CN113861110B - 一种多取代磺酰胺类化合物、制备方法及其医药用途 - Google Patents
一种多取代磺酰胺类化合物、制备方法及其医药用途 Download PDFInfo
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- CN113861110B CN113861110B CN202111303760.6A CN202111303760A CN113861110B CN 113861110 B CN113861110 B CN 113861110B CN 202111303760 A CN202111303760 A CN 202111303760A CN 113861110 B CN113861110 B CN 113861110B
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- ALVRETDOJATHCM-UHFFFAOYSA-N 5-chloro-8-nitroisoquinoline Chemical compound C1=NC=C2C([N+](=O)[O-])=CC=C(Cl)C2=C1 ALVRETDOJATHCM-UHFFFAOYSA-N 0.000 description 1
- IFAMHAYSMRYQCQ-UHFFFAOYSA-N 8-chloro-5-nitroisoquinoline Chemical compound N1=CC=C2C([N+](=O)[O-])=CC=C(Cl)C2=C1 IFAMHAYSMRYQCQ-UHFFFAOYSA-N 0.000 description 1
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- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
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- 230000015556 catabolic process Effects 0.000 description 1
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- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
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- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
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- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明公开了一种多取代磺酰胺类化合物、制备方法及其医药用途。本发明提供的多取代磺酰胺类化合物对Keap1‑p62PPI具有明显的抑制活性,为一种有效的Keap1‑p62PPI抑制剂,具有开发成Keap1‑p62相互作用抑制剂药物的前景。
Description
技术领域
本发明属于药物化学领域,涉及一种多取代磺酰胺类化合物、制备方法及其医药用途。
背景技术
自噬适配器p62与肿瘤的发生发展密切相关,被认为是透明细胞肾细胞癌的致病靶点。p62常被观察到在癌细胞中表达水平升高,因此可以作为一种很好的肿瘤预后生物标志物。
细胞质中的Keap1蛋白是E3泛素连接酶的适配蛋白,是细胞防御机制的组成成分之一。p62通过Keap1-p62相互作用竞争性地结合Keap1蛋白,导致Keap1蛋白被p62介导的选择性自噬降解,使得下游基因持续激活,从而诱发癌症。因此抑制Keap1-p62的相互作用可以作为一种治疗癌症的可行策略。
发明内容
本发明的目的在于提供一种多取代磺酰胺类化合物、制备方法及其医药用途。
本发明上述目的通过如下技术方案实现:
一种多取代磺酰胺类化合物,化学结构式如下:
其中:
A=喹啉、异喹啉、茚、苯环、2-甲基苯基、3-甲基苯基、2,5-二甲基苯基、2-甲氧基苯基或3-甲氧基苯基;
B=2-甲基苯、2-溴苯、4-甲基苯、4-甲氧基苯、4-乙酰氨基苯、4-氟苯、4-氯苯、4-溴苯、4-乙基苯、4-异丙基苯、2,4-二甲基苯、2,4,6-三甲基苯、2,6-二甲基-4-溴苯、2,6-二甲基-4-氯苯、2,4,6-三乙基苯、2,4,6-三异丙基苯、2,3,5,6-四甲基苯或2,3,4,5,6-五甲基苯。
上述多取代磺酰胺类化合物的制备方法,合成路线如下:
其中:
A=喹啉、异喹啉、茚、苯环、2-甲基苯基、3-甲基苯基、2,5-二甲基苯基、2-甲氧基苯基或3-甲氧基苯基;
B=2-甲基苯、2-溴苯、4-甲基苯、4-甲氧基苯、4-乙酰氨基苯、4-氟苯、4-氯苯、4-溴苯、4-乙基苯、4-异丙基苯、2,4-二甲基苯、2,4,6-三甲基苯、2,6-二甲基-4-溴苯、2,6-二甲基-4-氯苯、2,4,6-三乙基苯、2,4,6-三异丙基苯、2,3,5,6-四甲基苯或2,3,4,5,6-五甲基苯;
X=Cl或Br。
上述多取代磺酰胺类化合物用于制备Keap1-p62相互作用抑制剂的用途。
有益效果:
本发明提供的多取代磺酰胺类化合物对Keap1-p62 PPI具有明显的抑制活性,为一种有效的Keap1-p62 PPI抑制剂,具有开发成Keap1-p62相互作用抑制剂药物的前景。
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:
(S)-3-((4-((4-甲氧基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
步骤1:(S)-3-((4-硝基异喹啉-1-基)氨基)丁酸甲酯的制备
将1-氯-4-硝基异喹啉(5.4g,25.9mmol)、(S)-3-氨基丁酸甲酯(5.76g,38.8mmol)溶于30ml DMF中,加入碳酸钾(10.7g,77.7mmol),100℃加热搅拌8h。反应完全后冷却至室温,加入200ml水,EA萃取三次,合并有机相,饱和食盐水洗、硫酸钠干燥,旋干有机相,制砂,柱层析(PE:EA=4:1),得黄色固体7.1g,产率94.8%。
步骤2:(S)-3-((4-氨基异喹啉-1-基)氨基)丁酸甲酯的制备
将(S)-3-((4-硝基异喹啉-1-基)氨基)丁酸甲酯(2g,7.7mmol)溶于20ml无水甲醇中,加入催化量的10%Pd/C,用氢气置换反应瓶中的空气,常温条件下搅拌6h。反应完全后用硅藻土滤去固体,甲醇洗三次,合并有机相,旋干得到目标产物,不经纯化可直接投入下一步。
步骤3:(S)-3-((4-((叔丁氧羰基)氨基)异喹啉-1-基)氨基)丁酸甲酯的制备
将(S)-3-((4-氨基异喹啉-1-基)氨基)丁酸甲酯(3g,11.5mmol)溶于30mlEA,加入(Boc)2O(3g,13.7mmol),常温条件下搅拌4h。反应完全后旋干EA,制砂,柱层析(PE:EA=4:1),得淡黄色油状液体3.6g,产率86.5%。
步骤4:(S)-3-((4-((叔丁氧羰基)氨基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯的制备
将(S)-3-((4-((叔丁氧羰基)氨基)异喹啉-1-基)氨基)丁酸甲酯(3g,7.5mmol)溶于10mlDMF中,加入碳酸铯(7.4g,22.5mmol),常温搅拌5min后加入3-溴丙炔(1.8g,15mmol),继续常温搅拌3h。反应完全后,加入100ml水,EA萃取三次,合并有机相,饱和食盐水洗、硫酸钠干燥,旋干有机相,制砂,柱层析(PE:EA=6:1),得黄色固体2.8g,产率84.3%。
步骤5:(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯的制备
将(S)-3-((4-((叔丁氧羰基)氨基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(2g,5.0mmol)溶于5mlDCM中,加入5ml三氟乙酸,常温搅拌2h。反应完全后,旋干DCM,加入30ml饱和碳酸氢钠溶液,EA萃取三次,合并有机相,饱和食盐水洗、硫酸钠干燥,旋干有机相得到目标产物,不经纯化可直接投入下一步。
步骤6:(S)-3-((4-((4-甲氧基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯的制备
将(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(200mg,0.67mmol)溶于无水乙腈中,加入1ml三乙胺,常温搅拌5min后,加入4-甲氧基苯磺酰氯(206mg,1mmol),60℃反应8h。反应完全后,旋干乙腈,制砂,柱层析(DCM),得到淡黄色油状液体150mg,产率47.7%。
步骤7:标题化合物的制备
将(S)-3-((4-((4-甲氧基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(100mg,0.2mmol)溶于10ml甲醇中,常温下滴加2M LiOH(1ml,2mmol),继续常温搅拌16h,反应完全后,旋干甲醇,加入10ml水,用1M HCL调pH=4,有固体析出,过滤、水洗滤饼、干燥得淡黄色固体84mg,产率86.6%。1H NMR(300MHz,Methanol-d4)δ8.30(d,J=8.4Hz,1H),8.02(d,J=8.3Hz,1H),7.84-7.79(m,3H),7.66(t,J=7.7Hz,1H),7.40(d,J=6.3Hz,1H),7.13(d,J=8.9Hz,2H),4.78(dd,J=17.9,2.5Hz,1H),4.64(q,J=6.6Hz,1H),4.34(dt,J=18.0,2.4Hz,1H),3.93(s,3H),2.86(dt,J=16.0,7.0Hz,1H),2.74-2.63(m,2H),1.45(d,J=3.4Hz,3H).HRMS(ESI):calcd For C23H24N3O5S[M+H]+454.14312,found454.14247.
实施例2:
(S)-3-((4-((4-甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
步骤1:(S)-3-((4-((4-甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯的制备
将实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯(200mg,0.67mmol)溶于无水乙腈中,加入1ml三乙胺,常温搅拌5min后,加入4-甲基苯磺酰氯(195mg,1mmol),60℃反应8h。反应完全后,旋干乙腈,制砂,柱层析(DCM),得到淡黄色油状液体138mg,产率45.4%。
步骤2:标题化合物的制备
本品用上述(S)-3-((4-((4-甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯经水解得到,方法同实施例1。得到黄色粉末,产率85.6%。1H NMR(300MHz,Methanol-d4)δ8.30(d,J=8.4Hz,1H),8.01(d,J=8.3Hz,1H),7.84-7.74(m,3H),7.70-7.63(m,1H),7.44(d,J=8.1Hz,2H),7.36(d,J=5.2Hz,1H),4.79(dd,J=17.9,2.5Hz,1H),4.64(q,J=6.5Hz,1H),4.36(dt,J=17.9,2.3Hz,1H),2.86(dt,J=16.0,7.3Hz,1H),2.74-2.63(m,2H),2.49(s,3H),1.44(d,J=3.7Hz,3H).HRMS(ESI):calcd For C23H24N3O4S[M+H]+438.14820,found 438.14753.
实施例3:
(S)-3-((4-((2,4,6-三甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,4,6-三甲基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率73.2%。1H NMR(300MHz,DMSO-d6)δ8.26(d,J=8.3Hz,1H),7.68-7.54(m,3H),7.52-7.40(m,2H),6.99(s,2H),4.81(dt,J=18.0,2.9Hz,1H),4.67(p,J=7.0Hz,1H),4.41(dt,J=18.0,2.7Hz,1H),2.74(dd,J=15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),2.25(s,3H),1.31(d,J=12.2Hz,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17860.
实施例4:
(S)-3-((4-((4-乙酰胺基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-乙酰胺基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率75.4%。1HNMR(300MHz,DMSO-d6)δ10.51(s,1H),8.42(s,1H),7.91-7.73(m,6H),7.64(s,1H),7.35(s,1H),4.73-4.55(m,2H),4.42(dt,J=18.1,3.1Hz,1H),3.25(d,J=2.1Hz,1H),2.85-2.75(m,1H),2.63-2.54(m,1H)2.14(s,3H),1.31(d,J=5.7Hz,3H).HRMS(ESI):calcd ForC24H24N4NaO5S[M+Na]+503.13596,found 503.13549.
实施例5:
(S)-3-((4-((4-氟苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-氟苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率61.2%。1H NMR(300MHz,Methanol-d4)δ8.24(d,J=8.2Hz,1H),8.00-7.92(m,3H),7.81-7.73(m,1H),7.62(t,J=7.8Hz,1H),7.49(d,J=1.7Hz,1H),7.38(t,J=8.7Hz,2H),4.85(dd,J=17.9,2.6Hz,1H),4.77-4.64(m,1H),4.35(dd,J=17.9,2.1Hz,1H),2.88-2.79(m,1H),2.74(t,J=2.5Hz,1H),2.71-2.60(m,1H),1.44(d,J=2.9Hz,3H).HRMS(ESI):calcd For C22H21FN3O4S[M+H]+442.12313,found 442.12307.
实施例6:
(S)-3-((4-((4-氯苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-氯苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率59.8%。1H NMR(300MHz,Methanol-d4)δ8.36(d,J=8.4Hz,1H),8.05-7.99(m,1H),7.91-7.85(m,3H),7.66(d,J=8.6Hz,2H),7.49-7.44(m,1H),7.38(d,J=7.1Hz,1H),4.85(dd,J=18.0,2.4Hz,1H),4.63(q,J=6.6Hz,1H),4.37(dt,J=18.1,2.2Hz,1H),2.88(dt,J=14.6,7.2Hz,1H),2.79-2.66(m,2H),1.46(d,J=3.5Hz,3H).HRMS(ESI):calcd For C22H21ClN3O4S[M+H]+458.09358,found458.09321.
实施例7:
(S)-3-((4-((4-溴苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-溴苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率64.6%。1H NMR(300MHz,Methanol-d4)δ8.20(d,J=8.3Hz,1H),7.93(d,J=8.3Hz,1H),7.79-7.70(m,5H),7.62-7.56(m,1H),7.46(s,1H),4.84(dd,J=17.9,2.5Hz,1H),4.73-4.66(m,1H),4.33(dt,J=18.0,2.1Hz,1H),2.81(dt,J=15.4,5.5Hz,1H),2.72(d,J=2.5Hz,1H),2.66-2.54(m,1H),1.44(d,J=2.9Hz,3H).HRMS(ESI):calcd For C22H21BrN3O4S[M+H]+502.04307,found502.04296.
实施例8:
(S)-3-((4-((4-乙基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-乙基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率75.8%。1H NMR(300MHz,Methanol-d4)δ8.20(d,J=8.3Hz,1H),7.94(d,J=8.3Hz,1H),7.77(d,J=7.9Hz,2H),7.72(t,J=7.6Hz,1H),7.58(t,J=7.7Hz,1H),7.48-7.43(m,3H),4.78(dd,J=17.8,2.5Hz,1H),4.67(q,J=6.5Hz,1H),4.35(dt,J=17.8,2.0Hz,1H),2.80(q,J=7.6Hz,3H),2.69-2.66(m,1H),2.65-2.55(m,1H),1.42(dd,J=10.8,6.6Hz,3H),1.31(d,J=7.6Hz,3H).HRMS(ESI):calcd For C24H26N3O4S[M+H]+452.16385,found452.16371.
实施例9:
(S)-3-((4-((4-异丙基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和4-异丙基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率75.8%。1H NMR(300MHz,Methanol-d4)δ8.19(d,J=8.4Hz,1H),7.91(d,J=8.3Hz,1H),7.78(d,J=8.3Hz,2H),7.73-7.66(m,1H),7.61-7.53(m,1H),7.48(dd,J=5.6,2.6Hz,3H),4.78(dd,J=17.9,2.4Hz,1H),4.68(q,J=6.5Hz,1H),4.35(dt,J=17.9,2.2Hz,1H),3.06(p,J=6.9Hz,1H),2.86-2.75(m,1H),2.69-2.54(m,2H),1.42(dd,J=11.0,6.5Hz,3H),1.34(s,3H),1.32(s,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17884.
实施例10:
(S)-3-((4-((2-甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和邻甲基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率84.2%。1H NMR(300MHz,Methanol-d4)δ8.46(s,1H),8.26(dd,J=8.7,1.6Hz,1H),8.13-8.09(m,1H),7.76(dd,J=8.5,1.6Hz,1H),7.66-7.55(m,2H),7.47-7.37(m,2H),7.32-7.30(m,1H),4.32-4.25(m,3H),2.73(dd,J=15.4,7.7Hz,1H),2.68-2.61(m,5H),1.31(d,J=6.6Hz,3H).HRMS(ESI):calcd For C23H24N3O4S[M+H]+438.14820,found438.14842.
实施例11:
(S)-3-((4-((2-溴苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和邻溴苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率62.8%。1H NMR(300MHz,Methanol-d4)δ8.46(s,1H),8.26(d,J=8.7Hz,1H),8.11(d,J=8.0Hz,1H),7.91(d,J=8.4Hz,1H),7.69(d,J=7.9Hz,1H),7.66-7.61(m,1H),7.60-7.51(m,2H),7.42-7.37(m,1H),4.33-4.21(m,3H),2.77-2.57(m,3H),1.31(d,J=6.6Hz,3H).HRMS(ESI):calcd ForC22H21BrN3O4S[M+H]+502.04307,found 502.04328.
实施例12:
(S)-3-((4-((2,4-二甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,4-二甲基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率43.8%。1H NMR(300MHz,Methanol-d4)δ8.19(d,J=8.4Hz,1H),7.88(d,J=8.4Hz,1H),7.74-7.66(m,2H),7.60-7.52(m,2H),7.21(s,1H),7.14(d,J=8.2Hz,1H),4.88-4.78(m,1H),4.66(q,J=6.5,6.0Hz,1H),4.37(d,J=17.9Hz,1H),2.81(dd,J=15.9,6.1Hz,1H),2.70(d,J=2.8Hz,1H),2.66-2.59(m,1H),2.48(s,3H),2.38(s,3H),1.31(d,J=7.6Hz,3H).HRMS(ESI):calcd ForC24H26N3O4S[M+H]+452.16385,found452.16307.
实施例13:
(S)-3-((4-((2,6-二甲基-4-溴苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,6-二甲基-4-溴苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率35.4%。1HNMR(300MHz,DMSO-d6)δ8.26(d,J=8.3Hz,1H),7.68-7.54(m,3H),7.52-7.39(m,2H),6.95(s,2H),4.81(dt,J=18.0,2.9Hz,1H),4.67(p,J=7.0Hz,1H),4.41(dt,J=18.0,2.7Hz,1H),2.74(dd,J=15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),1.31(d,J=7.8Hz,3H).HRMS(ESI):calcd For C24H25BrN3O4S[M+H]+530.07436,found 530.07468
实施例14:
(S)-3-((4-((2,6-二甲基-4-氯苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,6-二甲基-4-氯苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率28.5%。1HNMR(300MHz,DMSO-d6)δ8.46(s,1H),8.26(dd,J=8.7,1.6Hz,1H),8.15-8.08(m,1H),7.67-7.52(m,2H),7.37(s,2H),4.32-4.20(m,3H),2.76-2.62(m,3H),2.60(s,6H),1.31(d,J=6.6Hz,3H).HRMS(ESI):calcd For C24H25ClN3O4S[M+H]+486.12487,found486.12496.
实施例15:
(S)-3-((4-((2,3,5,6-四甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,3,5,6-四甲基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率42.6%。1HNMR(300MHz,Methanol-d4)δ8.22(t,J=8.0Hz,1H),7.81-7.72(m,2H),7.65(q,J=7.1,6.2Hz,1H),7.59-7.52(m,1H),7.16(s,1H),4.93-4.88(m,1H),4.70-4.60(m,1H),4.45(dt,J=18.4,2.6Hz,1H),2.89-2.75(m,2H),2.72-2.58(m,1H),2.34(s,6H),2.20(s,6H),1.42(d,J=7.6Hz,3H).HRMS(ESI):calcd For C26H30N3O4S[M+H]+480.19515,found 480.19449.
实施例16:
(S)-3-((4-((2,3,4,5,6-五甲基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,3,4,5,6-五甲基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率41.5%。1HNMR(300MHz,Methanol-d4)δ8.21(dd,J=8.4,5.2Hz,1H),7.82(dd,J=14.8,9.3Hz,2H),7.70-7.62(m,1H),7.60-7.51(m,1H),4.99(d,J=3.3Hz,1H),4.72-4.59(m,1H),4.47(dt,J=17.8,2.8Hz,1H),2.89-2.76(m,2H),2.71-2.61(m,1H),2.38(s,6H),2.27(d,J=1.7Hz,3H),2.20(s,6H),1.43(d,J=3.3Hz,3H).HRMS(ESI):calcd For C27H32N3O4S[M+H]+494.21080,found 494.20973.
实施例17:
(S)-3-((4-((2,4,6-三乙基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,4,6-三乙基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率54.2%。1H NMR(300MHz,Methanol-d4)δ8.46(s,1H),8.27-8.24(m,1H),8.12-8.09(m,1H),7.68-7.52(m,2H),7.11(q,J=1.0Hz,2H),4.34-4.21(m,3H),2.85-2.70(m,5H),2.68-2.58(m,4H),1.31(d,J=6.6Hz,3H),1.25-1.19(m,9H).HRMS(ESI):calcd For C28H34N3O4S[M+H]+508.22645,found 508.22631.
实施例18:
(S)-3-((4-((2,4,6-三异丙基苯基)磺酰胺基)异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由实施例1中制得的(S)-3-((4-氨基异喹啉-1-基)(丙-2-炔-1-基)氨基)丁酸甲酯和2,4,6-三异丙基苯磺酰氯制得,方法同实施例2。得到黄色粉末,产率67.5%。1HNMR(300MHz,Methanol-d4)δ8.46(s,1H),8.26(dd,J=8.7,1.6Hz,1H),8.13-8.07(m,1H),7.66-7.55(m,2H),7.19(d,J=0.7Hz,2H),4.32-4.23(m,3H),4.15-4.10(m,2H),2.99-2.92(m,1H),2.73(dd,J=15.4,7.7Hz,1H),2.69-2.59(m,2H),1.31(d,J=6.6Hz,3H),1.25-1.18(m,18H).HRMS(ESI):calcd For C31H40N3O4S[M+H]+550.27340,found 550.27386.
实施例19:
(S)-3-((5-((2,4,6-三甲基苯基)磺酰胺基)喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
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本品由5-硝基-8-氯喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率37.5%。1HNMR(300MHz,DMSO-d6)δ8.69(dd,J=4.2,1.6Hz,1H),8.04(dd,J=8.6,1.7Hz,1H),7.42(dd,J=8.5,4.2Hz,1H),7.27(d,J=8.4Hz,1H),6.95(s,2H),6.78(d,J=7.9Hz,1H),6.65(dd,J=8.7,2.0Hz,1H),4.73(dd,J=17.9,1.2Hz,1H),4.53(dd,J=18.0,2.5Hz,1H),4.06(t,J=7.5Hz,1H),3.27(q,J=2.3Hz,1H),2.74-2.58(m,2H),2.27(d,J=2.3Hz,6H),2.22(s,3H),1.31(d,J=6.6Hz,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17884.
实施例20:
(S)-3-((5-((2,3,4,5,6-五甲基苯基)磺酰胺基)喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-硝基-8-氯喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,4,5,6-五甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率37.5%。1H NMR(300MHz,Chloroform-d)δ8.68(dd,J=4.2,1.7Hz,1H),8.30(dt,J=8.6,1.8Hz,1H),7.48(t,J=8.8Hz,1H),7.33(dd,J=8.4,4.0Hz,1H),6.64(dd,J=8.4,2.9Hz,1H),4.83(dt,J=17.5,2.9Hz,1H),4.55(dd,J=17.6,2.5Hz,1H),4.18(q,J=6.4Hz,1H),2.90(d,J=15.4Hz,1H),2.60(dd,J=16.5,9.0Hz,1H),2.33(d,J=2.2Hz,6H),2.25(d,J=3.2Hz,3H),2.22(d,J=2.4Hz,1H),2.18(d,J=2.4Hz,6H),1.47(d,J=6.4Hz,3H).HRMS(ESI):calcd ForC27H32N3O4S[M+H]+494.21080,found 494.21019.
实施例21:
(S)-3-((5-((2,3,5,6-四甲基苯基)磺酰胺基)喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-硝基-8-氯喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,5,6-四甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率54.6%。1H NMR(300MHz,Chloroform-d)δ8.68(d,J=4.2Hz,1H),8.24(dt,J=8.7,2.3Hz,1H),7.44(t,J=8.5Hz,1H),7.34(dd,J=4.2,1.8Hz,1H),7.10(s,1H),6.64(dd,J=8.5,3.1Hz,1H),4.82(dt,J=17.5,2.8Hz,1H),4.56(dd,J=17.5,2.3Hz,1H),4.27-4.11(m,1H),2.98-2.86(m,1H),2.60(dt,J=15.3,7.5Hz,1H),2.30(s,6H),2.24-2.19(m,7H),1.49(d,J=6.4Hz,3H).HRMS(ESI):calcdFor C26H29N3NaO4S[M+Na]+502.17710,found 502.17621.
实施例22:
(S)-3-((5-((2,6-二甲基-4-溴苯基)磺酰胺基)喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-硝基-8-氯喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,6-二甲基-4-溴苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率48.2%。1H NMR(300MHz,Chloroform-d)δ8.69(dd,J=4.2,1.6Hz,1H),8.04(dd,J=8.6,1.7Hz,1H),7.42(dd,J=8.5,4.2Hz,1H),7.25(d,J=8.4Hz,1H),6.87(s,2H),6.78(d,J=7.9Hz,1H),6.65(dd,J=8.7,2.0Hz,1H),4.73(dd,J=17.9,1.2Hz,1H),4.53(dd,J=18.0,2.5Hz,1H),4.06(t,J=7.5Hz,1H),3.27(q,J=2.3Hz,1H),2.74-2.58(m,2H),2.27(d,J=2.3Hz,6H),1.31(d,J=6.6Hz,3H).HRMS(ESI):calcd For C24H25BrN3O4S[M+H]+530.07436,found 530.07403.
实施例23:
(S)-3-((5-((2,6-二甲基-4-氯苯基)磺酰胺基)喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-硝基-8-氯喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,6-二甲基-4-氯苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率25.6%。1H NMR(300MHz,Chloroform-d)δ8.68(d,J=4.2Hz,1H),8.02(dd,J=8.6,1.7Hz,1H),7.43(dd,J=8.5,4.3Hz,1H),7.27(d,J=8.2Hz,1H),6.90(s,2H),6.75(d,J=7.7Hz,1H),6.65(dd,J=8.6,2.1Hz,1H),4.74(dd,J=17.7,1.2Hz,1H),4.53(dd,J=18.0,2.5Hz,1H),4.07-4.03(m,1H),3.25(q,J=2.5Hz,1H),2.74-2.58(m,2H),2.27(d,J=2.3Hz,6H),1.34(d,J=7.2Hz,3H).HRMS(ESI):calcd For C24H25ClN3O4S[M+H]+486.12487,found486.12454.
实施例24:
(S)-3-((5-((2,4,6-三甲基苯基)磺酰胺基)异喹啉-8-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-硝基-8-氯异喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率67.4%。1H NMR(300MHz,Chloroform-d)δ9.88(d,J=3.3Hz,1H),8.30(s,1H),8.13(dd,J=8.3,6.3Hz,1H),7.76-7.58(m,2H),6.84(d,J=7.2Hz,2H),6.60(t,J=8.9Hz,1H),4.79(dt,J=17.6,1.9Hz,1H),4.56(ddd,J=17.5,8.8,2.5Hz,1H),4.14(s,1H),2.95(dt,J=11.9,6.3Hz,1H),2.77(dd,J=15.4,3.3Hz,1H),2.38(d,J=7.9Hz,6H),2.26(t,J=4.3Hz,4H),1.46(d,J=6.3Hz,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17919.
实施例25:
(S)-3-((8-((2,4,6-三甲基苯基)磺酰胺基)异喹啉-5-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由5-氯-8-硝基异喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率56.4%。1HNMR(300MHz,Chloroform-d)δ10.46(s,1H),7.61(d,J=9.1Hz,1H),7.31(s,1H),7.01(s,3H),6.84-6.75(m,2H),4.99(q,J=6.9Hz,1H),4.14(d,J=2.5Hz,2H),2.99(dd,J=15.9,6.9Hz,1H),2.85(dd,J=16.0,7.1Hz,1H),2.69(s,6H),2.35(s,3H),2.26(t,J=2.5Hz,1H),1.65(d,J=6.8Hz,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17934.
实施例26:
(S)-3-((1-((2,4,6-三甲基苯基)磺酰胺基)异喹啉-4-基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由4-氯-1-硝基异喹啉、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率15.2%。1HNMR(300MHz,DMSO-d6)δ8.28(d,J=8.1Hz,1H),7.68-7.51(m,3H),7.49-7.40(m,2H),7.02(s,2H),4.83(dt,J=18.0,2.9Hz,1H),4.56(p,J=7.0Hz,1H),4.41(dt,J=18.0,2.7Hz,1H),2.82(dd,J=15.3,6.1Hz,1H),2.49-2.40(m,2H),2.34(s,6H),2.25(s,3H),1.32(d,J=11.8Hz,3H).HRMS(ESI):calcd For C25H28N3O4S[M+H]+466.17950,found466.17848.
实施例27:
(S)-3-((7-((2,4,6-三甲基苯基)磺酰胺基)-2,3-二氢-1H-茚-4-基)(丙-2-炔-1-基)氨基)丁酸的制备
步骤1:(S)-3-((7-硝基-2,3-二氢-1H-茚-4-基)氨基)丁酸甲酯的制备
将7-硝基-4-溴-2,3-二氢-1H-茚(1g,3.2mmol)溶于30ml甲苯中,搅拌条件下加入Pd2(dba)3(147mg,0.16mmol)、BINAP(300mg,0.54mmol)、碳酸铯(3.14g,9.6mmol),加热回流16h。反应完全后,旋干甲苯,加入100ml水,EA萃取三次,合并有机相,饱和食盐水洗、硫酸钠干燥,旋干有机相,制砂,柱层析(PE:EA=6:1),得到黄色固体650mg,产率64.3%。
步骤2:标题化合物的制备
本品由上述(S)-3-((7-硝基-2,3-二氢-1H-茚-4-基)氨基)丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例1,得到黄色固体,产率24.3%。1H NMR(300MHz,Chloroform-d)δ7.31(s,1H),6.97(s,2H),6.64(d,J=7.9Hz,1H),6.43(d,J=7.9Hz,1H),3.88(d,J=2.4Hz,3H),2.98(t,J=7.3Hz,2H),2.85(t,J=7.5Hz,2H),2.72(d,J=14.8Hz,3H),2.56(s,6H),2.34(s,3H),2.13-2.06(m,2H),1.48-1.26(m,3H).HRMS(ESI):calcd For C25H30N2NaO4S[M+Na]+477.18185,found 477.18166.
实施例28:
(S)-3-((4-((2,4,6-三甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由对溴硝基苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率75.9%。1H NMR(300MHz,Chloroform-d)δ7.10-7.01(m,2H),6.91(s,2H),6.60-6.51(m,2H),4.49(d,J=2.5Hz,2H),3.99-3.88(m,1H),2.75-2.63(m,1H),2.56-2.50(m,1H),2.47(s,6H),2.32(s,3H),2.28(t,J=2.4Hz,1H),1.33(d,J=6.4Hz,3H).HRMS(ESI):calcd For C22H26N2NaO4S[M+Na]+437.15055,found437.14998.
实施例29:
(S)-3-((2-甲基-4-((2,3,5,6-四甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由2-溴-5-硝基甲苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,5,6-四甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率68.3%。1H NMR(300MHz,DMSO-d6)δ9.99(s,1H),7.23(s,1H),7.10(d,J=8.6Hz,1H),6.80(d,J=2.6Hz,1H),6.71(dd,J=8.5,2.7Hz,1H),3.79-3.58(m,3H),2.99-2.96(m,1H),2.46(s,6H),2.40(dd,J=14.9,4.1Hz,1H),2.22(s,6H),2.19-2.12(m,1H),2.11(s,3H),1.07(d,J=6.4Hz,3H).HRMS(ESI):calcdFor C24H30N2NaO4S[M+Na]+465.18185,found 465.18154.
实施例30:
(S)-3-((3-甲基-4-((2,3,5,6-四甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由2-硝基-5-溴甲苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,5,6-四甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率58.6%。1H NMR(300MHz,DMSO-d6)δ9.14(s,1H),7.22(s,1H),6.74-6.63(m,2H),6.57(dd,J=8.8,2.9Hz,1H),4.23(q,J=7.1,6.5Hz,1H),4.03-3.89(m,2H),3.07-3.02(m,1H),2.44(t,J=6.8Hz,2H),2.29(s,6H),2.21(s,6H),2.05(s,3H),1.19(d,J=6.5Hz,3H).HRMS(ESI):calcd For C24H30N2NaO4S[M+Na]+465.18185,found465.18158.
实施例31:
(S)-3-((2,5-二甲基-4-((2,3,5,6-四甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由2,5-二甲基-4-溴硝基苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,5,6-四甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率72.6%。1H NMR(300MHz,DMSO-d6)δ7.21(s,1H),6.99(s,1H),6.75(s,1H),3.81-3.62(m,2H),3.44(ddd,J=10.1,6.6,3.7Hz,1H),2.96-2.90(m,1H),2.33(dd,J=14.5,3.6Hz,1H),2.26(s,6H),2.19(s,6H),2.11(d,J=9.9Hz,1H),2.06(s,3H),1.97(s,3H),1.06(d,J=6.3Hz,3H).HRMS(ESI):calcdFor C25H32N2NaO4S[M+Na]+479.19750,found 479.19669.
实施例32:
(S)-3-((3-甲氧基-4-((2,3,5,6-四甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由2-甲氧基-4-溴硝基苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,3,5,6-四甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率42.8%。1H NMR(300MHz,Methanol-d4)δ7.19-7.14(m,2H),6.51(dd,J=8.8,2.7Hz,1H),6.45(d,J=2.6Hz,1H),4.37(dt,J=8.0,6.2Hz,1H),4.01(t,J=2.2Hz,2H),3.40(s,3H),2.66(dd,J=15.2,5.9Hz,1H),2.58-2.48(m,2H),2.40(s,6H),2.25(s,6H),1.32(d,J=6.7Hz,3H).HRMS(ESI):calcd For C24H30N2NaO5S[M+Na]+481.17676,found481.17605.
实施例33:
(S)-3-((3-甲基-4-((2,4,6-三甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
本品由2-硝基-5-溴甲苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率84.3%。1H NMR(300MHz,DMSO-d6)δ9.13(s,1H),7.00(s,2H),6.74(d,J=8.7Hz,1H),6.66-6.56(m,2H),4.24(q,J=6.8Hz,1H),3.98(d,J=2.4Hz,2H),3.06(d,J=2.2Hz,1H),2.49(d,J=7.7Hz,2H),2.37(s,6H),2.28(s,3H),1.94(s,3H),1.20(d,J=6.6Hz,3H).HRMS(ESI):calcd For C23H28N2NaO4S[M+Na]+451.16620,found451.16551.
实施例34:
(S)-3-((2,5-二甲基-4-((2,4,6-三甲基苯基)磺酰胺基)苯基)(丙-2-炔-1-基)氨基)丁酸的制备
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本品由2,5-二甲基-4-溴硝基苯、(S)-3-氨基丁酸甲酯、3-溴丙炔和2,4,6-三甲基苯磺酰氯制得,制备方法同实施例27,得到黄色固体,产率64.8%。1H NMR(300MHz,Methanol-d4)δ7.15(s,1H),6.99(s,2H),6.72(s,1H),3.83(dd,J=17.6,2.4Hz,1H),3.77-3.67(m,2H),2.60-2.49(m,2H),2.41(s,6H),2.33(s,3H),2.31-2.24(m,1H),2.08(d,J=13.6Hz,6H),1.23(d,J=6.4Hz,3H).HRMS(ESI):calcd For C24H30N2NaO4S[M+Na]+465.18185,found465.18116.
药效实施例:
采用荧光偏振的方法(FP实验)测试化合物对Keap1-p62 PPI的抑制活性。
测试使用384孔黑板(型号为Corning 3575),测试终体积选择40μL,分别按20μL不同浓度的化合物,10μL Keap1 Kelch结构域蛋白(40nM,终浓度10nM),10μLFITC-Acp-VDPpSTGEL荧光探针(16nM,终浓度4nM)的顺序加入孔中。每次实验设置空白对照(30μLTris缓冲液+10μL FITC-Acp-VDPpSTGEL荧光探针)和阴性对照(20μL Tris缓冲液+10μLKeap1 Kelch结构域蛋白+10μL FITC-Acp-VDPpSTGEL荧光探针)。加毕将板盖上于摇床上孵育30min后,利用多功能酶标仪在激发波长485nm发射波长为525nm的条件下得到偏振值P,利用以下公式计算抑制率,利用GraphPad软件计算IC50值,结果见表1(a化合物的结构见具体实施例)。抑制率=[1-(P化合物-P空白)/(P阴性对照-P空白)]×100%。该类小分子通过抑制Keap1-p62 PPI,阻止了下游基因持续激活,从而抑制肝细胞癌发生发展。
表1本发明化合物对Keap1-p62 PPI的IC50值
综上可见,本发明提供的多取代磺酰胺类化合物对Keap1-p62 PPI具有明显的抑制活性,为一种有效的Keap1-p62 PPI抑制剂,具有开发成Keap1-p62相互作用抑制剂药物的前景。
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 (2)
1.一种多取代磺酰胺类化合物,其特征在于,其化学结构式为:
2.权利要求1所述多取代磺酰胺类化合物用于制备Keap1-p62相互作用抑制剂的用途。
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