CN114524778A - 苯并五元含氮杂环类化合物及其制备方法和用途 - Google Patents
苯并五元含氮杂环类化合物及其制备方法和用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种能够阻断VISTA信号通路的苯并五元含氮杂环类化合物及其制备方法和用途,该类化合物如下式Ⅰ所示;本发明所述化合物结构新颖,可口服给药,对于阻断VISTA信号通路具有明显的作用,能够有效治疗和缓解癌症等疾病,且作为小分子抑制剂制备简单,方便工业生产。
Description
技术领域
本发明涉及化学医药技术领域,具体涉及阻断VISTA信号通路的苯并五元含氮杂环类化合物及其制备方法和用途。
背景技术
恶性肿瘤是当今世界上最复杂、最难治疗的疾病之一,严重威胁人类健康和生命。肿瘤治疗的方式主要包括手术、放疗、化疗以及靶向治疗等。肿瘤免疫治疗,是指通过刺激机体免疫系统来提高抗肿瘤免疫效应,从而抑制和杀伤肿瘤细胞的一种治疗方法。随着肿瘤学,免疫学以及分子生物学的综合发展和交叉渗透,对肿瘤发病机制的深入研究,免疫治疗已经取得了多方面的成果,为肿瘤治疗带来了新希望。
肿瘤免疫治疗中的免疫检查点抑制剂是目前比较火热的免疫治疗药物。肿瘤细胞通过上调免疫检查点受体的表达,抑制免疫细胞T细胞活性,完成肿瘤细胞的免疫逃逸。免疫检查点抑制剂则是通过抑制免疫检查点通路,解除免疫细胞T细胞的抑制,激活机体对肿瘤细胞的免疫杀伤,实现肿瘤治疗的作用。目前,已发现的免疫检查点有CTLA-4(cytotoxicT lymphocyte-associated antigen-4),PD-1(Programmed cell death 1)和TIM3(T cellmembrane 3)等(见Drew M.Pardoll,Nature Review Cancer,2012,12,252)。
T细胞激活抑制物免疫球蛋白可变区结构域(VISTA)是一类主要表达于造血细胞组织的免疫检查点。此外,骨髓细胞、神经质细胞和中性粒细胞中也高表达VISTA。与其他免疫检查点在免疫反应激活后诱导表达的特征不同,VISTA在免疫细胞稳态时期就处于稳定表达。多项研究显示VISTA对免疫系统具有抑制作用。因此,抑制VISTA信号通路,可修复机体抗肿瘤免疫活性,以VISTA信号通路为靶点的抑制剂研究也成为一项研究热点。目前为止,市场上仍没有VISTA信号通路的小分子抑制剂上市。因此,研制具有良好抗肿瘤活性的新型VISTA小分子抑制剂具有重大意义。
发明内容
发明目的:针对现有市场没有VISTA抑制剂药物上市的现状,本发明提供了一种VISTA小分子抑制剂化合物及其制备方法和用途。
技术方案:为了实现上述目的,本发明公开了一种如下式I所示的苯并五元含氮杂环类化合物,其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物:
其中,环A和环B独立地为芳环或芳杂环;
X1独立地为C,O,N或S;
R1独立地为氢、氘、卤素、氰基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基,或氨基酸;
R2独立地为氢、氘、卤素、氰基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、或相邻两个R2与B环的两个原子形成4-7元取代或未取代的碳环或杂环;
R3为氢、氘、卤素、氰基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基;
m为1、2或3;
n为1、2或3。
进一步地,每个R1中,所述的取代的烷基或取代的烷氧基的取代基可以是下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;所述的取代的羟基或取代的氨基中的取代基为下列基团中的一个或多个:C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基;其中所述C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基任选地可被以下一个或多个取代基取代:羟基、羧基、氰基、氨基、环烷基、芳基、杂环基、烯基、炔基;当取代基为多个时,所述的取代基相同或不同。
进一步地,每个R2中,所述的取代的烷基或取代的烷氧基的取代基可以是下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;所述的取代的羟基或取代的氨基中的取代基为下列基团中的一个或多个:C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基;其中所述C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基任选地可被以下一个或多个取代基取代:羟基、羧基、氰基、氨基、环烷基、芳基、杂环基、烯基、炔基;当相邻的两个R2和与它们相连的B环上的两个原子共同形成4-7元的取代的碳环或取代的杂环时,所述的取代的碳环或取代的杂环的取代基为下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;当取代基为多个时,所述的取代基相同或不同。
优选的,所述的如式I所示结构的苯并五元含氮杂环化合物,为如下任一种:
进一步地,该化合物还包括其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。
上述的苯并五元含氮杂环类化合物的制备方法,当X为O,N,S时,所述化合物的合成路线如下所示:
其中,A,B,R1,R2,R3,m,n与所述式I中的定义一致,合成步骤如下:
(1)化合物II与化合物III经缩合关环反应得到化合物IV;
(2)化合物IV与化合物V经Suzuki偶联反应得到化合物VI;
(3)化合物VI经还原反应得到化合物VII;
(4)化合物VII经氧化反应得到化合物VIII;
(5)化合物VIII经还原胺化反应得到化合物IX。
一种药物组合物,其含有治疗有效量的一种或多种具有通式I所述结构的苯并五元含氮杂环类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物作为活性成分和药学上可接受的载体。
所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
如式I所述结构的苯并五元含氮杂环类化合物在制备作为免疫检查点抑制剂、具有VISTA信号通路抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
所述药物组合物在制备作为免疫检查点抑制剂、具有VISTA信号通路抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
有益效果:本发明的苯并五元含氮杂环类化合物结构新颖,可口服给药,对于阻断VISTA信号通路具有明显的作用,能够有效治疗和缓解癌症等疾病,且作为小分子抑制剂制备简单,方便工业生产。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1
合成路线:
化合物2的合成
将原料1(5g,26.59mmol)和3-甲醛苯甲酸甲酯(4.8g,29.25mmol)用邻二甲苯(40mL)溶解,加入8g活性炭,通氧气,置油浴140℃回流反应6h。TLC监测,原料反应完全,将反应液用硅藻土抽滤,浓缩滤液,用二氯甲烷溶解,浓缩制砂,经柱层析(石油醚:乙酸乙酯=60:1)纯化,得化合物2(4g,45%)。
化合物3的合成
将化合物2(1g,3.01mmol),对氟苯硼酸(463mg,3.31mmol),四三苯基膦钯(104mg,0.09mmol),碳酸钾(624mg,4.52mmol)用1,4-二氧六环(10mL)和水(10mL)溶解,充氮气球保护,于油浴80℃条件下搅拌12h。TLC检测,原料反应完全,硅藻土过滤,乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩制砂,经柱层析(石油醚:乙酸乙酯=20:1)纯化,得化合物3(760mg,73%)。
化合物4的合成
将化合物3(500mg,1.44mmol)用四氢呋喃(10mL)溶解,在冰浴条件下,分批加入氢化铝锂(164mg,4.32mmol),于0℃下反应1h。TLC监测,原料反应完。滴加甲醇淬灭反应,用乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液浓缩制砂,经柱层析(石油醚:乙酸乙酯=2:1)纯化,得化合物4(390mg,85%)。
化合物5的合成
将化合物4(145mg,0.454mmol)溶于5mL二氯甲烷中,冰浴条件下加入戴斯马丁试剂(76mg,0.908mmol),后移至室温反应1h,TLC监测反应完毕,加入饱和硫代硫酸钠溶液和饱和碳酸氢钠溶液淬灭,二氯甲烷萃取,饱和食盐水洗涤,无水硫酸钠干燥,过滤,化合物JC-1的合成
将化合物6(60mg)和乙醇胺(24mg)用甲醇(2mL)和二氯甲烷(2mL)溶解,加入1滴冰醋酸,室温搅拌1h,然后加入氰基硼氢化钠(60mg),继续室温搅拌12h,TLC监测反应完毕,加入饱和碳酸氢钠溶液洗涤,二氯甲烷萃取,无水硫酸钠干燥,过滤,滤液浓缩制砂,经柱层析(二氯甲烷:甲醇=20:1)得化合物JC-1(58mg,85%)1H NMR(300MHz,Chloroform-d)δ8.30–8.11(m,2H),7.87–7.71(m,2H),7.65–7.48(m,5H),7.26–7.11(m,2H),3.95(s,2H),3.73(dd,J=5.8,4.5Hz,2H),2.89(dd,J=5.7,4.6Hz,2H).MS(ESI,m/z):363.5[M+H]+.
实施例2
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.16(d,J=2.0Hz,1H),8.06(dt,J=7.4,1.7Hz,1H),7.75(d,J=1.6Hz,1H),7.71–7.60(m,3H),7.58–7.47(m,3H),7.16(t,J=8.7Hz,2H),3.85(s,2H),3.36(t,J=6.4Hz,2H),2.75(t,J=6.4Hz,2H),1.96(s,3H).MS(ESI,m/z):404.6[M+H]+.
实施例3
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.29–8.06(m,1H),7.80–7.72(m,2H),7.67–7.57(m,4H),7.48–7.35(m,2H),7.22–7.17(m,2H),3.96(dt,J=5.8,1.0Hz,2H),2.80(td,J=5.6,4.1Hz,2H),2.63(t,J=5.6Hz,2H),2.45(s,6H).MS(ESI,m/z):390.7[M+H]+.
实施例4
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.28–8.12(m,2H),7.85–7.71(m,2H),7.62–7.49(m,5H),7.26–7.11(m,2H),3.95(s,2H),3.72(dd,J=5.8,4.5Hz,2H),2.90(dd,J=5.7,4.6Hz,2H).MS(ESI,m/z):379.9[M+H]+.
实施例5
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.17(d,J=2.0Hz,1H),8.06(dt,J=7.4,1.7Hz,1H),7.75(d,J=1.6Hz,1H),7.71–7.60(m,3H),7.58–7.47(m,3H),7.16(t,J=8.7Hz,2H),3.85(s,2H),3.36(t,J=6.4Hz,2H),2.75(t,J=6.4Hz,2H),1.96(s,3H).MS(ESI,m/z):420.9[M+H]+.
实施例6
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.28–8.05(m,1H),7.78–7.70(m,2H),7.65–7.55(m,4H),7.49–7.35(m,2H),7.21–7.17(m,2H),3.95(dt,J=5.6,1.0Hz,2H),2.81(td,J=5.5,4.1Hz,2H),2.64(t,J=5.5Hz,2H),2.45(s,6H).MS(ESI,m/z):406.7[M+H]+.
实施例7
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.18–8.01(m,2H),7.75–7.68(m,2H),7.58–7.42(m,5H),7.26–7.10(m,2H),3.98(s,2H),3.64(dd,J=5.0,3.9Hz,2H),2.85(dd,J=5.9,3.6Hz,2H).MS(ESI,m/z):413.2[M+H]+.
实施例8
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19(d,J=2.2Hz,1H),8.03(dt,J=6.4,1.9Hz,1H),7.79(d,J=1.4Hz,1H),7.74–7.65(m,3H),7.55–7.42(m,3H),7.26(t,J=7.5Hz,2H),3.76(s,2H),3.46(t,J=5.4Hz,2H),2.78(t,J=6.4Hz,2H),1.94(s,3H).MS(ESI,m/z):454.6[M+H]+.
实施例9
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.15–8.02(m,1H),7.75–7.68(m,2H),7.63–7.51(m,4H),7.43–7.31(m,2H),7.21–7.12(m,2H),3.95(dt,J=5.5,1.0Hz,2H),2.86(td,J=4.5,4.1Hz,2H),2.64(t,J=6.5Hz,2H),2.46(s,6H).MS(ESI,m/z):440.4[M+H]+.
实施例10
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.20–8.05(m,2H),7.92–7.75(m,2H),7.60–7.43(m,5H),7.23–7.05(m,2H),3.97(s,2H),3.74(dd,J=5.3,4.3Hz,2H),2.86(dd,J=5.4,4.8Hz,2H).MS(ESI,m/z):370.5[M+H]+.
实施例11
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.13(d,J=2.0Hz,1H),8.02(dt,J=7.0,1.5Hz,1H),7.76(d,J=1.4Hz,1H),7.71–7.60(m,3H),7.58–7.47(m,3H),7.16(t,J=8.7Hz,2H),3.85(s,2H),3.36(t,J=6.3Hz,2H),2.75(t,J=6.0Hz,2H),1.96(s,3H).MS(ESI,m/z):411.7[M+H]+.
实施例12
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.25–8.04(m,2H),7.75–7.68(m,2H),7.61–7.51(m,3H),7.47–7.34(m,2H),7.21–7.18(m,2H),3.94(dt,J=5.6,1.0Hz,2H),2.82(td,J=5.5,4.1Hz,2H),2.65(t,J=5.5Hz,2H),2.46(s,6H).MS(ESI,m/z):397.3[M+H]+.
实施例13
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.21–8.03(m,2H),7.95–7.78(m,2H),7.57–7.41(m,5H),7.21–7.07(m,2H),3.96(s,2H),3.80(s,3H),3.74(dd,J=5.2,4.3Hz,2H),2.86(dd,J=5.4,4.6Hz,2H).MS(ESI,m/z):375.5[M+H]+.
实施例14
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.11(d,J=2.0Hz,1H),8.01(dt,J=6.9,1.2Hz,1H),7.75(d,J=1.5Hz,1H),7.70–7.60(m,3H),7.56–7.45(m,3H),7.14(t,J=8.5Hz,2H),3.85(s,2H),3.78(s,3H),3.35(t,J=6.2Hz,2H),2.73(t,J=5.9Hz,2H),1.96(s,3H).MS(ESI,m/z):416.9[M+H]+.
实施例15
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.01(m,2H),7.71–7.65(m,2H),7.58–7.48(m,3H),7.41–7.32(m,2H),7.20–7.15(m,2H),3.92(dt,J=5.3,1.0Hz,2H),3.75(s,3H),2.80(td,J=5.1,4.0Hz,2H),2.66(t,J=5.2Hz,2H),2.46(s,6H).MS(ESI,m/z):402.5[M+H]+.
实施例16
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.15–8.00(m,1H),7.78–7.71(m,2H),7.69–7.63(m,3H),7.47–7.38(m,4H),4.08(t,J=7.1Hz,1H),3.93(dt,J=5.8,1.1Hz,2H),3.84–3.78(m,3H),3.01(td,J=6.7,4.1Hz,2H).MS(ESI,m/z):381.6[M+H]+.
实施例17
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.03(m,1H),7.75–7.65(m,2H),7.65–7.58(m,3H),7.42–7.35(m,4H),4.06(t,J=7.5Hz,1H),3.92(dt,J=5.3,1.0Hz,2H),3.84–3.80(m,3H),3.03(td,J=6.2,4.0Hz,2H).MS(ESI,m/z):422.7[M+H]+.
实施例18
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.07(m,2H),7.75–7.65(m,2H),7.61–7.55(m,2H),7.47–7.37(m,2H),7.26–7.18(m,2H),3.92(dt,J=5.6,1.0Hz,2H),2.82(td,J=5.3,4.0Hz,2H),2.65(t,J=5.2Hz,2H),2.45(s,6H).MS(ESI,m/z):408.2[M+H]+.
实施例19
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.14–8.00(m,1H),7.76–7.70(m,2H),7.68–7.62(m,3H),7.47–7.39(m,4H),4.08(t,J=7.0Hz,1H),3.93(dt,J=5.7,1.1Hz,2H),3.85–3.79(m,3H),3.00(td,J=6.7,4.0Hz,2H).MS(ESI,m/z):397.9[M+H]+.
实施例20
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.21–8.03(m,1H),7.74–7.66(m,2H),7.63–7.57(m,3H),7.42–7.34(m,4H),4.05(t,J=7.4Hz,1H),3.91(dt,J=5.3,1.0Hz,2H),3.85–3.80(m,3H),3.03(td,J=6.2,3.9Hz,2H).MS(ESI,m/z):438.9[M+H]+.
实施例21
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19–8.07(m,2H),7.77–7.68(m,2H),7.61–7.58(m,2H),7.46–7.37(m,2H),7.26–7.20(m,2H),3.92(dt,J=5.6,1.0Hz,2H),2.81(td,J=5.2,4.0Hz,2H),2.66(t,J=5.1Hz,2H),2.46(s,6H).MS(ESI,m/z):424.6[M+H]+.
实施例22
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.29–8.07(m,2H),7.82–7.62(m,2H),7.61–7.49(m,5H),7.22–7.05(m,2H),3.94(s,2H),3.72(dd,J=5.7,4.5Hz,2H),2.89(dd,J=5.7,4.5Hz,2H).MS(ESI,m/z):363.2[M+H]+.
实施例23
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.12(d,J=1.9Hz,1H),8.02(dt,J=7.2,1.2Hz,1H),7.71(d,J=1.9Hz,1H),7.62–7.57(m,3H),7.52–7.49(m,3H),7.11(t,J=8.4Hz,2H),3.85(s,2H),3.35(t,J=6.1Hz,2H),2.74(t,J=6.4Hz,2H),1.95(s,3H).MS(ESI,m/z):404.4[M+H]+.
实施例24
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.23–8.02(m,1H),7.84–7.76(m,2H),7.65–7.52(m,4H),7.47–7.30(m,2H),7.20–7.14(m,2H),3.95(dt,J=5.8,1.0Hz,2H),2.82(td,J=5.5,4.1Hz,2H),2.65(t,J=5.6Hz,2H),2.45(s,6H).MS(ESI,m/z):390.6[M+H]+.
实施例25
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.71–8.61(m,2H),8.26–8.08(m,2H),7.89–7.72(m,2H),7.60(dd,J=8.2,1.8Hz,1H),7.55–7.43(m,4H),3.92(s,2H),3.74(t,J=5.1Hz,2H),2.86(t,J=5.1Hz,2H).MS(ESI,m/z):346.1[M+H]+.
实施例26
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.70–8.62(m,2H),8.22(d,J=1.9Hz,1H),8.13(dtt,J=6.2,4.4,2.1Hz,1H),7.81(d,J=8.3Hz,2H),7.61(dd,J=8.1,1.8Hz,1H),7.52(ddd,J=8.7,4.9,1.8Hz,4H),6.61(t,J=5.5Hz,1H),3.89(s,2H),3.40(q,J=5.7Hz,2H),2.82(t,J=5.8Hz,2H),2.01(s,3H).MS(ESI,m/z):387.8[M+H]+.
实施例27
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.72–8.61(m,2H),8.20(d,J=1.8Hz,1H),8.12(dtt,J=6.1,4.3,2.1Hz,1H),7.80(d,J=8.2Hz,2H),7.60(dd,J=8.0,1.8Hz,1H),7.50(ddd,J=8.5,4.5,1.9Hz,4H),3.87(s,2H),3.42(q,J=5.7Hz,2H),2.80(t,J=5.7Hz,2H),2.44(s,6H).MS(ESI,m/z):373.2[M+H]+.
实施例28
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.68–8.60(m,2H),8.25–8.13(m,2H),7.90–7.75(m,2H),7.61(dd,J=8.1,2.3Hz,1H),7.59–7.41(m,4H),3.91(s,2H),3.75(t,J=5.1Hz,2H),2.88(t,J=5.0Hz,2H).MS(ESI,m/z):346.6[M+H]+.
实施例29
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.74–8.65(m,2H),8.20(d,J=1.6Hz,1H),8.10(dtt,J=6.0,4.2,2.6Hz,1H),7.80(d,J=8.0Hz,2H),7.65(dd,J=8.1,1.5Hz,1H),7.50(ddd,J=8.5,4.2,1.5Hz,4H),6.60(t,J=5.3Hz,1H),3.93(s,2H),3.42(q,J=5.3Hz,2H),2.80(t,J=5.8Hz,2H),2.00(s,3H).MS(ESI,m/z):387.7[M+H]+.
实施例30
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.75–8.59(m,2H),8.15(d,J=2.4Hz,1H),8.10(dtt,J=5.6,4.0,2.5Hz,1H),7.75(d,J=8.0Hz,2H),7.64(dd,J=8.3,1.6Hz,1H),7.48(ddd,J=8.0,4.2,2.6Hz,4H),3.85(s,2H),3.40(q,J=5.7Hz,2H),2.86(t,J=5.2Hz,2H),2.40(s,6H).MS(ESI,m/z):373.3[M+H]+.
实施例31
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.17–8.06(m,1H),7.80–7.65(m,3H),7.54–7.39(m,5H),7.03–6.95(m,2H),4.05(t,J=6.0Hz,1H),3.95(dt,J=5.3,1.3Hz,2H),3.86–3.78(m,6H),3.25–3.16(m,4H),3.02(td,J=4.9,3.5Hz,2H).MS(ESI,m/z):430.5[M+H]+.
实施例32
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.05(d,J=1.6Hz,1H),7.76(d,J=8.0Hz,1H),7.61–7.57(m,2H),7.40(m,1H),7.39–7.30(m,4H),6.95–6.80(m,2H),3.91(dt,J=5.1,1.3Hz,2H),3.75(t,J=5.7Hz,4H),3.35(td,J=5.7,4.1Hz,2H),3.25–3.13(m,4H),3.04(td,J=5.0,4.6Hz,2H),1.96(s,3H).MS(ESI,m/z):471.6[M+H]+.
实施例33
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.08(d,J=1.5Hz,1H),7.78(d,J=8.2Hz,1H),7.60–7.55(m,2H),7.43(m,1H),7.38–7.30(m,4H),6.98–6.85(m,2H),3.90(dt,J=5.4,1.1Hz,2H),3.76(t,J=5.2Hz,4H),3.37(td,J=5.7,4.5Hz,2H),3.28–3.13(m,4H),3.04(td,J=5.4,4.1Hz,2H),2.43(s,6H).MS(ESI,m/z):457.8[M+H]+.
实施例34
合成方法如实施例1。1H NMR(300MHz,Chloroform-d)δ8.25(s,1H),8.17(dt,J=6.3,2.1Hz,1H),7.85–7.77(m,2H),7.69–7.58(m,3H),7.56–7.44(m,4H),7.43–7.34(m,1H),3.94(s,2H),3.71(t,J=5.2Hz,2H),2.87(t,J=5.2Hz,2H).MS(ESI,m/z):345.4[M+H]+.
实施例35
合成方法如实施例1。1H NMR(300MHz,Chloroform-d)δ8.25(d,J=1.8Hz,1H),8.20–8.13(m,1H),7.84–7.77(m,2H),7.63(ddd,J=16.3,8.5,1.6Hz,3H),7.53–7.45(m,4H),7.43–7.34(m,1H),6.10(s,1H),3.90(s,2H),3.38(q,J=5.6Hz,2H),2.82(t,J=5.8Hz,2H),2.00(s,3H).MS(ESI,m/z):386.5[M+H]+.
实施例36
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.29(s,1H),8.10–8.02(m,3H),7.63–7.52(m,4H),7.49–7.34(m,2H),7.22–7.17(m,2H),3.96(dt,J=5.98,1.0Hz,2H),2.81(td,J=5.6,4.1Hz,2H),2.64(t,J=5.1Hz,2H),2.45(s,6H).MS(ESI,m/z):372.5[M+H]+.
实施例37
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.22–8.08(m,2H),7.64–7.56(m,3H),7.40–7.38(m,2H),7.25–7.10(m,3H),3.97(s,2H),3.75(t,J=5.4Hz,2H),2.81(t,J=5.8Hz,2H),2.55(s,3H).MS(ESI,m/z):377.6[M+H]+.
实施例38
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.15–8.09(m,2H),7.57(d,J=8.0Hz,1H),7.45–7.34(m,4H),7.10(q,J=8.9,7.5Hz,3H),6.36(s,1H),3.83(s,2H),3.36(q,J=6.1Hz,2H),2.75(t,J=6.2Hz,2H),2.56(s,3H),1.99(s,3H).MS(ESI,m/z):418.2[M+H]+.
实施例39
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.20(s,1H),8.15(d,J=7.5Hz,1H),7.51–7.45(m,1H),7.32(t,J=7.4Hz,1H),7.30–7.26(m,3H),7.13–7.06(m,3H),4.40(s,1H),3.86(s,2H),2.70(t,J=5.4Hz,2H),2.52(s,3H),2.45(t,J=5.8Hz,2H),2.20(s,6H).MS(ESI,m/z):404.6[M+H]+.
实施例40
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.09(m,2H),7.60–7.54(m,3H),7.43–7.35(m,2H),7.27–7.15(m,3H),3.99(s,2H),3.76(t,J=5.0Hz,2H),2.80(t,J=5.9Hz,2H),2.54(s,3H).MS(ESI,m/z):393.7[M+H]+.
实施例41
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.18–8.04(m,2H),7.56(d,J=7.6Hz,1H),7.45–7.38(m,4H),7.14(q,J=8.1,7.9Hz,3H),6.35(s,1H),3.81(s,2H),3.35(q,J=6.1Hz,2H),2.75(t,J=6.1Hz,2H),2.56(s,3H),2.01(s,3H).MS(ESI,m/z):434.9[M+H]+.
实施例42
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.24(s,1H),8.18(d,J=7.0Hz,1H),7.50–7.45(m,1H),7.31(t,J=7.5Hz,1H),7.30–7.27(m,3H),7.13–7.08(m,3H),4.41(s,1H),3.86(s,2H),2.71(t,J=5.4Hz,2H),2.54(s,3H),2.45(t,J=5.8Hz,2H),2.20(s,6H).MS(ESI,m/z):420.8[M+H]+.
实施例43
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.05(m,2H),7.61–7.48(m,3H),7.43–7.34(m,2H),7.23–7.12(m,3H),3.97(s,2H),3.74(t,J=5.5Hz,2H),2.84(t,J=5.5Hz,2H),2.54(s,3H).MS(ESI,m/z):376.2[M+H]+.
实施例44
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.18–8.05(m,2H),7.53(d,J=8.2Hz,1H),7.44–7.28(m,4H),7.12(q,J=8.5,7.9Hz,3H),6.35(s,1H),3.79(s,2H),3.35(q,J=6.1Hz,2H),2.72(t,J=6.2Hz,2H),2.55(s,3H),1.98(s,3H).MS(ESI,m/z):417.8[M+H]+.
实施例45
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.18(s,1H),8.10(d,J=7.7Hz,1H),7.56–7.48(m,1H),7.38(t,J=7.6Hz,1H),7.35–7.29(m,3H),7.16–7.07(m,3H),4.42(s,1H),3.84(s,2H),2.72(t,J=5.8Hz,2H),2.54(s,3H),2.47(t,J=5.9Hz,2H),2.22(s,6H).MS(ESI,m/z):403.7[M+H]+.
实施例46
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.14–8.00(m,2H),7.49(t,J=8.3Hz,3H),7.41–7.25(m,4H),7.10(d,J=8.3Hz,1H),3.91(s,2H),3.73(t,J=5.5Hz,2H),2.80(t,J=5.6Hz,2H),2.50(s,3H).MS(ESI,m/z):312.5[M+H]+.
实施例47
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.17–8.05(m,2H),7.54(d,J=8.3Hz,1H),7.44–7.28(m,6H),7.13(d,J=8.3Hz,1H),6.40(d,J=6.1Hz,1H),3.75(s,2H),3.33(q,J=6.1Hz,2H),2.68(t,J=6.2Hz,2H),2.55(s,3H).MS(ESI,m/z):433.6[M+H]+.
实施例48
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.16(s,1H),8.05(d,J=7.3Hz,1H),7.54–7.46(m,1H),7.35(t,J=7.5Hz,1H),7.35–7.28(m,3H),7.15–7.07(m,3H),4.42(s,1H),3.83(s,2H),2.72(t,J=5.3Hz,2H),2.54(s,3H),2.47(t,J=5.3Hz,2H),2.21(s,6H).MS(ESI,m/z):419.8[M+H]+.
实施例49
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19–8.04(m,2H),7.77(d,J=8.1Hz,2H),7.70–7.51(m,5H),7.21(d,J=8.3Hz,1H),3.95(s,2H),3.74(t,J=5.6Hz,2H),2.82(t,J=5.6Hz,2H),2.58(s,3H).MS(ESI,m/z):426.5[M+H]+.
实施例50
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19–8.04(m,2H),7.77(d,J=8.0Hz,2H),7.69–7.49(m,5H),7.21(d,J=8.3Hz,1H),3.92(s,2H),3.38(t,J=6.3Hz,2H),3.33(s,3H),2.79(t,J=6.4Hz,2H),1.96(s,3H).MS(ESI,m/z):467.8[M+H]+.
实施例51
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.11(s,1H),8.02(d,J=7.3Hz,1H),7.58–7.49(m,1H),7.35(t,J=6.9Hz,1H),7.35–7.22(m,3H),7.18–7.07(m,3H),4.46(s,1H),3.81(s,2H),2.75(t,J=5.1Hz,2H),2.55(s,3H),2.50(t,J=5.3Hz,2H),2.23(s,6H).MS(ESI,m/z):455.1[M+H]+.
实施例52
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.18–8.03(m,2H),7.81(d,J=8.2Hz,2H),7.57(dd,J=8.1,5.5Hz,5H),7.18(d,J=8.3Hz,1H),3.94(s,2H),3.73(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H),2.57(s,3H).MS(ESI,m/z):383.7[M+H]+.
实施例53
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.18–8.02(m,2H),7.86–7.77(m,2H),7.63–7.50(m,6H),7.18(d,J=8.3Hz,1H),3.91(s,2H),3.38(t,J=6.4Hz,4H),2.78(t,J=6.4Hz,2H),2.57(s,3H),1.96(s,3H).MS(ESI,m/z):424.2[M+H]+.
实施例54
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.12(s,1H),8.05(d,J=7.0Hz,1H),7.55–7.49(m,1H),7.31(t,J=6.9Hz,1H),7.35–7.25(m,3H),7.15–7.02(m,3H),4.45(s,1H),3.84(s,2H),2.79(t,J=5.1Hz,2H),2.61(s,3H),2.47(t,J=5.3Hz,2H),2.25(s,6H).MS(ESI,m/z):410.8[M+H]+.
实施例55
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.18–8.02(m,2H),7.62–7.44(m,3H),7.35–7.24(m,2H),7.16(d,J=8.3Hz,1H),7.06–6.95(m,2H),3.94(s,2H),3.86(s,3H),3.73(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H),2.55(s,3H).MS(ESI,m/z):388.7[M+H]+.
实施例56
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.18–8.02(m,2H),7.62–7.44(m,3H),7.36–7.24(m,2H),7.16(d,J=8.3Hz,1H),7.07–6.95(m,2H),3.92(s,2H),3.87(s,3H),3.38(t,J=6.4Hz,2H),2.79(t,J=6.4Hz,2H),2.55(s,3H),1.96(s,3H).MS(ESI,m/z):429.3[M+H]+.
实施例57
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.21–8.00(m,2H),7.73–7.65(m,2H),7.56–7.48(m,3H),7.44–7.32(m,2H),7.20–7.16(m,2H),3.92(dt,J=5.3,1.0Hz,2H),3.76(s,3H),2.80(td,J=5.1,4.0Hz,2H),2.65(t,J=5.2Hz,2H),2.45(s,6H).MS(ESI,m/z):415.2[M+H]+.
实施例58
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19–8.03(m,2H),7.61–7.48(m,3H),7.41–7.25(m,2H),7.18(t,J=6.6Hz,2H),3.94(s,2H),3.73(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H),2.56(s,3H).MS(ESI,m/z):394.4[M+H]+.
实施例59
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.14(s,1H),8.07(t,J=4.2Hz,1H),7.60–7.50(m,3H),7.38–7.24(m,2H),7.21–7.11(m,2H),3.91(s,2H),3.38(t,J=6.4Hz,2H),2.79(t,J=6.4Hz,2H),2.56(s,3H),1.96(s,3H).MS(ESI,m/z):435.8[M+H]+.
实施例60
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.21–8.07(m,2H),7.76–7.65(m,2H),7.63–7.55(m,2H),7.45–7.37(m,2H),7.24–7.17(m,2H),3.91(dt,J=5.6,1.0Hz,2H),2.83(td,J=5.0,3.5Hz,2H),2.65(t,J=5.5Hz,2H),2.45(s,6H).MS(ESI,m/z):421.7[M+H]+.
实施例61
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.17–8.01(m,2H),7.61–7.41(m,4H),7.37–7.23(m,2H),7.14(t,J=5.9Hz,1H),3.93(d,J=3.1Hz,2H),3.73(t,J=5.6Hz,2H),2.81(t,J=5.6Hz,2H),2.54(d,J=2.8Hz,3H).MS(ESI,m/z):410.2[M+H]+.
实施例62
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.12–7.99(m,2H),7.56–7.40(m,4H),7.31–7.23(m,2H),7.10(d,J=8.3Hz,1H),3.87(s,2H),3.36(t,J=6.4Hz,2H),2.76(t,J=6.4Hz,2H),2.52(s,3H),1.94(s,3H).MS(ESI,m/z):451.8[M+H]+.
实施例63
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.14–8.07(m,2H),7.71–7.65(m,2H),7.56–7.50(m,2H),7.42–7.33(m,2H),7.24–7.14(m,2H),3.91(dt,J=5.0,1.0Hz,2H),2.73(td,J=5.2,4.0Hz,2H),2.64(t,J=5.1Hz,2H),2.57(s,3H),2.46(s,6H).MS(ESI,m/z):437.2[M+H]+.
实施例64
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.25–8.09(m,2H),7.75–7.62(m,2H),7.55–7.43(m,5H),7.20–7.05(m,2H),3.94(s,2H),3.72(dd,J=5.3,4.9Hz,2H),2.89(dd,J=5.7,4.5Hz,2H),2.52(s,3H).MS(ESI,m/z):376.8[M+H]+.
实施例65
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.10(d,J=1.5Hz,1H),8.05(dt,J=6.5,1.2Hz,1H),7.70(d,J=1.5Hz,1H),7.60–7.53(m,3H),7.50–7.43(m,3H),7.11(t,J=8.3Hz,2H),3.82(s,2H),3.36(t,J=5.4Hz,2H),2.70(t,J=6.1Hz,2H),2.51(s,3H),1.93(s,3H).MS(ESI,m/z):417.1[M+H]+.
实施例66
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.05(m,1H),7.80–7.73(m,2H),7.65–7.51(m,4H),7.47–7.28(m,2H),7.23–7.14(m,2H),3.95(dt,J=5.8,1.0Hz,2H),2.81(td,J=5.0,4.0Hz,2H),2.65(t,J=5.1Hz,2H),2.52(s,3H),2.45(s,6H).MS(ESI,m/z):403.2[M+H]+.
实施例67
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.64–8.56(m,2H),8.16(d,J=1.9Hz,1H),8.09(ddd,J=5.6,3.6,1.8Hz,1H),7.56(dd,J=4.7,3.6Hz,3H),7.52–7.45(m,2H),7.21(d,J=8.3Hz,1H),3.98(s,2H),3.75(t,J=5.6Hz,2H),2.86(t,J=5.5Hz,2H),2.60(s,3H).MS(ESI,m/z):359.5[M+H]+.
实施例68
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.63–8.57(m,2H),8.16(s,1H),8.08(dq,J=7.7,3.2,2.2Hz,1H),7.61–7.53(m,3H),7.52–7.47(m,2H),7.21(d,J=8.4Hz,1H),3.94(s,2H),3.39(t,J=6.4Hz,2H),2.81(t,J=6.4Hz,2H),2.61(s,3H),1.96(s,3H).MS(ESI,m/z):400.3[M+H]+.
实施例69
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.75–8.64(m,2H),8.24(d,J=1.7Hz,1H),8.15(dtt,J=6.0,4.6,2.5Hz,1H),7.85(d,J=8.0Hz,2H),7.64(dd,J=7.5,1.8Hz,1H),7.56(ddd,J=8.0,4.1,1.7Hz,4H),3.85(s,2H),3.45(q,J=5.2Hz,2H),2.81(t,J=5.7Hz,2H),2.59(s,3H),2.43(s,6H).MS(ESI,m/z):386.7[M+H]+.
实施例70
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.61–8.53(m,2H),8.16(s,1H),8.12–8.05(m,1H),7.91(d,J=7.8Hz,1H),7.57(dd,J=8.6,4.3Hz,4H),7.19(d,J=8.3Hz,1H),3.95(s,2H),3.74(t,J=5.6Hz,2H),2.83(t,J=5.6Hz,2H),2.58(s,3H).MS(ESI,m/z):359.8[M+H]+.
实施例71
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.57(d,J=11.1Hz,2H),8.15(s,1H),8.11–8.04(m,1H),7.89(d,J=7.3Hz,1H),7.55(t,J=6.6Hz,4H),7.18(d,J=7.8Hz,1H),3.92(d,J=4.8Hz,2H),3.42–3.30(m,3H),2.79(t,J=6.7Hz,2H),2.58(d,J=4.0Hz,3H),1.96(s,3H).MS(ESI,m/z):400.9[M+H]+.
实施例72
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.77–8.61(m,2H),8.27(d,J=1.5Hz,1H),8.15(dtt,J=5.8,4.3,2.8Hz,1H),7.87(d,J=7.8Hz,2H),7.62(dd,J=7.0,1.8Hz,1H),7.56(ddd,J=8.5,4.2,1.3Hz,4H),3.86(s,2H),3.44(q,J=5.2Hz,2H),2.82(t,J=5.7Hz,2H),2.61(s,3H),2.44(s,6H).MS(ESI,m/z):386.4[M+H]+.
实施例73
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.16–8.05(m,1H),7.80–7.65(m,2H),7.52–7.36(m,5H),7.03–6.94(m,2H),3.95(dt,J=5.4,1.0Hz,2H),3.85–3.76(m,6H),3.26–3.16(m,4H),3.02(td,J=6.0,4.5Hz,2H),2.43(s,3H).MS(ESI,m/z):443.7[M+H]+.
实施例74
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.05(d,J=1.6Hz,1H),7.76(d,J=8.0Hz,1H),7.61–7.57(m,2H),7.40(m,1H),7.39–7.30(m,4H),6.95–6.80(m,2H),3.91(dt,J=5.1,1.3Hz,2H),3.75(t,J=5.7Hz,4H),3.35(td,J=5.7,4.1Hz,2H),3.25–3.13(m,4H),3.04(td,J=5.0,4.6Hz,2H),2.52(s,3H),1.96(s,3H).MS(ESI,m/z):484.8[M+H]+.
实施例75
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.08(d,J=1.5Hz,1H),7.78(d,J=8.2Hz,1H),7.60–7.55(m,2H),7.43(m,1H),7.38–7.30(m,4H),6.98–6.85(m,2H),3.90(dt,J=5.4,1.1Hz,2H),3.76(t,J=4.3Hz,4H),3.37(td,J=6.3,4.5Hz,2H),3.28–3.13(m,4H),3.04(td,J=5.4,4.1Hz,2H),2.52(s,3H),2.43(s,6H).MS(ESI,m/z):470.2[M+H]+.
实施例76
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.35–8.17(m,2H),7.85–7.74(m,2H),7.68–7.52(m,5H),7.24–7.16(m,2H),3.96(s,2H),3.72(dd,J=5.1,4.3Hz,2H),2.89(dd,J=5.4,4.9Hz,2H).MS(ESI,m/z):379.9[M+H]+.
实施例77
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.36–8.18(m,2H),7.89–7.78(m,2H),7.69–7.51(m,5H),7.26–7.18(m,2H),3.95(s,2H),3.75(dd,J=5.4,4.7Hz,2H),2.89(dd,J=5.1,4.5Hz,2H),1.96(s,3H).MS(ESI,m/z):420.2[M+H]+.
实施例78
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.30–8.19(m,2H),7.85–7.76(m,2H),7.64–7.55(m,5H),7.24–7.13(m,2H),3.95(s,2H),3.75(dd,J=5.4,4.7Hz,2H),2.89(dd,J=5.1,4.5Hz,2H),2.45(s,6H).MS(ESI,m/z):406.5[M+H]+.
实施例79
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.32–8.15(m,2H),7.87–7.76(m,2H),7.66–7.50(m,5H),7.26–7.18(m,2H),3.95(s,2H),3.75(dd,J=5.0,4.5Hz,2H),2.90(dd,J=5.0,4.5Hz,2H),2.56(s,3H).MS(ESI,m/z):393.7[M+H]+.
实施例80
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.36–8.18(m,2H),7.89–7.78(m,2H),7.69–7.51(m,5H),7.26–7.18(m,2H),3.95(s,2H),3.75(dd,J=5.4,4.7Hz,2H),2.89(dd,J=5.1,4.5Hz,2H),2.55(s,3H),1.95(s,3H).MS(ESI,m/z):434.7[M+H]+.
实施例81
合成方法参照实施例1。1H NMR(300MHz,Chloroform-d)δ8.38–8.15(m,2H),7.85–7.74(m,2H),7.65–7.53(m,5H),7.28–7.19(m,2H),3.96(s,2H),3.75(dd,J=5.0,4.4Hz,2H),2.90(dd,J=5.1,4.5Hz,2H),2.54(s,3H),2.44(s,6H).MS(ESI,m/z):420.2[M+H]+.
实施例82
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.24–8.04(m,2H),7.62–7.49(m,3H),7.46–7.37(m,2H),7.21–7.15(m,3H),3.96(s,2H),3.75(t,J=5.0Hz,2H),2.86(t,J=5.4Hz,2H).MS(ESI,m/z):380.3[M+H]+.
实施例83
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.22–8.07(m,2H),7.60–7.45(m,3H),7.41–7.34(m,2H),7.20–7.13(m,3H),3.95(s,2H),3.78(t,J=4.8Hz,2H),2.86(t,J=5.3Hz,2H).MS(ESI,m/z):440.9[M+H]+.
实施例84
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.04(m,2H),7.65–7.47(m,3H),7.42–7.30(m,2H),7.23–7.15(m,3H),3.97(s,2H),3.78(t,J=4.8Hz,2H),2.85(t,J=5.3Hz,2H).MS(ESI,m/z):430.8[M+H]+.
实施例85
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.22–8.06(m,2H),7.64–7.48(m,3H),7.39–7.26(m,2H),7.21–7.14(m,3H),3.96(s,2H),3.78(t,J=4.5Hz,2H),2.85(t,J=5.0Hz,2H).MS(ESI,m/z):387.1[M+H]+.
实施例86
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.15–8.01(m,2H),7.74–7.36(m,5H),7.14–7.08(m,3H),3.99(s,2H),3.84(t,J=5.6Hz,2H),2.89(t,J=4.3Hz,2H).MS(ESI,m/z):381.4[M+H]+.
实施例87
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.19–8.05(m,2H),7.79–7.51(m,5H),7.14–7.08(m,3H),3.94(s,2H),3.82(t,J=5.8Hz,2H),2.83(t,J=4.0Hz,2H).MS(ESI,m/z):441.8[M+H]+.
实施例88
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.24–8.06(m,2H),7.81–7.47(m,5H),7.11–7.01(m,3H),3.96(s,2H),3.88(t,J=4.8Hz,2H),2.76(t,J=3.0Hz,2H).MS(ESI,m/z):431.6[M+H]+.
实施例89
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.20–8.10(m,2H),7.85–7.55(m,5H),7.23–7.08(m,3H),3.94(s,2H),3.80(t,J=6.0Hz,2H),2.70(t,J=.0Hz,2H).MS(ESI,m/z):388.8[M+H]+.
实施例90
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.28–8.16(m,2H),7.80–7.44(m,5H),7.12–7.01(m,3H),3.90(s,2H),3.86(t,J=6.4Hz,2H),2.87(t,J=3.3Hz,2H).MS(ESI,m/z):397.5[M+H]+.
实施例91
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.27–8.15(m,2H),7.76–7.50(m,5H),7.15–7.05(m,3H),3.88(s,2H),3.81(t,J=6.4Hz,2H),2.83(t,J=3.3Hz,2H).MS(ESI,m/z):457.7[M+H]+.
实施例92
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.33–8.25(m,2H),7.86–7.57(m,5H),7.25–7.09(m,3H),4.01(s,2H),3.85(t,J=5.4Hz,2H),2.88(t,J=3.9Hz,2H).MS(ESI,m/z):447.6[M+H]+.
实施例93
合成方法参照实施例1。1H NMR(300MHz,Methanol-d4)δ8.30–8.23(m,2H),7.88–7.59(m,5H),7.23–7.12(m,3H),3.99(s,2H),3.83(t,J=3.5Hz,2H),2.89(t,J=4.2Hz,2H).MS(ESI,m/z):404.2[M+H]+.
试验例1化合物与VISTA蛋白结合能力实验
(一)实验设备及试剂
1、本实验所用机型:Biacore S200。
2、S系列CM5芯片。货号:29-1049-88(一片装),BR-1005-30(三片装),29-1496-03(十片装),购买地为GE Healthcare。
3、氨基偶联试剂盒。货号:BR-1000-50,购买地为GE Healthcare。
4、缓冲液:10x PBS-P+(货号:28-9950-84),购买地为GE Healthcare。
5、分析纯DMSO,去离子水(0.22μm膜过滤)。
6、蛋白:糖基化修饰的VISTA蛋白。
7、其他耗材:无盖1.5ml EP管(货号:BR-1002-87),橡胶瓶盖2型(货号:BR-1004-11),96孔板(货号:BR-1005-03),96孔板封口膜(货号:28-9758-16),购买地为GEHealthcare。
(二)实验步骤
利用Biacore S200系统和CM5芯片测试化合物与VISTA蛋白的结合能力,用1.05*PBS-P稀释10mM化合物母液至10个浓度梯度(5μM,2.5μM,1.25μM,0.625μM,0.3125μM,0.156μM,0.078μM,0.039μM,0.0195μM,0.00975μM),测试得到不同浓度亲和力数据,并拟合得到化合物KD数值。
(三)实验结果
下表为实施例化合物与VISTA蛋白结合的KD数值。
以上对本发明的具体实施例进行了描述,但需要理解的是,本发明并不局限于上述特定的实施方式,本领域技术人员可以在不脱离本发明构思的前提下,做出各种变形和修改,这些都属于本发明的保护范围。
Claims (10)
1.一种如式I所示的苯并五元含氮杂环类化合物,其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物:
其中,环A和环B独立地为芳环或芳杂环;
X1独立地为C,O,N或S;
R1独立地为氢、氘、卤素、氰基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基,或氨基酸;
R2独立地为氢、氘、卤素、氰基、取代或未取代的羟基、取代或未取代的氨基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、或相邻两个R2与B环的两个原子形成4-7元取代或未取代的碳环或杂环;
R3为氢、氘、卤素、氰基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基;
m为1、2或3;
n为1、2或3。
2.根据权利要求1所述的苯并五元含氮杂环类化合物,其特征在于,每个R1中,所述的取代的烷基或取代的烷氧基的取代基可以是下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;所述的取代的羟基或取代的氨基中的取代基为下列基团中的一个或多个:C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基;其中所述C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基任选地可被以下一个或多个取代基取代:羟基、羧基、氰基、氨基、环烷基、芳基、杂环基、烯基、炔基;当取代基为多个时,所述的取代基相同或不同。
3.根据权利要求1所述的苯并五元含氮杂环类化合物,其特征在于,每个R2中,所述的取代的烷基或取代的烷氧基的取代基可以是下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;所述的取代的羟基或取代的氨基中的取代基为下列基团中的一个或多个:C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基;其中所述C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基任选地可被以下一个或多个取代基取代:羟基、羧基、氰基、氨基、环烷基、芳基、杂环基、烯基、炔基;当相邻的两个R2和与它们相连的B环上的两个原子共同形成4-7元的取代的碳环或取代的杂环时,所述的取代的碳环或取代的杂环的取代基为下列基团中的一个或多个:卤素、氰基、羟基、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4羧基、C1-4酯基或C1-4酰胺基;当取代基为多个时,所述的取代基相同或不同。
5.根据权利要求1-4任一项所述苯并五元含氮杂环类化合物,其特征在于:该化合物还包括其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。
7.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1-5任一项所述的苯并五元含氮杂环类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物作为活性成分和药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
9.权利要求1-5任一项所述苯并五元含氮杂环类化合物在制备作为免疫检查点抑制剂、具有VISTA信号通路抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
10.权利要求7-8任一项所述药物组合物在制备作为免疫检查点抑制剂、具有VISTA信号通路抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
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