CN114380780B - 一种新型的长栲利素a衍生物、其制备方法及医药用途 - Google Patents

一种新型的长栲利素a衍生物、其制备方法及医药用途 Download PDF

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CN114380780B
CN114380780B CN202210083925.1A CN202210083925A CN114380780B CN 114380780 B CN114380780 B CN 114380780B CN 202210083925 A CN202210083925 A CN 202210083925A CN 114380780 B CN114380780 B CN 114380780B
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徐进宜
姚鸿
何晨
徐盛涛
刘俊凯
薛松涛
杜翩
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Abstract

本发明公开一种新型的长栲利素A类似物及衍生物、其制备方法及医药用途，新型长栲利素A的C‑14位羟基衍生物，结构如式I所示；本发明还公开了这些新型化合物的制备方法以及其在治疗肿瘤疾病领域的应用。

Description

一种新型的长栲利素A衍生物、其制备方法及医药用途
技术领域
本发明涉及天然药物及药物化学领域，具体涉及一类新型的长栲利素A 14位羟基衍生物。本发明还公开了这些新型化合物的制备方法以及其在治疗肿瘤疾病领域的应用。
背景技术
三阴性乳腺癌(Triple Negative Breast Cancer,TNBC)是指缺乏雌激素受体、孕激素受体和人表皮生长因子受体-2(Her-2)的乳腺癌，是当前最具侵略性和致命性的乳腺癌亚型，约占乳腺癌的15％-20％。目前，三阴性乳腺癌的治疗手段以手术、放疗和化疗为主。由于手术不能控制术后复发，放疗副作用较大，化疗缺乏合适的治疗靶点，且易产生耐药性，三种治疗手段效果有限(Journal of Medicinal Chemistry,2021,64,23,17346-17365)。因此，迫切需要新的疗法以提高患者的生存率。
Longikaurin-A(长栲利素A)是从唇形科(Labtea)香茶菜属(Rabdosia)植物longituba中分离得到的一种四环二萜，据报道，该化合物对大鼠乳腺癌细胞显示显著的体外抗增殖活性(Journal of the Chemical Society Chemical Communications,1980,5,205-207)。虽然长栲利素A具有一定抗三阴乳腺癌活性，但其活性不够强，还需进行结构修饰提升。目前尚未见有关长栲利素A结构修饰改造的文献或专利报道。
发明内容
本发明通过对长栲利素A进行结构修饰改造，提供一类具有抗肿瘤活性的新化合物。与长栲利素A相比，本发明的化合物不仅能很好地抑制三阴乳腺癌肿瘤细胞的生长，对其他肿瘤细胞的生长也表现出抑制作用，此外，还具有优良的选择性，对正常乳腺细胞毒性较小。
本发明是通过以下技术方案实现的。
通式Ⅰ所示的长栲利素A衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐：
其中，M是下列基团中的任意一个：(1)氘原子，(2)C1-16脂肪链酰基或C1-16脂肪链磺酰基，(3)C3-10碳环酰基或C3-10碳环磺酰基，(4)C1-6卤代烷酰基或C1-6卤代烷磺酰基，(5)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基或未被取代或被1、2、3、4个取代基所取代的C6-10芳基磺酰基，(6)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳基酰基或未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳基磺酰基，(7)C2-6烯酰基或C2-6烯基磺酰基，(8)C2-6炔酰基或C2-6炔基磺酰基，(9)氨基酸，(10)磷酰基，(11)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基。
在本发明的一些实施方案中，M为：(1)C1-16脂肪链酰基或C1-8脂肪链磺酰基，(2)C3-10碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳酰基，(5)C2-6烯酰基，(6)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基。
在本发明的一些实施方案中，M为：(1)C1-10脂肪链酰基或C1-6脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-或-CH2-S-CH2-；m等于1、2、3、4；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
在本发明的一些实施方案中，M为：(1)C1-8脂肪链酰基或C1-3脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-；m等于1、2；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
本发明所述的取代基选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基或C1-3烷基磺酰基，在一些实施例中，例如为Br、Cl、F、甲基、乙基、甲基磺酰基、乙基磺酰基、甲氧基、乙氧基、三氟甲基等。
在本发明的一些实施方案中，本发明所述的杂芳基可以选自：吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、吲哚基、喹啉基、苯并氧五环、咪唑基、噁唑基、噻唑基、吡唑基、异喹啉基、嘌呤基、吖啶基、咔唑基、噌啉基、喹噁啉基、吲哚基、苯并三唑基、苯并噻吩基、苯并呋喃基、异噁唑基、吡嗪基、哒嗪基、四唑基、三嗪基和咔唑基等。
本发明的长栲利素A衍生物其部分具体化合物选自如下结构：
。
本发明还提供式Ⅰ所示的长栲利素A类似物的制备方法：
其中，M的定义如前所述。
本发明还提供一种药物组合物，其包含本发明通式Ⅰ所示的长栲利素A类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，以及药学上可用的载体。
本发明还提供通式Ⅰ所示的长栲利素A类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐或包含他们的药物组合物在制备抗肿瘤药物中的应用。
本发明所述的肿瘤是机体在各种致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的异常病变，包括但不限于三阴性乳腺癌和白血病。
关于本发明的使用术语的定义：除非另有说明，本文中的基团或者术语提供的初始定义用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予的含义。术语“取代”是指分子中的氢原子或分子所替换，包括一个取代基或多个取代基的情况。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)或砹(At)离子。
术语“烷基”表示具有所述数目之碳原子的直链或支链饱和烃基。术语“C1-C16脂肪链”是指具有1-6个碳原子的直链或支链饱和烃基。C1-C6烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、2,2-二甲基丁基和2,3-二甲基丁基等。
术语“烯基”指直链、支链或环状的，主链含有2～6个碳原子及至少一个碳-碳双键的非芳香烃基。因此，“C2-C6烯基”指主链具有2～6个碳原子的烯基。烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基等。烯基的直链、支链或环状部分可含有双键且如果指明了取代的烯基则此部分可被取代。
术语“炔基”指直链、支链或环状的，主链含有2～6个碳原子及至少一个碳碳三键的非芳香烃基。因此，“C2-C6炔基”指具有2～6个碳原子的炔基。炔基包括乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基的直链、支链或环状部分可含有三键且如果指明了取代的炔基则此部分可被取代。
术语“杂环”表示3到6个环原子的饱和环状基团，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C，其中一个或两个C原子可以可选地被羰基代替。杂环基的环可以可选地独立地被一个、两个或三个取代基取代。
术语“芳香环”、“芳基”表示6至10个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳香环或芳基的非限制性实例有苯基、萘基和蒽基。
术语“杂芳香环”、“杂芳基”表示5至10个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。未取代的杂芳基地非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑。杂芳香环或杂芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更为优选一个或两个。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为来自常规生化试剂商店购买得到的。
实施例1【化合物1】
将长栲利素A(50mg,0.15mmol)溶于5mL无水的二氯甲烷中，加入催化量的DMAP(5mg,0.04mmol)，0.03mL醋酸酐，0.1mL三乙胺，室温搅拌3h。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物2(44mg,收率78％)。1HNMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.14(m,1H),2.22(m,1H),2.05(s,2H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.45(m,5H),1.47–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,170.20,151.37,118.59,99.07,75.43,72.91,66.27,61.87,58.18,52.89,45.67,41.35,38.64,34.25,32.39,30.95,28.76,28.68,21.08,20.58,19.07；MS(ESI)m/z:391.2[M+H]+.
实施例2【化合物2】
将长栲利素A(50mg，0.15mmol)，溶于5mL二氯甲烷中，戊酸(15mg，0.15mmol)加入催化量的DMAP(5mg,0.04mmol)，EDCI(47mg，0.3mmol)，室温反应24h。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物25mg(收率39％)。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝6.0Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.18–3.10(m,1H),2.36–2.25(m,2H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.67(m,2H),1.67–1.41(m,8H),1.44–1.37(m,2H),1.36(d,J＝7.0Hz,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H),0.92(t,J＝7.3Hz,3H)；13C NMR(75MHz,CDCl3)δ207.79,173.77,151.37,118.59,99.08,76.63,72.91,66.27,62.01,58.18,52.96,45.64,41.35,38.64,34.43,34.25,32.39,30.95,28.76,28.68,26.92,22.78,20.58,19.07,14.16；MS(ESI)m/z:433.3[M+H]+.
实施例3【化合物3】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝6.0Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.18–3.10(m,1H),2.30(m,2H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.67(m,2H),1.67–1.57(m,2H),1.60–1.54(m,1H),1.55(m,1H),1.56–1.49(m,3H),1.52–1.45(m,1H),1.47–1.37(m,1H),1.36–1.23(m,9H),1.02(dd,J＝3.9,1.6Hz,6H),0.94–0.85(m,3H)；13C NMR(75MHz,CDCl3)δ207.79,173.75,151.37,118.59,99.08,76.63,72.91,66.27,62.01,58.18,52.96,45.64,41.35,38.64,34.25,32.39,31.66,30.95,29.95,29.32,29.16,28.76,28.68,25.18,22.65,20.58,19.07,14.07；MS(ESI)m/z:475.3[M+H]+.
实施例4【化合物4】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.21(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.14(m,1H),2.53(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.15(d,J＝7.1Hz,3H),1.10(d,J＝7.0Hz,3H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.71,176.31,151.37,118.59,99.07,77.23,72.91,66.27,62.03,58.18,53.01,45.62,41.35,38.64,34.87,34.25,32.39,30.95,28.76,28.68,20.58,19.07,18.17；MS(ESI)m/z:419.2[M+H]+.
实施例5【化合物5】
将长栲利素A(50mg,0.15mol)溶解于5mL无水二氯甲烷中，加入30μL三乙胺，将混合液冷却至0℃，滴加20μL甲磺酰氯，反应30min。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，快速柱层析得化合物47mg(收率77％)。1H NMR((300MHz,CDCl3)δ5.75(dd,J＝3.2,1.9Hz,1H),5.66(dd,J＝3.3,2.0Hz,1H),4.92(d,J＝6.4Hz,1H),4.51(s,1H),4.01(dd,J＝12.6,5.7Hz,2H),3.89(d,J＝5.5Hz,1H),3.81(d,J＝12.4Hz,1H),3.12(m,1H),2.98(s,2H),2.22(m,1H),1.86–1.76(m,2H),1.76–1.64(m,2H),1.67–1.50(m,4H),1.53–1.45(m,1H),1.47–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.49,151.02,118.59,99.02,82.87,73.14,66.27,62.09,58.11,52.74,46.18,41.34,38.65,38.63,34.25,32.40,30.86,28.71,28.62,20.59,19.07；MS(ESI)m/z:427.2[M+H]+.
实施例6【化合物6】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.22(d,J＝6.0Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.18–3.10(m,1H),2.30(m,2H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.67(m,2H),1.67–1.54(m,5H),1.57–1.51(m,1H),1.54–1.48(m,1H),1.51–1.41(m,1H),1.44–1.34(m,1H),1.34(m,3H),1.34–1.29(m,1H),1.32–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H),0.94–0.84(m,3H)；13C NMR(75MHz,CDCl3)δ207.79,173.75,151.37,118.59,99.08,76.63,72.91,66.27,62.01,58.18,52.96,45.64,41.35,38.64,34.52,34.25,32.39,30.95,30.57,28.76,28.68,25.23,22.41,20.58,19.07,13.98；MS(ESI)m/z:447.3[M+H]+.
实施例7【化合物7】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.14(m,1H),2.34(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.67(m,2H),1.67–1.36(m,7H),1.34–1.25(m,1H),1.13–1.03(m,2H),1.02(dd,J＝3.9,1.6Hz,6H),1.00–0.93(m,1H),0.96–0.88(m,1H)；13C NMR(75MHz,CDCl3)δ207.71,174.10,151.37,118.59,99.07,77.33,72.91,66.27,62.06,58.18,53.01,45.61,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07,15.37,8.75；MS(ESI)m/z:416.2[M+H]+.
实施例8【化合物8】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.14(m,1H),2.38(m,1H),2.22(m,1H),1.90–1.78(m,4H),1.74–1.36(m,16H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.71,175.59,151.37,118.59,99.07,77.33,72.91,66.27,62.06,58.18,53.01,45.61,43.44,41.35,38.64,34.25,32.39,30.95,29.06,28.76,28.68,25.94,25.59,20.58,19.07；MS(ESI)m/z:459.3[M+H]+.
实施例9【化合物9】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.03–7.97(m,2H),7.58–7.51(m,1H),7.49–7.42(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.01,151.50,133.40,130.46,129.69,129.02,118.59,99.12,77.88,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:453.2[M+H]+.
实施例10【化合物10】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.86–7.80(m,2H),7.29–7.23(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.39(d,J＝0.9Hz,3H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.11,151.50,143.59,130.08,129.71,127.48,118.59,99.12,77.88,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,21.36,20.58,19.07；MS(ESI)m/z:467.2[M+H]+.
实施例11【化合物11】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.83–7.76(m,1H),7.30(m,3H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.21(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.53(s,3H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,169.10,151.50,136.46,133.03,129.93,129.75,128.52,127.16,118.59,99.12,77.83,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,21.60,20.58,19.07；MS(ESI)m/z:467.2[M+H]+.
实施例12【化合物12】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.83–7.76(m,1H),7.30(m,3H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.21(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.53(s,3H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,169.10,151.50,136.46,133.03,129.93,129.75,128.52,127.16,118.59,99.12,77.83,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,21.60,20.58,19.07；MS(ESI)m/z:467.2[M+H]+.
实施例13【化合物13】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.07–8.00(m,2H),7.94–7.88(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.24(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.18(s,3H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.67(m,2H),1.67–1.54(m,3H),1.57–1.45(m,2H),1.47–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.59,151.50,144.09,134.88,131.00,127.91,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,44.44,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:531.2[M+H]+.
实施例14【化合物14】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.07–8.00(m,2H),7.25–7.18(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.76,165.62,164.74,151.50,132.42,132.36,126.31,126.29,118.59,115.76,115.60,99.12,77.88,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:471.2[M+H]+.
实施例15【化合物15】
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参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.72–7.66(m,2H),7.66–7.60(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.19(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.29,151.50,131.66,130.50,129.07,128.63,118.59,99.12,77.88,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:531.1[M+H]+.
实施例16【化合物16】
参照实施例2中化合物2的合成方法。1H NMR 300MHz,CDCl3)δ7.55(d,J＝2.1Hz,1H),7.25(m,1H),7.18–7.12(m,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.21(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.53(d,J＝1.0Hz,2H),2.38–2.35(m,2H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13CNMR(75MHz,CDCl3)δ207.76,168.98,151.50,138.14,135.70,132.48,130.95,130.89,128.25,118.59,99.12,77.83,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.91,20.75,20.58,19.07；MS(ESI)m/z:481.3[M+H]+.
实施例17【化合物17】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.58(m,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.22(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.19(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.81,163.58,163.56,163.53,163.52,163.49,163.47,151.47,149.41,149.38,149.34,149.32,149.25,149.22,149.18,149.16,147.41,147.39,147.37,147.35,147.33,147.30,147.25,147.23,147.21,147.19,147.17,147.14,147.06,147.00,146.90,146.84,145.40,145.37,145.33,145.31,145.24,145.21,145.17,145.15,145.05,144.98,144.89,144.82,141.67,141.61,141.52,141.45,141.35,141.29,139.66,139.59,139.50,139.43,139.34,139.27,118.59,116.98,116.96,116.92,116.89,116.85,116.83,116.82,116.80,116.76,116.73,116.69,116.67,112.36,112.34,112.30,112.27,112.23,112.21,112.20,112.17,112.13,112.11,112.07,112.05,99.11,77.90,72.91,66.27,62.11,58.18,52.34,45.64,41.35,38.64,34.25,32.39,30.96,28.76,28.68,20.58,19.07；MS(ESI)m/z:525.2[M+H]+.
实施例18【化合物18】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.66(t,J＝1.9Hz,1H),8.31(d,J＝8.5Hz,1H),8.05(dd,J＝8.6,1.9Hz,1H),7.98(m,1H),7.91–7.83(m,1H),7.52(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.24(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.59,151.50,136.02,133.10,130.42,130.01,128.19,127.66,127.57,127.40,127.13,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:503.2[M+H]+.
实施例19【化合物19】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ9.85(d,J＝6.8Hz,1H),7.14(dd,J＝6.5,1.7Hz,1H),7.03(m,1H),6.13(dd,J＝6.5,3.6Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.19(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13CNMR(75MHz,CDCl3)δ207.65,161.01,151.38,125.24,123.53,118.59,117.03,111.11,99.10,77.81,72.91,66.27,62.11,58.18,52.39,45.63,41.35,38.64,34.25,32.39,30.94,28.76,28.68,20.58,19.07；MS(ESI)m/z:442.2[M+H]+.
实施例20【化合物20】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.68(t,J＝1.6Hz,1H),7.38(dd,J＝4.9,1.8Hz,1H),6.57(dd,J＝4.9,1.6Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.19(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.75,159.56,151.48,147.31,144.31,119.03,118.59,112.58,99.10,78.08,72.91,66.27,62.11,58.18,52.66,45.48,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:443.2[M+H]+.
实施例21【化合物21】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.82(dd,J＝6.3,1.7Hz,1H),7.59(dd,J＝5.4,1.7Hz,1H),7.11(dd,J＝6.3,5.4Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.28(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.19(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.80,161.59,151.47,134.03,133.89,132.83,128.14,118.59,99.13,78.01,72.91,66.27,62.07,58.18,52.34,45.64,41.35,38.64,34.25,32.39,30.96,28.76,28.68,20.58,19.07；MS(ESI)m/z:459.2[M+H]+.
实施例22【化合物22】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.80–8.75(m,2H),7.96–7.92(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.82,151.50,150.61,137.68,123.43,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:454.2[M+H]+.
实施例23【化合物23】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.80–8.75(m,2H),7.96–7.92(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.82,151.50,150.61,137.68,123.43,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:454.2[M+H]+.
实施例24【化合物24】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.80–8.75(m,2H),7.96–7.92(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.82,151.50,150.61,137.68,123.43,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:454.2[M+H]+.
实施例25【化合物25】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.90(dd,J＝4.2,1.7Hz,1H),8.70(d,J＝2.1Hz,1H),8.31(d,J＝8.7Hz,1H),8.18–8.12(m,1H),8.04(dd,J＝8.7,1.9Hz,1H),7.41(dd,J＝7.6,4.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.24(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.40,151.50,149.91,148.51,131.28,129.41,128.46,128.28,127.93,125.78,121.68,118.59,99.12,77.86,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:504.2[M+H]+.
实施例26【化合物26】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.90(dd,J＝4.2,1.7Hz,1H),8.70(d,J＝2.1Hz,1H),8.31(d,J＝8.7Hz,1H),8.18–8.12(m,1H),8.04(dd,J＝8.7,1.9Hz,1H),7.41(dd,J＝7.6,4.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.24(d,J＝5.7Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,166.40,151.50,149.91,148.51,131.28,129.41,128.46,128.28,127.93,125.78,121.68,118.59,99.12,77.86,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:504.2[M+H]+.
实施例27【化合物27】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.10(m,1H),6.00(m,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88(dd,J＝5.9,1.5Hz,3H),1.87–1.78(m,2H),1.70(m,2H),1.67–1.57(m,2H),1.61–1.54(m,1H),1.57–1.49(m,2H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.86,166.86,151.50,146.48,121.29,118.59,99.11,77.10,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07,17.83；MS(ESI)m/z:417.2[M+H]+.
实施例28【化合物28】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ9.70(d,J＝6.8Hz,1H),7.52–7.46(m,1H),7.07(m,1H),6.83–6.77(m,1H),6.54(d,J＝15.6Hz,1H),6.24(dd,J＝6.6,3.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,165.88,151.50,133.40,131.89,123.26,118.59,117.62,115.67,108.98,99.11,77.08,72.91,66.27,61.92,58.18,52.68,45.62,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:468.2[M+H]+.
实施例29【化合物29】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.65–7.54(m,3H),7.41–7.29(m,3H),6.37(d,J＝15.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.13(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.44(m,6H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.16,151.50,145.97,134.80,130.15,129.06,128.94,118.59,117.38,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:479.2[M+H]+.
实施例30【化合物30】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ9.17(d,J＝6.8Hz,1H),7.84–7.79(m,1H),7.69(d,J＝1.9Hz,1H),7.65–7.58(m,1H),7.52–7.47(m,1H),7.22(dd,J＝6.6,3.1Hz,1H),6.62–6.57(m,1H),6.35(d,J＝15.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,151.50,144.12,136.75,129.59,129.48,125.09,121.92,121.31,118.59,116.25,110.97,102.63,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:518.2[M+H]+.
实施例31【化合物31】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.59(d,J＝16.1Hz,1H),7.13–7.07(m,2H),6.86(d,J＝8.7Hz,1H),6.36(d,J＝16.1Hz,1H),6.00(d,J＝1.3Hz,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.52(m,4H),1.55–1.49(m,1H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,151.50,148.91,148.09,146.20,129.48,124.36,118.59,116.46,109.65,109.32,101.10,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:523.2[M+H]+.
实施例32【化合物32】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.62–8.57(m,2H),7.56(dd,J＝15.9,0.9Hz,1H),7.42–7.37(m,2H),6.51(d,J＝15.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.16,151.50,150.30,145.69,141.70,122.55,118.59,117.68,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:480.2[M+H]+.
实施例33【化合物33】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.62–8.57(m,2H),7.56(dd,J＝15.9,0.9Hz,1H),7.42–7.37(m,2H),6.51(d,J＝15.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.16,151.50,150.30,145.69,141.70,122.55,118.59,117.68,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:480.2[M+H]+.
实施例34【化合物34】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.62–8.57(m,2H),7.56(dd,J＝15.9,0.9Hz,1H),7.42–7.37(m,2H),6.51(d,J＝15.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.16,151.50,150.30,145.69,141.70,122.55,118.59,117.68,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:480.2[M+H]+.
实施例35【化合物35】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.87–8.82(m,3H),7.67(d,J＝17.2Hz,1H),6.42(d,J＝17.2Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.57(m,2H),1.61–1.55(m,1H),1.57–1.52(m,1H),1.52(m,1H),1.52–1.44(m,1H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.41,158.37,154.81,151.50,142.63,127.39,118.75,118.59,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:481.2[M+H]+.
实施例36【化合物36】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.73(d,J＝2.2Hz,1H),7.91–7.84(m,1H),7.65(m,1H),7.15(t,J＝8.0Hz,1H),6.41(d,J＝16.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.44(m,6H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.29,164.43,162.42,151.50,150.49,150.38,142.75,137.28,137.21,128.73,128.71,118.59,117.23,110.93,110.77,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:498.2[M+H]+.
实施例37【化合物37】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.53(d,J＝2.2Hz,1H),7.91–7.85(m,1H),7.66(d,J＝16.9Hz,1H),7.00(d,J＝8.1Hz,1H),6.41(d,J＝16.8Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.90(s,3H),3.82(d,J＝12.3Hz,1H),3.16–3.09(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.29,164.45,151.50,149.04,142.65,136.56,125.41,118.59,117.23,110.98,99.11,77.02,72.91,66.27,61.92,58.18,54.53,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:510.2[M+H]+.
实施例38【化合物38】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ7.75(dd,J＝16.5,0.7Hz,1H),7.63(m,1H),7.43(s,0H),7.30(dd,J＝7.5,1.3Hz,1H),6.80(d,J＝16.5Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.44(m,6H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,166.98,152.53,151.50,142.40,139.29,138.29,127.31,122.21,120.40,118.59,99.11,77.06,72.91,66.27,61.92,58.18,52.68,45.62,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:558.1[M+H]+.
实施例39【化合物39】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.67(d,J＝1.6Hz,1H),8.60(dd,J＝4.6,1.5Hz,1H),7.71–7.64(m,1H),7.43(dd,J＝4.4,0.7Hz,1H),6.49(d,J＝16.5Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,166.52,152.48,151.50,148.42,143.18,138.81,123.56,119.58,119.24,118.59,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:557.1[M+H]+.
实施例40【化合物40】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.22(d,J＝8.1Hz,1H),8.04–7.99(m,1H),7.91–7.86(m,1H),7.77–7.65(m,3H),7.51(m,1H),6.78(d,J＝16.5Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.44(m,6H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,166.99,151.50,150.38,149.63,139.63,135.31,129.85,129.17,128.24,126.85,125.32,121.10,120.28,118.59,99.11,77.06,72.91,66.27,61.92,58.18,52.68,45.62,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:530.2[M+H]+.
实施例41【化合物41】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.46(dd,J＝4.4,1.7Hz,1H),8.34(dd,J＝8.0,1.6Hz,1H),7.71–7.64(m,1H),7.55(m,1H),6.45(d,J＝16.3Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.44(m,6H),1.46–1.36(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,166.80,157.88,155.86,151.50,146.78,146.74,137.55,137.39,137.38,137.32,125.91,125.75,122.89,122.83,120.33,120.30,118.59,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:498.2[M+H]+.
实施例42【化合物42】
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参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.67(d,J＝1.6Hz,1H),8.60(dd,J＝4.6,1.5Hz,1H),7.71–7.64(m,1H),7.43(dd,J＝4.4,0.7Hz,1H),6.49(d,J＝16.5Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.23(d,J＝5.5Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,166.52,152.48,151.50,148.42,143.18,138.81,123.56,119.58,119.24,118.59,99.11,77.05,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:557.1[M+H]+.
实施例43【化合物43】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.53(d,J＝3.7Hz,1H),7.82(d,J＝2.0Hz,1H),7.61–7.54(m,1H),7.33–7.28(m,1H),6.52(d,J＝16.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,151.50,149.37,149.36,149.34,149.32,148.97,148.72,148.46,148.21,145.97,141.37,141.35,141.33,141.32,125.96,123.81,123.44,121.67,119.53,119.07,119.04,119.01,118.98,118.59,116.95,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:548.2[M+H]+.
实施例44【化合物44】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.10(d,J＝4.6Hz,1H),7.68–7.61(m,1H),7.47–7.42(m,1H),6.83(d,J＝1.8Hz,1H),6.50(d,J＝16.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.92–3.87(m,4H),3.82(d,J＝12.3Hz,1H),3.16–3.09(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.36(m,8H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,164.37,151.50,148.78,146.14,141.38,118.59,117.87,117.08,108.17,99.11,77.02,72.91,66.27,61.92,58.18,53.79,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:510.2[M+H]+.
实施例45【化合物45】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.50–8.46(m,2H),7.20–7.16(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.22(d,J＝6.0Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.18–3.10(m,1H),2.98–2.89(m,2H),2.69–2.58(m,2H),2.22(m,1H),1.88–1.78(m,2H),1.74–1.67(m,2H),1.67–1.57(m,2H),1.61–1.54(m,1H),1.57–1.49(m,2H),1.52–1.44(m,1H),1.46–1.37(m,1H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,173.00,151.37,149.50,148.43,123.40,118.59,99.08,76.62,72.91,66.27,62.01,58.18,53.01,45.64,41.35,38.64,35.78,34.25,32.39,30.95,30.51,28.76,28.68,20.58,19.07；MS(ESI)m/z:482.2[M+H]+.
实施例46【化合物46】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.55(d,J＝5.8Hz,1H),8.08(dd,J＝5.8,1.9Hz,1H),7.62(dd,J＝8.0,2.0Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.18(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.67,165.65,163.94,161.93,151.50,150.08,149.97,143.65,143.58,120.45,120.43,118.59,109.58,109.42,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:472.2[M+H]+.
实施例47【化合物47】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.55(d,J＝5.8Hz,1H),8.08(dd,J＝5.8,1.9Hz,1H),7.62(dd,J＝8.0,2.0Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.18(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.67,165.65,163.94,161.93,151.50,150.08,149.97,143.65,143.58,120.45,120.43,118.59,109.58,109.42,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:472.2[M+H]+.
实施例48【化合物48】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.56(d,J＝4.7Hz,1H),7.88(dd,J＝4.8,1.8Hz,1H),7.69(d,J＝2.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.48(s,2H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.67(m,2H),1.67–1.36(m,6H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.79,157.23,151.50,148.48,138.34,121.58,121.38,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,23.75,20.58,19.07；MS(ESI)m/z:468.2[M+H]+.
实施例49【化合物49】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.23(d,J＝4.9Hz,1H),7.93(dd,J＝4.8,2.0Hz,1H),7.25(d,J＝1.9Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.18(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.93–3.87(m,4H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.67(m,2H),1.67–1.51(m,4H),1.54–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.60,164.18,151.50,149.10,139.58,118.59,117.65,108.06,99.12,77.87,72.91,66.27,62.12,58.18,53.52,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:484.2[M+H]+.
实施例50【化合物50】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.65–8.60(m,1H),7.96–7.91(m,2H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.9Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.17(m,1H),2.22(m,1H),1.86–1.76(m,2H),1.74–1.36(m,9H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.76,165.98,151.50,149.29,149.28,149.26,149.24,148.35,148.10,147.84,147.58,140.16,140.14,140.13,140.11,125.82,123.67,123.33,121.53,119.38,119.31,119.27,119.24,119.21,118.59,99.12,77.87,72.91,66.27,62.12,58.18,52.53,45.65,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:522.2[M+H]+.
实施例51【化合物51】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.34(d,J＝5.6Hz,1H),7.63(dd,J＝16.0,0.6Hz,1H),7.49–7.43(m,1H),7.28(dd,J＝8.0,2.0Hz,1H),6.51(d,J＝16.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,165.38,163.37,151.50,150.51,150.40,146.30,146.28,144.31,144.24,121.03,121.01,118.59,117.13,108.30,108.14,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,20.58,19.07；MS(ESI)m/z:498.2[M+H]+.
实施例52【化合物52】
参照实施例2中化合物2的合成方法。1H NMR(300MHz,CDCl3)δ8.43(d,J＝4.6Hz,1H),7.54(dd,J＝16.1,0.7Hz,1H),7.28–7.23(m,1H),7.14(d,J＝1.8Hz,1H),6.51(d,J＝16.1Hz,1H),5.74(dd,J＝3.3,2.0Hz,1H),5.67(dd,J＝3.2,1.9Hz,1H),5.20(d,J＝5.3Hz,1H),4.52(s,1H),4.05–3.97(m,2H),3.90(d,J＝5.5Hz,1H),3.82(d,J＝12.3Hz,1H),3.12(m,1H),2.51(s,3H),2.22(m,1H),1.88–1.78(m,2H),1.70(m,2H),1.67–1.49(m,5H),1.52–1.36(m,2H),1.34–1.25(m,1H),1.02(dd,J＝3.9,1.6Hz,6H)；13C NMR(75MHz,CDCl3)δ207.79,167.10,159.04,151.50,148.43,146.03,140.70,121.48,120.78,118.59,117.02,99.11,77.02,72.91,66.27,61.92,58.18,52.68,45.60,41.35,38.64,34.25,32.39,30.95,28.76,28.68,24.23,20.58,19.07；MS(ESI)m/z:494.2[M+H]+.
实施例53【片剂】
取上述配方，用常规方法制备成片剂。
【药理活性】
药理试验证明，本发明的新型长栲利素A衍生物具有抗三阴性乳腺癌细胞生长的作用，同时对其他肿瘤细胞的生长也具有抑制作用，对正常乳腺细胞毒性较小，可以用于制备抗三阴性乳腺癌或其它肿瘤疾病药物。优选治疗的肿瘤疾病是三阴性乳腺癌和白血病；相对应的用于药理试验的肿瘤细胞株为DU4475和K562，正常细胞株为MCF-10A。
下面是本发明部分化合物的药理实验结果：
1、部分化合物对三阴性乳腺癌、白血病及正常乳腺细胞生长的影响
实验设备与试剂：
仪器超净工作台(苏州艾可林净化设备有限公司)
恒温CO2培养箱(日本SANYO)
酶联免疫检测仪(美国BIO-RAD)
倒置生物显微镜(日本OLYMPUS)
试剂青、链霉素混合液(南京凯基生物科技发展有限公司)
胰蛋白酶消化液(南京凯基生物科技发展有限公司)
PBS(南京凯基生物科技发展有限公司)
MTT(BIOSHARP)
DMSO(SIGMA)
细胞株人三阴性乳腺癌细胞DU4475
人慢性髓原白血病细胞K562
正常乳腺细胞MCF-10A
实验方法：
1.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞)；
2. 96孔板置于37℃，5％CO2培养箱中培养24h；
3.用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基，同时设立阴性对照组，溶媒对照组，阳性对照组；
4. 96孔板置于37℃，5％CO2培养箱中培养72h；
5.将96孔板进行MTT染色，λ＝490nm，测定OD值。
1)每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4h；
2)弃去培养基，每孔加入150μL DMSO溶解，摇床10min轻轻混匀；λ＝490nm，酶标仪读出每孔的OD值，计算抑制率。
细胞抑制率％＝100％×(阴性对照组OD值-化合物组OD值)/阴性对照组OD值
化合物对人类癌细胞生长影响的实验结果，如表1所示。
表1.部分化合物对体外3种细胞生长的影响(IC50：单位μmol/ml)
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2、部分化合物对体内肿瘤生长的影响：
选取体重为18-22g并成功接种三阴乳腺癌细胞DU4475细胞的雌性ICR小鼠(来自上海思捷实验动物中心)，随机分组，每组8只。其中一组为空白对照，注射同样给药体积的生理盐水溶液；另一组为阳性药对照组，给予6mg/kg的紫杉醇(购自四川太极制药有限公司，货号为17100021)；剩余的组别分别给予一定剂量的化合物。紫杉醇及上述化合物的溶解溶剂为DMF:吐温80:5％生理盐水＝10:2:88(V:V:V)，给药方式为1天给药一次，连续给药21天。实验结束后，处死老鼠并手术剥离肿瘤称重。得到的数据用SPSS 17.0进行统计分析。部分化合物体内抑制肿瘤生长的结果，如表2所示。
表2.部分化合物体内抑制肿瘤生长的结果
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以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应该指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (4)

1.如下结构式所示的长栲利素A衍生物或其可药用盐：
。
2.一种药物组合物，其包含权利要求1所述的长栲利素A类似物或其可药用盐，以及药学上可用的载体。
3.权利要求1所示的长栲利素A类似物的制备方法：
其中，M的定义如权利要求1中化合物所示。
4.权利要求1所述长栲利素A衍生物或其可药用盐，或者权利要求2所述的组合物在用于制备治疗抗肿瘤药物中的应用，所述肿瘤为三阴性乳腺癌和白血病。
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