CN116410106A - 一种苯甲酰胺类hbv衣壳蛋白抑制剂及其制备方法与应用 - Google Patents
一种苯甲酰胺类hbv衣壳蛋白抑制剂及其制备方法与应用 Download PDFInfo
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- CN116410106A CN116410106A CN202310392180.1A CN202310392180A CN116410106A CN 116410106 A CN116410106 A CN 116410106A CN 202310392180 A CN202310392180 A CN 202310392180A CN 116410106 A CN116410106 A CN 116410106A
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- chloride
- dichloromethane
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- 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
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种苯甲酰胺类HBV衣壳蛋白抑制剂及其制备方法和应用，所述化合物具有通式Ⅰ或II所示的结构。本发明还涉及含有通式Ⅰ或II结构化合物的制备方法，药物组合物以及提供上述化合物在制备的抗HBV药物中的应用。
Description
技术领域
本发明属于医药化学领域，具体涉及一种苯甲酰胺类乙型肝炎病毒(HBV)衣壳蛋白抑制剂及其制备方法与应用。
背景技术
乙型肝炎病毒(HBV)，简称乙肝，是由HBV持续感染导致的以肝脏损伤为主的传染性疾病，进一步发展会引起肝代谢失常、肝功能衰竭、肝硬化和肝癌等并发症。目前，被美国FDA批准用于临床的抗HBV药物主要包括聚乙二醇干扰素α(PEG-IFNα)和核苷酸类似物两类。PEG-IFNα主要通过免疫调节发挥抗病毒作用，由于只对部分患者有效且具有不同程度的副作用，限制了其广泛的临床应用。核苷类似物通过竞争性地抑制病毒聚合酶的活性从而抑制HBV基因组复制，并最终达到抗乙肝病毒的作用，但是无法彻底清除体内的乙肝病毒，需要长期服药且易产生耐药性，停药后复发率高。临床上联合使用核苷类似物和干扰素可以显著抑制病毒的复制，提高患者的生活质量和寿命，但却无法彻底治愈HBV，需要长期服药。因此，因此迫切地需要探索新的治疗策略和研发新的抗病毒药物。
当前，随着对HBV衣壳蛋白的结构生物学研究的不断发展，HBV衣壳蛋白已成为抗乙肝病毒药物研究领域备受瞩目的新靶点。目前在研的衣壳蛋白抑制剂可以分为两类：Ⅰ型衣壳蛋白抑制剂干扰病毒核衣壳的正常组装，使之形成多种形态的非衣壳结构，如杂芳基二氢嘧啶类(Bay 41-4109和GLS4等)；Ⅱ型衣壳蛋白抑制剂则促进结构“正常”但无前基因组RNA(pgRNA)的空衣壳形成，如苯基丙烯酰胺类(AT-130等)和苯磺酰胺类(JNJ-6379和NVR3-778等)。
发明内容
为了克服上述现有技术所存在的缺陷，本发明提供了一种苯甲酰胺类HBV衣壳蛋白抑制剂及其制备方法，本发明还提供了上述化合物作为非核苷类HBV抑制剂的活性筛选结果及其应用。
本发明的技术方案如下：
一、苯甲酰胺类HBV衣壳蛋白抑制剂
一种苯甲酰胺类HBV衣壳蛋白抑制剂，具有如下通式Ⅰ或II所示的结构：
其中，Z为羰基、硫代羰基、双羰基；
M为羰基，硫代羰基；
L为C2-3烯基、苯乙烯基、3-6元环烷基、卤素取代的苄基、5元杂芳基、卤素取代的苯基、含有杂原子取代或未取代的C1-3烷基取代的苯基、3-6元环烷基胺基、含有杂原子取代或未取代的C2-5脂肪胺基、卤素取代的芳胺基、卤代烃基取代的芳胺基、卤素取代的苄胺基、含有杂原子取代或未取代的C1-4烷基取代的苄基；
W为C3-5脂肪胺基、5-6元环烷基胺基、卤素取代的芳胺基、卤代烃基取代的芳胺基、卤素取代的苄胺基、卤代烃基取代的苄胺基；
R1为甲基或溴原子；
R2为甲基或氟原子；
R3为氢原子或氟原子。
根据本发明优选的，通式Ⅰ或II中，Z为
M为/>
L为/>
根据本发明进一步优选的，所述的苯甲酰胺类HBV衣壳蛋白抑制剂，其特征在于，是具有下列结构的化合物之一：
二、苯甲酰胺类HBV衣壳蛋白抑制剂的制备方法
苯甲酰胺类HBV衣壳蛋白抑制剂的制备方法，以2-溴-4-氟苯甲酸、2-甲基-4-氟苯甲酸和2-溴-6-氟苯甲酸为原料，经过以下合成路线之一制备本发明中公开的化合物；
合成路线1如下：
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3-氟-4-甲基苯胺或3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)不同类型的酰氯，吡啶，二氯甲烷，4h，rt.。
所述的不同类型的酰氯选自：4-氰基苯甲酰氯，4-溴苯甲酰氯，4-甲基苯甲酰氯，4-正丙基苯甲酰氯，2-噻吩甲酰氯，(E)-苯丙烯酰氯，3,4,5-三氟苯甲酰氯，4-三氟甲基苯甲酰氯，3-甲氧基丙酰氯，4-氟苯甲酰氯，4-氟苯乙酰氯，丙烯酰氯，2-丁烯酰氯，环丙基甲酰氯，环丁基甲酰氯，环戊基甲酰氯，环己基甲酰氯。
合成路线2如下：
试剂及其条件：(i)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
所述的不同类型的胺选自：4-羟基苄胺，3,5-二氟苄胺，3-甲基-4-氟苄胺，4-三氟甲基苄胺，4-氟苄胺，3-氨甲基吡啶，3,4,5-三氟苄胺，3-戊胺，异丙胺，3,4,5-三氟苯胺，4-叔丁基苄胺，4-羟基哌啶，4-三氟甲基苯胺，环戊胺，4-羟基环己胺，4-甲氧基苄胺。
合成路线3如下：
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
所述的不同类型的胺选自：异丙胺，4-氟苄胺，3,5-二氟苄胺，3-甲基-4-氟苄胺，环丙胺，乙胺，烯丙胺，1,1,1-三氟丙-2-胺，4-三氟甲基苄胺，4-氨甲基苯硼酸，N-异丙基甲胺。
合成路线4如下：
试剂及其条件：(i)草酰氯单乙酯，二氯甲烷，3h，rt.；(ii)NaOH，甲醇，水，4h，rt.；(iii)不同类型的胺，HATU，N,N-二异丙基乙胺，二氯甲烷，6h，rt.。
所述的不同类型的胺选自：异丙胺，环戊胺，1-氨基-2-甲基-2-丙醇，环丙胺。
合成路线5如下：
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(vi)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
所述的不同类型的胺选自：异丙胺，环己胺，3,4,5-三氟苯胺，4-三氟甲基苯胺，3,4,5-三氟苄胺，4-三氟甲基苄胺，4-氟苄胺，4-甲氧基苄胺。
合成路线6如下：
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
所述的不同类型的胺选自：3-戊胺，环戊胺，(S)-3-氨基四氢呋喃，环己胺。
以上路线中的R1、R2、R3、L、W如上述通式Ⅰ或II化合物相应位置所述。
三、苯甲酰胺类HBV衣壳蛋白抑制剂的应用
本发明公开了苯甲酰胺类HBV衣壳蛋白抑制剂的抗HBV活性筛选结果及其作为抗HBV抑制剂的应用。通过实验证明本发明的苯甲酰胺类化合物可作为经典的HBV非核苷类抑制剂应用。
如表1所示，选择先导化合物NVR 3-778为阳性对照，对所合成的目标化合物6a-6s、8a-8r、10a-10h、13a-13d、20a-20h、22a-22d，进行了体外抗HBV活性评价，通过CCK-8法测定了药物的体外细胞毒性；同时，通过定量PCR法测定了药物抑制HBV DNA复制活性。
本发明的苯甲酰胺类HBV衣壳蛋白抑制剂是一类结构新型的非核苷类HBV抑制剂，可作为抗HBV的先导化合物。
本发明的苯甲酰胺类HBV衣壳蛋白抑制剂可作为非核苷类HBV抑制剂应用。具体地说作为HBV抑制剂用来制备抗乙肝药物。
一种抗HBV药物组合物，包括本发明的苯甲酰胺类HBV衣壳蛋白抑制剂和一种或多种药学上可接受载体或赋形剂。
本发明公开此类苯甲酰胺类HBV衣壳蛋白抑制剂、其制备方法、抗HBV活性筛选结果及其作为抗HBV抑制剂的首次应用，实验证明苯甲酰胺类HBV衣壳蛋白抑制剂可作为HBV抑制剂用于制备抗乙肝药物。
具体实施方式
通过下述实例有利于理解本发明，但是不能限制本发明的内容，在下列实例中所有目标化合物的编号与上文相同。
合成方案1
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3-氟-4-甲基苯胺或3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)不同类型的酰氯，吡啶，二氯甲烷，4h，rt.。
实施例1：中间体2a的制备，取100mL圆底烧瓶，加入22.5mL浓H2SO4，冰浴下加入22.83mmol 2-溴-4-氟苯甲酸，缓慢滴加2mL浓HNO3，室温反应12h。反应结束后逐滴加入200mL冰水中，抽滤，水洗，干燥得黄白色固体4.2813g，产率71％。
实施例2：中间体2b的制备，操作同例1，所不同的是把2-溴-4-氟苯甲酸换做2-甲基-4-氟苯甲酸。
实施例3：中间体3a的制备，取50ml圆底烧瓶，将3.21mmol中间体2a溶于10mL氯化亚砜中，加入2滴N,N-二甲基甲酰胺，80℃回流反应，反应结束后冷却至室温，旋蒸后得油状产物。
实施例4：中间体3b的制备，操作同例3，所不同的是把原料2a换做2b。
实施例5：中间体4a的制备，取50mL圆底烧瓶，将中间体3a溶于15mL乙腈中，加入3-甲基-4-氟苯胺，60℃回流反应，反应结束后冷却至室温，浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。
实施例6：中间体4b的制备，操作同例5，所不同的是把3-甲基-4-氟苯胺换做3,4,5-三氟苯胺。
实施例7：中间体4c的制备，操作同例5，所不同的是把原料3a换做3b。
实施例8：中间体5a的制备，取100mL圆底烧瓶，将5.39mmol中间体4a溶于甲醇(10mL)与水(10mL)的混合溶剂中，加入18.86mmol Fe粉，10.78mmol NH4Cl，90℃回流反应。反应结束后使用硅藻土趁热抽滤，滤液浓缩，干燥得白色固体，产率75％。
实施例9：中间体5b的制备，操作同例8，所不同的是把原料4a换做4b，得白色固体，产率72％。
实施例10：中间体5c的制备，操作同例8，所不同的是把原料4a换做4c，得白色固体，产率69％。
实施例11：化合物6a的制备，取50mL圆底烧瓶，将1.03mmol 5a溶于8mL二氯甲烷中，加入1.23mmol 4-氰基苯甲酰氯，加入3.08mmol吡啶，室温搅拌。TLC监测反应，反应完全后，旋蒸除去二氯甲烷，加2N HCl溶液进行萃取，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，重结晶得到目标化合物。产物为白色固体，产率为62％，熔点216.5-218.3℃。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.54(s,1H),8.13(d,J＝8.0Hz,2H),8.05(d,J＝8.1Hz,2H),7.86–7.83(m,2H),7.66–7.63(m,1H),7.52–7.48(m,1H),7.13(t,J＝9.2Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.03,164.79,158.66,138.01,135.98,133.08,129.19,126.76,125.65,125.52,124.94,124.76,123.09,123.04,121.09,120.86,119.40,119.32,118.71,116.20,115.63,115.41,114.82,14.87,14.84.ESI-MS:470.03271[M+H]+,C22H14BrF2N3O2[469.02375].
实施例12：化合物6b的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-溴苯甲酰氯，产物为白色固体，产率为55％，熔点210.5-212.8℃。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.42(s,1H),7.94–7.91(m,2H),7.84–7.76(m,4H),7.65(d,J＝7.1Hz,1H),7.50(dt,J＝8.0,3.5Hz,1H),7.13(t,J＝9.2Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.14,165.08,158.67,154.64,135.88,135.32,133.11,132.07,130.47,126.78,126.43,125.80,124.94,124.76,123.10,123.05,121.05,120.81,119.41,119.33,115.94,115.85,115.64,115.41,14.88,14.85.ESI-MS:546.9269[M+Na]+,C26H21F4N3O4S[523.93696].
实施例13：化合物6c的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-甲基苯甲酰氯，产物为白色固体，产率为65％，熔点215.5-217.1℃。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.23(s,1H),7.89(d,J＝7.8Hz,2H),7.82–7.79(m,2H),7.65(d,J＝7.0Hz,1H),7.52–7.48(m,1H),7.35(d,J＝7.8Hz,2H),7.14(d,J＝9.2Hz,1H),2.39(s,3H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.81,165.12,156.27,142.69,135.82,135.78,135.32,135.30,131.16,129.53,128.38,126.74,126.11,124.92,124.74,123.09,123.04,120.97,120.74,119.40,119.32,115.63,115.40,21.52,14.88,14.85.ESI-MS:457.038[M-H]-,C22H17BrF2N2O2[458.04415].
实施例14：化合物6d的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-正丙基苯甲酰氯，产物为白色固体，产率为59％，熔点225.2-226.9℃。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.24(s,1H),7.91(d,J＝6.5Hz,2H),7.82(q,J＝3.3,2.1Hz,2H),7.66(d,J＝6.1Hz,1H),7.52–7.50(m,1H),7.37(d,J＝7.8Hz,2H),7.14(s,1H),2.65(s,2H),2.25(s,3H),1.63(d,J＝7.5Hz,2H),0.91(d,J＝1.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.88,165.12,147.21,135.79,135.30,131.50,128.94,128.40,126.66,126.13,124.92,124.75,123.09,123.04,120.97,120.73,119.40,119.32,115.63,115.40,37.53,24.32,14.87,14.84,14.04.ESI-MS:487.08411[M+H]+,C24H21BrF2N2O2[486.07545].
实施例15：化合物6e的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成2-噻吩甲酰氯，产物为淡黄色固体，产率为55％，熔点214.9-216.1℃。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),10.41(s,1H),8.06(d,J＝3.7Hz,1H),7.90(d,J＝5.0Hz,1H),7.80(dd,J＝15.1,8.8Hz,2H),7.65(d,J＝7.1Hz,1H),7.50(dt,J＝7.6,2.8Hz,1H),7.24(d,J＝3.4Hz,1H),7.12(d,J＝8.3Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.04,160.46,157.21,156.27,138.98,135.90,135.86,135.32,135.29,132.96,130.61,128.74,126.96,125.60,125.47,124.92,124.74,123.09,123.05,121.05,120.82,119.41,119.33,115.94,115.85,115.62,115.39,14.88,14.85.ESI-MS:450.99308[M+H]+,C19H13BrF2N2O2S[449.98492].
实施例16：化合物6f的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成(E)-苯丙烯酰氯，产物为白色固体，产率为57％，熔点208.2-210.7℃。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),10.21(s,1H),8.39(d,J＝7.9Hz,1H),7.80(d,J＝10.3Hz,1H),7.64(d,J＝6.8Hz,4H),7.47(dd,J＝15.9,7.8Hz,4H),7.16–7.09(m,2H),2.25(s,3H).13C NMR(100MHz,DMSO-d6)δ165.34,164.69,156.29,152.03,141.86,135.90,135.32,135.04,130.56,129.55,128.38,126.81,126.70,123.10,123.06,122.93,121.88,120.57,120.34,119.40,119.33,115.65,115.42,113.37,14.88,14.85.ESI-MS:493.0342[M+Na]+,C23H17BrF2N2O2[470.04415].
实施例17：化合物6g的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成3,4,5-三氟苯甲酰氯，产物为白色固体，产率为55％，熔点217.5-219.4℃。1H NMR(400MHz,DMSO-d6)δ10.55(d,J＝5.2Hz,2H),7.95(t,J＝7.5Hz,2H),7.86–7.80(m,2H),7.65(d,J＝7.0Hz,1H),7.52–7.48(m,1H),7.13(s,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ164.99,162.86,156.28,135.28,126.85,124.94,124.76,123.03,121.15,120.91,119.40,119.32,116.37,115.64,115.41,113.71,113.65,113.49,14.87,14.84.ESI-MS:499.009[M+H]+,C21H12BrF5N2O2[498.00023].
实施例18：化合物6h的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-三氟甲基苯甲酰氯，产物为白色固体，产率为55％，熔点221.2-224.6℃。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.54(s,1H),8.17(d,J＝8.0Hz,2H),7.94(d,J＝8.1Hz,2H),7.85(dd,J＝8.6,3.3Hz,2H),7.65(dd,J＝7.1,2.6Hz,1H),7.52–7.47(m,1H),7.13(t,J＝9.2Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.06,164.99,158.68,156.29,137.84,135.98,135.32,135.29,126.79,126.06,126.02,124.95,124.77,123.10,123.05,121.10,120.86,119.41,119.33,116.14,116.05,115.65,115.42,14.87,14.84.ESI-MS:513.0228[M+H]+,512.01588.
实施例19：化合物6i的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成3-甲氧基丙酰氯，产物为白色固体，产率为63％，熔点218.3-220.5℃。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.99(s,1H),8.18(d,J＝7.9Hz,1H),7.75(dd,J＝10.5,1.5Hz,1H),7.63(d,J＝7.0Hz,1H),7.50–7.47(m,1H),7.12(t,J＝9.2Hz,1H),3.63–3.59(m,2H),3.24(d,J＝1.5Hz,3H),2.66(t,J＝6.1Hz,2H),2.24(s,3H).13C NMR(101MHz,DMSO-d6)δ170.60,165.28,158.65,135.78,135.28,135.25,126.53,126.41,124.92,124.74,123.29,123.10,123.05,120.53,120.30,119.40,119.32,115.61,115.38,68.43,58.43,36.86,14.86,14.83.ESI-MS:427.047[M+H]+,C18H17BrF2N2O3[426.03906].
实施例20：化合物6j的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-氟苯甲酰氯，产物为白色固体，产率为55％，熔点217.2-218.5℃。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝4.4Hz,1H),8.54(d,J＝8.4Hz,1H),8.04–7.99(m,4H),7.52(ddd,J＝8.6,4.5,1.5Hz,1H),7.32(td,J＝8.8,1.6Hz,4H).13C NMR(101MHz,DMSO-d6)δ166.84,166.63,164.14,151.59,140.09,135.11,132.62,132.53,131.09,129.34,127.83,127.80,121.20,116.20,115.98,14.83.ESI-MS:463.0268[M+H]+,C21H14BrF3N2O2[462.01907].
实施例21：化合物6k的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成4-氟苯乙酰氯，产物为白色固体，产率为62％，熔点224.9-225.3℃。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.24(s,1H),8.14(d,J＝7.7Hz,1H),7.77(d,J＝10.1Hz,1H),7.62(d,J＝6.9Hz,1H),7.48(dd,J＝9.3,4.6Hz,1H),7.40–7.35(m,2H),7.15(dd,J＝15.0,8.7Hz,3H),3.77(s,2H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ170.36,165.21,162.83,160.42,156.26,152.34,135.80,135.26,132.21,131.56,131.48,126.44,126.33,124.92,124.74,123.51,123.09,123.04,120.62,120.38,119.39,119.31,115.62,115.41,42.02,14.86,14.83.ESI-MS:477.042[M+H]+,C22H16BrF3N2O2[476.03472].
实施例22：化合物6l的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成丙烯酰氯，产物为白色固体，产率为57％，熔点214.2-216.3℃。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),10.22(s,1H),8.27(d,J＝7.9Hz,1H),7.80(d,J＝10.3Hz,1H),7.64(d,J＝6.1Hz,1H),7.50(dd,J＝8.6,4.1Hz,1H),7.15(d,J＝9.2Hz,1H),6.68–6.61(m,1H),6.31(d,J＝17.0Hz,1H),5.83(d,J＝10.2Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.24,164.21,158.65,156.26,152.31,135.86,135.82,135.29,135.26,131.42,128.70,126.40,126.29,124.94,124.76,123.46,123.07,123.03,120.63,120.40,119.38,119.30,115.64,115.40,113.88,14.88,14.84.ESI-MS:395.020[M+H]+,C17H13BrF2N2O2[394.01285].
实施例23：化合物6m的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成2-丁烯酰氯，产物为白色固体，产率为57％，熔点215.6-216.2℃。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),10.04(s,1H),8.31(d,J＝7.9Hz,1H),7.81(d,J＝10.4Hz,1H),7.69(dd,J＝7.1,2.5Hz,1H),7.56–7.52(m,1H),7.19(d,J＝9.2Hz,1H),6.90(dd,J＝15.0,7.3Hz,1H),6.39(d,J＝15.3Hz,1H),2.29(s,3H),1.92(d,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.29,164.47,154.72,141.96,135.80,135.76,135.30,135.27,126.69,126.58,125.57,124.93,124.75,123.34,123.07,123.02,120.52,120.29,119.37,119.29,115.63,115.40,113.43,113.34,18.12,14.87,14.84.ESI-MS:409.036[M+H]+,C18H15BrF2N2O2[408.02850].
实施例24：化合物6n的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成环丙基甲酰氯，产物为白色固体，产率为66％，熔点213.2-215.7℃。1H NMR(600MHz,DMSO-d6)δ10.46(s,1H),10.26(s,1H),8.18(d,J＝8.0Hz,1H),7.76(d,J＝10.4Hz,1H),7.64–7.62(m,1H),7.49–7.47(m,1H),7.13(d,J＝9.2Hz,1H),2.24(d,J＝1.9Hz,3H),2.04(t,J＝5.2Hz,1H),0.84–0.82(m,4H).13C NMR(150MHz,DMSO-d6)δ173.04,165.28,158.23,156.64,154.09,152.42,135.73,135.70,135.28,135.27,126.65,126.57,124.88,124.77,123.36,123.05,123.02,120.47,120.32,119.35,119.30,115.58,115.42,14.87,14.85,14.55,8.26.ESI-MS:409.036[M+H]+,C18H15BrF2N2O2[408.02850].
实施例25：化合物6o的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成环丁基甲酰氯，产物为白色固体，产率为62％，熔点218.2-220.8℃。1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),9.79(s,1H),8.15(d,J＝7.9Hz,1H),7.74(d,J＝10.3Hz,1H),7.65–7.63(m,1H),7.50–7.48(m,1H),7.12(d,J＝9.1Hz,1H),3.41–3.38(m,1H),2.24(d,J＝1.9Hz,3H),2.22–2.18(m,2H),2.12(dt,J＝7.7,3.4Hz,2H),1.94(d,J＝10.8Hz,1H),1.84–1.80(m,1H).13C NMR(150MHz,DMSO-d6)δ174.13,165.28,156.64,154.52,135.73,135.70,135.29,135.27,126.60,126.52,124.89,124.77,123.74,123.06,123.03,120.50,120.35,119.36,119.31,115.58,115.43,113.37,25.04,18.20,14.87,14.85.ESI-MS:423.051[M+H]+,C19H17BrF2N2O2[422.04415].
实施例26：化合物6p的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成环戊基甲酰氯，产物为白色固体，产率为65％，熔点224.3-225.2℃。1H NMR(600MHz,DMSO-d6)δ10.47(s,1H),9.90(s,1H),8.13(d,J＝8.0Hz,1H),7.74(d,J＝10.3Hz,1H),7.64–7.62(m,1H),7.50–7.48(m,1H),7.13(t,J＝9.2Hz,1H),2.97–2.94(m,1H),2.24(d,J＝1.9Hz,3H),1.85(p,J＝3.7Hz,2H),1.73–1.66(m,4H),1.57–1.54(m,2H).13C NMR(150MHz,DMSO-d6)δ175.73,165.28,158.23,156.64,152.84,135.71,135.68,135.27,126.67,126.59,124.88,124.76,123.79,123.06,123.04,120.50,120.34,119.36,119.31,115.57,115.42,113.42,113.36,45.00,30.57,26.19,14.87,14.85.ESI-MS:437.067[M+H]+,C20H19BrF2N2O2[436.05980].
实施例27：化合物6q的制备，操作同例11，所不同的是把4-氰基苯甲酰氯换成环己基甲酰氯，产物为白色固体，产率为61％，熔点228.3-229.2℃。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.86(s,1H),8.14–8.12(m,1H),7.76–7.73(m,1H),7.64(t,J＝3.6Hz,1H),7.49(dt,J＝4.4,2.3Hz,1H),7.13(s,1H),2.54(d,J＝11.6Hz,1H),2.24(d,J＝1.8Hz,3H),1.76(dt,J＝8.8,4.4Hz,4H),1.65(d,J＝11.4Hz,2H),1.39(d,J＝11.0Hz,2H),1.26(q,J＝4.6,2.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ175.52,165.28,135.70,135.66,135.27,126.70,126.58,124.91,123.66,123.06,123.02,120.52,120.29,119.37,119.29,115.62,115.39,113.29,44.53,29.56,25.82,25.59,14.88,14.85.ESI-MS:451.083[M+H]+,C21H21BrF2N2O2[450.07545].
实施例28：化合物6r的制备，操作同例12，所不同的是把原料5a换成5b，产物为白色固体，产率为51％，熔点225.5-227.2℃。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.46(s,1H),7.93(d,J＝8.1Hz,1H),7.88(s,2H),7.78(d,J＝8.2Hz,2H),7.72(d,J＝8.2Hz,1H),7.62(dd,J＝10.2,6.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ165.61,165.14,154.87,135.10,133.02,132.18,132.07,131.77,130.46,126.93,126.47,126.02,125.90,121.24,121.00,115.89,115.80,104.52,104.28.ESI-MS:546.910[M+H]+,C20H10Br2F4N2O2[545.90247].
实施例29：化合物6s的制备，操作同13，所不同的是原料5a换成5b，得白色固体，产率：56％，熔点220.3-223.1℃。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.26(s,1H),7.89(s,2H),7.85(d,J＝9.8Hz,2H),7.64–7.60(m,2H),7.36(d,J＝7.8Hz,2H),2.40(s,3H).13CNMR(100MHz,DMSO-d6)δ165.83,165.66,157.43,154.89,142.74,134.98,131.10,129.53,128.38,126.90,126.36,126.24,121.17,120.93,104.53,104.29,21.52.ESI-MS:481.018[M+H]+,C21H13BrF4N2O3[480.00965].
合成方案2
试剂及其条件：(i)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
实施例30：中间体7a的制备，取50mL圆底烧瓶，将2.93mmol 5a溶于10mL二氯甲烷中，加入3.52mmol氯甲酸苯酯，加入8.79mmol吡啶，室温搅拌。TLC监测反应，反应完全后，旋蒸除去二氯甲烷，加2N HCl溶液进行萃取，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，重结晶得到目标化合物。产物为白色固体，产率为65％，熔点224.5-226.3℃。
实施例31：中间体7b的制备，操作同30，所不同的是原料5a换成5b，得白色固体，产率：56％，熔点228.1-229.9℃。
实施例32：化合物8a的制备，取50mL圆底烧瓶，将1.08mmol 7a溶于8mL二氯甲烷中，加入1.30mmol 4-羟基苄胺，加入1.63mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率为52％，熔点245.5-246.2℃。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.32(s,1H),8.61(s,1H),8.39(d,J＝8.2Hz,1H),7.67–7.62(m,2H),7.51–7.47(m,1H),7.13–7.09(m,3H),7.03(t,J＝5.8Hz,1H),6.74–6.71(m,2H),4.18(d,J＝5.5Hz,2H),2.24(s,3H).13CNMR(100MHz,DMSO-d6)δ165.68,156.87,156.25,154.97,135.82,135.79,135.35,130.19,129.13,128.59,124.91,124.73,123.10,123.06,119.79,119.40,119.32,115.61,115.38,56.51,19.03.ESI-MS:512.0406[M+Na]+,C22H18BrF2N3O3[489.04996].
实施例33：化合物8b的制备，同实例32，将4-羟基苄胺换做3,5-二氟苄胺，得白色固体，产率：49％，熔点236.2-238.9℃。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.79(d,J＝2.6Hz,1H),8.34(d,J＝8.3Hz,1H),7.68(d,J＝10.8Hz,1H),7.64–7.61(m,1H),7.50–7.46(m,1H),7.25(t,J＝6.1Hz,1H),7.14–7.08(m,2H),7.01(d,J＝7.6Hz,2H),4.35(d,J＝6.0Hz,2H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ165.59,164.17,164.04,161.59,155.17,145.42,135.82,135.32,135.29,128.46,128.35,124.88,124.71,123.08,123.04,119.38,115.58,115.35,110.53,110.28,102.65,42.57,14.85,14.83.ESI-MS:510.04529[M+H]+,C22H16BrF4N3O2[509.03620].
实施例34：化合物8c的制备，同实例32，将4-羟基苄胺换做3-甲基-4-氟苄胺，得白色固体，产率：53％，熔点233.2-235.9℃。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.67(s,1H),8.37(d,J＝8.3Hz,1H),7.67–7.62(m,2H),7.49(dd,J＝8.6,4.0Hz,1H),7.20(d,J＝7.9Hz,1H),7.13(d,J＝10.0Hz,3H),7.10–7.06(m,1H),4.26(d,J＝5.7Hz,2H),2.23(d,J＝5.4Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.64,158.61,155.03,152.86,136.07,135.79,135.34,135.31,130.93,130.88,129.83,128.60,126.94,126.86,124.89,124.71,124.55,124.38,123.08,123.03,119.81,119.37,119.29,115.69,115.59,115.35,115.13,109.60,55.38,48.10,42.57,21.13.ESI-MS:506.06995[M+H]+,C23H19BrF3N3O2[505.06127].
实施例35：化合物8d的制备，同实例32，将4-羟基苄胺换做4-三氟甲基苄胺，得白色固体，产率：49％，熔点238.2-239.5℃。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.78(s,1H),8.35(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,2H),7.67(d,J＝10.8Hz,1H),7.64–7.60(m,1H),7.52(d,J＝8.1Hz,2H),7.50–7.46(m,1H),7.28(t,J＝6.0Hz,1H),7.11(t,J＝9.2Hz,1H),4.42(d,J＝5.8Hz,2H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ165.63,158.63,156.24,155.21,150.50,145.37,135.81,135.33,128.51,128.40,128.20,127.84,126.19,125.76,125.72,123.10,123.05,119.87,119.77,119.64,119.39,119.31,115.60,115.37,55.38,42.85,14.86,14.82.ESI-MS:564.0378[M+Na]+,C23H17BrF5N3O2[541.04243].
实施例36：化合物8e的制备，同实例32，将4-羟基苄胺换做4-氟苄胺，得白色固体，产率：54％，熔点231.3-232.6℃。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.69(s,1H),8.37(d,J＝8.1Hz,1H),7.66(d,J＝10.8Hz,1H),7.63(d,J＝7.4Hz,1H),7.48(dt,J＝7.9,3.5Hz,1H),7.34(dd,J＝8.2,5.6Hz,2H),7.19–7.09(m,4H),4.30(d,J＝5.7Hz,2H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ165.63,162.89,158.61,156.23,155.08,136.49,136.46,135.82,135.79,135.33,135.31,129.68,129.60,128.57,128.47,124.90,124.72,123.08,123.04,119.83,119.66,119.60,119.38,119.30,115.68,115.47,42.53,14.86,14.83.ESI-MS:514.0361[M+Na]+,C22H17BrF3N3O2[491.04562].
实施例37：化合物8f的制备，同实例32，将4-羟基苄胺换做3-氨甲基吡啶，得白色固体，产率：54％，熔点235.5-236.8℃。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.74(s,1H),8.53(s,1H),8.47(d,J＝4.5Hz,1H),8.35(d,J＝8.3Hz,1H),7.74–7.62(m,3H),7.52–7.46(m,1H),7.37(dd,J＝7.9,4.8Hz,1H),7.23(t,J＝6.0Hz,1H),7.12(t,J＝9.1Hz,1H),4.35(d,J＝5.8Hz,2H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.63,155.18,149.19,148.67,135.80,135.52,135.33,124.91,124.73,124.01,123.11,123.06,119.88,119.79,119.65,119.40,119.32,115.61,115.38,40.97,14.86,14.83.ESI-MS:497.0408[M+Na]+,C21H17BrF2N4O2[474.05029].
实施例38：化合物8g的制备，同实例32，将4-羟基苄胺换做3,4,5-三氟苄胺，得白色固体，产率：51％，熔点237.2-238.5℃。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.79(s,1H),8.32(d,J＝8.3Hz,1H),7.68(d,J＝10.8Hz,1H),7.62(dd,J＝7.2,2.5Hz,1H),7.48(dd,J＝8.6,4.0Hz,1H),7.24(dd,J＝9.4,6.7Hz,3H),7.12(t,J＝9.2Hz,1H),4.31(d,J＝5.9Hz,2H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ165.61,158.63,155.17,150.59,138.13,135.84,135.33,128.43,128.33,124.90,124.72,123.09,123.04,119.90,119.67,119.39,119.31,115.60,115.38,111.99,111.94,111.83,111.78,109.93,109.84,42.24,14.86,14.83.ESI-MS:550.0128[M+Na]+,C22H15BrF5N3O2[527.02678].
实施例39：化合物8h的制备，同实例32，将4-羟基苄胺换做3-戊胺，得白色固体，产率：58％，熔点227.3-228.7℃。1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.48(s,1H),8.40(d,J＝8.3Hz,1H),7.66–7.62(m,2H),7.51–7.47(m,1H),7.13(d,J＝9.1Hz,1H),6.54(d,J＝8.5Hz,1H),4.36(d,J＝1.5Hz,1H),2.23(s,3H),1.08–1.04(m,4H),0.87–0.83(m,6H).13CNMR(100MHz,DMSO-d6)δ165.72,154.89,135.80,135.36,128.78,124.90,124.72,123.09,123.05,119.72,119.49,119.39,119.31,119.20,115.60,115.37,56.51,27.43,19.03,10.56.ESI-MS:452.07928[M-H]-,C20H22BrF2N3O2[453.08635].
实施例40：化合物8i的制备，同实例32，将4-羟基苄胺换做异丙胺，得白色固体，产率：58％，熔点226.3-227.5℃。1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.42(s,1H),8.38(d,J＝8.3Hz,1H),7.64(t,J＝7.9Hz,2H),7.48(dt,J＝6.9,3.1Hz,1H),7.12(t,J＝9.2Hz,1H),6.62(d,J＝7.3Hz,1H),3.74(q,J＝6.6Hz,1H),2.23(s,3H),1.10(dd,J＝6.5,1.6Hz,6H).13C NMR(100MHz,DMSO-d6)δ165.70,154.28,135.80,135.37,135.33,128.78,128.67,124.90,124.72,123.08,123.04,119.73,119.50,119.38,119.31,115.61,115.38,109.20,109.10,41.58,23.27,14.87,14.84.ESI-MS:448.0464[M+Na]+,C18H18BrF2N3O2[425.05505].
实施例41：化合物8j的制备，同实例32，将4-羟基苄胺换做3,4,5-三氟苯胺，得白色固体，产率：52％，熔点236.2-237.3℃。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.43(s,1H),8.97(s,1H),8.29(d,J＝8.2Hz,1H),7.75(d,J＝10.7Hz,1H),7.64(d,J＝6.9Hz,1H),7.50(dt,J＝7.9,3.3Hz,1H),7.38(dd,J＝10.6,6.2Hz,2H),7.13(t,J＝9.2Hz,1H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.44,156.28,152.35,136.01,135.97,135.30,127.35,127.24,124.94,124.76,123.11,123.07,120.64,120.18,119.95,119.41,119.33,115.63,115.40,111.43,111.34,14.87,14.83.ESI-MS:536.0032[M+Na]+,C21H13BrF5N3O2[513.01113].
实施例42：化合物8k的制备，同实例32，将4-羟基苄胺换做4-叔丁基苄胺，得白色固体，产率：55％，熔点235.5-236.8℃。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.66(s,1H),8.40(s,1H),7.65(t,J＝9.9Hz,3H),7.49(d,J＝4.7Hz,1H),7.36(d,J＝6.7Hz,2H),7.24(s,2H),7.12(s,2H),4.27(s,2H),2.24(s,3H),1.27(d,J＝1.5Hz,9H).13C NMR(100MHz,DMSO-d6)δ165.64,155.03,152.82,149.82,137.12,135.79,135.34,127.51,125.61,124.89,123.08,119.80,119.57,119.29,115.59,115.36,48.05,42.98,34.64,31.63,14.87,14.84.ESI-MS:530.12647[M+H]+,C26H26BrF2N3O2[529.11765].
实施例43：化合物8l的制备，同实例32，将4-羟基苄胺换做4-羟基哌啶，得白色固体，产率：57％，熔点225.5-226.7℃。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.51(s,1H),7.68–7.62(m,3H),7.51–7.47(m,1H),7.13(t,J＝9.2Hz,1H),4.75(d,J＝3.7Hz,1H),3.80(d,J＝13.7Hz,2H),3.68(dq,J＝8.9,4.4Hz,1H),3.08(td,J＝11.3,10.5,5.2Hz,2H),2.24(s,3H),1.78–1.72(m,2H),1.35(dd,J＝11.4,7.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ165.37,156.25,154.92,135.41,135.36,128.41,128.30,125.38,124.90,124.72,123.08,123.03,120.49,120.25,119.38,119.31,115.61,115.38,113.02,66.20,42.20,34.59,14.87,14.84.ESI-MS:466.05905[M-H]-,C20H20BrF2N3O3[467.06561].
实施例44：化合物8m的制备，同实例32，将4-羟基苄胺换做4-三氟甲基苯胺，得白色固体，产率：47％，熔点237.5-239.2℃。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.53(s,1H),8.93(d,J＝2.4Hz,1H),8.35(d,J＝8.2Hz,1H),7.66(s,6H),7.50(dt,J＝7.4,3.5Hz,1H),7.13(t,J＝9.2Hz,1H),2.24(d,J＝1.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ165.47,152.29,143.28,135.32,126.72,124.93,124.75,123.13,120.35,119.42,119.35,118.47,115.64,115.40,19.13.ESI-MS:550.0153[M+Na]+,C22H15BrF5N3O2[527.02678].
实施例45：化合物8n的制备，同实例32，将4-羟基苄胺换做环戊胺，得白色固体，产率：62％，熔点225.9-226.5℃。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.43–8.37(m,2H),7.64(dd,J＝9.6,5.8Hz,2H),7.49(dt,J＝7.5,3.4Hz,1H),7.13(t,J＝9.2Hz,1H),6.77(d,J＝7.0Hz,1H),3.93(q,J＝6.5Hz,1H),2.24(s,3H),1.84(dd,J＝12.7,6.2Hz,2H),1.59(dq,J＝25.1,7.6Hz,4H),1.37(dd,J＝12.7,6.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ165.70,154.53,135.77,135.36,128.78,128.67,124.90,124.72,123.08,123.04,119.73,119.50,119.38,119.30,115.61,115.38,51.41,33.20,23.56,14.87,14.84.ESI-MS:450.06363[M-H]-,C20H20BrF2N3O2[451.07070].
实施例46：化合物8o的制备，同实例32，将4-羟基苄胺换做4-羟基环己胺，得白色固体，产率：60％，熔点228.5-229.2℃。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.45(s,1H),8.38(d,J＝8.1Hz,1H),7.64(t,J＝7.9Hz,2H),7.49(dd,J＝8.0,3.6Hz,1H),7.13(t,J＝9.1Hz,1H),6.65(d,J＝7.4Hz,1H),4.55(d,J＝4.3Hz,1H),2.24(s,3H),1.88–1.78(m,4H),1.21(dq,J＝20.1,11.6Hz,5H),0.97–0.91(m,1H).13C NMR(100MHz,DMSO-d6)δ165.70,154.33,152.72,135.75,135.35,135.33,128.63,124.91,124.73,123.08,123.03,119.74,119.52,119.38,119.30,115.61,115.38,68.28,48.15,39.35,34.01,30.92,14.84.ESI-MS:480.0741[M-H]-,C21H22BrF2N3O3[481.08126].
实施例47：化合物8p的制备，同实例32，将4-羟基苄胺换做4-甲氧基苄胺，得白色固体，产率：52％，熔点213.5-214.2℃。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.64(s,1H),8.39(d,J＝8.3Hz,1H),7.65(s,2H),7.51–7.48(m,1H),7.23(d,J＝8.1Hz,2H),7.15–7.09(m,2H),6.92–6.90(m,2H),4.24(d,J＝4.9Hz,2H),3.74(d,J＝1.5Hz,3H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ165.65,158.78,158.61,156.23,155.00,135.78,135.34,132.05,129.06,128.65,128.55,124.90,124.72,123.08,123.04,119.80,119.57,119.38,119.29,115.60,115.37,114.27,55.54,42.73,19.03.ESI-MS:504.073[M+H]+,C23H20BrF2N3O3[503.06561].
实施例48：化合物8q的制备，同实例35，将原料7a做7b，得白色固体，产率：48％，熔点230.5-232.2℃。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.83(s,1H),8.39(d,J＝8.2Hz,1H),7.71(d,J＝7.4Hz,3H),7.62–7.58(m,2H),7.52(d,J＝7.9Hz,2H),7.29(t,J＝5.8Hz,1H),4.42(d,J＝5.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ166.14,155.17,145.32,128.53,128.18,127.83,126.16,125.78,125.74,125.70,125.66,120.08,119.85,119.77,104.49,104.24,42.86.ESI-MS:564.017[M+H]+,C22H13BrF7N3O2[563.00794].
实施例49：化合物8r的制备，同实例36，将原料7a做7b，得白色固体，产率：56％，熔点238.5-240.4℃。1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.74(s,1H),8.40(d,J＝7.9Hz,1H),7.71(d,J＝10.7Hz,1H),7.63–7.58(m,2H),7.36–7.32(m,2H),7.17(t,J＝8.1Hz,3H),4.30(d,J＝5.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ166.17,162.89,155.06,136.46,136.43,129.67,129.59,120.05,119.82,119.66,115.68,115.47,109.47,104.49,104.24,42.53.ESI-MS:514.020[M+H]+,C21H13BrF5N3O2[513.01113].
合成方案3
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
实施例50：中间体9a的制备，取50mL圆底烧瓶，将2.93mmol 5a溶于10mL二氯甲烷中，加入3.52mmol硫代氯甲酸苯酯，加入8.79mmol吡啶，室温搅拌。TLC监测反应，反应完全后，旋蒸除去二氯甲烷，加2N HCl溶液进行萃取，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷溶剂重结晶。产物为黄色固体，产率：61％，熔点230.4-232.9℃。
实施例51：中间体9b的制备，操作同50，所不同的是原料5a换成5b，得黄色固体，产率：65％，熔点235.1-238.0℃。
实施例52：中间体9c的制备，操作同50，所不同的是原料5a换成5c，得黄色固体，产率：54％，熔点231.5-232.8℃。
实施例53：化合物10a的制备，取50mL圆底烧瓶，将1.05mmol 9a溶于8mL二氯甲烷中，加入1.26mmol 4-羟基苄胺，加入1.57mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率为61％，熔点238.5-239.2℃。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.20(s,1H),8.14(s,1H),8.09–8.04(m,1H),7.72(d,J＝9.4Hz,1H),7.65(d,J＝6.8Hz,1H),7.51–7.48(m,1H),7.13(s,1H),4.39–4.34(m,1H),2.24(s,3H),1.18(d,J＝1.6Hz,3H),1.17(d,J＝1.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ180.09,165.17,158.62,135.33,135.27,135.23,124.90,124.72,123.08,123.03,120.58,120.34,119.38,119.30,115.60,115.37,22.31,14.87,14.84.ESI-MS:442.040[M+H]+,C18H18BrF2N3OS[441.03220].
实施例54：化合物10b的制备，操作同53，所不同的是异丙胺换成4-氟苄胺，得白色固体，产率：50％，熔点246.1-247.7℃。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.53(s,1H),8.55(s,1H),8.00(d,J＝7.9Hz,1H),7.75(d,J＝9.9Hz,1H),7.65(s,1H),7.51–7.48(m,1H),7.39(d,J＝2.4Hz,2H),7.19(s,1H),7.14(d,J＝9.2Hz,2H),4.74–4.71(m,2H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ181.91,165.06,158.64,156.26,135.43,135.28,130.00,129.92,124.91,124.73,123.10,123.05,120.85,120.62,119.40,119.33,115.68,115.62,115.41,115.38,47.18,14.87,14.84.ESI-MS:508.031[M+H]+,C22H17BrF3N3OS[507.02278].
实施例55：化合物10c的制备，操作同53，所不同的是异丙胺换成3,5-二氟苄胺，得白色固体，产率：55％，熔点249.5-250.9℃。1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),9.67(s,1H),8.58(s,1H),7.92(d,J＝7.8Hz,1H),7.77(d,J＝9.9Hz,1H),7.65–7.64(m,1H),7.51–7.49(m,1H),7.14–7.11(m,2H),7.05–7.03(m,2H),4.77(d,J＝5.0Hz,2H),2.24(d,J＝1.9Hz,3H).13C NMR(150MHz,DMSO-d6)δ182.41,165.01,163.65,163.56,162.02,161.93,158.23,156.64,135.61,135.59,135.30,135.29,124.87,124.75,123.08,123.05,120.98,120.82,119.39,119.34,115.57,115.41,110.72,110.69,110.59,110.56,102.89,102.72,102.55,47.11,14.87,14.85.ESI-MS:526.022[M+H]+,C22H16BrF4N3OS[525.01336].
实施例56：化合物10d的制备，操作同53，所不同的是异丙胺换成3-甲基-4-氟苄胺，得白色固体，产率：52％，熔点245.1-247.7℃。1H NMR(600MHz,DMSO-d6)δ10.47(s,1H),9.51(s,1H),8.53(s,1H),8.02(d,J＝7.9Hz,1H),7.75(d,J＝10.0Hz,1H),7.65–7.64(m,1H),7.51–7.48(m,1H),7.26–7.24(m,1H),7.20(q,J＝3.0Hz,1H),7.12(dd,J＝8.8,7.2Hz,2H),4.68(d,J＝5.0Hz,2H),2.24(d,J＝1.9Hz,3H),2.22(d,J＝1.8Hz,3H).13C NMR(150MHz,DMSO-d6)δ181.80,165.07,159.47,135.45,135.42,135.31,135.30,134.86,131.23,131.20,127.30,127.24,127.18,124.88,124.76,124.45,124.34,123.06,123.03,120.80,120.64,119.36,119.31,115.57,115.42,115.26,115.12,47.27,14.87,14.85,14.68,14.66.ESI-MS:522.047[M+H]+,C23H19BrF3N3OS[521.03843].
实施例57：化合物10e的制备，取50mL圆底烧瓶，将1.05mmol 9b溶于8mL二氯甲烷中，加入1.26mmol环丙胺，加入1.57mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。得白色固体，产率：63％，熔点241.9-242.9℃。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.26(s,1H),8.74(s,1H),8.23(d,J＝59.0Hz,1H),7.77(d,J＝9.8Hz,1H),7.62(dd,J＝10.2,6.4Hz,2H),2.81(d,J＝134.6Hz,1H),0.77(d,J＝6.9Hz,2H),0.59(s,2H).13C NMR(100MHz,DMSO-d6)δ165.68,151.81,151.77,151.71,149.43,149.38,149.34,136.81,135.45,134.54,134.36,129.83,120.84,120.60,119.25,115.67,104.53,104.46,104.28,27.56,7.33.ESI-MS:461.990[M+H]+,C17H12BrF4N3OS[460.98206].
实施例58：化合物10f的制备，操作同53，所不同的是异丙胺换成乙胺，得白色固体，产率：65％，熔点232.5-234.7℃。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.36(s,1H),8.12(s,1H),8.03(d,J＝8.0Hz,1H),7.75(s,1H),7.66–7.64(m,1H),7.51–7.48(m,1H),7.13(s,1H),3.48(t,J＝6.8Hz,2H),2.24(d,J＝1.9Hz,3H),1.13(s,3H).13C NMR(100MHz,DMSO-d6)δ181.12,165.12,158.62,156.23,135.38,135.34,124.90,124.73,123.05,123.01,120.74,120.50,119.37,119.29,115.61,115.39,14.88,14.85,14.46.ESI-MS:428.024[M+H]+,C17H16BrF2N3OS[427.01655].
实施例59：化合物10g的制备，操作同53，所不同的是异丙胺换成1,1,1-三氟丙-2-胺，得白色固体，产率：54％，熔点239.1-241.3℃。1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.57(s,1H),8.66(d,J＝8.8Hz,1H),7.99(d,J＝7.9Hz,1H),7.78(d,J＝10.0Hz,1H),7.65(dd,J＝7.1,2.6Hz,1H),7.50(dt,J＝8.0,3.6Hz,1H),7.13(t,J＝9.2Hz,1H),5.35(s,1H),2.24(s,3H),1.34(d,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.72,165.01,158.64,156.25,135.50,135.47,135.30,124.91,124.73,123.08,123.04,120.86,120.62,119.40,119.32,115.62,115.39,51.39,51.10,14.87,14.84,13.99.ESI-MS:496.005[M+H]+,C18H15BrF5N3OS[495.00394].
实施例60：化合物10h的制备，操作同53，所不同的是异丙胺换成4-三氟甲基苄胺，得白色固体，产率：57％，熔点244.5-246.2℃。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.66(s,1H),8.63(d,J＝6.2Hz,1H),7.96(d,J＝7.9Hz,1H),7.77(d,J＝9.9Hz,1H),7.71(d,J＝8.1Hz,2H),7.66–7.64(m,1H),7.54(d,J＝8.0Hz,2H),7.51(d,J＝5.0Hz,1H),7.13(s,1H),4.85(d,J＝5.5Hz,2H),2.24(d,J＝1.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.30,165.03,156.25,144.24,135.52,135.31,135.29,128.40,128.16,125.67,125.63,125.60,124.91,124.73,123.07,123.02,120.97,120.73,119.38,119.30,115.61,115.38,47.42,14.87,14.84.ESI-MS:558.027[M+H]+,C23H17BrF5N3OS[557.01959].
实施例61：化合物10i的制备，操作同53，所不同的是异丙胺换成4-氨甲基苯硼酸，得白色固体，产率：57％，熔点250.2-251.9℃。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.54(s,1H),8.58(d,J＝5.8Hz,1H),8.06(d,J＝7.8Hz,1H),8.02(s,2H),7.77(d,J＝6.8Hz,3H),7.65(d,J＝7.2Hz,1H),7.50(dd,J＝8.1,3.5Hz,1H),7.30(d,J＝7.5Hz,2H),7.13(t,J＝8.7Hz,1H),4.75(d,J＝5.5Hz,2H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ181.92,165.09,140.83,135.44,135.32,134.66,127.16,126.92,123.10,123.05,120.82,120.58,119.41,119.33,115.61,115.38,48.05,14.88,14.85.ESI-MS:532.0350[M-H]-,C22H19BBrF2N3O3S[533.03916].
实施例62：化合物10j的制备，操作同53，所不同的是异丙胺换成烯丙胺，得白色固体，产率：59％，熔点237.1-239.9℃。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.48(s,1H),8.25(s,1H),8.04(d,J＝8.0Hz,1H),7.75(d,J＝10.0Hz,1H),7.67–7.64(m,1H),7.52–7.48(m,1H),7.14(d,J＝9.2Hz,1H),5.90(ddd,J＝12.0,10.3,5.2Hz,1H),5.24–5.18(m,1H),5.15–5.11(m,1H),4.15(s,2H),2.24(d,J＝1.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ181.66,165.09,158.62,156.24,135.33,135.30,134.85,124.91,124.73,123.06,123.01,120.77,120.53,119.37,119.29,116.45,115.61,115.38,46.83,14.88,14.85.ESI-MS:440.0246[M+H]+,C18H16BrF2N3OS[439.01655].
实施例63：化合物10k的制备，取50mL圆底烧瓶，将1.05mmol 9c溶于8mL二氯甲烷中，加入1.26mmol异丙胺，加入1.57mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率为59％，熔点235.5-238.9℃。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.08(s,1H),7.87(s,2H),7.69–7.67(m,1H),7.52(dd,J＝8.8,4.1Hz,1H),7.21(d,J＝11.5Hz,1H),7.11(s,1H),4.38(s,1H),2.37(s,3H),2.24(s,3H),1.18(s,3H),1.16(s,3H).13C NMR(100MHz,DMSO-d6)δ180.49,166.88,158.48,156.10,135.63,135.60,133.13,124.73,124.55,123.16,123.12,119.43,119.35,118.09,117.88,115.48,115.25,22.40,19.44,14.89,14.86.ESI-MS:378.144[M+H]+,C19H21F2N3OS[377.13734].
实施例64：化合物10l的制备，操作同63，所不同的是异丙胺换成烯丙胺，得白色固体，产率：51％，熔点241.7-242.8℃。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.36(s,1H),8.05(s,1H),7.78(d,J＝7.3Hz,1H),7.68(d,J＝4.5Hz,1H),7.52(d,J＝4.8Hz,1H),7.25(s,1H),7.12(s,1H),5.91(dd,J＝11.3,5.6Hz,1H),5.22(s,1H),5.13(s,1H),4.15(s,2H),2.38(s,3H),2.23(s,3H).13C NMR(100MHz,DMSO-d6)δ182.00,166.79,158.49,156.11,135.61,135.59,135.14,133.29,124.74,124.56,123.18,123.14,119.45,119.37,118.28,118.08,116.23,115.49,115.26,46.85,19.48,14.89,14.86.ESI-MS:376.126[M+H]+,C19H19F2N3OS[375.12169].
实施例65：化合物10m的制备，操作同63，所不同的是异丙胺换成4-氨甲基苯硼酸，得白色固体，产率：48％，熔点253.5-255.9℃。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.41(s,1H),8.36(s,1H),8.02(d,J＝1.8Hz,2H),7.81(s,1H),7.76(d,J＝7.6Hz,2H),7.66(d,J＝7.1Hz,1H),7.53–7.49(m,1H),7.29(d,J＝7.5Hz,2H),7.24(d,J＝11.3Hz,1H),7.11(t,J＝9.2Hz,1H),4.75(d,J＝5.2Hz,2H),2.38(s,3H),2.24(s,3H).13C NMR(100MHz,DMSO-d6)δ182.24,166.76,141.14,135.58,134.62,133.27,126.83,124.75,124.57,123.22,119.50,119.41,118.35,118.15,115.49,115.26,48.04,19.49,14.88,14.86.
实施例66：化合物10n的制备，操作同63，所不同的是异丙胺换成N-异丙基甲胺，得白色固体，产率：57％，熔点233.6-235.0℃。ESI-MS:392.161[M+H]+,C20H23F2N3OS[391.15299].
合成方案4
试剂及其条件：(i)草酰氯单乙酯，二氯甲烷，3h，rt.；(ii)NaOH，甲醇，水，4h，rt.；(iii)不同类型的胺，HATU，N,N-二异丙基乙胺，二氯甲烷，6h，rt.。
实施例67：中间体11的制备，取100mL圆底烧瓶，将5.86mmol 5a溶于15mL二氯甲烷中，加入5.86mmol草酰氯单乙酯，室温搅拌。TLC监测反应，反应完全后，浓缩，干法上样，快速制备色谱硅胶柱分离，二氯甲烷溶剂重结晶。产物为白色固体，产率：64％，熔点217.6-218.5℃。
实施例68：中间体12的制备，取50mL圆底烧瓶，将2.27mmol 11溶于4mL甲醇中，加入1mL4N NaOH溶液，冰浴下搅拌。TLC监测反应，反应完全后，采用2N HCl调节pH至3-4，加乙酸乙酯进行萃取(20mL×3)，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷溶剂重结晶。产物为淡黄色固体，产率：56％，熔点225.7-227.9℃。
实施例69：化合物13a的制备，取50mL圆底烧瓶，将1.02mmol 12溶于6mL二氯甲烷中，加入1.22mmol异丙胺、3.05mmol HATU、3.05mmol N,N-二异丙基乙胺，室温搅拌。TLC监测反应，反应完全后，加入水(20mL×3)，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备色谱硅胶柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率53％，熔点232.2-234.6℃。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),10.48(s,1H),8.89(d,J＝8.4Hz,1H),7.85–7.81(m,2H),7.65(d,J＝6.4Hz,1H),7.51–7.48(m,1H),7.13(s,1H),4.02–3.97(m,1H),2.24(s,3H),1.17(d,J＝1.7Hz,3H),1.15(d,J＝1.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.96,159.42,158.65,154.07,135.97,135.27,125.55,124.96,124.78,123.04,122.99,121.03,120.80,119.35,119.27,115.65,115.42,41.89,22.21,14.87,14.83.ESI-MS:454.057[M+H]+,C19H18BrF2N3O3[453.04996].
实施例70：化合物13b的制备，操作同69，所不同的是异丙胺换成环戊胺，得白色固体，产率：42％，熔点235.5-237.2℃。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.49(s,1H),8.98(d,J＝8.0Hz,1H),7.85–7.80(m,2H),7.64(d,J＝7.0Hz,1H),7.51–7.47(m,1H),7.15(d,J＝9.2Hz,1H),4.14–4.08(m,1H),2.24(s,3H),1.88–1.83(m,2H),1.71–1.66(m,2H),1.55(dt,J＝10.8,5.9Hz,4H).13C NMR(100MHz,DMSO-d6)δ164.96,159.37,159.25,156.27,154.08,135.96,135.27,125.58,124.96,124.89,124.78,123.02,122.97,121.04,120.81,119.34,119.26,115.65,115.42,51.44,32.06,24.04,14.87,14.84.ESI-MS:480.073[M+H]+,C21H20BrF2N3O3[479.06561].
实施例71：化合物13c的制备，操作同69，所不同的是异丙胺换成1-氨基-2-甲基-2-丙醇，得白色固体，产率：39％，熔点238.0-239.7℃。ESI-MS:calculated forC20H20BrF2N3O4[M-H]-483.06053,found 484.068.
实施例72：化合物13d的制备，操作同69，所不同的是异丙胺换成环丙胺，得白色固体，产率：35％，熔点232.7-234.3℃。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.51(s,1H),9.13(d,J＝5.3Hz,1H),7.82(d,J＝9.3Hz,1H),7.64(dd,J＝7.1,2.6Hz,1H),7.52(d,J＝4.0Hz,1H),7.49–7.46(m,1H),7.14(d,J＝9.2Hz,1H),2.85(dd,J＝8.1,3.8Hz,1H),2.24(d,J＝1.9Hz,3H),0.69(dd,J＝6.7,4.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ164.96,160.88,159.13,158.65,151.60,135.96,135.92,135.27,135.24,135.10,129.34,125.62,124.78,121.20,121.04,119.32,119.24,115.65,115.42,23.53,14.88,14.84,5.92.ESI-MS:452.041[M+H]+,C19H16BrF2N3O3[451.03431].
合成方案5
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(vi)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
实施例73：化合物15的制备，取100mL圆底烧瓶，加入22.5mL浓H2SO4，冰浴下加入22.83mmol 2-溴-6-氟苯甲酸，缓慢滴加2mL浓HNO3，室温反应12h。反应结束后逐滴加入200mL冰水中，抽滤，水洗，干燥得黄白色固体4.1004g，产率68％。
实施例74：化合物16的制备，取50ml圆底烧瓶，将3.21mmol中间体15溶于10mL氯化亚砜中，加入2滴N,N-二甲基甲酰胺，80℃回流反应，反应结束后冷却至室温，旋蒸后得油状产物。
实施例75：中间体17的制备，取50mL圆底烧瓶，将中间体16溶于15mL乙腈中，加入3,4,5-三氟苯胺，60℃回流反应，反应结束后冷却至室温，浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。
实施例76：中间体18的制备，取100mL圆底烧瓶，将5.39mmol中间体17溶于甲醇(10mL)与水(10mL)的混合溶剂中，加入18.86mmol Fe粉，10.78mmol NH4Cl，90℃回流反应，反应结束后使用硅藻土趁热抽滤，滤液浓缩，干燥得白色固体，产率78％。
实施例77：中间体19的制备，取50mL圆底烧瓶，将2.93mmol 18溶于10mL二氯甲烷中，加入3.52mmol氯甲酸苯酯，加入8.79mmol吡啶，室温搅拌。TLC监测反应，反应完全后，旋蒸除去二氯甲烷，加2N HCl溶液进行萃取，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，重结晶得到目标化合物。产物为白色固体，产率为60％，熔点207.1-208.7℃。
实施例78：化合物20a的制备，取50mL圆底烧瓶，将1.08mmol 19溶于8mL二氯甲烷中，加入1.30mmol 4-羟基苄胺，加入1.63mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率为58％，熔点234.1-236.4℃。1H-NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.71–7.64(m,1H),7.52(d,J＝8.6Hz,1H),7.43–7.33(m,2H),4.90(d,J＝7.5Hz,1H),3.50(h,J＝6.7Hz,1H),1.11(dd,J＝6.6,1.7Hz,6H).13C-NMR(100MHz,Chloroform-d)δ160.20,156.55,153.98,150.01,131.29,129.14,129.10,128.71,128.56,128.39,128.17,126.46,126.42,104.89,104.82,104.71,104.64,60.55,46.97,29.72,26.93,23.60,21.06,14.16.ESI-MS:523.096[M-H]-,C24H20F4N2O5S[524.10291].
实施例79：化合物20b的制备，操作同例78，所不同的是把异丙基换成环己胺，产物为白色固体，产率为60％，熔点238.6-241.2℃。1H-NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.13(dd,J＝9.3,5.6Hz,1H),7.91(s,1H),7.66–7.54(m,2H),7.36(t,J＝8.8Hz,1H),7.03(d,J＝7.6Hz,1H),3.48(d,J＝9.3Hz,1H),1.88–1.77(m,2H),1.72–1.62(m,2H),1.55(d,J＝12.6Hz,1H),1.23(dq,J＝45.3,11.3,10.8Hz,5H).13C-NMR(100MHz,DMSO-d6)δ176.50,175.40,169.73,162.32,154.46,152.22,152.03,132.43,130.96,123.69,117.56,104.38,104.14,34.48,33.28,26.56,25.69,24.72,22.38,18.72.ESI-MS:488.0424[M+H]+,C20H18BrF4N3O2[487.05185].
实施例80：化合物20c的制备，操作同例78，所不同的是把异丙基换成3,4,5-三氟苯胺，产物为白色固体，产率为47％，熔点221.7-223.6℃。1H-NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.59(dd,J＝10.0,6.4Hz,2H),7.13(t,J＝8.8Hz,1H),6.91(dd,J＝9.2,5.3Hz,1H),5.44(s,2H),4.38(d,J＝1.5Hz,1H).13C-NMR(100MHz,DMSO-d6)δ162.92,151.27,149.53,148.92,143.78,131.82,129.00,127.47,127.25,116.41,116.33,116.19,115.97,104.28,104.22,104.03,65.54,56.51,29.52,19.01.ESI-MS:533.9669[M-H]-,C22H16BrF4N3O3[534.97664].
实施例81：化合物20d的制备，操作同例78，所不同的是把异丙基换成4-三氟甲基苯胺，产物为白色固体，产率为45％，熔点229.8-232.4℃。1H-NMR(400MHz,DMSO-d6)δ11.05(s,2H),7.59(dd,J＝10.2,6.4Hz,4H),7.12(td,J＝8.8,1.6Hz,2H),6.95–6.86(m,2H),4.27–3.94(m,1H).13C-NMR(100MHz,DMSO-d6)δ162.91,152.00,151.26,149.57,148.91,143.80,127.48,127.26,116.40,116.32,116.19,115.97,104.27,104.22,104.03,34.77,31.62,30.83,30.40,30.30.ESI-MS:547.9852[M-H]-,C21H11BrF7N3O2[548.99229].
实施例82：化合物20e的制备，操作同例78，所不同的是把异丙基换成3,4,5-三氟苄胺，产物为白色固体，产率为54％，熔点252.4-255.8℃。1H-NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.17(s,1H),8.12–8.06(m,1H),7.72(d,J＝7.9Hz,2H),7.62–7.51(m,5H),7.37(t,J＝8.8Hz,1H),4.42(d,J＝5.8Hz,2H).13C-NMR(100MHz,DMSO-d6)δ162.25,155.54,155.02,152.59,152.07,145.42,143.29,135.41,128.26,127.87,126.19,125.77,125.73,124.66,123.49,115.82,115.60,104.41,104.16,56.50,42.95,19.02.ESI-MS:547.9963[M-H]-,C21H11BrF7N3O2[548.99229].
实施例83：化合物20f的制备，操作同例78，所不同的是把异丙基换成4-三氟甲基苯胺，产物为白色固体，产率为57％，熔点249.3-252.0℃。1H-NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.17(s,1H),8.12–8.06(m,1H),7.72(d,J＝7.9Hz,2H),7.62–7.51(m,5H),7.37(t,J＝8.8Hz,1H),4.42(d,J＝5.8Hz,2H).13C-NMR(100MHz,DMSO-d6)δ162.25,155.54,155.02,152.59,152.07,145.42,143.29,135.41,128.26,127.87,126.19,125.77,125.73,124.66,123.49,115.82,115.60,104.41,104.16,56.50,42.95,19.02.ESI-MS:562.0042[M-H]-,C22H13BrF7N3O2[563.00794].
实施例84：化合物20g的制备，操作同例78，所不同的是把异丙基换成4-氟苄胺，产物为白色固体，产率为61％，熔点245.1-248.7℃。1H-NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.15–8.06(m,2H),7.59(dd,J＝10.1,6.4Hz,2H),7.47(d,J＝5.9Hz,1H),7.40–7.33(m,3H),7.18(td,J＝8.9,1.7Hz,2H),4.31(d,J＝5.6Hz,2H).13C-NMR(100MHz,DMSO-d6)δ162.92,162.26,155.40,152.49,136.52,136.48,135.49,135.46,129.76,129.68,127.62,124.43,124.35,115.80,115.70,115.58,115.49,111.46,104.40,104.16.ESI-MS:514.0276[M+H]+,C22H13BrF5N3O2[513.01113].
实施例85：化合物20h的制备，操作同例78，所不同的是把异丙基换成4-甲氧基苄胺，产物为白色固体，产率为59％，熔点253.5-256.2℃。1H-NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.13(dd,J＝9.5,5.6Hz,1H),8.05(s,1H),7.59(dd,J＝10.0,6.3Hz,2H),7.38(q,J＝8.9,7.9Hz,2H),7.24(d,J＝8.0Hz,2H),6.95–6.87(m,2H),4.24(d,J＝5.5Hz,2H),3.74(d,J＝1.5Hz,3H).13C-NMR(100MHz,DMSO-d6)δ162.27,158.81,155.30,154.81,152.39,135.57,132.08,129.16,127.60,124.16,115.79,115.57,114.29,111.25,104.39,104.15,55.56,42.88.ESI-MS:526.0609[M+H]+,C22H16BrF4N3O3[525.03112].
合成方案6
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.。
实施例86：中间体21的制备，取50mL圆底烧瓶，将2.93mmol 18溶于10mL二氯甲烷中，加入3.52mmol硫代氯甲酸苯酯，加入8.79mmol吡啶，室温搅拌。TLC监测反应，反应完全后，旋蒸除去二氯甲烷，加2N HCl溶液进行萃取，合并有机相，饱和食盐水洗(20mL×3)，无水硫酸钠干燥，浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷溶剂重结晶。产物为淡黄色固体，产率：59％，熔点213.8-214.6℃。
实施例87：化合物22a的制备，取50mL圆底烧瓶，将1.05mmol 21溶于8mL二氯甲烷中，加入1.26mmol 3-戊胺，加入1.57mmol N,N-二异丙基乙胺，室温搅拌。反应结束后浓缩，干法上样，快速制备硅胶色谱柱分离，二氯甲烷-正己烷混合溶剂重结晶。产物为白色固体，产率为61％，熔点240.0-242.7℃。1H-NMR(600MHz,DMSO-d6)δ11.23(s,1H),8.97(s,1H),7.93(d,J＝8.5Hz,1H),7.82–7.77(m,1H),7.60(dd,J＝9.9,6.3Hz,2H),7.41(t,J＝8.7Hz,1H),4.20(d,J＝7.1Hz,1H),1.61–1.52(m,2H),1.51–1.44(m,2H),0.89(t,J＝7.4Hz,6H).13C-NMR(150MHz,DMSO-d6)δ182.24,162.06,155.24,151.56,149.93,135.61,135.28,135.20,132.41,127.79,118.76,115.32,115.17,104.39,104.25,104.22,56.74,26.71,10.62.ESI-MS:492.038[M-H]-,C19H18BrF4N3OS[491.02901].
实施例88：化合物22b的制备，操作同例87，所不同的是把3-戊胺换成环戊胺，产物为白色固体，产率为65％，熔点242.7-245.2℃。1H-NMR(600MHz,DMSO-d6)δ11.24(s,1H),8.94(s,1H),8.18(d,J＝6.9Hz,1H),7.85(d,J＝19.0Hz,1H),7.60(dd,J＝9.9,6.4Hz,2H),7.40(t,J＝8.7Hz,1H),4.50(s,1H),2.00–1.92(m,2H),1.72–1.62(m,2H),1.60–1.52(m,2H),1.48(s,2H).13C-NMR(150MHz,DMSO-d6)δ162.07,151.57,149.94,135.30,132.09,127.77,127.62,115.29,115.14,104.39,56.01,33.23,32.59,23.87,23.63.ESI-MS:490.023[M+H]+,C19H16BrF4N3OS[489.01336].
实施例89：化合物22c的制备，操作同例87，所不同的是把3-戊胺换成(S)-3-氨基四氢呋喃，产物为白色固体，产率为45％，熔点248.1-253.9℃。1H-NMR(600MHz,DMSO-d6)δ11.24(s,1H),9.06(s,1H),8.41(d,J＝6.7Hz,1H),7.60(dd,J＝9.8,6.3Hz,2H),7.42(t,J＝8.7Hz,1H),4.74(s,1H),3.89–3.77(m,2H),3.72(d,J＝5.6Hz,1H),3.65(dd,J＝9.6,3.0Hz,1H),2.26–2.18(m,1H),1.86(s,1H).13C-NMR(150MHz,DMSO-d6)δ162.02,151.56,149.94,135.25,135.17,127.85,127.69,115.41,115.26,104.39,104.22,73.03,66.84,60.25,55.39,55.28,32.58,14.55.ESI-MS:492.000[M+H]+,C18H14BrF4N3O2S[490.99202].
实施例90：化合物22d的制备，操作同例87，所不同的是把3-戊胺换成环己胺，产物为白色固体，产率为60％，熔点239.7-244.6℃。1H-NMR(600MHz,DMSO-d6)δ11.24(s,1H),8.99(s,1H),8.09–7.99(m,1H),7.81(s,1H),7.60(dd,J＝9.8,6.3Hz,2H),7.40(t,J＝8.7Hz,1H),4.08(s,1H),1.94(dt,J＝12.4,3.9Hz,2H),1.70(dq,J＝7.6,3.6Hz,2H),1.57(dd,J＝10.9,6.9Hz,1H),1.36–1.14(m,5H).13C-NMR(150MHz,DMSO-d6)δ162.06,151.56,149.93,135.58,135.28,132.22,127.78,127.63,118.47,115.30,115.15,104.38,104.25,104.21,52.95,32.36,25.60,24.90.ESI-MS:502.028[M-H]-,C20H18BrF4N3OS[503.02901].
实施例91：目标化合物体外抗HBV细胞活性实验
HBV细胞株及培养条件
将HepAD38复苏，待细胞状态良好，待长满后消化，计数，于培养基中加入Tetracycline(终浓度为300ng/mL)以及G418(终浓度为400μg/mL)，Tetracycline存在下病毒不表达，用含10％FBS的DMEM/F-12K培养基(包含终浓度为300μg/mL的Tetracycline以及终浓度为400μg/ml的G418，1％双抗)稀释成浓度为2×105/mL细胞悬液，以每孔100μL的量接种于96孔板(整块板铺满)，置于37℃、5％CO2恒温培养箱中孵育24h。24h后，弃去旧培养基，加入200μL新鲜的含2％FBS及1％双抗DMEM/F-12K培养基。
(1)细胞毒性实验
体外细胞毒性实验中化合物配制和细胞处理：用DMSO溶解化合物至20mM。加系列稀释的化合物1μL每孔到上述细胞板中，实验最高终浓度为100μM(200倍稀释)。Staurosporine(星苞菌素，Selleck,CAS No.62996-74-1)作为阳性对照化合物，最高浓度为1μM。阴性对照孔加入1μLDMSO，终浓度为0.5％。
72h后，弃去旧培养基，加入含有10％CCK8溶液的培养基，孵育20-40min，于酶标仪中检测，得到OD值，导出数据计算抑制率，用Graphpad Prism 8软件对实验数据进行分析处理，服从正态分布的定量资料采用均数±标准误(Means±SEM)进行统计学描述。
(2)抑制HBV DNA活性实验(定量PCR方法)
抗病毒实验中化合物配制和细胞处理：用DMSO溶解化合物至20mM，然后进行8个稀释度的4倍稀释，最高浓度为20μM，2复孔。使用圣湘生物48人份(PCR-荧光探针法)一步法的乙型肝炎病毒核酸定量检测试剂盒进行QPCR，吸取2.5μL上清进行Q-PCR,使用前待试剂盒试剂融化后涡旋混匀，离心后将酶混合液放置冰上待用，并保证后续步骤在冰上完成。于Q-PCR板中每孔加入2.5μL样本释放剂，2.5μL测试样本上清(实验组，对照组，标准曲线组)。Q-PCR反应后得到各孔病毒DNA拷贝数。用Graphpad Prism 8软件对实验数据进行分析处理，服从正态分布的定量资料采用均数±标准误(Means±SEM)进行统计学描述。
表1定向合成化合物和先导化合物NVR 3-778的抗乙肝病毒活性
活性结果表明，新合成的苯甲酰胺类HBV衣壳蛋白抑制剂呈现出显著的抗HBV活性。其中，化合物10l活性最好(EC50＝0.012±0.002μM)，显著优于先导化合物NVR 3-778，具有进一步研究的价值。
实施例92：目标化合物体外抗HBV靶点活性实验
将HBV核心蛋白与荧光染料4℃孵育过夜以标记C150蛋白，葡聚糖凝胶过滤除去多余的荧光染料，然后将荧光标记的HBV核心蛋白与不同浓度的化合物室温孵育15分钟，加入NaCl，然后室温孵育1小时后用酶标仪SpectraMax M2测定荧光信号值(Ex485/Em535)。
化合物测试起始浓度为30μM，3倍系列稀释，共8个浓度，2复孔。化合物测试试验体系中荧光标记的HBV核心蛋白终浓度为1.5μM，NaCl终浓度为150mM，DMSO浓度为0.5％，同时设置0％组装对照孔(0M NaCl)和100％组装对照孔(1M NaCl)。
组装活性％＝[1-(样品荧光–1M NaCl平均对照荧光值)/(0M NaCl平均对照荧光值-1M NaCl平均对照荧光值)]×100。用Graphpad Prism 5软件对实验数据及图片进行分析处理，并进行统计学描述。
表2先导化合物及化合物10a、10i和10l靶点活性测定结果
根据靶点活性结果表明，10i(EC50＝22.3650±2.52μM)的靶点活性弱于先导化合物NVR 3-778(EC50＝1.5260±0.19μM)，而10a(EC50＝0.7412μM)和10l(EC50＝0.8780±0.04μM)靶点活性优于先导化合物。
Claims (6)
1.一种苯甲酰胺类HBV衣壳蛋白抑制剂，其特征在于，具有如下通式Ⅰ或II所示的结构：
其中，Z为羰基、硫代羰基、双羰基；
M为羰基，硫代羰基；
L为C2-3烯基、苯乙烯基、3-6元环烷基、卤素取代的苄基、5元杂芳基、卤素取代的苯基、含有杂原子取代或未取代的C1-3烷基取代的苯基、3-6元环烷基胺基、含有杂原子取代或未取代的C2-5脂肪胺基、卤素取代的芳胺基、卤代烃基取代的芳胺基、卤素取代的苄胺基、含有杂原子取代或未取代的C1-4烷基取代的苄基；
W为C3-5脂肪胺基、5-6元环烷基胺基、卤素取代的芳胺基、卤代烃基取代的芳胺基、卤素取代的苄胺基、卤代烃基取代的苄胺基；
R1为甲基或溴原子；
R2为甲基或氟原子；
R3为氢原子或氟原子。
2.如权利要求1所述的苯甲酰胺类HBV衣壳蛋白抑制剂，其特征在于，通式Ⅰ或II中，Z为
M为/>
L为/>
W为
R1为-CH3或Br，R2为-CH3或F，R3为H或F。
3.如权利要求1或2所述的苯甲酰胺类HBV衣壳蛋白抑制剂，其特征在于，是具有下列结构的化合物之一：
4.如权利要求3所述的苯甲酰胺类HBV衣壳蛋白抑制剂的制备方法，其特征在于以2-溴-4-氟苯甲酸、2-甲基-4-氟苯甲酸和2-溴-6-氟苯甲酸为原料，经过以下合成路线之一制备：
合成路线1如下：
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3-氟-4-甲基苯胺或3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)不同类型的酰氯，吡啶，二氯甲烷，4h，rt.；
所述的不同类型的酰氯选自：4-氰基苯甲酰氯，4-溴苯甲酰氯，4-甲基苯甲酰氯，4-正丙基苯甲酰氯，2-噻吩甲酰氯，(E)-苯丙烯酰氯，3,4,5-三氟苯甲酰氯，4-三氟甲基苯甲酰氯，3-甲氧基丙酰氯，4-氟苯甲酰氯，4-氟苯乙酰氯，丙烯酰氯，2-丁烯酰氯，环丙基甲酰氯，环丁基甲酰氯，环戊基甲酰氯，环己基甲酰氯；
合成路线2如下：
试剂及其条件：(i)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.；
所述的不同类型的胺选自：4-羟基苄胺，3,5-二氟苄胺，3-甲基-4-氟苄胺，4-三氟甲基苄胺，4-氟苄胺，3-氨甲基吡啶，3,4,5-三氟苄胺，3-戊胺，异丙胺，3,4,5-三氟苯胺，4-叔丁基苄胺，4-羟基哌啶，4-三氟甲基苯胺，环戊胺，4-羟基环己胺，4-甲氧基苄胺；
合成路线3如下：
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.；
所述的不同类型的胺选自：异丙胺，4-氟苄胺，3,5-二氟苄胺，3-甲基-4-氟苄胺，环丙胺，乙胺，烯丙胺，1,1,1-三氟丙-2-胺，4-三氟甲基苄胺，4-氨甲基苯硼酸，N-异丙基甲胺；
合成路线4如下：
试剂及其条件：(i)草酰氯单乙酯，二氯甲烷，3h，rt.；(ii)NaOH，甲醇，水，4h，rt.；(iii)不同类型的胺，HATU，N,N-二异丙基乙胺，二氯甲烷，6h，rt.；
所述的不同类型的胺选自：异丙胺，环戊胺，1-氨基-2-甲基-2-丙醇，环丙胺；
合成路线5如下：
试剂及其条件：(i)浓HNO3，浓H2SO4，0℃，12h，rt.；(ii)氯化亚砜，N,N-二甲基甲酰胺，6h，80℃；(iii)乙腈，3,4,5-三氟苯胺，6h，60℃；(iv)Fe粉，NH4Cl，甲醇，水，12h，90℃；(v)氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(vi)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.；
所述的不同类型的胺选自：异丙胺，环己胺，3,4,5-三氟苯胺，4-三氟甲基苯胺，3,4,5-三氟苄胺，4-三氟甲基苄胺，4-氟苄胺，4-甲氧基苄胺；
合成路线6如下：
试剂及其条件：(i)硫代氯甲酸苯酯，吡啶，二氯甲烷，6h，rt.；(ii)不同类型的胺，N,N-二异丙基乙胺，二氯甲烷，4h，rt.；
所述的不同类型的胺选自：3-戊胺，环戊胺，(S)-3-氨基四氢呋喃，环己胺；
以上路线中的R1、R2、R3、L、W如上述通式Ⅰ或II化合物相应位置所述。
5.如权利要求1-3任一项所述的苯甲酰胺类HBV衣壳蛋白抑制剂在制备抗乙肝药物中的应用。
6.一种抗HBV药物组合物，包括权利要求1-3任一项所述的苯甲酰胺类HBV衣壳蛋白抑制剂和一种或多种药学上可接受载体。
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| CN105209031A (zh) * | 2012-12-27 | 2015-12-30 | 德雷克塞尔大学 | 针对hbv感染的新型抗病毒剂 |
| WO2020255013A1 (en) * | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and capsid assembly modulators being amide derivatives |
| CN113200956A (zh) * | 2021-05-18 | 2021-08-03 | 潍坊医学院 | 一种磺胺苯甲酰胺类衍生物及其制备方法和应用 |
| CN113801153A (zh) * | 2021-10-12 | 2021-12-17 | 山东大学 | 一种含硼酸及硼酸频哪醇酯基团的苯磺酰胺类hbv衣壳蛋白抑制剂及其制备方法与应用 |
| CN115677545A (zh) * | 2022-10-28 | 2023-02-03 | 潍坊医学院 | 一种抗hbv磺胺苯甲酰胺类衍生物及其制备方法和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105209031A (zh) * | 2012-12-27 | 2015-12-30 | 德雷克塞尔大学 | 针对hbv感染的新型抗病毒剂 |
| WO2020255013A1 (en) * | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and capsid assembly modulators being amide derivatives |
| CN113200956A (zh) * | 2021-05-18 | 2021-08-03 | 潍坊医学院 | 一种磺胺苯甲酰胺类衍生物及其制备方法和应用 |
| CN113801153A (zh) * | 2021-10-12 | 2021-12-17 | 山东大学 | 一种含硼酸及硼酸频哪醇酯基团的苯磺酰胺类hbv衣壳蛋白抑制剂及其制备方法与应用 |
| CN115677545A (zh) * | 2022-10-28 | 2023-02-03 | 潍坊医学院 | 一种抗hbv磺胺苯甲酰胺类衍生物及其制备方法和应用 |
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