(s,1H),3.93(s,3H),3.75(s,2H),2.99–2.91(m,1H),2.59(dd,J＝14.8,4.1Hz,1H),2.38(dd,J＝15.8,9.1Hz,1H),1.23–1.15(m,3H)；HRMS(ESI):found545.1143(C26H25ClN2O7S,[M+H]+,requires 545.1143)；HPLC(85:15methanol:water with1‰TFA):tR＝9.96min,98.99％.
(S)-3-((4-((4-甲氧基-3-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(116)的合成
Figure BDA0002142422810000422
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与3-甲基4-甲氧基苯磺酰氯(0.18g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体116 0.22g，产率为67％；1H NMR(300MHz,Chloroform-d)δ8.33–8.21(m,1H),7.88(dd,J＝15.4,8.0Hz,1H),7.61(dd,J＝8.7,2.4Hz,1H),7.47(ddd,J＝21.5,11.3,6.4Hz,4H),7.30(d,J＝3.5Hz,1H),6.89(s,1H),6.77(dd,J＝9.4,3.9Hz,1H),4.12–4.00(m,1H),4.00–3.88(m,2H),3.86(s,3H),3.60(d,J＝7.2Hz,3H),2.68(dd,J＝15.0,4.7Hz,1H),2.42(dd,J＝15.1,8.7Hz,1H),2.21(t,J＝2.3Hz,1H),2.13(d,J＝3.1Hz,3H),1.35(q,J＝3.9,3.0Hz,3H)；ESI-MS m/z:481.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)-3-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-甲基)基)氨基)丁酸甲酯(117)的合成
Figure BDA0002142422810000423
与化合物49的合成方法相同，以化合物116(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体11770.40mg，产率为64％；ESI-MS m/z:553.2[M+H]+.
(S)-3-((4-((4-甲氧基-3-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1216)的合成
Figure BDA0002142422810000431
与化合物DDO-1160的合成方法相同，以化合物116(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1216 58.00mg，产率为60％；1HNMR(300MHz,DMSO-d6)δ9.87(s,1H),8.15(d,J＝8.2Hz,1H),8.04(d,J＝8.0Hz,1H),7.55–7.36(m,4H),7.27(d,J＝8.0Hz,1H),7.06–6.97(m,2H),3.92(d,J＝9.1Hz,2H),3.82(s,3H),3.70(s,1H),2.95(d,J＝2.2Hz,1H),2.61–2.53(m,1H),2.33(dd,J＝15.2,9.3Hz,1H),2.08(s,3H),1.24–1.11(m,3H)；HRMS(ESI):found 467.1640(C25H26N2O5S,[M+H]+,requires467.1635)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.51min,99.41％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基-3-甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1217)的合成
Figure BDA0002142422810000432
与化合物DDO-1161的合成方法相同，以化合物117(70.40mg,0.13mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1217 48.30mg，产率为70％；1HNMR(300MHz,DMSO-d6)δ8.16(dt,J＝6.8,3.4Hz,2H),7.51(dt,J＝15.9,7.9Hz,3H),7.35(s,1H),7.27(d,J＝8.1Hz,1H),7.07(dd,J＝8.2,4.0Hz,2H),4.40(s,2H),3.96(d,J＝10.5Hz,2H),3.87(s,3H),3.76(s,1H),2.99(s,1H),2.59(d,J＝14.5Hz,1H),2.46–2.35(m,1H),2.13(s,3H),1.20(dd,J＝7.2,4.4Hz,3H)；HRMS(ESI):found 525.1699(C27H28N2O7S,[M+H]+,requires 525.1699)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.42min,99.45％.
(S)-3-((4-((4-甲氧基-2,3,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(118)的合成
Figure BDA0002142422810000433
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与4-甲氧基-2,3,6-三甲基苯磺酰氯(0.20g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体1180.24g，产率为69％；1H NMR(300MHz,Chloroform-d)δ8.28–8.22(m,1H),8.08–8.02(m,1H),7.55–7.47(m,2H),7.32(s,1H),7.00(d,J＝8.0Hz,1H),6.70(s,1H),6.53(s,1H),4.05–3.97(m,1H),3.95–3.88(m,2H),3.86(s,3H),3.59(s,3H),2.67–2.60(m,1H),2.56(s,3H),2.45(s,3H),2.42–2.32(m,1H),2.17(d,J＝2.3Hz,1H),2.15(s,3H),1.33–1.29(m,3H)；ESI-MS m/z:509.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)-2,3,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-酮)炔-1-基)氨基)丁酸甲酯(119)的合成
Figure BDA0002142422810000441
与化合物49的合成方法相同，以化合物118(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体11971.06mg，产率为61％；ESI-MS m/z:581.2[M+H]+.
(S)-3-((4-((4-甲氧基-2,3,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1218)的合成
Figure BDA0002142422810000442
与化合物DDO-1160的合成方法相同，以化合物118(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1218 60.60mg，产率为60％；1HNMR(300MHz,DMSO-d6)δ12.28(s,1H),9.86(s,1H),8.21(d,J＝8.1Hz,1H),8.13(d,J＝8.1Hz,1H),7.52(dq,J＝13.4,6.6Hz,2H),7.30(d,J＝8.0Hz,1H),7.02(d,J＝7.9Hz,1H),6.74(s,1H),3.98(d,J＝9.1Hz,2H),3.84(s,3H),3.74(s,1H),2.98(s,1H),2.61(s,1H),2.41(s,3H),2.36(s,1H),2.33(s,3H),2.08(s,3H),1.22(d,J＝6.4Hz,3H)；HRMS(ESI):found 495.1946(C27H30N2O5S,[M+H]+,requires 495.1948)；HPLC(85:15methanol:waterwith 1‰TFA):tR＝10.17min,97.3％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基-2,3,6-三甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1219)的合成
Figure BDA0002142422810000443
与化合物DDO-1161的合成方法相同，以化合物119(71.06mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1219 47.20mg，产率为70％；1HNMR(400MHz,DMSO-d6)δ12.50(s,2H),8.17–8.09(m,1H),7.92(t,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.47–7.41(m,1H),7.38–7.34(m,1H),7.32(dd,J＝8.2,2.0Hz,1H),6.57(d,J＝10.4Hz,1H),4.66(d,J＝17.7Hz,1H),4.43(d,J＝17.7Hz,1H),4.02–3.86(m,2H),3.74(d,J＝3.0Hz,3H),3.71(s,1H),2.96(dt,J＝4.7,2.3Hz,1H),2.56(dd,J＝15.3,4.3Hz,1H),2.42–2.34(m,1H),2.20(d,J＝14.3Hz,3H),2.13(d,J＝2.6Hz,3H),1.96(d,J＝7.0Hz,3H),1.22(d,J＝5.6Hz,3H)；HRMS(ESI):found 553.2000(C29H32N2O7S,[M+H]+,requires553.2003)；HPLC(85:15methanol:water with 1‰TFA):tR＝9.69min,95.7％.
(S)-3-((4-((4-甲氧基-2,6-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(120)的合成
Figure BDA0002142422810000451
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2,6-二甲基-4-甲氧基苯磺酰氯(0.19g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体120 0.22g，产率为65％；1H NMR(300MHz,Chloroform-d)δ8.31–8.20(m,1H),8.05–7.98(m,1H),7.51(dt,J＝7.7,4.5Hz,2H),7.31(s,1H),7.00(d,J＝7.9Hz,1H),6.68(s,1H),6.61(s,2H),4.06–3.98(m,1H),3.92(dd,J＝13.0,2.4Hz,2H),3.83(d,J＝3.5Hz,3H),3.60(s,3H),2.65(dd,J＝14.9,4.6Hz,1H),2.50(s,6H),2.40(dd,J＝14.9,8.6Hz,1H),2.17(t,J＝2.3Hz,1H),1.32(d,J＝6.2Hz,4H)；ESI-MS m/z:495.2[M+H]+.
(S)-3-((4-((4-甲氧基-N-(2-甲氧基-2-氧代乙基)-2,6-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-甲基)-1-基)氨基)丁酸甲酯(121)的合成
Figure BDA0002142422810000452
与化合物49的合成方法相同，以化合物120(0.10g,0.20mmol)、溴乙酸甲酯(36.72mg,0.24mmol)和K2CO3(82.80mg,0.60mmol)为原料反应得到淡黄色固体12168.60mg，产率为60％；ESI-MS m/z:567.2[M+H]+.
(S)-3-((4-((4-甲氧基-2,6-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1220)的合成
Figure BDA0002142422810000453
与化合物DDO-1160的合成方法相同，以化合物120(0.10g,0.20mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1220 58.20mg，产率为60％；1HNMR(300MHz,DMSO-d6)δ12.19(s,1H),9.79(s,1H),8.15(d,J＝8.3Hz,1H),8.01(d,J＝8.5Hz,1H),7.45(p,J＝7.1Hz,2H),7.25(d,J＝7.9Hz,1H),6.94(d,J＝8.2Hz,1H),6.66(s,2H),4.01–3.83(m,2H),3.74(d,J＝2.1Hz,3H),3.69(s,1H),2.93(s,1H),2.56(s,0H),2.37(s,0H),2.31(d,J＝2.4Hz,6H),1.26–1.07(m,3H)；13C NMR(75MHz,DMSO-d6)δ172.86,162.25,144.52,131.97,131.03,130.90,128.96,128.84,125.78,123.70,123.62,122.95,119.59,114.14,81.10,74.57,55.57,54.44,38.66,37.47,17.19；HRMS(ESI):found481.1787(C26H28N2O5S,[M+H]+,requires 481.1791)；HPLC(85:15methanol:water with1‰TFA):tR＝8.86min,99.13％.
(S)-3-((4-((N-(羧甲基)-4-甲氧基-2,6-二甲基苯基)磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1221)的合成
Figure BDA0002142422810000454
与化合物DDO-1161的合成方法相同，以化合物121(68.60mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1221 46.60mg，产率为71％；1HNMR(300MHz,DMSO-d6)δ8.13(t,J＝7.5Hz,1H),7.88(d,J＝8.4Hz,1H),7.53–7.41(m,2H),7.40–7.29(m,2H),6.59(d,J＝8.9Hz,2H),4.69(d,J＝17.7Hz,1H),4.43(d,J＝17.7Hz,1H),3.96(s,2H),3.72(s,1H),3.72–3.63(m,3H),2.96(s,1H),2.57(d,J＝14.1Hz,1H),2.37(t,J＝11.9Hz,1H),2.16(d,J＝3.4Hz,6H),1.25–1.14(m,3H)；13C NMR(75MHz,DMSO-d6)δ172.83,170.00,146.54,132.83,132.48,129.82,126.97,125.99,124.63,123.61,119.10,114.17,81.07,74.69,55.68,54.58,53.11,38.67,37.12,17.11；HRMS(ESI):found539.1842(C28H30N2O7S,[M+H]+,requires 539.1846)；HPLC(85:15methanol:water with1‰TFA):tR＝8.66min,98.77％.
(S)-3-((4-((2,3-二氢苯并呋喃)-5-磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(122)的合成
Figure BDA0002142422810000461
与化合物48合成方法相同，化合物77(0.27g,0.68mmol)脱Boc后与2,3-二氢苯并呋喃-5-磺酰氯(0.18g,0.82mmol)、吡啶(0.16g,2.04mmol)反应得到白色固体122 0.21g，产率为65％；1H NMR(300MHz,Chloroform-d)δ8.26(dd,J＝7.7,1.9Hz,1H),7.88(dd,J＝7.6,1.8Hz,1H),7.63–7.56(m,1H),7.54–7.39(m,4H),7.33(d,J＝8.4Hz,1H),6.87(s,1H),6.73(d,J＝8.4Hz,1H),4.62(t,J＝8.8Hz,2H),4.04(d,J＝5.1Hz,1H),4.01–3.79(m,2H),3.61(d,J＝6.8Hz,3H),3.12(t,J＝8.8Hz,2H),2.69(dt,J＝15.1,5.2Hz,1H),2.51–2.39(m,1H),2.22(t,J＝2.3Hz,1H),1.38–1.32(m,3H)；ESI-MS m/z:479.2[M+H]+.
(S)-3-((N-(2-(2-甲氧基-2-氧代乙基)-2,3-二氢苯并呋喃)-5-磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(123)的合成
Figure BDA0002142422810000462
与化合物49的合成方法相同，以化合物122(0.10g,0.21mmol)、溴乙酸甲酯(38.56mg,0.25mmol)和K2CO3(86.94mg,0.63mmol)为原料反应得到淡黄色固体12368.21mg，产率为60％；ESI-MS m/z:551.2[M+H]+.
(S)-3-((4-((2,3-二氢苯并呋喃)-5-磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1222)的合成
Figure BDA0002142422810000463
与化合物DDO-1160的合成方法相同，以化合物122(0.10g,0.21mmol)和2M LiOH水溶液(1.00mL,2.00mmol)为原料，反应得到白色固体DDO-1222 57.00mg，产率为58％；1HNMR(300MHz,DMSO-d6)δ12.15(s,1H),9.85(s,1H),8.22–8.12(m,1H),8.06–7.99(m,1H),7.50–7.41(m,4H),7.28(d,J＝8.1Hz,1H),7.07–7.00(m,1H),6.81(dd,J＝8.3,2.9Hz,1H),4.59(t,J＝8.8Hz,2H),4.02–3.83(m,2H),3.70(p,J＝5.1,4.6Hz,1H),3.13(t,J＝8.8Hz,2H),2.95(s,1H),2.61–2.52(m,1H),2.34(dd,J＝15.1,9.3Hz,1H),1.23–1.14(m,3H)；HRMS(ESI):found 465.1476(C25H24N2O5S,[M+H]+,requires 465.1479)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.27min,98.79％.
(S)-3-((4-((N-(羧甲基)-2,3-二氢苯并呋喃)-5-磺酰胺基)萘-1-基)(丙-2-炔-1-基)氨基)丁酸(DDO-1223)的合成
Figure BDA0002142422810000471
与化合物DDO-1161的合成方法相同，以化合物123(68.21mg,0.12mmol)和2M LiOH水溶液(1.50mL,3.00mmol)为原料，反应得到白色固体DDO-1223 49.30mg，产率为79％；1HNMR(300MHz,DMSO-d6)δ12.43(s,2H),8.20–8.07(m,2H),7.56–7.48(m,2H),7.46(d,J＝7.7Hz,1H),7.36(dq,J＝8.7,3.0,2.6Hz,1H),7.28(d,J＝8.1Hz,1H),7.15–7.08(m,1H),6.85(d,J＝9.0Hz,1H),4.65(t,J＝8.9Hz,2H),4.46–4.32(m,2H),4.08–3.88(m,2H),3.76(d,J＝7.1Hz,1H),3.19(t,J＝8.9Hz,2H),3.00(d,J＝2.6Hz,1H),2.59(ddd,J＝15.0,7.7,4.4Hz,1H),2.39(dd,J＝15.1,9.2Hz,1H),1.27–1.14(m,3H)；HRMS(ESI):found 523.1530(C25H24N2O5S,[M+H]+,requires 523.1533)；HPLC(85:15methanol:water with 1‰TFA):tR＝8.10min,99.18％.
实施例2：化合物的活性测试
1、基于荧光偏振的Keap1-Nrf2PPI竞争性抑制试验(FP实验)
FP实验使用的是Corning生产的型号为3676的384孔黑板，反应总体积为40μL。按照20μL化合物，10μL 4nM的FITC标记的Nrf2 9肽，10μL 12nM的Keap1 Kelch结构域蛋白的顺序加入到孔中。阳性对照使用20μL 200nM DDO-1002，10μL 4nM的FITC标记的Nrf2 9肽，10μL 12nM的Keap1 Kelch结构域蛋白，阴性对照使用，20μL HEPES缓冲液，10μL 4nM的FITC标记的Nrf2 9肽，10μL 12nM的Keap1 Kelch结构域蛋白空白对照使用10μL 4nM的FITC标记的Nrf2 9肽，30μL的HEPES缓冲液。加料完毕后，于室温下孵育30min。检测仪器为SpectraMax Multi-Mode Microplate Reader(Molecular Devices)，选用的激发光波长为485nm,发射光波长为545nm，检测水平和垂直方向的荧光强度计算偏振值。抑制率的计算公式为：inhibition％＝1-(Pobs-Pmin)/(Pmax-Pmin)。其中，Pobs为化合物孔的偏振值，Pmax为阴性对照孔的偏振值，Pmin为空白孔的偏振值。使用GraghPad Prism进行数据处理，采用浓度-抑制率曲线计算化合物的IC50。各化合物的IC50值如前所述。
2、ARE荧光素酶报告基因实验
将处于对数生长期的HepG2-ARE-C8细胞(此细胞由Rutgers大学A.N.Tony Kong赠与)用0.1％胰酶消化，制成细胞悬液，以4×105/mL的细胞浓度加入96孔酶标板内，每孔100μL，培养过夜后，以DMSO组为阴性对照，以t-BHQ为阳性对照，细胞培养裂解试剂作为背景值。化合物作用12h，设三复孔，仔细地将生长培养基从待检细胞吸出，加入100μL预冷的PBS漂洗细胞，移去后加入事先稀释的5X裂解缓冲液(使用前在室温平衡1X缓冲液)，每孔30μL，冰上裂解15min，吸取20μL上清液放入luminoskan ascent(Thermo scientific,USA)检测。每孔加入100μL荧光素酶检测试剂，立即读数。本反应的光强度可以在将近1分钟时间内保持稳定，随后缓慢衰退，半衰期大约为10分钟。典型的延迟时间为2秒，典型的读数时间为10秒，最后测得的数据与DMSO组相除，得到的比值越大，说明诱导性越好。
通过基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验，我们已经证实，在靶标层面上，一些化合物(化合物编号见图1)能够有效地竞争性结合Keap1从而激活Nrf2。为了进一步验证该系列化合物是否能在细胞层面上有效激活Nrf2，我们使用ARE荧光素酶报告基因实验，选择活性较好的化合物(见图1)进行测试(阳性药t-BHQ)。ARE荧光素酶报告基因试验，其基本原理是通过将ARE基因插入到荧光素酶表达序列前方的质粒中，并转染至细胞，使细胞稳定表达该质粒，当小分子激活Nrf2时，Nrf2能够入核与ARE结合，进而上调荧光素酶的表达，当底物中存在荧光素时，荧光素酶能够氧化荧光素发出荧光，通过荧光强度间接反映化合物对Nrf2的激活能力。图1为荧光素酶报告基因试验结果。
从图1可以看出，选择的化合物均能在一定程度上上调Nrf2的表达。在FP试验中，靶标活性最优的化合物DDO-1221其细胞活性并不是最优的，其单酸形式DDO-1220细胞活性最佳，可能由于单酸形式分子极性较小，透膜性优于双酸形式。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (8)

1.一种萘磺酰胺类化合物，其特征在于，化学结构如通式Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ或Ⅵ所示：
Figure FDA0002413355550000011
其中，通式Ⅰ或Ⅱ中，取代基R为：
Figure FDA0002413355550000012
Figure FDA0002413355550000013
其中，通式Ⅲ或Ⅳ中，取代基R为：
Figure FDA0002413355550000014
Figure FDA0002413355550000021
其中，通式Ⅴ或Ⅵ中，取代基R为：
Figure FDA0002413355550000022
2.一种制备权利要求1中通式Ⅰ或Ⅱ所示化合物的方法，其特征在于，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与取代溴化苄在K2CO3和NaI作用下反应得到中间体23；中间体23用三氟乙酸脱Boc后得到中间体24，中间体24与4-甲氧基苯磺酰氯反应得到关键中间体25；中间体25在K2CO3作用下与溴乙酸甲酯反应得到化合物26，化合物26在LiOH的作用下脱甲酯得到通式Ⅱ双酸化合物，或中间体25在LiOH的作用下脱甲酯得到通式Ⅰ单酸化合物；合成路线如下：
Figure FDA0002413355550000023
3.一种制备权利要求1中通式Ⅲ或Ⅳ所示化合物的方法，其特征在于，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与溴丙炔在K2CO3和NaI作用下反应得到中间体35；中间体35用三氟乙酸脱Boc后得到中间体36，中间体36与不同取代基的苯磺酰氯反应得到关键中间体37；中间体37在K2CO3作用下与溴乙酸甲酯反应得到化合物38，化合物38在LiOH的作用下脱甲酯得到通式Ⅳ双酸化合物，或中间体37在LiOH的作用下脱甲酯得到通式Ⅲ单酸化合物；合成路线如下：
Figure FDA0002413355550000031
4.一种制备权利要求1中通式Ⅴ或Ⅵ所示化合物的方法，其特征在于，步骤如下：
以1-硝基萘为原料，通过亲核取代得到化合物18，再与Tf2O反应得到具有易离去基团化合物19，化合物19与(S)-氨基丁酸甲酯经Buchwald-Hartwig C-N偶联反应得到中间体20，中间体20在Pd/C和H2作用下还原硝基得到中间体21，中间体21与二碳酸二叔丁酯反应得到中间体22；中间体22与溴丙炔在K2CO3和NaI作用下反应得到中间体35；中间体35用三氟乙酸脱Boc后得到中间体36，中间体36与不同取代基的4-甲氧基苯磺酰氯反应得到关键中间体39；中间体39在K2CO3作用下与溴乙酸甲酯反应得到化合物40，化合物40在LiOH的作用下脱甲酯得到通式Ⅵ双酸化合物，或中间体39在LiOH的作用下脱甲酯得到通式Ⅴ单酸化合物；合成路线如下：
Figure FDA0002413355550000041
5.权利要求1所述萘磺酰胺类化合物用于制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂的用途。
6.权利要求1所述萘磺酰胺类化合物用于制备氧化应激状态下提高抗氧化能力的药物的用途。
7.权利要求1所述萘磺酰胺类化合物用于制备治疗或缓解疾病的炎症的药物的用途。
8.根据权利要求7所述的用途，其特征在于：所述疾病为炎性疾病或神经退行性疾病，选自慢性阻塞性肺疾病、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病、糖尿病、肠部炎症、类风湿性关节炎。
CN201910673326.3A 2019-07-24 2019-07-24 一种萘磺酰胺类化合物、制备方法和应用 Active CN110256305B (zh)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN201910673326.3A CN110256305B (zh) 2019-07-24 2019-07-24 一种萘磺酰胺类化合物、制备方法和应用
PCT/CN2020/084460 WO2021012721A1 (zh) 2019-07-24 2020-04-13 一种萘磺酰胺类化合物、制备方法和应用
EP20843918.2A EP3978471B1 (en) 2019-07-24 2020-04-13 Naphthalenesulfonamide compound, preparation method, and application
AU2020317159A AU2020317159B2 (en) 2019-07-24 2020-04-13 Naphthalenesulfonamide compound, preparation method, and application
KR1020227001409A KR20220027958A (ko) 2019-07-24 2020-04-13 나프탈렌술폰아미드계 화합물, 제조 방법 및 응용
US17/626,505 US11773057B2 (en) 2019-07-24 2020-04-13 Naphthalenesulfonamide compound, preparation method, and application
CA3147319A CA3147319C (en) 2019-07-24 2020-04-13 Naphthalenesulfonamide compound, preparation method, and application
JP2022502268A JP7301433B2 (ja) 2019-07-24 2020-04-13 ナフタレンスルホンアミド化合物、調製方法、および用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910673326.3A CN110256305B (zh) 2019-07-24 2019-07-24 一种萘磺酰胺类化合物、制备方法和应用

Publications (2)

Publication Number Publication Date
CN110256305A CN110256305A (zh) 2019-09-20
CN110256305B true CN110256305B (zh) 2020-05-26

Family

ID=67928057

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910673326.3A Active CN110256305B (zh) 2019-07-24 2019-07-24 一种萘磺酰胺类化合物、制备方法和应用

Country Status (8)

Country Link
US (1) US11773057B2 (zh)
EP (1) EP3978471B1 (zh)
JP (1) JP7301433B2 (zh)
KR (1) KR20220027958A (zh)
CN (1) CN110256305B (zh)
AU (1) AU2020317159B2 (zh)
CA (1) CA3147319C (zh)
WO (1) WO2021012721A1 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10947252B2 (en) 2018-08-20 2021-03-16 Janssen Pharmaceutica Nv Inhibitors of KEAP1-Nrf2 protein-protein interaction
CN110256305B (zh) 2019-07-24 2020-05-26 中国药科大学 一种萘磺酰胺类化合物、制备方法和应用
CN111362857B (zh) * 2020-04-23 2023-02-28 中国药科大学 一类具有吲哚啉骨架的化合物、制备方法及其医药用途
CN113861110B (zh) * 2021-11-05 2024-03-01 中国药科大学 一种多取代磺酰胺类化合物、制备方法及其医药用途
CN116574107A (zh) * 2023-05-12 2023-08-11 暨南大学 一种钩吻碱胶体金检测试纸、制备方法及应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7317391A (en) * 1990-02-14 1991-09-03 Chugai Seiyaku Kabushiki Kaisha Inhibitor of denatured ldl formation
GB0428250D0 (en) 2004-12-23 2005-01-26 Novartis Ag Organic compounds
JP6463366B2 (ja) 2013-10-10 2019-01-30 イースタン バージニア メディカル スクール １２−リポキシゲナーゼ阻害物質としての４−（（２−ヒドロキシ−３−メトキシベンジル）アミノ）ベンゼンスルホンアミド誘導体
EP2998294A1 (en) * 2014-09-16 2016-03-23 Sanofi Naphthyl sulfonamide phenyl derivatives as KEAP-1 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
CN105566241B (zh) * 2016-01-18 2018-05-25 中国药科大学 1-磺酰胺基-4-芳氧基类化合物、制备方法及其医药用途
CN108101821B (zh) * 2017-12-18 2020-11-20 中国药科大学 萘基磺酰胺氨基酸衍生物、制备方法及其医药用途
CN108752245A (zh) * 2018-07-16 2018-11-06 宁夏医科大学 萘磺酰胺乙酰胺类化合物及其应用和药物组合物
CN110256305B (zh) * 2019-07-24 2020-05-26 中国药科大学 一种萘磺酰胺类化合物、制备方法和应用

Also Published As

Publication number Publication date
CA3147319A1 (en) 2021-01-28
AU2020317159B2 (en) 2022-11-17
AU2020317159A1 (en) 2022-02-03
CA3147319C (en) 2023-10-17
JP7301433B2 (ja) 2023-07-03
JP2022541180A (ja) 2022-09-22
WO2021012721A1 (zh) 2021-01-28
KR20220027958A (ko) 2022-03-08
EP3978471B1 (en) 2023-02-22
EP3978471A4 (en) 2022-08-03
US20220251035A1 (en) 2022-08-11
EP3978471A1 (en) 2022-04-06
CN110256305A (zh) 2019-09-20
US11773057B2 (en) 2023-10-03

Similar Documents

Publication Publication Date Title
CN110256305B (zh) 一种萘磺酰胺类化合物、制备方法和应用
Riaz et al. Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone
ES2458596T3 (es) Compuestos orgánicos
SK4382002A3 (en) 2'-substituted 1,1'-biphenyl-2-carbonamides, method for the production thereof, use thereof as a medicament and pharmaceutical preparations containing said compounds
WO2021212740A1 (zh) 一类具有吲哚啉骨架的化合物、制备方法及其医药用途
CN106045892B (zh) 赛洛多辛及其中间体的新制备方法
CN113264859B (zh) 萘磺胺异硫氰酸酯类双功能小分子及其制备方法和应用
Wang et al. Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease
CN108069954A (zh) 含no供体的喹唑啉酮化合物
EP1346993A1 (en) Lactam compounds and medicinal use thereof
Pogaku et al. Synthesis and biological evaluation of new benzo [d][1, 2, 3] triazol-1-yl-pyrazole-based dihydro-[1, 2, 4] triazolo [4, 3-a] pyrimidines as potent antidiabetic, anticancer and antioxidant agents
JP2016037468A (ja) スルホンアミド誘導体及びその医薬用途
US20220401419A1 (en) Hydrogen peroxide-responsive keap1-nrf2 ppi inhibitor prodrug, and preparation method therefor
Vaz et al. Synthesis and biological evaluation of 4-hydroxy-methylpiperidinyl-N-benzyl-acylarylhydrazone hybrids designed as novel multifunctional drug candidates for Alzheimer’s disease
CN106431998B (zh) N‑[4‑(异海松酰胺基)苯基]芳磺酰胺类化合物及其制备方法与抗癌活性应用
Wei et al. Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders
EP3620454B1 (en) Carboxylic acid derivative as at2r receptor antagonist
CN115160193B (zh) 一种萘磺酰胺类小分子化合物及其应用
CN113999148B (zh) 一种n-(4-(取代磺酰基氨基)苯基)磺酰胺类化合物及其应用
BRPI0920459A2 (pt) atropoisomeros de derivados de (hidroxialquil) pirrol
Consalvi et al. A Series of COX‐2 Inhibitors Endowed with NO‐Releasing Properties: Synthesis, Biological Evaluation, and Docking Analysis
AU2003221636B2 (en) Amino acid analogues
CA3127990A1 (en) Pipecolic esters for inhibition of the proteasome
CN110294738A (zh) 硫辛酸衍生物及其制备方法和用途
CN114539106B (zh) 一种稳定同位素标记的牛磺酰胺盐酸盐的合成方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant