CN114989085B - 一种芳基内酰胺环类化合物、药物组合物及其应用 - Google Patents

一种芳基内酰胺环类化合物、药物组合物及其应用 Download PDF

Info

Publication number
CN114989085B
CN114989085B CN202210564652.2A CN202210564652A CN114989085B CN 114989085 B CN114989085 B CN 114989085B CN 202210564652 A CN202210564652 A CN 202210564652A CN 114989085 B CN114989085 B CN 114989085B
Authority
CN
China
Prior art keywords
nmr
compound
dmso
synthesis
hrms
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
CN202210564652.2A
Other languages
English (en)
Other versions
CN114989085A (zh
Inventor
刘明明
王洋
梁玉茹
乔雨
石静波
刘新华
刘学松
李�荣
李涛
闫尧瑶
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.)
Anhui Medical University
Original Assignee
Anhui Medical 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 Anhui Medical University filed Critical Anhui Medical University
Priority to CN202210564652.2A priority Critical patent/CN114989085B/zh
Publication of CN114989085A publication Critical patent/CN114989085A/zh
Application granted granted Critical
Publication of CN114989085B publication Critical patent/CN114989085B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C07D217/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

本发明涉及药物化学技术领域，具体涉及一种芳基内酰胺环类化合物、药物组合物及其应用，公开了芳基内酰胺环类化合物其化学结构，与已有的缺氧诱导因子‑1抑制剂均不相同，是一类全新结构的缺氧诱导因子‑1抑制剂这些化合物可以抑制缺氧诱导因子‑1信号通路，且具有理想的代谢稳定性，从而可能成为预防和(或)治疗转移性恶性肿瘤和(或)视网膜血管病理性生长相关疾病的药物。

Description

一种芳基内酰胺环类化合物、药物组合物及其应用
技术领域
本发明涉及药物化学技术领域，具体涉及一种芳基内酰胺环类化合物、药物组合物及其应用。
背景技术
缺氧诱导因子-1(hypoxiainduciblefactor-1，缺氧诱导因子-1)是一种普遍存在于人和哺乳动物细胞内的转录因子，在缺氧条件下，缺氧诱导因子-1的α与β亚基形成异二聚体后进入细胞核中，与下游靶基因启动子的缺氧反应元件(HREs)结合，并激活基因转录。缺氧诱导因子-1的下游靶基因相当广泛，参与了包括血管生成和恶性肿瘤细胞获得迁移侵袭能力的生物学过程(上皮间质转化，EMT)。
恶性肿瘤生长旺盛，处于缺氧状态，可激活缺氧诱导因子-1α，促进了下游多种基因的转录和表达，包括血管表皮生长因子(VEGF)、基质金属蛋白酶(MMPs)、葡萄糖转运蛋白(GLUT1)、上皮-间质转化(EMT)相关转录因子snail、twist等，通过促进血管生成、肿瘤代谢重编程、EMT、免疫逃逸、凋亡抑制等多个途径，增强了肿瘤的侵袭转移能力和放化疗抵抗性，促进肿瘤的发生发展和转移。
视网膜微血管网的渐进性损伤导致组织缺血、缺氧诱导因子-1上调、VEGF分泌的刺激，最终导致了视网膜血管病理性生长以及各种相关疾病，包括早产儿视网膜病变、糖尿病视网膜病变、年龄相关性黄斑变性和视网膜静脉阻塞、高血压性视网膜病变和视网膜动脉阻塞等,这些疾病是视力丧失的主要原因。
因此，缺氧诱导因子-1可以作为治疗恶性肿瘤、特别是转移性恶性肿瘤，以及视网膜血管病理性生长相关疾病的药物作用靶点。缺氧诱导因子-1抑制剂可以抑制VEGF水平、抑制新生血管生长、抑制细胞侵袭和迁移能力，从而对恶性肿瘤、特别是转移性恶性肿瘤，以及视网膜血管病理性生长相关疾病起到预防和治疗作用。
但目前临床上缺少以缺氧诱导因子-1为靶点，用于治疗和预防转移性恶性肿瘤以及视网膜血管病理性生长相关疾病的药物。
鉴于上述缺陷，本发明创作者经过长时间的研究和实践终于获得了本发明。
发明内容
本发明的目的在于解决临床上缺少以缺氧诱导因子-1为药物作用靶点，用于预防和(或)治疗转移性恶性肿瘤和(或)视网膜血管病理性生长相关疾病的药物的问题，提供了一种芳基内酰胺环类化合物、药物组合物及其应用。
为了实现上述目的，本发明公开了一种芳基内酰胺环类化合物，具有以下通式：
其中，X选自-CH2-、-O-、-CH2CH2-、-OCH2-；Ar1选自以下芳香环或芳香环系：
Ar2选自以下芳香环或芳香环系：
所述芳基内酰胺环类化合物为以下任意一种化合物：
所述芳基内酰胺环类化合物在人肝微粒体代谢中，具有药物开发所需的理想的稳定性。
本发明还公开了包含上述芳基内酰胺环类化合物的药物组合物，还包括药学上可以接受的辅料。
本发明还公开了上述芳基内酰胺环类化合物在制备预防和/或治疗缺氧诱导因子-1上调导致的疾病的药物中的应用；所述疾病包括乳腺癌、卵巢癌、肺癌、肝癌、宫颈癌、胃癌、肠癌以及视网膜血管病理性生长疾病。本发明公开的代表性化合物通过阻断缺氧诱导因子-1信号通路，从而抑制了肿瘤细胞的侵袭和转移能力，可以作为预防和(或)治疗恶性肿瘤的药物或药物组合物。同时，本发明公开的代表性化合物通过阻断缺氧诱导因子-1信号通路，抑制了血管表皮生长因子VEGF的信使RNA，因此，可以作为预防和(或)治疗与血管病理学生产相关疾病的药物或药物组合物。在人肝微粒体代谢检测实验中，与已公开的芳基甲酰胺类化合物相比，本发明所公开的代表性化合物具有适宜的代谢稳定性，而具有适宜的代谢稳定性是成为药物的前提条件。
与现有技术比较本发明的有益效果在于：本发明公开的芳基内酰胺环类化合物的化学结构与已有的缺氧诱导因子-1抑制剂均不相同，是一类全新结构的缺氧诱导因子-1抑制剂。此外，与公认的缺氧诱导因子-1抑制剂LW-6相比，本发明公开的芳基内酰胺环类化合物具有更强的抑制作用。与已公开的芳基甲酰胺类缺氧诱导因子-1抑制剂的化学结构相比，本发明公开的化合物在化学结构上，对其酰胺部分进行环合，形成了二氢异喹啉酮、苯并氮杂酮、苯并二氢噁嗪酮和苯并二氢氧氮杂/>酮四个类别的新型缺氧诱导因子-1抑制剂。与芳基甲酰胺类缺氧诱导因子-1抑制剂的代谢稳定性相比，本发明公开的芳基内酰胺环类化合物具有更好的代谢稳定性，在肝微粒体酶存在的条件下，半衰期比芳基甲酰胺类代表性化合物AMSP-30m提高了16～45倍。虽然环合是药物化学中结构改造的一种方法，但在实施之前并不能预测环合之后是否能够保持对缺氧诱导因子-1的抑制作用，以及是否可以增加代谢稳定性。因此，本发明所公开的化合物具有明显的新颖性和创造性，这种芳基内酰胺环类化合物，在细胞学实验中对缺氧条件下缺氧诱导因子-1信号通路具有较好的抑制作用，同时，对人肝微粒体酶代谢酶具有适宜的代谢性质，在制备预防或治疗抗肿瘤或抗视网膜血管性病变的药物上，具有良好的预防或治疗效果，并有一定的成药性。
具体实施方式
以下结合具体实施例，对本发明上述的和另外的技术特征和优点作更详细的说明。
实施例1
合成7-苯基-3-(2-苯乙基)-3,4-二氢-2H-1,3-苯并恶嗪-4-酮
反应式如下：
合成步骤如下：
(1)取反应瓶将2-溴-4羟基苯甲酸(1mmol)与苯乙胺(1monl)溶于DCM(5mL)中，加HATU(1.3mmol)在常温下搅拌反应5h。反应结束后，用水(10mL×2)洗除HATU，再用饱和食盐水(10mL×1)洗涤后，加入无水硫酸镁干燥30min后过滤浓缩，经柱分离后得到中间体A1。
(2)取中间体A1(1mmol)溶于TFA(5mL)中，经超声振荡完全溶解后加入多聚甲醛(1mmol)在室温下用磁力搅拌器搅拌反应12h。反应结束后，加入冰水(15mL)，用二氯甲烷(30mL×2)萃取，合并有机相，用饱和食盐水(15mL×1)洗涤，加入无水硫酸镁干燥后过滤浓缩，经柱分离后得到中间体A2。
(3)取封管将中间体A2(1mmol)溶于二氧六环(4mL)中，加入苯硼酸(1.3mmol)与K2CO3(1.8mmol)，在加入水(1mL)后，通入氩气后加入Pd(PPh3)2Cl2(0.1mmol)在110℃下回流12h，反应结束后真空浓缩后经柱分离后得到白色固体7-苯基-3-(2-苯乙基)-3,4-二氢-2H-1,3-苯并恶嗪-4-酮，产率78.5％。
1H NMR(600MHz,CDCl3)δ8.03(d,J＝8.1Hz,1H),7.59(d,J＝7.5Hz,2H),7.45(t,J＝7.5Hz,2H),7.41–7.26(m,6H),7.24(d,J＝7.2Hz,1H),7.15(s,1H),4.93(s,2H),3.81(t,J＝7.1Hz,2H),2.99(t,J＝7.1Hz,2H)。13C NMR(151MHz,CDCl3)δ161.44,157.52,146.46,139.02,138.25,128.31,128.26,128.15,128.13,127.74,126.58,126.08,120.94,117.13,114.02,78.40,46.89,34.41。ESI-HRMS(m/z)calcd[M+H]+＝330.1489,found 330.1484。
实施例2
合成7-(2-氟苯基)-3-苯乙基-2,3-二氢-4H-苯并[e][1,3]恶嗪-4-酮
选取2-氟苯硼酸为原料，其他实施方式同实施例1。制备的化合物为白色固体，产率为76.0％。
1H NMR(600MHz,CDCl3)δ8.03(d,J＝8.1Hz,1H),7.59(d,J＝7.5Hz,2H),7.45(t,J＝7.5Hz,2H),7.35(ddd,J＝24.0,14.7,7.3Hz,5H),7.24(d,J＝7.2Hz,1H),7.15(s,1H),4.93(s,2H),3.81(t,J＝7.1Hz,2H),2.99(t,J＝7.1Hz,2H)。13C NMR(151MHz,CDCl3)δ161.29,159.10(d,JC-F＝990HZ),157.11,140.99,138.22,129.92,129.37,129.35(d,JC-F＝30HZ),128.13,127.76,127.03(d,JC-F＝54HZ),126.09,123.90(d,JC-F＝12HZ),122.80,117.51,116.18(d,JC-F＝12HZ),115.70(d,JC-F＝90HZ),78.41,46.91,34.39。ESI-HRMS(m/z)calcd[M+H]+＝348.1394,found 348.1391。
实施例3
合成7-(2-甲氧基苯基)-3-苯乙基-2,3-二氢-4H-苯并[e][1,3]恶嗪-4-酮
选取2-甲氧基苯硼酸为原料，其他实施方式同实施例1。制备的化合物为白色固体，产率为84.0％。
1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.0Hz,1H),7.40–7.36(m,1H),7.34(t,J＝7.5Hz,3H),7.31(dd,J＝8.1,1.4Hz,1H),7.29(s,1H),7.28–7.24(m,2H),7.14(d,J＝1.3Hz,1H),7.06(t,J＝7.5Hz,1H),7.01(d,J＝8.3Hz,1H),4.94(s,2H),3.86–3.81(m,5H),3.01(t,J＝7.1Hz,2H)。13C NMR(151MHz,CDCl3)δ161.54,156.83,155.78,144.02,138.31,130.04,128.93,128.51,128.27,128.12,127.21,126.05,123.49,120.30,116.85,116.56,110.69,78.39,54.93,46.89,34.43。ESI-HRMS(m/z)calcd[M+H]+＝360.1594,found360.1591。
实施例4
合成3-(2-氟苯乙基)-7-苯基-2,3-二氢-4H-苯并[e][1,3]恶嗪-4-酮
选取2-氟苯乙胺为原料，其他实施方式同实施例1。制备的化合物为白色固体，产率为76.8％。
1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.1Hz,1H),7.59(d,J＝7.3Hz,2H),7.45(t,J＝7.6Hz,2H),7.39(t,J＝7.3Hz,1H),7.35(dd,J＝8.1,1.5Hz,1H),7.26–7.21(m,2H),7.15(d,J＝1.4Hz,1H),7.10–7.03(m,2H),5.00(s,2H),3.82(t,J＝7.1Hz,2H),3.04(t,J＝7.1Hz,2H)。13C NMR(151MHz,CDCl3)δ161.44,159.83,157.54,146.48,139.01,130.81(d,JC-F＝18HZ),128.31,128.16,128.01(d,JC-F＝30HZ),127.74,126.58,125.01(d,JC-F＝66HZ),123.77(d,JC-F＝12HZ),120.95,117.08,114.79(d,JC-F＝90HZ),114.03,78.34,45.18,27.99。ESI-HRMS(m/z)calcd[M+H]+＝348.1394,found 348.1395。
实施例5
合成3-(2-氟苯乙基)-7-苯基-2,3-二氢-4H-苯并[e][1,3]恶嗪-4-酮
选取2-氟苯乙胺和2-氟苯硼酸为原料，其他实施方式同实施例1。制备的化合物为白色固体，产率为72.7％。
1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.1Hz,1H),7.43(td,J＝7.7,1.6Hz,1H),7.38–7.34(m,1H),7.32–7.27(m,1H),7.25–7.20(m,3H),7.19–7.13(m,2H),7.10–7.02(m,2H),5.00(s,2H),3.82(t,J＝7.1Hz,2H),3.04(t,J＝7.1Hz,2H)。13C NMR(151MHz,CDCl3)δ161.67(d,JC-F＝942HZ),161.30,159.03(d,JC-F＝960HZ),157.14,141.02,130.81(d,JC-F＝18HZ),129.92,129.36(d,JC-F＝30HZ),128.02(d,JC-F＝36HZ),127.77,127.01(d,JC-F＝48HZ),125.99(d,JC-F＝66HZ),123.90(d,JC-F＝12HZ),123.78(d,JC-F＝12HZ),122.82,117.46,116.19(d,JC-F＝12HZ),115.70(d,JC-F＝90HZ),114.79(d,JC-F＝84HZ),78.35,45.21,27.98。ESI-HRMS(m/z)calcd[M+H]+＝366.1300,found 366.1306。
实施例6
合成3-(2-氟苯乙基)-7-(2-甲氧基苯基)-2,3-二氢-4H-苯并[e][1,3]恶嗪-4-酮
选取2-氟苯乙胺和2-甲氧基苯硼酸为原料，其他实施方式同实施例1。制备的化合物为白色固体，产率为80.3％。
1H NMR(600MHz,CDCl3)δ7.98(d,J＝8.0Hz,1H),7.37–7.34(m,1H),7.31(dd,J＝7.5,1.6Hz,1H),7.30–7.27(m,1H),7.25–7.20(m,2H),7.13(d,J＝1.3Hz,1H),7.05(dt,J＝15.2,7.3Hz,3H),6.99(d,J＝8.3Hz,1H),4.99(s,2H),3.83–3.79(m,5H),3.03(t,J＝7.0Hz,2H)。13C NMR(151MHz,CDCl3)δ161.54,160.64(d,JC-F＝972HZ),156.85,155.78,144.05,130.84(d,JC-F＝18HZ),130.04,128.94,128.50,127.98(d,JC-F＝30HZ),127.22,125.07(d,JC-F＝66HZ),123.76(d,JC-F＝12HZ),123.50,120.30,116.81,116.58,114.77(d,JC-F＝84HZ),110.69,78.32,54.93,45.18,28.01。ESI-HRMS(m/z)calcd[M+H]+＝360.1594,found 360.1592。
实施例7
合成2-苯乙基-6-苯基-3,4-二氢异喹啉-1(2H)-酮
反应式如下：
合成步骤如下：
(1)系列化合物合成：取封管将6-溴-1,2,3,4-四氢异喹啉(1mmol)溶于二氧六环(4mL)中，加入苯硼酸(1.3mmol)与K2CO3(1.8mmol)，在加入水(1mL)后，通入氩气后加入Pd(PPh3)2Cl2(0.1mmol)在110℃下回流12h，反应结束后真空浓缩，经柱分离后得到中间体B1。
(2)先取苯乙醇(1mmol)与甲基磺酰氯(3mmol)溶于二氯甲烷(3mL)中，加入三乙胺(3mmol)常温反应3h后旋干，加入乙腈(2mL)后，加入装有溶于乙腈(5mL)的B1(1mmol)反应瓶中，加入与三乙胺(2mmol)在80℃下回流反应8h，反应结束后真空浓缩，反应结束后真空浓缩，经柱分离后得到中间体B2。
(3)取反应瓶将中间体B2(R1＝苯基，R2＝苯基)(1mmol)溶于浓度为6％次氯酸钠(2mmol)水溶液中，在80℃下回流反应24h，反应结束后加入二氯甲烷(20mL×3)萃取，合并有机相用饱和食盐水(20mL×1)洗涤，加入无水硫酸镁干燥30min后过滤浓缩，经柱分离后得到无色油状2-苯乙基-6-苯基-3,4-二氢异喹啉-1(2H)-酮，产率67.3％。
1H NMR(600MHz,CDCl3)δ7.40–7.27(m,6H),7.23(dd,J＝6.8,2.6Hz,5H),7.19(d,J＝7.5Hz,1H),7.13(d,J＝7.5Hz,1H),3.75(t,J＝7.1Hz,2H),3.41(t,J＝6.3Hz,2H),2.91(t,J＝7.1Hz,2H),2.83(t,J＝6.3Hz,2H)。13C NMR(151MHz,CDCl3)δ162.90,143.32,142.20,139.29,138.70,129.99,129.63,128.37,127.86,127.66,127.49,127.02,126.05,125.70,125.46,48.88,46.20,33.82,28.97。ESI-HRMS(m/z)calcd[M+H]+＝328.1696,found 328.1699。
实施例8
选取苯乙醇和2-甲氧基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为61.3％。
1H NMR(600MHz,CDCl3)δ8.12(d,J＝8.0Hz,1H),7.50(dd,J＝8.0,1.4Hz,1H),7.36–7.33(m,1H),7.32–7.27(m,6H),7.25–7.21(m,1H),7.04(t,J＝7.5Hz,1H),7.00(d,J＝8.2Hz,1H),3.84–3.79(m,5H),3.42(t,J＝6.6Hz,2H),2.99(t,J＝7.3Hz,2H),2.89(t,J＝6.5Hz,2H)。13C NMR(151MHz,CDCl3)δ163.74,155.82,141.32,138.74,137.07,130.15,129.14,128.59,128.33,127.91,127.84,127.70,127.26,127.23,125.76,120.28,110.64,54.96,49.36,46.56,33.75,27.57。ESI-HRMS(m/z)calcd[M+H]+＝358.1802,found358.1805。
实施例9
合成2-((3E，5Z，7E)-8-氟八-3,5,7-三烯-1-基)-6-(2-甲氧基苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-甲氧基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为57.8％。
1H NMR(600MHz,CDCl3)δ8.11(d,J＝8.0Hz,1H),7.50(d,J＝7.8Hz,1H),7.34(t,J＝7.6Hz,1H),7.30(t,J＝9.6Hz,3H),7.24–7.18(m,1H),7.07(t,J＝6.0Hz,1H),7.04(t,J＝8.0Hz,2H),6.99(d,J＝8.2Hz,1H),3.85–3.80(m,5H),3.46(t,J＝6.4Hz,2H),3.04(t,J＝7.0Hz,2H),2.89(t,J＝6.3Hz,2H)。13C NMR(151MHz,CDCl3)δ163.78,160.72(d,JC-F＝972HZ),155.81,141.34,137.10,130.92(d,JC-F＝18HZ),130.15,129.12,128.59,127.70,127.65,127.60,127.41,127.25(d,JC-F＝12HZ),125.54(d,JC-F＝66HZ),123.57(d,JC-F＝12HZ),120.27,114.60(d,JC-F＝90HZ),110.64,54.95,47.69,46.48,27.59,27.21。ESI-HRMS(m/z)calcd[M+H]+＝377.1789,found 377.1785。
实施例10
合成2-(2-氟苯乙基)-6-(2-氟苯)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-氟苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为57.8％。
1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.44(td,J＝7.7,1.6Hz,1H),7.36–7.33(m,2H),7.25–7.20(m,2H),7.19–7.14(m,2H),7.07(dd,J＝12.2,4.5Hz,1H),7.02(dd,J＝14.3,9.0Hz,1H),3.83(t,J＝7.2Hz,2H),3.47(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.91(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.54,160.74(d,JC-F＝954HZ),159.10(d,JC-F＝972HZ),138.40,137.53,130.89(d,JC-F＝18HZ),130.05,128.98(d,JC-F＝30HZ),127.88(d,JC-F＝342HZ),127.73,127.56(d,JC-F＝48HZ),126.87(d,JC-F＝12HZ),126.86,126.27,125.47(d,JC-F＝60HZ),123.85(d,JC-F＝12HZ),123.59(d,JC-F＝12HZ),115.60(d,JC-F＝90HZ),114.62(d,JC-F＝84HZ),47.74,46.44,27.55,27.21。ESI-HRMS(m/z)calcd[M+H]+＝364.1507,found 364.1504。
实施例11
合成2-(2-氟苯乙基)-6-(4-氟苯)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和3-氟苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为64.7％。
1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.0Hz,1H),7.54(dd,J＝8.0,1.1Hz,1H),7.43–7.36(m,2H),7.34(s,1H),7.32–7.26(m,2H),7.24–7.19(m,1H),7.10–7.00(m,3H),3.82(t,J＝7.2Hz,2H),3.47(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.91(t,J＝6.6Hz,2H).13CNMR(151MHz,CDCl3)δ163.48,162.55(d,JC-F＝978HZ),160.72(d,JC-F＝972HZ),142.36,141.85(d,JC-F＝30HZ),138.06,130.87(d,JC-F＝18HZ),129.75(d,JC-F＝36HZ),128.24(d,JC-F＝36HZ),128.21,127.70(d,JC-F＝30HZ),125.45(d,JC-F＝66HZ),125.16,124.91,123.59(d,JC-F＝12HZ),122.24,114.63(d,JC-F＝84HZ),114.12(d,JC-F＝84HZ),113.50(d,JC-F＝90HZ),47.74,46.40,27.59,27.20.ESI-HRMS(m/z)calcd[M+H]+＝364.1507,found 364.1503.
实施例12
合成2-(2-氟苯乙基)-6-(3-(三氟甲氧基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和3-三氟甲基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为60.1％。
1H NMR(500MHz,DMSO)δ7.92(d,J＝8.0Hz,1H),7.77(d,J＝7.8Hz,1H),7.68(d,J＝7.7Hz,2H),7.65–7.60(m,2H),7.41(d,J＝8.1Hz,1H),7.34(d,J＝7.4Hz,1H),7.27(dd,J＝14.0,6.8Hz,1H),7.19–7.08(m,2H),3.73(t,J＝7.1Hz,2H),2.98–2.90(m,4H),2.54–2.48(m,2H)。13C NMR(126MHz,DMSO)δ163.28,162.23,160.30,149.45,141.65,139.88,131.89,131.47,129.25,128.90,128.56,126.50,126.39,126.23,125.69,124.86,121.61,120.90,119.95,115.67,47.60,46.34,27.82,27.23。ESI-HRMS(m/z)calcd[M+H]+＝430.1425,found 430.1427。
实施例13
合成2-(2-氟苯乙基)-6-(2-(三氟甲基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-三氟甲基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为58.2％。
1H NMR(600MHz,CDCl3)δ8.11(d,J＝7.9Hz,1H),7.75(d,J＝7.8Hz,1H),7.57(t,J＝7.5Hz,1H),7.49(t,J＝7.7Hz,1H),7.30(dd,J＝11.4,6.6Hz,3H),7.24–7.19(m,1H),7.11–7.02(m,3H),3.82(dd,J＝13.8,6.4Hz,2H),3.48(t,J＝6.6Hz,2H),3.04(dd,J＝12.7,5.5Hz,2H),2.89(t,J＝6.6z,2H)。13C NMR(151MHz,CDCl3)δ163.53,160.71(d,JC-F＝972HZ),142.53,139.86,136.89,131.07,130.88(d,JC-F＝18HZ),130.76,129.83(d,JC-F＝192HZ),128.20(q,JC-F＝30HZ),127.71,127.65(q,JC-F＝60HZ),127.16(q,JC-F＝72HZ),127.08(d,JC-F＝36HZ),126.81,126.30(q,JC-F＝120HZ),125.54(q,JC-F＝18HZ),125.52,123.59(d,JC-F＝12HZ),114.63(d,JC-F＝90HZ),47.73,46.37,27.42,27.22。ESI-HRMS(m/z)calcd[M+H]+＝414.1476,found 414.1472。
实施例14
合成2-(2-氟苯乙基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和3-甲氧基苯硼酸为原料，其他实施方式同实施例7。
制备的化合物为无色油状，产率为54.2％。
1H NMR(600MHz,CDCl3)δ8.13(d,J＝8.0Hz,1H),7.55(dd,J＝8.0,1.5Hz,1H),7.39–7.33(m,2H),7.31–7.26(m,1H),7.21(ddd,J＝17.3,8.4,4.8Hz,2H),7.13–7.11(m,1H),7.09–7.01(m,2H),6.93(dd,J＝8.1,2.2Hz,1H),3.87(s,3H),3.82(t,J＝7.2Hz,2H),3.46(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.91(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.64,160.72(d,JC-F＝972HZ),159.37,143.59,141.10,137.91,130.88(d,JC-F＝24HZ),129.26,128.06,127.88,127.68(d,JC-F＝30HZ),125.49(d,JC-F＝66HZ),125.24,124.96,123.58(d,JC-F＝12HZ),119.08,114.62(d,JC-F＝90HZ),112.73,112.31,54.73,47.72,46.44,27.63,27.21。ESI-HRMS(m/z)calcd[M+H]+＝376.1727,found 376.1724。
实施例15
合成2-(2-氟苯乙基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和4-甲氧基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为57.6％。
1H NMR(600MHz,CDCl3)δ8.11(d,J＝8.1Hz,1H),7.53(dd,J＝14.8,8.4Hz,3H),7.31(s,1H),7.30–7.26(m,1H),7.21(dd,J＝13.2,6.3Hz,1H),7.09–7.01(m,2H),6.98(d,J＝8.6Hz,2H),3.86(s,3H),3.82(t,J＝7.2Hz,2H),3.46(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.90(t,J＝6.5Hz,2H)。13C NMR(151MHz,CDCl3)δ163.76,160.72(d,JC-F＝978HZ),159.06,143.31,137.93,132.00,130.89(d,JC-F＝18HZ),128.08,127.65,127.15,125.52(d,JC-F＝66HZ),124.67,124.50(d,JC-F＝204HZ),124.33,123.57(d,JC-F＝12HZ),114.61(d,JC-F＝90HZ),113.69,54.74,47.70,46.46,27.67,27.21。ESI-HRMS(m/z)calcd[M+H]+＝376.1727,found376.1721。
实施例16
合成2-(2-氟苯乙基)-6-(4-氟苯)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和4-氟苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为64.6％。
1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.0Hz,1H),7.54(dd,J＝8.0,1.1Hz,1H),7.43–7.36(m,2H),7.34(s,1H),7.32–7.26(m,2H),7.24–7.19(m,1H),7.10–7.00(m,3H),3.82(t,J＝7.2Hz,2H),3.47(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.91(t,J＝6.6Hz,2H)。13CNMR(151MHz,CDCl3)δ163.48,162.55(d,JC-F＝978HZ),160.72(d,JC-F＝972HZ),142.36,141.85(d,JC-F＝30HZ),138.06,130.87(d,JC-F＝18HZ),129.75(d,JC-F＝36HZ),128.24(d,JC-F＝36HZ),128.21,127.70(d,JC-F＝30HZ),125.45(d,JC-F＝66HZ),125.16,124.91,123.59(d,JC-F＝12HZ),122.24,114.63(d,JC-F＝84HZ),114.12(d,JC-F＝84HZ),113.50(d,JC-F＝90HZ),47.74,46.40,27.59,27.20。ESI-HRMS(m/z)calcd[M+H]+＝364.1507,found 364.1503。
实施例17
合成2-(2-氟苯乙基)-6-(呋喃-2-基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-呋喃硼酸为原料，其他实施方式同实施例7。制备的化合物为红棕色油状，产率为69.7％。
1H NMR(600MHz,CDCl3)δ8.08(d,J＝8.1Hz,1H),7.62(dd,J＝8.1,1.3Hz,1H),7.50(d,J＝1.2Hz,1H),7.45(s,1H),7.27(dd,J＝5.6,4.4Hz,1H),7.21(tdd,J＝7.4,5.3,1.6Hz,1H),7.09–7.01(m,2H),6.74(d,J＝3.3Hz,1H),6.49(dd,J＝3.3,1.8Hz,1H),3.81(dd,J＝12.9,5.8Hz,2H),3.44(t,J＝6.6Hz,2H),3.03(t,J＝7.3Hz,2H),2.88(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.54,160.70(d,JC-F＝972HZ),152.51,142.23,138.00,132.91,130.87(d,JC-F＝18HZ),128.04,127.67(d,JC-F＝30HZ),127.52,125.47(d,JC-F＝66HZ),123.57(d,JC-F＝18HZ),121.67,121.18,114.61(d,JC-F＝90HZ),111.31,106.11,47.73,46.36,27.56,27.19。ESI-HRMS(m/z)calcd[M+H]+＝336.1394,found336.1398。
实施例18
合成2-(2-氟苯乙基)-6-(呋喃-3-基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和3-呋喃硼酸为原料，其他实施方式同实施例7。制备的化合物为红棕色油状，产率为56.9％。
1H NMR(500MHz,DMSO)δ8.26(d,J＝0.8Hz,1H),7.83(d,J＝8.0Hz,1H),7.77(d,J＝1.4Hz,1H),7.58(d,J＝8.1Hz,1H),7.52(s,1H),7.34(t,J＝7.6Hz,1H),7.30–7.23(m,1H),7.18–7.09(m,2H),7.02–6.98(m,1H),3.71(t,J＝7.2Hz,2H),2.94–2.87(m,4H),2.58–2.41(m,2H)。13C NMR(126MHz,DMSO)δ163.43,162.22,160.29,145.03,140.81,139.70,135.48,131.84,128.89,128.39,128.06,125.66,124.86,124.52,124.24,115.66,109.11,47.56,46.33,27.85,27.25。ESI-HRMS(m/z)calcd[M+H]+＝336.1394,found 336.1391。
实施例19
合成2-(2-氟苯乙基)-6-(噻吩-2-基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-噻吩硼酸为原料，其他实施方式同实施例7。制备的化合物为棕色油状，产率为68.5％。
1H NMR(600MHz,CDCl3)δ8.08(d,J＝8.1Hz,1H),7.58(dd,J＝8.1,1.5Hz,1H),7.38(d,J＝3.8Hz,2H),7.33(dd,J＝5.0,0.7Hz,1H),7.27(t,J＝5.2Hz,1H),7.21(td,J＝7.4,1.5Hz,1H),7.10(dd,J＝5.0,3.7Hz,1H),7.08–7.01(m,2H),3.81(t,J＝7.3Hz,2H),3.44(t,J＝6.6Hz,2H),3.03(t,J＝7.2Hz,2H),2.88(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.46,160.71(d,JC-F＝90HZ),142.69,138.16,136.70,130.89,128.25,127.73(d,JC-F＝30HZ),127.63(d,JC-F＝24HZ),127.61,125.47(d,JC-F＝66HZ),125.27,123.74,123.58(d,JC-F＝12HZ),123.51,123.38,114.62(d,JC-F＝90HZ),47.72,46.36,27.53,27.20。ESI-HRMS(m/z)calcd[M+H]+＝352.1166,found 352.1164。
实施例20
合成2-(2-氟苯乙基)-6-(3-(三氟甲基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和3-三氟甲基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为67.2％。
1H NMR(600MHz,CDCl3)δ8.17(d,J＝8.0Hz,1H),7.84(s,1H),7.78(d,J＝7.7Hz,1H),7.64(d,J＝7.7Hz,1H),7.57(t,J＝8.2Hz,2H),7.37(s,1H),7.28(t,J＝7.6Hz,1H),7.22(dd,J＝14.1,6.7Hz,1H),7.09–7.02(m,2H),3.83(t,J＝7.2Hz,2H),3.48(t,J＝6.6Hz,2H),3.05(t,J＝7.2Hz,2H),2.93(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.41,160.72(d,JC-F＝972HZ),142.14,140.41,138.20,130.86(d,JC-F＝18HZ),130.68(q,JC-F＝132HZ),129.86,128.76,128.39(d,JC-F＝84HZ),128.32,127.72(d,JC-F＝30HZ),125.42(d,JC-F＝60HZ),125.25,125.01,123.95(d,JC-F＝12HZ),123.59(d,JC-F＝12HZ),123.45(d,JC-F＝1080HZ),123.38(d,JC-F＝18HZ),114.64(d,JC-F＝84HZ),47.76,46.40,27.58,27.19。ESI-HRMS(m/z)calcd[M+H]+＝414.1476,found 414.1474。
实施例21
合成2-(2-氟苯乙基)-6-(2-(三氟甲氧基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-三氟甲氧基苯硼酸为原料，其他实施方式同实施例7。制备的化合物为无色油状，产率为58.2％。
1H NMR(600MHz,CDCl3)δ8.14(d,J＝8.0Hz,1H),7.45–7.41(m,2H),7.40(dd,J＝7.6,2.0Hz,1H),7.38–7.34(m,2H),7.29(td,J＝7.6,1.3Hz,1H),7.24(s,1H),7.21(dd,J＝10.4,4.6Hz,1H),7.10–7.06(m,1H),7.06–7.02(m,1H),3.82(t,J＝7.3Hz,2H),3.48(t,J＝6.6Hz,2H),3.05(t,J＝7.3Hz,2H),2.91(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.54,160.71(d,JC-F＝972HZ),145.52,139.47,137.40,133.81,130.88(d,JC-F＝18HZ),130.75,128.56,128.15,127.68(d,JC-F＝30HZ),127.54,127.40,127.01,126.49,125.46(d,JC-F＝60HZ),123.58(d,JC-F＝12HZ),120.75,119.76(d,JC-F＝1020HZ),114.62(d,JC-F＝84HZ),47.74,46.39,27.48,27.22。ESI-HRMS(m/z)calcd[M+H]+＝430.1425,found430.1429。
实施例22
合成2-(2-氟苯乙基)-6-(吡啶-4-基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和4-吡啶硼酸为原料，其他实施方式同实施例7。制备的化合物为黄色油状，产率为48.5％。
1H NMR(600MHz,CDCl3)δ8.68(d,J＝6.0Hz,2H),8.18(d,J＝8.0Hz,1H),7.60(dd,J＝8.0,1.4Hz,1H),7.51(dd,J＝4.6,1.5Hz,2H),7.40(s,1H),7.28(d,J＝7.5Hz,1H),7.24–7.19(m,1H),7.09–7.01(m,2H),3.83(t,J＝7.2Hz,2H),3.47(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.93(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.21,160.71(d,JC-F＝972HZ),149.74,146.80,140.54,138.28,130.84(d,JC-F＝18HZ),129.36,128.42,127.74(d,JC-F＝30HZ),125.37(d,JC-F＝60HZ),125.10,124.91,123.60(d,JC-F＝12HZ),121.05,114.65(d,JC-F＝90HZ),47.78,46.34,27.55,27.17。ESI-HRMS(m/z)calcd[M+H]+＝347.1554,found 347.1550。
实施例23
合成2-(2-氟苯乙基)-6-(2-(甲硫基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-硫醚苯硼酸为原料，其他实施方式同实施例7。制备的化合物为红棕色油状，产率为60.2％。
1H NMR(500MHz,DMSO)δ7.88(d,J＝7.9Hz,1H),7.43–7.31(m,4H),7.26(t,J＝9.1Hz,2H),7.23–7.08(m,4H),3.73(t,J＝7.2Hz,2H),3.50(t,J＝6.5Hz,2H),2.92(dt,J＝13.6,6.8Hz,4H),2.38(s,3H)。13C NMR(126MHz,DMSO)δ163.32,162.24,143.65,139.49,138.95,137.08,131.87,130.07,129.02,128.97,128.73,128.31,128.01,127.66,126.30,125.47,125.14,124.90,115.69,47.59,46.33,27.78,27.29,15.45。ESI-HRMS(m/z)calcd[M+H]+＝392.1479,found 392.1475.
实施例24
合成2-(2-氟苯乙基)-6-(2-(甲硫基)苯基)-3,4-二氢异喹啉-1(2H)-酮
选取2-氟苯乙醇和2-噻吩硼酸为原料，其他实施方式同实施例7。制备的化合物为红棕色油状，产率为57.2％。
1H NMR(600MHz,CDCl3)δ8.10(d,J＝8.1Hz,1H),7.57(dd,J＝8.1,1.4Hz,1H),7.52(t,J＝2.1Hz,1H),7.40(d,J＝2.1Hz,2H),7.36(s,1H),7.30–7.27(m,1H),7.24–7.19(m,1H),7.09–7.01(m,2H),3.81(t,J＝7.3Hz,2H),3.45(t,J＝6.6Hz,2H),3.04(t,J＝7.2Hz,2H),2.89(t,J＝6.6Hz,2H)。13C NMR(151MHz,CDCl3)δ163.60,160.71(d,JC-F＝972HZ),140.76,138.15,138.04,130.88(d,JC-F＝18HZ),128.18,127.67(d,JC-F＝30HZ),127.54,125.94,125.58,125.49(d,JC-F＝60HZ),124.41,124.05,123.57(d,JC-F＝12HZ),120.87,114.62(d,JC-F＝90HZ),47.71,46.41,27.61,27.20。ESI-HRMS(m/z)calcd[M+H]+＝352.1166,found 352.1168。
实施例25
合成2-苯乙基-7-苯基-2,3,4,5-四氢-1H-苯并[c]氮杂-1-酮
反应式如下：
合成步骤如下：
(1)将1,2,3,4-四氢异喹啉(1mmol)在二氯甲烷(5mL)中的搅拌溶液中，在20分钟内分批加入N-溴代琥珀酰亚胺(NBS)(1.5mmol)。添加完成后，搅拌混合物直至TLC指示起始材料(约45min)。加入氢氧化钠(1.5mL的30％水溶液)，并在25℃下继续搅拌1h。分离有机层并用水(10mL)洗涤，产物用10％HCl(2×8mL)萃取。合并的酸性萃取液用二氯甲烷(10mL)洗涤并用浓氨水(pH＝9)调成碱性，再用二氯甲烷(10mL×1)萃取，合并有机相，用无水硫酸镁干燥过滤浓缩，经柱分离后得到无色油状中间体C1。
(2)取反应瓶将中间体C1(1mmol)溶于乙酸(1.8mL)中，加入溶于水(1.4mL)的浓硫酸(0.21mL)，在-5℃的条件下，缓慢加入硝酸钠(1.2mmol)，在0℃反应2h后，缓慢加入溶于水(2mL)的碘化钾(10mmol)，在0℃的条件下反应4h后，加入溶于水(1.4mL)的亚硝酸钠(10mmol)，搅拌反应2h后真空浓缩，经柱分离得到红棕色中间体C2。
(3)取封管将中间体C2(1mmol)溶于二氧六环(4mL)中，加入苯硼酸(1.3mmol)与K2CO3(1.8mmol)，在加入水(1mL)后，通入氩气后加入Pd(PPh3)2Cl2(0.1mmol)在110℃下回流12h，反应结束后真空浓缩后经柱分离后得到白色固体中间体C3。
(4)取反应瓶将中间体C3(R1＝2-甲氧基苯基)(1mmol)溶于乙腈(5mL)中，在通风条件下将NaH(3mmol)加入反应瓶中，在室温下搅拌反应30min后，加入2-苯基乙基溴(3mmol)在80℃下反应8h，反应结束后后真空浓缩后经柱分离后得到无色油状2-苯乙基-7-苯基-2,3,4,5-四氢-1H-苯并[c]氮杂-1-酮，产率34.7％。
1H NMR(500MHz,DMSO)δ7.58–7.26(m,9H),7.24–6.98(m,3H),3.76(s,5H),3.16(s,2H),2.93(d,J＝6.3Hz,2H),2.60(s,2H),1.85(d,J＝5.3Hz,2H).13C NMR(126MHz,DMSO)δ170.16,156.59,140.85,139.66,137.45,135.21,130.85,129.71,129.48,129.22,128.82,128.20,128.04,126.68,121.25,112.24,55.98,48.79,46.69,34.84,30.14,29.74.ESI-HRMS(m/z)calcd[M+H]+＝372.1958,found 372.1954.
实施例26
合成7-(2-甲氧基苯基)-2-苯乙基-2,3,4,5-四氢-1H-苯并[c]氮杂-1-酮
选取2-甲氧基苯硼酸为原料，其他实施方式同实施例25。制备的化合物为无色油状，产率为37.2％。
1H NMR(500MHz,DMSO)δ7.58–7.26(m,9H),7.24–6.98(m,3H),3.76(s,5H),3.16(s,2H),2.93(d,J＝6.3Hz,2H),2.60(s,2H),1.85(d,J＝5.3Hz,2H)。13C NMR(126MHz,DMSO)δ170.16,156.59,140.85,139.66,137.45,135.21,130.85,129.71,129.48,129.22,128.82,128.20,128.04,126.68,121.25,112.24,55.98,48.79,46.69,34.84,30.14,29.74。ESI-HRMS(m/z)calcd[M+H]+＝372.1958,found 372.1954。
实施例27
合成2-(2-氟苯乙基)-7-(2-甲氧基苯基)-2,3,4,5-四氢-1H-苯并[c]氮杂-1-酮
选取2-氟苯基乙基溴和2-甲氧基苯硼酸为原料，其他实施方式同实施例25。制备的化合物为无色油状，产率为29.4％。
1H NMR(500MHz,DMSO)δ7.51–7.34(m,4H),7.29(s,3H),7.21–6.98(m,4H),3.76(s,5H),3.14(s,2H),2.96(s,2H),2.62(s,2H),1.85(s,2H)。13C NMR(126MHz,DMSO)δ170.24,162.28,160.35,156.59,140.89,137.38,135.14,131.79,130.85,129.71,129.49,128.90,128.20,128.06,126.36,124.86,121.25,115.70,112.24,55.98,47.51,46.71,30.10,29.63,28.06。ESI-HRMS(m/z)calcd[M+H]+＝390.1864,found 390.1869。
实施例28
合成4-苯乙基-8-苯基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
反应式如下：
合成步骤如下
(1)取反应瓶将2-溴-4羟基苯甲醛(1mmol)与苯乙胺(1monl)溶于DCM(5mL)中，在常温下搅拌反应5h。反应结束后加入NaBH4(3monl)继续反应4h，用水(10mL×2)洗除，再用饱和食盐水(10mL×1)洗涤后，加入无水硫酸镁干燥30min后过滤浓缩，经柱分离后得到中间体D1。
(2)取封管将中间体D1(1mmol)溶于乙腈(50mL)中，加入1,2-二溴乙烷(10mmol)在80℃下反应12h，反应结束后真空浓缩后经柱分离后得到白色固体中间体D2。
(3)取封管将中间体D2(R1＝苯基)(1mmol)溶于二氧六环(4mL)中，加入苯硼酸(1.3mmol)与K2CO3(1.8mmol)，在加入水(1mL)后，通入氩气后加入Pd(PPh3)2Cl2(0.1mmol)在110℃下回流12h，反应结束后真空浓缩后经柱分离后得到白色中间体D3。
(4)取反应瓶将中间体D3(1mmol)溶于丙酮(5mL)中，加入高锰酸钾(3mmol)在室温下反应12h，反应结束后真空浓缩后经柱分离后得到无色油状4-苯乙基-8-苯基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮，产率为58.8％。
1H NMR(500MHz,DMSO)δ8.15–7.67(m,4H),7.48(t,J＝7.4Hz,3H),7.39(dd,J＝13.4,6.8Hz,1H),7.27(dd,J＝38.5,6.9Hz,5H),4.42–4.23(m,2H),3.92–3.70(m,2H),3.54(d,J＝4.6Hz,2H),3.05–2.84(m,2H)。13C NMR(126MHz,DMSO)δ167.41,154.55,144.88,139.53,139.07,134.54,131.92,129.51,129.26,128.87,128.71,127.82,127.24,126.72,126.31,121.72,119.56,73.80,49.56,46.99,34.26。ESI-HRMS(m/z)calcd[M+H]+＝344.1645,found344.1647。
实施例29
合成8-(2-甲氧基苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取2-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为54.4％。
1H NMR(500MHz,DMSO)δ7.66(d,J＝8.1Hz,1H),7.36(t,J＝7.8Hz,1H),7.28(ddd,J＝16.3,12.1,4.4Hz,6H),7.21(t,J＝6.8Hz,1H),7.10(dd,J＝9.9,4.7Hz,2H),7.02(t,J＝7.4Hz,1H),4.23(t,J＝5.0Hz,2H),3.85–3.70(m,5H),3.52(t,J＝4.9Hz,2H),2.92–2.85(m,2H)。13C NMR(126MHz,DMSO)δ167.53,156.58,153.68,143.05,139.55,130.82,130.72,130.01,129.26,128.87,128.69,126.71,125.83,124.49,122.15,121.31,112.32,73.71,55.99,49.55,47.01,34.28。ESI-HRMS(m/z)calcd[M+H]+＝375.1829,found 375.1833。
实施例30
合成8-(3-甲氧基苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取3-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为53.1％。
1H NMR(500MHz,DMSO)δ7.78(d,J＝8.1Hz,1H),7.53(dd,J＝8.1,1.7Hz,1H),7.44(t,J＝7.9Hz,1H),7.39–7.25(m,8H),7.05–7.01(m,1H),4.32(t,J＝4.9Hz,2H),3.88(s,3H),3.84–3.78(m,3H),3.58(s,2H),2.95(t,J＝7.6Hz,2H)。13C NMR(126MHz,DMSO)δ167.45,160.24,154.49,144.80,140.59,139.51,131.82,130.58,129.25,128.87,126.72,126.44,121.87,119.69,119.55,114.49,112.54,73.79,55.65,49.56,47.01,34.24。ESI-HRMS(m/z)calcd[M+H]+＝374.1751,found 374.1754。
实施例31
合成8-(4-甲氧基苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取4-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为36.4％。
1H NMR(500MHz,DMSO)δ7.66(s,3H),7.48–6.82(m,9H),4.25(s,2H),3.77(d,J＝23.1Hz,5H),3.49(d,J＝35.4Hz,2H),2.89(s,2H)。13C NMR(126MHz,DMSO)δ167.47,159.96,154.58,144.54,139.54,131.87,131.29,129.25,128.87,128.41,126.71,125.52,121.13,118.81,114.91,73.72,55.68,49.56,47.03,34.27。ESI-HRMS(m/z)calcd[M+H]+＝374.1751,found 374.1754。
实施例32
合成8-(2-氟苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为47.7％。
1H NMR(500MHz,DMSO)δ7.75(s,1H),7.40(t,J＝59.6Hz,11H),4.27(s,2H),3.77(s,2H),3.53(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.28,160.51,158.55,154.08,139.79,139.51,131.55,131.14,130.78,129.26,128.87,127.33,126.74,125.55,123.91,121.84,116.81,73.88,49.57,46.95,34.24.ESI-HRMS(m/z)calcd[M+H]+＝362.1551,found 362.1557.
实施例33
合成8-(3-氟苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取3-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为36.4％。
1H NMR(500MHz,DMSO)δ7.74(s,1H),7.54(d,J＝29.7Hz,4H),7.28(t,J＝26.9Hz,7H),4.27(s,2H),3.76(s,2H),3.53(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.30,164.11,154.54,143.38,141.46,139.51,131.95,131.47,129.25,128.87,126.89,126.73,123.35,121.85,119.85,115.52,113.95,73.83,49.56,46.96,34.24。ESI-HRMS(m/z)calcd[M+H]+＝362.1551,found 362.1557。
实施例34
合成8-(4-氟苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取4-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为36.2％。
1H NMR(500MHz,DMSO)δ7.75(s,3H),7.37(d,J＝74.2Hz,9H),4.27(s,2H),3.76(s,2H),3.53(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.36,163.73,154.55,143.78,139.52,135.53,131.95,129.38,129.25,128.87,126.72,126.25,121.65,119.53,116.41,73.79,49.56,46.98,34.25。ESI-HRMS(m/z)calcd[M+H]+＝362.1551,found 362.1555。
实施例35
合成4-苯乙基-8-(2-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-三氟甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为45.4％。
1H NMR(500MHz,DMSO)δ7.74(t,J＝48.0Hz,4H),7.19(dd,J＝172.4,71.5Hz,8H),4.26(s,2H),3.77(s,2H),3.55(s,2H),2.91(s,2H)。13C NMR(126MHz,DMSO)δ167.22,153.45,144.05,139.70,139.50,132.89,132.24,131.04,129.25,128.97,128.88,127.24,126.73,126.66,126.62,126.54,123.98,121.89,73.85,49.63,47.02,34.21。ESI-HRMS(m/z)calcd[M+H]+＝412.1519,found 412.1515。
实施例36
合成4-苯乙基-8-(3-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取3-三氟甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为47.9％。
1H NMR(500MHz,DMSO)δ8.01(s,2H),7.66(d,J＝100.7Hz,4H),7.48–7.12(m,6H),4.28(s,2H),3.76(s,2H),3.54(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.29,154.61,143.16,140.14,139.51,132.04,131.41,130.64,130.46,129.26,128.87,127.14,126.73,125.69,125.24,123.76,122.04,120.10,73.88,49.55,46.94,34.25。ESI-HRMS(m/z)calcd[M+H]+＝412.1519,found 412.1517。
实施例37
合成4-苯乙基-8-(4-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取4-三氟甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为40.8％。
1H NMR(500MHz,DMSO)δ7.84(s,5H),7.31(s,7H),4.29(s,2H),3.77(s,2H),3.51(s,2H),2.91(s,2H)。13C NMR(126MHz,DMSO)δ167.24,154.58,143.19,143.08,139.50,135.14,132.10,129.25,129.07,128.87,128.13,127.27,126.73,126.33,122.07,120.15,73.90,49.56,46.93,34.23。ESI-HRMS(m/z)calcd[M+H]+＝412.1519,found 412.1516。
实施例38
合成8-(2-羟基苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取2-羟基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为30.7％。
1H NMR(500MHz,DMSO)δ9.69(s,1H),7.66(d,J＝3.6Hz,1H),7.28(t,J＝34.7Hz,9H),6.99–6.85(m,2H),4.24(s,2H),3.75(s,2H),3.52(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.63,154.92,153.66,143.48,139.56,130.74,130.63,129.67,129.26,128.87,126.72,126.58,125.59,124.27,121.96,120.01,116.68,73.71,49.53,47.02,34.30。ESI-HRMS(m/z)calcd[M+H]+＝360.1594,found 360.1598。
实施例39
合成2-(5-氧代-4-苯乙基-2,3,4,5-四氢苯并[f][1,4]氧氮杂-8-基)苯甲腈
选取2-氰基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为39.8％。
1H NMR(500MHz,DMSO)δ7.97(d,J＝7.7Hz,1H),7.90–7.75(m,2H),7.72–7.57(m,2H),7.45–7.12(m,7H),4.29(d,J＝4.6Hz,2H),3.85–3.68(m,2H),3.57(d,J＝4.6Hz,2H),2.91(d,J＝7.2Hz,2H)。13C NMR(126MHz,DMSO)δ167.11,154.06,143.42,142.40,139.49,134.46,134.17,134.13,131.80,130.52,129.26,128.88,127.38,126.74,123.79,121.91,118.80,110.53,73.93,49.62,46.95,34.21。ESI-HRMS(m/z)calcd[M+H]+＝369.1598,found 369.1593。
实施例40
合成4-苯乙基-8-(2-(三氟甲氧基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-三氟甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为50.4％。
1H NMR(500MHz,DMSO)δ7.81(d,J＝8.0Hz,1H),7.59(ddd,J＝17.7,10.7,5.8Hz,4H),7.40–7.25(m,6H),7.15(s,1H),4.32(t,J＝4.5Hz,2H),3.85–3.79(m,2H),3.60(s,2H),2.96(t,J＝7.6Hz,2H)。13C NMR(126MHz,DMSO)δ167.27,153.94,145.63,140.89,139.48,133.68,131.93,131.45,130.50,129.24,128.87,128.58,126.74,126.64,124.11,122.14,122.03,121.46,73.87,49.61,47.00,34.21。ESI-HRMS(m/z)calcd[M+H]+＝428.1468,found 428.1463。
实施例41
合成8-(2-氟-4-甲基苯基)-4-苯乙基-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟-4-甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为56.8％。
1H NMR(500MHz,DMSO)δ7.73(d,J＝8.0Hz,1H),7.54–7.42(m,1H),7.41–7.27(m,5H),7.27–7.08(m,4H),4.27(d,J＝4.4Hz,2H),3.87–3.70(m,2H),3.54(d,J＝4.1Hz,2H),2.90(d,J＝7.1Hz,2H),2.36(s,3H)。13C NMR(126MHz,DMSO)δ167.31,160.36,154.08,141.09,139.90,139.51,131.50,130.73,129.25,128.87,126.72,126.48,126.18,124.28,123.74,121.62,117.15,73.85,49.56,46.95,34.24,21.02。ESI-HRMS(m/z)calcd[M+H]+＝376.1707,found 376.1702。
实施例42
合成4-苯乙基-8-(3,4,5-三甲氧基苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取3，4，5-三甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为30.6％。
1H NMR(500MHz,DMSO)δ7.72(s,1H),7.51(s,1H),7.32(s,6H),6.96(d,J＝5.4Hz,2H),4.28(s,2H),3.79(dd,J＝79.2,9.9Hz,11H),3.54(s,2H),2.91(s,2H)。13C NMR(126MHz,DMSO)δ167.46,154.44,153.71,145.04,139.53,138.12,134.80,131.64,129.25,128.87,126.72,126.18,121.85,119.66,104.68,73.76,60.53,56.45,49.56,47.00,34.27。ESI-HRMS(m/z)calcd[M+H]+＝434.1962,found 434.1966。
实施例43
合成4-苯乙基-8-(间甲苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为43.2％。
1H NMR(500MHz,DMSO)δ7.72(d,J＝7.6Hz,1H),7.59–7.40(m,3H),7.30(dd,J＝43.7,23.2Hz,8H),4.26(s,2H),3.75(s,2H),3.53(s,2H),2.89(s,2H),2.37(s,3H)。13C NMR(126MHz,DMSO)δ167.44,154.52,145.00,139.53,139.01,138.71,131.85,129.39,129.25,128.87,127.89,126.72,126.26,124.33,121.71,119.52,73.80,49.55,46.99,34.27,21.53。ESI-HRMS(m/z)calcd[M+H]+＝358.1802,found 358.1803。
实施例44
合成4-苯乙基-8-(吡啶-4-基)-3,4-二氢苯并[f][1,4]恶氮杂-5(2H)-酮
选取4-吡啶苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为37.4％。
1H NMR(500MHz,DMSO)δ8.65(s,2H),7.76(d,J＝14.7Hz,3H),7.52(d,J＝79.3Hz,3H),7.26(d,J＝32.2Hz,4H),4.28(s,2H),3.76(s,2H),3.54(s,2H),2.90(s,2H)。13C NMR(126MHz,DMSO)δ167.16,154.63,150.83,145.95,141.79,139.49,132.15,129.26,128.88,128.03,126.74,121.82,121.74,120.02,73.94,49.56,46.90,34.22。ESI-HRMS(m/z)calcd[M+H]+＝345.1598,found 345.1595。
实施例45
合成4-苯乙基-8-(噻吩-3-基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取3-噻吩硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为49.4％。
1H NMR(500MHz,DMSO)δ8.01(s,1H),7.62(dd,J＝46.9,26.7Hz,4H),7.29(t,J＝36.0Hz,6H),4.26(s,2H),3.74(s,2H),3.52(s,2H),2.89(s,2H)。13C NMR(126MHz,DMSO)δ167.41,154.62,140.47,139.74,139.53,131.85,129.25,128.87,127.84,126.72,126.63,123.05,121.13,118.84,73.73,49.56,47.00,34.27。ESI-HRMS(m/z)calcd[M+H]+＝350.1209,found350.1206。
实施例46
合成4-(2-氟苯乙基)-8-苯基-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为49.4％。
1H NMR(500MHz,DMSO)δ7.79(d,J＝8.1Hz,1H),7.64–7.54(m,4H),7.41–7.26(m,7H),4.33(t,J＝4.9Hz,2H),3.84–3.78(m,2H),2.96(t,J＝7.6Hz,2H),2.58–2.54(m,2H)。13CNMR(126MHz,DMSO)δ167.30,164.11,154.54,143.38,141.46,139.51,131.95,131.47,129.25,128.87,126.89,126.73,123.35,121.85,119.85,115.52,113.95,73.83,49.56,46.96,34.24。ESI-HRMS(m/z)calcd[M+H]+＝362.1551,found 362.1557。
实施例47
合成4-(2-氟苯基乙基)-8-(2-氟苯基)-3,4-二氢苯并[f][1,4]恶氮杂-5(2H)-酮
选取2-氟苯乙胺和2-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为50.3％。
1H NMR(500MHz,DMSO)δ7.72(d,J＝8.0Hz,1H),7.58(t,J＝7.7Hz,1H),7.46(dd,J＝12.5,6.5Hz,1H),7.43–7.25(m,5H),7.16(dd,J＝17.0,8.5Hz,3H),4.29(t,J＝4.5Hz,2H),3.78(t,J＝7.2Hz,2H),3.54(t,J＝4.4Hz,2H),2.95(t,J＝7.0Hz,2H)。13C NMR(126MHz,DMSO)δ167.34,162.24,160.30,158.54,154.05,139.82,131.86,131.51,131.15,130.78,128.99,127.32,126.68,126.07,125.55,124.89,123.93,121.85,116.81,116.63,115.70,73.79,48.16,46.94,27.54。ESI-HRMS(m/z)calcd[M+H]+＝380.1457,found380.1455。
实施例48
合成4-(2-氟苯基乙基)-8-(3-氟苯基)-3,4-二氢苯并[f][1,4]恶氮杂-5(2H)-酮
选取2-氟苯乙胺和3-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为36.9％。
1H NMR(500MHz,DMSO)δ7.70(d,J＝8.1Hz,1H),7.56(t,J＝8.8Hz,2H),7.53–7.48(m,2H),7.35(dd,J＝14.5,4.3Hz,2H),7.27(ddd,J＝23.6,11.9,4.9Hz,2H),7.19–7.11(m,2H),4.29(t,J＝4.8Hz,2H),3.78(t,J＝7.3Hz,2H),2.95(t,J＝7.3Hz,2H),2.52–2.49(m,2H)。13CNMR(126MHz,DMSO)δ167.41,164.10,162.23,160.30,154.51,143.42,141.44,131.91,131.84,131.49,129.00,126.81,126.18,124.86,123.36,121.88,119.83,115.52,114.10,73.75,48.16,46.97,27.52。ESI-HRMS(m/z)calcd[M+H]+＝380.1457,found380.1453。
实施例49
合成4-(2-氟苯基乙基)-8-(4-氟苯基)-3,4-二氢苯并[f][1,4]恶氮杂-5(2H)-酮
选取2-氟苯乙胺和4-氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为49.4％。
1H NMR(500MHz,DMSO)δ7.79–7.72(m,2H),7.69(d,J＝8.1Hz,1H),7.45(dd,J＝8.1,1.5Hz,1H),7.36(t,J＝7.6Hz,1H),7.32–7.25(m,4H),7.20–7.10(m,2H),4.29(t,J＝4.7Hz,2H),3.77(t,J＝7.3Hz,2H),2.94(t,J＝7.3Hz,2H),2.53–2.49(m,2H)。13C NMR(126MHz,DMSO)δ182.34,167.46,163.73,162.23,161.78,160.30,154.52,143.83,135.50,131.91,131.84,129.32,128.93,126.18,124.86,121.68,119.53,116.41,115.69,73.72,48.16,46.99,27.53。ESI-HRMS(m/z)calcd[M+H]+＝380.1457,found 380.1454。
实施例50
合成4-(2-氟苯乙基)-8-(2-甲氧基苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和2-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为50.6％。
1H NMR(500MHz,DMSO)δ7.60(d,J＝8.1Hz,1H),7.38(dd,J＝8.1,1.6Hz,1H),7.33–7.25(m,2H),7.24–7.16(m,3H),7.13(s,1H),7.10–7.03(m,2H),6.89(dd,J＝8.2,1.8Hz,1H),4.20(t,J＝4.8Hz,2H),3.74(s,3H),3.69(t,J＝7.3Hz,2H),2.86(t,J＝7.3Hz,2H),2.44–2.40(m,2H)。13C NMR(126MHz,DMSO)δ167.51,162.23,160.30,160.23,154.46,144.83,140.57,131.84,131.78,130.58,128.93,126.38,126.19,124.86,121.89,119.55,115.69,114.49,112.53,73.71,55.65,48.15,46.99,27.53。ESI-HRMS(m/z)calcd[M+H]+＝392.1656,found 392.1653。
实施例51
合成4-(2-氟苯乙基)-8-(3-甲氧基苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和3-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为38.5％。
1H NMR(500MHz,DMSO)δ7.60(d,J＝8.1Hz,1H),7.38(dd,J＝8.1,1.6Hz,1H),7.33–7.25(m,2H),7.24–7.16(m,3H),7.13(s,1H),7.10–7.03(m,2H),6.89(dd,J＝8.2,1.8Hz,1H),4.20(t,J＝4.8Hz,2H),3.74(s,3H),3.69(t,J＝7.3Hz,2H),2.86(t,J＝7.3Hz,2H),2.44–2.40(m,2H)。13C NMR(126MHz,DMSO)δ167.51,162.23,160.30,160.23,154.46,144.83,140.57,131.84,131.78,130.58,128.93,126.38,126.19,124.86,121.89,119.55,115.69,114.49,112.53,73.71,55.65,48.15,46.99,27.53。ESI-HRMS(m/z)calcd[M+H]+＝392.1656,found 392.1652。
实施例52
合成4-(2-氟苯乙基)-8-(4-甲氧基苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和4-甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为60.8％。
1H NMR(500MHz,DMSO)δ7.66(dd,J＝8.5,2.5Hz,3H),7.38(ddd,J＝15.2,7.9,1.6Hz,2H),7.30–7.22(m,2H),7.19–7.11(m,2H),7.03(d,J＝8.8Hz,2H),4.27(t,J＝5.0Hz,2H),3.80(s,3H),3.77(dd,J＝12.5,5.3Hz,2H),3.51(t,J＝5.0Hz,2H),2.94(t,J＝7.2Hz,2H)。13C NMR(126MHz,DMSO)δ167.53,162.23,160.30,159.96,154.56,144.57,131.84,131.28,128.98,128.41,126.10,125.45,124.89,121.14,118.81,115.53,114.91,73.64,55.68,48.15,47.02,27.57。ESI-HRMS(m/z)calcd[M+H]+＝392.1656,found392.1651。
实施例53
合成4-(2-氟苯乙基)-8-(2-(三氟甲氧基)苯基)-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取2-氟苯乙胺和2-三氟甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为39.7％。
1H NMR(500MHz,DMSO)δ7.74–7.69(m,1H),7.53(ddd,J＝27.7,10.8,7.6Hz,4H),7.37(t,J＝7.4Hz,1H),7.32–7.23(m,2H),7.20–7.13(m,2H),7.10(d,J＝1.2Hz,1H),4.29(t,J＝4.6Hz,2H),3.78(t,J＝7.3Hz,2H),2.95(t,J＝7.3Hz,2H),2.53–2.49(m,2H)。13CNMR(126MHz,DMSO)δ167.34,162.23,160.29,153.91,145.62,140.92,133.66,131.93,131.83,131.41,130.50,128.95,128.58,126.59,124.87,124.13,122.13,122.04,121.45,115.69,73.80,48.19,46.99,27.51。ESI-HRMS(m/z)calcd[M+H]+＝446.1374,found446.1377。
实施例54
合成4-(2-氟苯乙基)-8-(3-(三氟甲氧基)苯基)-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取2-氟苯乙胺和3-三氟甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为43.7％。
1H NMR(500MHz,DMSO)δ7.77(d,J＝7.8Hz,1H),7.73–7.66(m,2H),7.62(t,J＝8.0Hz,1H),7.51(d,J＝8.1Hz,1H),7.41(d,J＝8.2Hz,1H),7.36(dd,J＝8.8,4.5Hz,2H),7.29(dd,J＝13.7,6.7Hz,1H),7.20–7.11(m,2H),4.30(d,J＝4.5Hz,2H),3.78(t,J＝7.3Hz,2H),2.95(t,J＝7.2Hz,2H),2.53–2.48(m,2H)。13C NMR(126MHz,DMSO)δ167.38,162.23,160.30,154.54,149.43,143.06,141.41,131.97,131.80,131.49,129.00,127.03,126.44,126.05,124.89,121.96,121.07,119.98,119.91,115.51,73.79,48.15,46.94,27.52。ESI-HRMS(m/z)calcd[M+H]+＝446.1374,found 446.1375。
实施例55
合成4-(2-氟苯乙基)-8-(4-(三氟甲氧基)苯基)-3,4-二氢苯并[f][1,4]氧杂氮-5(2H)-酮
选取2-氟苯乙胺和4-三氟甲氧基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为46.8％。
1H NMR(500MHz,DMSO)δ7.84(d,J＝8.7Hz,2H),7.71(d,J＝8.1Hz,1H),7.48(dd,J＝13.3,5.1Hz,3H),7.36(t,J＝7.5Hz,1H),7.34–7.25(m,2H),7.19–7.10(m,2H),4.30(t,J＝4.8Hz,2H),3.78(t,J＝7.3Hz,2H),2.95(t,J＝7.2Hz,2H),2.51(s,2H)。13C NMR(126MHz,DMSO)δ167.38,162.23,160.30,154.53,148.80,143.39,138.34,131.99,131.84,129.25,129.00,126.60,126.06,124.89,121.94,121.58,119.80,115.69,73.75,48.16,46.97,27.52。ESI-HRMS(m/z)calcd[M+H]+＝446.1374,found 446.1378。
实施例56
合成4-(2-氟苯乙基)-8-(2-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和2-三氟甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为35.5％。
1H NMR(500MHz,DMSO)δ7.72(dd,J＝58.1,42.2Hz,4H),7.54–7.03(m,6H),6.93(s,1H),4.28(s,2H),3.78(s,2H),3.54(s,2H),2.95(s,2H)。13C NMR(126MHz,DMSO)δ167.28,162.24,160.30,153.42,144.07,139.69,132.88,132.24,131.85,131.00,128.97,127.00,126.65,126.49,126.19,124.90,124.00,123.47,121.90,115.71,73.77,48.21,47.00,27.53。ESI-HRMS(m/z)calcd[M+H]+＝430.1425,found 430.1424。
实施例57
合成4-(2-氟苯乙基)-8-(3-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和3-三氟苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为40.5％。
1H NMR(500MHz,DMSO)δ8.07(d,J＝13.0Hz,2H),7.79(dt,J＝15.1,7.5Hz,3H),7.60(dd,J＝8.1,1.2Hz,1H),7.42(dd,J＝15.2,7.6Hz,2H),7.34(dd,J＝13.5,6.3Hz,1H),7.24–7.16(m,2H),4.36(d,J＝4.6Hz,2H),3.83(t,J＝7.3Hz,2H),3.00(t,J＝7.2Hz,2H),2.60–2.53(m,2H)。13C NMR(126MHz,DMSO)δ167.38,162.24,160.30,154.57,143.20,140.12,132.00,131.84,131.39,130.64,130.21,129.00,127.05,126.18,125.28,124.86,123.74,123.52,122.06,120.08,115.69,73.80,48.15,46.95。ESI-HRMS(m/z)calcd[M+H]+＝430.1425,found 430.1423。
实施例58
合成4-(2-氟苯乙基)-8-(4-(三氟甲基)苯基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和4-三氟甲基苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为36.9％。
1H NMR(500MHz,DMSO)δ7.94(d,J＝8.0Hz,2H),7.83(d,J＝8.2Hz,2H),7.76–7.71(m,1H),7.54(dd,J＝8.1,1.6Hz,1H),7.37(dd,J＝10.1,4.5Hz,2H),7.32–7.26(m,1H),7.19–7.12(m,2H),4.31(d,J＝4.7Hz,2H),3.78(t,J＝7.3Hz,2H),2.95(t,J＝7.2Hz,2H),2.53–2.47(m,2H)。13C NMR(126MHz,DMSO)δ167.33,162.24,160.30,154.55,143.24,132.05,131.81,129.01,128.94,128.13,127.19,126.33,126.30,126.05,124.87,122.10,120.14,115.52,73.82,48.16,46.93,27.52。ESI-HRMS(m/z)calcd[M+H]+＝430.1425,found 430.1428。
实施例59
合成4-(2-氟苯乙基)-8-(噻吩-3-基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和3-噻吩苯硼酸为原料，其他实施方式同实施例28。制备的化合物为红棕色油状，产率为64.2％。
1H NMR(500MHz,DMSO)δ8.03–7.97(m,1H),7.69–7.58(m,3H),7.52(d,J＝8.1Hz,1H),7.39–7.33(m,2H),7.29(dd,J＝14.1,6.7Hz,1H),7.20–7.11(m,2H),4.28(s,2H),3.76(t,J＝7.3Hz,2H),2.94(t,J＝7.2Hz,2H),2.54–2.48(m,2H)。13C NMR(126MHz,DMSO)δ167.51,162.23,160.29,154.59,140.45,139.78,131.81,128.99,127.84,126.61,126.08,125.79,124.86,123.05,121.16,118.83,115.69,73.65,48.15,47.02,27.54。ESI-HRMS(m/z)calcd[M+H]+＝368.1115,found 368.1119。
实施例60
合成4-(2-氟苯乙基)-8-(呋喃-3-基)-3,4-二氢苯并[f][1,4]恶嗪-5(2H)-酮
选取2-氟苯乙胺和3-呋喃苯硼酸为原料，其他实施方式同实施例28。制备的化合物为红色油状，产率为53.9％。
1H NMR(500MHz,DMSO)δ8.23(d,J＝54.9Hz,1H),7.73(dd,J＝22.8,1.5Hz,1H),7.64–7.59(m,1H),7.44–7.33(m,2H),7.31–7.22(m,3H),7.13(dd,J＝16.4,9.2Hz,2H),4.27(s,2H),3.76(t,J＝7.3Hz,2H),2.93(t,J＝7.3Hz,2H),2.53–2.49(m,2H)；13C NMR(126MHz,DMSO)δ160.29,154.58,145.02,144.69,140.98,136.95,131.79,131.72,128.98,125.68,125.23,124.88,120.65,118.29,115.51,109.14,109.10,73.64,48.13,47.00,27.54。ESI-HRMS(m/z)calcd[M+H]+＝352.1343,found 352.1342。
实施例61
合成4-(2-氟苯乙基)-8-(吡啶-4-基)-3,4-二氢苯并[f][1,4]恶氮杂-5(2H)-酮
选取2-氟苯乙胺和4-吡啶苯硼酸为原料，其他实施方式同实施例28。制备的化合物为无色油状，产率为37.2％。
1H NMR(500MHz,DMSO)δ8.71(dd,J＝4.6,1.5Hz,2H),7.82–7.77(m,3H),7.65(dd,J＝8.1,1.5Hz,1H),7.50(d,J＝1.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.34(dd,J＝13.3,6.3Hz,1H),7.25–7.17(m,2H),4.36(t,J＝4.9Hz,2H),3.84(t,J＝7.3Hz,2H),3.00(t,J＝7.2Hz,2H),2.56(s,2H)。13C NMR(126MHz,DMSO)δ167.26,162.23,160.30,154.59,150.80,145.96,141.83,132.10,131.81,129.02,127.96,126.16,124.89,121.75,120.02,115.70,73.86,48.15,46.89,27.51。ESI-HRMS(m/z)calcd[M+H]+＝363.1503,found 363.1506。
以下对实施例1～61制备的化合物的性能进行检测：
1、实施例1～61制备的化合物对HIF-l信号通路的抑制作用
将人肝癌细胞LM3接种到24孔板中。根据说明书，使用Lipofectamine2000转染试剂(Invitrogen公司产品)将含有5个拷贝的HIF-1结合元件(HRE)的萤火虫荧光素酶(fireflyluciferase)报告基因质粒(pGL3-HRE-Luc)和编码海肾荧光素酶(renillaluciferase)的pRL-SV40质粒共转染进入细胞。然后在常氧(21％O2)下孵育6小时。随后，将每孔的培养基换成含有DMSO(阴性对照)或10μM受试化合物的新鲜培养基，并将板在常氧条件下培养1小时后，在缺氧(1％O2)再孵育24小时。用PBS缓冲液洗涤细胞后，根据说明书，使用双荧光素酶报告基因测定试剂盒(Promega)和酶标仪(SpectraMaxM4，MolecularDevice)测量测定荧光素酶活性。萤火虫荧光素酶活力数值用海肾荧光素酶活力数值化归一(公式1)。以DMSO组(阴性对照)的抑制率为0％，计算受试化合物对荧光素酶的抑制率(公式2)，计算结果如表1所示。
公式1：
公式2：
表1实施例1～61制备的芳基内酰胺环类化合物在10μM浓度下对缺氧诱导因子-1的抑制率
注：*LW6为阳性对照，是含有金刚烷结构的HIF-1抑制剂。
2、肝微粒体酶代谢法检测实施例9、10、14、17、19、36、53、56制备的化合物的稳定性
实验在100mmol/L磷酸盐缓冲液(pH＝7.4)中进行，在37℃的条件下将最终浓度为1mg/mL的人肝微粒体蛋白质和终浓度为100μmol/L的底物预热10分钟，反应由加入终浓度为1mmol/L的NADPH启动。在37℃孵育条件下摇动反应液，并分别在0、5、15、30、45、60、90和120分钟时取样100μL，加至含有400μL冰乙腈的聚丙烯管中以停止反应，将混合液于12000r/min离心10min，取上清液，用于UPLC分析。处理液在254nm的UV波长下使用WONDASILC18色谱柱(4.6×150mm)，实验使用SHIMADZU的LC-20A HPLC系统，在30％水和70％的乙腈(含0.1％甲酸(条件下，以1mL/min的流速实现梯度洗脱20分钟进行分析检测(见表2)。
表2肝微粒体体外代谢稳定性实验
名称 半衰期(min) 名称 半衰期(min)
AMSP-30m* <5 实施例19 228
实施例9 <5 实施例36 156
实施例10 251 实施例53 <15
实施例14 174 实施例56 80
实施例17 136
注：*AMSP-30m是芳基甲酰胺类缺氧诱导因子-1抑制剂。
3、实时PCR法检测检测实施例9、10、14、17、19、36、53、56制备的化合物的对缺氧诱导的血管表皮生长因子(VEGF)信使RNA(mRNA)的影响
VEGF是HIF-1调控的下游基因。HIF-1α和HIF-1β的二聚体结合于VEGF基因的启动子序列上，推动了其转录，因此我们检测HIF-1抑制剂实施例51化合物是否能抑制缺氧诱导的VEGF基因转录，即VEGF的mRNA的增加。具体操作方法如下：人脐静脉内皮细胞(HUVEC)在常氧条件下用实施例9、10、14、17、19、36、53、56制备的化合物或DMSO(阴性对照)分别处理1小时，再在缺氧条件下处理24小时。使用TRIzol试剂(Invitrogen公司产品)提取总RNA，并使用primescriptRT试剂盒(Takara公司产品)进行逆转录以获得cDNA，随后使用SYBRPremixExTaqII(Takara公司产品)通过实时PCR扩增。通过2-ΔΔCt方法计算基因表达，并以GAPDH为内参，计算相对表达水平。结果表3所示，实施例9、10、14、17、19、36、53、56制备的化合物可以不同程度对VEGFmRNA水平产生抑制作用。所述的常氧条件是指氧气在细胞培养箱中所占的比例约是21％，缺氧条件是指氧气在细胞培养箱中所占的比例是1％。
表3化合物对缺氧诱导的VEGFmRNA的抑制率
名称 抑制率％@1μM 名称 抑制率％@1μM
实施例9 54 实施例19 44
实施例10 58 实施例36 53
实施例14 68 实施例53 47
实施例17 52 实施例56 65
4、Transwell实验检测实施例9、10、14、17、19、36、53、56制备的化合物对肿瘤细胞侵袭和迁移的影响
Transwell小室的底部有一层含有小孔的膜，孔径8μM。在小室膜表面预先包被一层基质胶，模拟体内的基底膜。无血清培养基混悬的细胞接种于细胞基质胶表面，并将小室置于含有血清的培养基中，由于血清中细胞因子的趋化作用，细胞通过侵袭穿过基质胶，再穿过小室底部含有小孔的膜，至膜背面，以先侵袭再迁移穿过小孔至膜背面的细胞数目表征细胞的侵袭能力。观察细胞侵袭时，具体操作如下：将2×105个MDA-MB-231细胞悬浮在每孔0.3mL无血清培养基中，接种到Transwell小室(Corning公司产品)中。对于侵袭测定，小室内预先包被基质胶(matrigel，Corning公司产品)。将小室置于24孔板中，并在下部孔板中加入含有10％FBS和实施例9、10、14、17、19、36、53或56制备的化合物或DMSO(阴性对照)的完全培养基。将孔板在常氧条件下孵育1小时并在低氧条件下再孵育24小时。用棉签将小室上表面未迁移穿过小孔的细胞擦去，迁移过小孔至膜背面的细胞用甲醇固定，结晶紫染色，随后在倒置显微镜下从每个孔的5个不同区域计数，取平均数，并与阴性对照组细胞平均数的比值计算抑制率。
表4化合物对肿瘤细胞侵袭的抑制率
名称 抑制率％@5μM 名称 抑制率％@5μM
实施例9 47 实施例19 63
实施例10 52 实施例36 57
实施例14 70 实施例53 50
实施例17 66 实施例56 62
以上所述仅为本发明的较佳实施例，对本发明而言仅仅是说明性的，而非限制性的。本专业技术人员理解，在本发明权利要求所限定的精神和范围内可对其进行许多改变，修改，甚至等效，但都将落入本发明的保护范围内。

Claims (7)

1.一种芳基内酰胺环类化合物，其特征在于，具有以下通式：
其中，X选自-CH2-、-O-、-CH2CH2-、-OCH2-；Ar1选自以下芳香环或芳香环系：
Ar2选自以下芳香环或芳香环系：
2.如权利要求1所述的一种芳基内酰胺环类化合物，其特征在于，所述芳基内酰胺环类化合物为以下任意一种化合物：
3.一种如权利要求1所述的芳基内酰胺环类化合物，其特征在于，所述芳基内酰胺环类化合物在人肝微粒体代谢中，具有药物开发所需的理想的稳定性。
4.一种药物组合物，其特征在于，包括如权利要求1～3任一项所述的芳基内酰胺环类化合物中的至少一种，以及药学上可以接受的辅料。
5.一种如权利要求1～3任一项所述的芳基内酰胺环类化合物在制备预防和/或治疗缺氧诱导因子-1上调导致的疾病的药物中的应用。
6.如权利要求5所述的芳基内酰胺环类化合物的应用，其特征在于，所述疾病为乳腺癌、卵巢癌、肺癌、肝癌、宫颈癌、胃癌、肠癌。
7.如权利要求5所述的芳基内酰胺环类化合物的应用，其特征在于，所述疾病为视网膜血管病理性生长疾病。
CN202210564652.2A 2022-05-23 2022-05-23 一种芳基内酰胺环类化合物、药物组合物及其应用 Active CN114989085B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210564652.2A CN114989085B (zh) 2022-05-23 2022-05-23 一种芳基内酰胺环类化合物、药物组合物及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210564652.2A CN114989085B (zh) 2022-05-23 2022-05-23 一种芳基内酰胺环类化合物、药物组合物及其应用

Publications (2)

Publication Number Publication Date
CN114989085A CN114989085A (zh) 2022-09-02
CN114989085B true CN114989085B (zh) 2023-11-24

Family

ID=83027583

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210564652.2A Active CN114989085B (zh) 2022-05-23 2022-05-23 一种芳基内酰胺环类化合物、药物组合物及其应用

Country Status (1)

Country Link
CN (1) CN114989085B (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105384687A (zh) * 2014-09-02 2016-03-09 广东东阳光药业有限公司 喹啉酮类化合物及其在药物中应用
CN106957290A (zh) * 2017-03-13 2017-07-18 武汉大学 一种芳香甲酰胺类化合物及其在制备抗甲型流感病毒药物中的应用
CN109180580A (zh) * 2016-02-28 2019-01-11 深圳市塔吉瑞生物医药有限公司 一种取代的杂芳基化合物及包含该化合物的组合物及其用途
CN110407824A (zh) * 2019-08-08 2019-11-05 安徽医科大学 芳基甲酰胺类化合物及其制备方法、药物组合物及用途
CN111499514A (zh) * 2019-01-31 2020-08-07 连云港润众制药有限公司 一种罗沙司他中间体的制备方法
CN113444038A (zh) * 2021-07-07 2021-09-28 新乡医学院 一类2-芳基异烟酸酰胺类lsd1/hdac双靶点抑制剂、其制备方法及应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019169267A1 (en) * 2018-03-01 2019-09-06 Reaction Biology Corp. Quinoline and isoquinoline based hdac inhibitors and methods of use thereof
KR102527205B1 (ko) * 2018-08-31 2023-05-03 서울대학교산학협력단 신규한 HIF-1α 억제제, 이의 제조방법 및 이를 유효성분으로 함유하는 신생혈관 관련 안질환의 예방 또는 치료용 약학적 조성물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105384687A (zh) * 2014-09-02 2016-03-09 广东东阳光药业有限公司 喹啉酮类化合物及其在药物中应用
CN109180580A (zh) * 2016-02-28 2019-01-11 深圳市塔吉瑞生物医药有限公司 一种取代的杂芳基化合物及包含该化合物的组合物及其用途
CN106957290A (zh) * 2017-03-13 2017-07-18 武汉大学 一种芳香甲酰胺类化合物及其在制备抗甲型流感病毒药物中的应用
CN111499514A (zh) * 2019-01-31 2020-08-07 连云港润众制药有限公司 一种罗沙司他中间体的制备方法
CN110407824A (zh) * 2019-08-08 2019-11-05 安徽医科大学 芳基甲酰胺类化合物及其制备方法、药物组合物及用途
CN113444038A (zh) * 2021-07-07 2021-09-28 新乡医学院 一类2-芳基异烟酸酰胺类lsd1/hdac双靶点抑制剂、其制备方法及应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Design, synthesis and biological evaluation of 2H-benzo[b][1,4] oxazine derivatives as hypoxia targeted compounds for cancer therapeutics;Bhaskar C. Das et al.;《Bioorg Med Chem Lett.》;第19卷(第15期);4204-4206 *
Discovery of Novel Aryl Carboxamide Derivatives as Hypoxia- Inducible Factor 1α Signaling Inhibitors with Potent Activities of Anticancer Metastasis;Mingming Liu et al.;《Journal of Medicinal Chemistry》;第62卷;9299-9314 *
FADD 在缺氧缺血性脑损伤新生大鼠中的表达及 头孢曲松干预作用;徐佳俊 等;《临床合理用药》;第9卷(第6A期);26-28 *
缺氧诱导因子-1抑制剂放射增敏作用的研究进展;曹金发 等;《中国药理学与毒理学杂志》;第28卷(第4期);600-605 *

Also Published As

Publication number Publication date
CN114989085A (zh) 2022-09-02

Similar Documents

Publication Publication Date Title
CN105452235B (zh) 取代的喹唑啉-4-酮衍生物
KR102575246B1 (ko) 페닐-2-히드록시-아세틸아미노-2-메틸-페닐 화합물
US8338392B2 (en) MicroRNA modulators and method for identifying and using the same
KR20080074161A (ko) ＥＰＨＢ 및 ＶＥＧＦＲ２ 키나아제 억제제로서의피라졸로[１,５-ａ]피리딘-３-카르복실산
CN104761541A (zh) Mdm2与p53间相互作用的抑制剂
US8029980B2 (en) Identification and use of agents that modulate oncogenic transcription agent activity
WO2020015343A1 (en) Novel compounds and their uses as acc inhibitors
CN111559991A (zh) 一种萘胺类化合物及其盐的制备方法和应用
US20130023498A1 (en) MicroRNA Modulators and Method for Identifying and Using the Same
CN114989085B (zh) 一种芳基内酰胺环类化合物、药物组合物及其应用
WO2020063968A1 (zh) Ar和bet双重抑制剂及其用途
JP2022521797A (ja) イミプリドン様薬剤に対する薬物反応のバイオマーカとしてのカゼイン分解プロテアーゼｐの機能の使用
CN104755084B (zh) 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途
CN111732584B (zh) 二芳基取代稠杂环类化合物及其制备方法和在制药中的用途
KR101268478B1 (ko) Ｄｋｋ３ 발현 또는 활성 억제제를 함유하는 암 예방 및 치료용 조성물
CN114908094B (zh) 一类反义寡核苷酸分子及其在制备治疗恶性肿瘤药物中的应用
CN111875588A (zh) 对野生型肺癌肿瘤细胞具有杀伤性能的厄洛替尼衍生物及其制备方法
JP2016094415A (ja) 抗腫瘍剤
CN114539129B (zh) 烯丙胺类双功能化合物及其用途
KR100938297B1 (ko) (3,4-다이하이드로-퀴나졸린-2-일)-인단-1-일-아민
CN115572247B (zh) 一类维生素k3衍生物及其医药用途
CN109824701B (zh) 一种吡啶并噻唑类化合物及其制备方法和应用
US20080248024A1 (en) Therapeutic agent for cancer, inflammation, and auto-immune disease containing inhibitor of zinc finger protein 91
CN115160340B (zh) 一种具有ack1抑制活性的小分子化合物及其应用
CN113929674B (zh) 含1,4-二氢喹唑啉结构的化合物及其制备方法与应用

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