专利摘要

本发明公开了一种米非司酮衍生物及其用途。所述的米非司酮衍生物的结构式如式(I)所示；其中R为酰基或者磺酰基；本发明还涉及米非司酮衍生物在制备治疗与KLF5调控的肿瘤药物中的用途，特别是治疗三阴性乳腺癌药物中的用途。该化合物结构简单，易于制备；抗肿瘤活性较米非司酮强，且剂量小，可用于治疗三阴性乳腺癌及与KLF5密切相关的肿瘤药物的制备，同时，本发明探索合成的一类具有高成药性的米非司酮衍生物，也为其他同类化合物的合成提供新的解决思路和方案。

权利要求

1.米非司酮衍生物，其结构式特征如下：

其中，R为酰基或者磺酰基；

当R为酰基时，其具体结构特征为R₁CO-，R₁为C1-C6烷基、氯代C1-C6烷基、苄基、萘基、苯基、卤代苯基、C1-C6烷基取代苯基、甲氧基取代苯基、羧酸取代苯基、硝基取代苯基、N，N-二甲基取代苯基、苯基取代苯基、烯烃、苯基取代烯烃或杂环，包括噻唑、2-噻吩、吡嗪、吡啶、卤代吡啶；

当R为磺酰基时，其具体结构特征为R₂SO₂-，R₂为苯基、C1-C6烷基取代苯基。

2.根据权利要求1所述的米非司酮衍生物，当R为酰基时，其中R1为氯代C1-C6烷基、卤代苯基、萘基、硝基取代苯基、C1-C6烷基取代苯基或苯基取代苯基。

3.根据权利要求2所述的米非司酮衍生物，R1为氯代甲烷基。

4.根据权利要求2所述的米非司酮衍生物，R1为氯或溴代苯基。

5.根据权利要求4所述的米非司酮衍生物，R1为3，4氯代苯基或2-溴4-氯代苯基。

6.根据权利要求2所述的米非司酮衍生物，R1为苯基。

7.根据权利要求2所述的米非司酮衍生物，R1为甲基取代苯基。

8.根据权利要求7所述的米非司酮衍生物，R1为甲基取代3-苯基或甲基取代4-苯基。

9.根据权利要求1所述的米非司酮衍生物在制备治疗与KLF5调控的肿瘤药物中的用途。

10.根据权利要求1所述的米非司酮衍生物在制备治疗三阴性乳腺癌药物中的用途。

说明书

技术领域

本发明属于医药技术领域，具体涉及米非司酮衍生物及其用途。

背景技术

研究发现，转录因子KLF5(Kruppel-like factor 5,锌指蛋白转录因子5)是与DNA结构域结合的转录调控因子家族。在正常组织中KLF5参与众多细胞的生物学进程，包括细胞的增殖、分化、迁移、炎症以及潜能性。在癌症组织中KLF5的表达和功能均有所改变，并参与调节癌细胞的增殖、调控、转移、肿瘤微环境以及肿瘤干细胞。KLF5主要参与许多控制细胞增殖的重要信号通路，无论在正常细胞还是在人类许多癌细胞中都具有促使细胞增殖的作用。三阴性乳腺癌(Triple Negative Breast Cancer,TNBC)，是雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体(HER2)均为阴性的一种特殊类型的乳腺癌，是乳腺癌中恶性程度最高的一种亚型，约占所有乳腺癌的10％-25％，至今仍未找到有效的靶向治疗药物。在乳腺癌细胞中，KLF5通过上调基因Cyclin A和DNA复制因子1(CDT1)等促进乳腺癌细胞增殖。也有研究发现KLF5主要通过上调靶基因FGF-BP(Fibroblast growth factor binding protein1)起促进细胞增殖的作用，同时促进ERK激酶活性，稳定MKP-1蛋白表达促进细胞生存。此外，KLF5在乳腺癌的发生发展过程中，起到很重要的作用。乳腺癌的KLF5在ER阴性乳腺癌中普遍高表达，且KLF5高表达的患者生存时间显著短于KLF5低表达的病人。前期研究也发现KLF5转录因子在Luminal类型的乳腺癌细胞T47D细胞中能够被孕激素所诱导，而该过程能够由孕激素受体抑制剂米非司酮(Mifepristone，MIF)所阻断。

前期新药筛选结果发现，米非司酮(Mifepristone)能够抑制三阴性乳腺癌细胞增殖、诱导细胞凋亡，并且在较高剂量下能够抑制人源性三阴性乳腺癌移植瘤在免疫缺陷小鼠体内的生长。进一步作用机制研究还发现米非司酮是通过诱导三阴性乳腺癌细胞中微小RNA-153的表达，从而抑制乳腺癌的增殖、生存和细胞干性的转录因子KLF5的表达(Theranostics 2016,6,533-44)。但是大量研究数据和前期活性测试结果均显示米非司酮必须在较高剂量下才能产生抗肿瘤活性，而且米非司酮的主要代谢产物单去甲基米非司酮(RU-42633,美她司酮)则没有明显的抗肿瘤活性。鉴于米非司酮在体内很快就代谢为单去甲基米非司酮，而且这个主要代谢产物在给药后0.5-2小时后血液中的浓度远超过母体化合物，大大限制了米非司酮可能作为一种较为理想的靶向抗肿瘤药物的进一步临床应用。

发明内容

针对以上技术问题，因此，本发明提供一类米非司酮衍生物，以其作为高效抗癌药物的活性成份，从而为寻找抗三阴性乳腺癌的靶向药物开辟新的途径。

基、苯基取代苯基、烯烃、苯基取代烯烃或杂环，包括噻唑、2-噻吩、吡嗪、吡啶、卤代吡啶；当R为磺酰基时，其具体结构特征为R₂SO₂-，R₂为苯基、C1-C6烷基取代苯基。

优选地，当R为酰基时，其中R1为氯代C1-C6烷基、卤代苯基、萘基、硝基取代苯基、C1-C6烷基取代苯基或苯基取代苯基。进一步优选地，R1为氯代甲烷基。优选地，R1为氯或溴代苯基。更加优选地，R1为3，4氯代苯基或2-溴4-氯代苯基。

优选地，R1为苯基或甲基取代苯基。更加优选地，R1为甲基取代3-苯基或甲基取代4-苯基。

本发明的米非司酮衍生物通过如下方法制备：

方法a：将1.0当量美她司酮和1.5当量的酰基氯或磺酰氯加入到0.1-0.2M乙酸乙酯溶液中，在0℃时加入3.0当量的三乙胺，将所得混合物在室温下搅拌16小时，然后用乙酸乙酯稀释该溶液，并用1M盐酸溶液和盐水洗涤。用无水硫酸钠干燥有机层，然后在减压下浓缩，残余物经石油醚/乙酸乙酯比例为4/1:1/1硅胶柱色谱法的柱层析，得到所需产物。

方法b：将1.2-2.0当量的一元芳香羧酸，1.0当量的美她司酮，1.5-2.0当量的苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和0.1-0.2M的N,N-二甲基甲酰胺，2.0-4.0当量的N，N-二异丙基乙胺混合，然后将该混合物在室温下搅拌直到美她司酮被反应完全，并通过薄层色谱法测定；用乙酸乙酯稀释混合物并用1M盐酸水溶液淬灭；用水和盐水洗涤洗涤有机层后，用无水硫酸钠干燥，并减压浓缩，将粗物质通过硅胶柱色谱法柱层析或用薄层色谱法纯化后，得到所需产物。

方法c：将1.2-2.0当量的一元芳香羧酸，1.0当量的美她司酮和3.0当量的1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，0.1-0.2M二氯甲烷混合，让混合物在室温下搅拌直到美她司酮被反应完全，通过薄层色谱法测定；用二氯甲烷稀释混合物并用1M盐酸水溶液淬灭；用水和盐水洗涤有机层，并用无水硫酸钠干燥，然后减压浓缩，将粗物质通过硅胶柱色谱法柱层析或用薄层色谱法纯化后，得到所需产物。

其中，所述的美她司酮Metapristone的制备方法参照前期研究结果及专利CN2013 10510394.0，名称为“一种合成美她司酮的方法”。

通常用TLC来跟踪测定反应的完成程度，反应完毕后一般用冰水淬灭，用乙酸乙酯、二氯甲烷、三氯甲烷等萃取，依次用水、饱和食盐水洗涤，干燥，低温减压除去溶剂，经柱层析得到最终产物，得到产物用核磁共振、高分辨质谱等方法验证其结构。

本发明的另一目的在于提供本发明米非司酮衍生物的用途，特别是在制备治疗与KLF5调控相关肿瘤方面的药物中的用途。

进一步地，本发明米非司酮衍生物在制备治疗三阴性乳腺癌药物中的用途。

本发明的有益效果：

1)本发明在前期探索工作的基础上，通过骨架再利用的药物设计原理，以米非司酮代谢敏感结构区域为结构改造位点，合理设计聚焦型化合物库，通过系统的结构优化，设计与合成了一类米非司酮衍生物，提供了米非司酮衍生物的结构式，该化合物结构简单易于制备且稳定，该米非司酮衍生物较米非司酮抗肿瘤活性强。

2)本发明的米非司酮衍生物作为治疗三阴性乳腺癌的药物活性较米非司酮强，且剂量小。

3)本发明提供的米非司酮衍生物用于制备成治疗三阴性乳腺癌的药物，为其他同类化合物的合成提供新的解决思路和方案。

具体实施方式

下述制备实施例中，用NMR定标：δH/C 7.26/77.16ppm(CDCl₃)；试剂主要由安耐吉试剂公司提供，产品纯化主要用柱色谱法，硅胶(200-300目或300-400目)，柱色谱法所用硅胶由阿达玛斯试剂公司提供(cas：63231-67-4)。

下述缩写词：EtOAc:乙酸乙酯；Et₃N：三乙胺；Na₂SO₄：硫酸钠；PE：石油醚；HBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；DMF：N,N-二甲基甲酰胺；DIPEA：N，N-二异丙基乙胺；TLC：硅胶色谱板；EDCI：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；CH₂Cl₂：二氯甲烷。

实施例1 FZU-0000-005

2-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylacetamide

将28mg,0.24mmol 2-氯乙酰氯,84mg,0.2mmol美她司酮和42mg,0.4mmol Et₃N加入到2.0mL EtOAc中搅拌16小时，PE/EtOAc＝1:1，按方法(a)制备得到90mg产物，得率92％，产物为白色固体，mp:124.3–125.5℃。

所得的产物进行氢谱¹HNMR、碳谱¹³CNMR及HRMS检测，结果如下：¹H NMR(400MHz,CDCl₃)δ7.27(d,J＝6.0Hz,2H),7.16(d,J＝7.7Hz,2H),5.80(s,1H),4.47(d,J＝6.9Hz,1H),3.82(s,2H),3.27(s,3H),2.85–2.75(m,1H),2.67–2.56(m,2H),2.53–2.38(m,4H),2.37–2.15(m,4H),2.10–2.01(m,1H),2.01–1.94(m,1H),1.91(s,3H),1.79–1.72(m,2H),1.56–1.47(m,1H),1.41–1.32(m,1H),0.50(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,166.42,156.52,145.54,144.96,140.31,129.93,128.68,127.12,123.32,82.75,82.21,80.03,49.75,46.96,41.54,40.19,39.27,39.16,38.96,38.08,36.81,31.13,27.36,25.99,23.40,13.97,3.94.

HRMS(ESI-TOF):calcd for C₃₀H₃₅ClNO₃[M+H]⁺492.2300；found 492.2290.

实施例2

2-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpropan amide(FZU-0010-001)

与实施例1不同之处在于：2-氯乙酰氯为30mg,Et₃N为40mg，得到80mg产物，得率为79％，其中PE/EtOAc＝2:1.产物为白色固体，mp:124.6–125.6℃。

¹H NMR(400MHz,CDCl₃)δ7.27(d,J＝7.9Hz,2H),7.18(d,J＝8.0Hz,2H),5.80(s,1H),4.48(d,J＝6.8Hz,1H),4.26(q,J＝6.3Hz,1H),3.28(s,3H),2.90–2.74(m,1H),2.68–2.58(m,2H),2.54–2.38(m,4H),2.32–2.19(m,2H),2.13–1.95(m,4H),1.91(s,3H),1.83–1.67(m,2H),1.56(d,J＝6.5Hz,3H),1.53–1.44(m,1H),1.40–1.28(m,1H),0.51(s,3H).¹³C NMR(101MHz,CDCl₃)δ199.43,169.57,156.55,145.37,145.09,140.51,129.98,128.61,127.30,123.37,82.82,82.26,80.11,49.85,47.01,40.25,39.29,39.19,39.02,38.15,36.85,31.16,27.41,26.04,23.44,21.36,14.00,13.99,3.94.

HRMS(ESI-TOF):calcd for C₃₁H₃₇ClNO₃[M+H]⁺506.2456；found 506.2456.

实施例3

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N,4-dimethylbenzenesulfo namide(FZU-0025-008)

与实施例1不同之处在于：用46mg，0.24mmol的对甲基苯磺酰氯替换28mg,0.24mmol 2-氯乙酰氯，根据方法a得到83mg白色固体，收率73％，mp:121.8–122.9℃。

¹H NMR(400MHz,CDCl₃)δ7.33(d,J＝7.9Hz,2H),7.19(d,J＝7.9Hz,2H),7.11(d,J＝8.2Hz,2H),7.01(d,J＝8.2Hz,2H),5.78(s,1H),4.42(d,J＝6.8Hz,1H),3.11(s,3H),2.87–2.66(m,1H),2.66–2.56(m,2H),2.51–2.36(m,6H),2.34–2.18(m,4H),2.14–1.97(m,3H),1.91(s,3H),1.82–1.68(m,2H),1.55–1.44(m,1H),1.35–1.28(m,1H),0.51(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.42,156.61,145.44,143.74,143.60,139.14,133.03,129.62,129.24,127.81,127.34,126.24,123.07,82.65,82.20,80.02,49.71,46.93,40.07,39.17,39.12,38.87,37.78,36.78,31.08,27.31,25.84,23.34,21.57,13.74,3.86.

HRMS(ESI-TOF):calcd for C₃₅H₄₀NO₄S[M+H]⁺592.2492；found 592.2472.

实施例4

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzenesulfonamide(FZU-0025-009)

与实施例1不同之处在于：用113mg，0.64mmol的苯磺酰氯替换28mg,0.24mmol 2-氯乙酰氯，将作为起始原料，根据方法a.得到63mg白色固体，收率57％，mp:120.3–121.5℃℃。

¹H NMR(400MHz,CDCl₃)δ7.58–7.54(m,1H),7.46(d,J＝7.2Hz,2H),7.40(d,J＝7.9Hz,2H),7.15–7.07(m,2H),7.02–6.96(m,2H),5.79(s,1H),4.42(d,J＝6.8Hz,1H),3.15(s,3H),2.85–2.73(m,1H),2.65–2.57(m,2H),2.54–2.35(m,5H),2.32–2.20(m,3H),2.11–1.98(m,3H),1.88(s,3H),1.80–1.67(m,2H),1.57–1.43(m,1H),1.40–1.31(m,1H),0.51(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,156.58,145.35,143.87,138.98,135.93,132.82,129.65,128.99,128.92,128.62,127.74,127.39,127.32,126.25,124.95,123.10,82.68,82.19,80.02,49.71,46.93,40.05,39.18,39.10,38.88,37.86,36.78,31.07,27.31,25.84,23.34,13.77,3.86.

HRMS(ESI-TOF):calcd for C₃₄H₃₈NO₄S[M+H]⁺578.2336；found 578.2314.

实施例5

3,4-Dichloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzamide(FZU-0000-008)

取8mg,0.24mmol 3,4-二氯苯甲酸、84mg,0.2mmol的美她司酮、112mg,0.6mmol的HBTU和76mg,0.6mmol DIPEA加入2.0mL DMF中搅拌16小时，PE/EtOAc＝2:1，按方法b制备得到84mg产物，得率为71％，产物为白色固体，mp:230.1–231.5℃。

¹H NMR(400MHz,CDCl₃)δ7.32(s,1H),7.12(d,J＝8.3Hz,1H),7.04(d,J＝8.0Hz,2H),7.01(d,J＝8.6Hz,1H),6.89(d,J＝7.9Hz,2H),5.72(s,1H),4.33(d,J＝6.9Hz,1H),3.42(s,3H),2.75–2.62(m,1H),2.60–2.48(m,2H),2.46–2.24(m,5H),2.23–2.09(m,3H),2.02–1.88(m,2H),1.83(s,3H),1.76–1.60(m,2H),1.49–1.36(m,1H),1.35–1.24(m,1H),0.38(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.30,167.82,156.47,145.04,144.11,141.82,135.51,133.91,131.97,130.98,129.70,129.59,128.17,128.10,126.91,123.15,82.47,82.25,79.92,49.57,46.87,40.01,39.21,39.06,38.85,38.33,36.70,31.08,27.32,25.77,23.31,13.73,3.87.

HRMS(ESI-TOF):calcd for C₃₅H₃₆Cl₂NO₃[M+H]⁺588.2067；found 588.2058.

实施例6

3-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenza mide(FZU-0002-016)

与实施例5不同之处在于：将8mg,0.24mmol 3,4-二氯苯甲酸替换为47mg,0.3mmol3-氯苯甲酸，HBTU为152mg,0.4mmol，DIPEA为103mg,0.8mmol，得100mg产物，得率为90％。产物为白色固体，mp:122.6–123.7℃。

¹H NMR(400MHz,CDCl₃)δ7.27(s,1H),7.19(d,J＝7.7Hz,1H),7.15–6.99(m,4H),6.94(d,J＝7.7Hz,2H),5.77(s,1H),4.36(d,J＝7.2Hz,1H),3.45(s,3H),2.80–2.67(m,1H),2.65–2.53(m,2H),2.51–2.30(m,4H),2.28–2.13(m,3H),2.05–1.97(m,1H),1.96–1.91(m,1H),1.89(s,3H),1.84–1.80(m,1H),1.80–1.66(m,2H),1.54–1.42(m,1H),1.38–1.27(m,1H),0.36(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.43,168.98,156.54,145.17,143.90,142.12,137.54,133.74,129.80,129.05,128.95,128.02,127.06,127.02,123.23,82.72,82.25,80.09,49.65,46.91,40.10,39.30,39.19,38.92,38.70,38.29,36.81,31.17,27.41,25.83,23.39,13.78,3.93.

HRMS(ESI-TOF):calcd for C₃₅H₃₅ClNO₃[M-H]^-552.2311；found 552.2293.

实施例7

3,6-Dichloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpicolinamide(FZU-0010-006)

与实施例5不同之处在于：将8mg,0.24mmol 3,4-二氯苯甲酸替换为46mg,0.24mmol 3,6-二氯吡啶甲酸，HBTU为114mg,0.3mmol，DIPEA为52mg,0.4mmol，PE/EtOAc＝1:1，得164mg产物，得率为99％。产物为白色固体，mp:126.5–127.6℃。

¹H NMR(400MHz,CDCl₃)δ7.41(d,J＝8.4Hz,1H),7.15–7.03(m,3H),7.03–6.96(m,2H),5.75(s,1H),4.30(d,J＝7.2Hz,1H),3.46(s,3H),2.72–2.60(m,1H),2.60–2.51(m,2H),2.48–2.26(m,4H),2.24–2.07(m,3H),2.05–1.95(m,2H),1.95–1.90(m,1H),1.87(s,3H),1.77–1.63(m,2H),1.49–1.37(m,1H),1.35–1.25(m,1H),0.21(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,164.94,156.52,153.28,148.52,145.11,144.81,139.73,139.53,129.79,127.68,127.38,127.10,124.98,123.23,82.77,82.18,80.05,49.61,46.78,40.12,39.39,39.17,38.86,36.80,36.68,31.13,27.39,25.81,23.39,13.32,3.90.

HRMS(ESI-TOF):calcd for C₃₄H₃₅Cl₂N₂O₃[M+H]⁺589.2019；found 589.2020.

实施例8

5-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylnicotinamide(FZU-0010-008)

与实施例7不同之处在于：将46mg,0.24mmol的3,6-二氯吡啶甲酸替换为38mg,0.24mmol的5-氯烟酸，得到109mg产物，得率为98％，产物为白色固体，mp:118.9–120.1℃℃。

¹H NMR(400MHz,CDCl₃)δ8.37(s,1H),8.32(s,1H),7.50(s,1H),7.08(d,J＝8.0Hz,2H),6.94(d,J＝7.9Hz,2H),5.75(s,1H),4.34(d,J＝7.1Hz,1H),3.46(s,3H),2.76–2.64(m,1H),2.60–2.50(m,2H),2.49–2.31(m,4H),2.29–2.26(m,1H),2.24–2.10(m,4H),2.08–1.93(m,3H),1.93–1.88(m,1H),1.86(s,3H),1.67(dt,J＝11.4,9.4Hz,2H),1.48–1.38(m,1H),1.35–1.27(m,1H),0.38(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.39,166.53,156.47,149.24,147.41,144.93,144.66,141.38,135.87,132.77,131.26,129.87,128.39,127.23,123.30,82.64,82.26,80.04,49.66,46.90,40.10,39.26,39.15,38.95,38.32,36.79,31.15,27.38,25.86,23.38,13.86,3.92.

HRMS(ESI-TOF):calcd for C₃₄H₃₆ClN₂O₃[M+H]⁺555.2409；found 555.2397.

实施例9

5-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpicolinamide(FZU-0010-009)

与实施例8不同之处在于：5-氯烟酸为45mg,0.28mmol，HBTU为152mg,0.4mmol，得到120mg产物，得率为90％。产物为白色固体，mp:124.1–125.5℃。

¹H NMR(400MHz,CDCl₃)δ8.17(s,1H),7.54(d,J＝6.6Hz,1H),7.48–7.35(m,1H),7.14–6.84(m,4H),5.77(s,1H),4.36(d,J＝6.8Hz,1H),3.48(s,3H),2.79–2.66(m,1H),2.62–2.53(m,2H),2.51–2.29(m,4H),2.28–2.16(m,3H),2.14–2.07(m,1H),2.06–1.90(m,3H),1.88(s,3H),1.80–1.66(m,1H),1.53–1.41(m,1H),1.38–1.28(m,1H),0.35(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,167.71,156.55,152.17,147.14,145.25,143.64,141.87,135.98,132.38,129.72,127.74,126.90,124.76,123.20,82.69,82.26,80.04,49.70,46.95,40.07,39.30,39.13,38.93,37.90,36.81,31.13,27.37,25.86,23.39,13.63,3.92.

实施例10

4-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpicolinamide(FZU-0010-010)

与实施例9不同之处在于：将5-氯烟酸替换为4-氯烟酸，得到140mg产物，产率为90％，PE/EtOAc＝1:2。产物为白色固体，mp:121.3–122.5℃。

¹H NMR(400MHz,CDCl₃)δ8.12(d,J＝8.0Hz,1H),7.46(s,1H),7.12(d,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,2H),6.95(d,J＝8.0Hz,2H),5.77(s,1H),4.36(d,J＝6.3Hz,1H),3.50(s,3H),2.80–2.65(m,1H),2.65–2.52(m,2H),2.51–2.30(m,4H),2.28–2.10(m,4H),2.06–1.93(m,2H),1.88(s,3H),1.80–1.57(m,2H),1.53–1.42(m,1H),1.35–1.23(m,1H),0.36(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.44,167.41,156.59,155.52,149.18,145.29,144.40,143.74,141.75,129.72,127.79,126.86,124.36,124.28,123.19,82.72,82.25,80.05,49.67,46.90,40.09,39.27,39.17,38.89,37.93,36.82,31.14,27.38,25.83,23.38,13.63,3.91.

HRMS(ESI-TOF):calcd for C₃₄H₃₆ClN₂O₃[M+H]⁺555.2409；found 588.2401.

实施例11

6-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylnicotinamide(FZU-0010-012)

与实施例9不同之处在于：将5-氯烟酸替换为6-氯烟酸，得到116mg产物，产率为90％，

PE/EtOAc＝2：3。产物为白色固体，mp:127.2–128.4℃。

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.41(d,J＝8.0Hz,1H),7.07(d,J＝8.1Hz,2H),7.03(d,J＝8.3Hz,1H),6.93(d,J＝8.0Hz,2H),5.75(s,1H),4.35(d,J＝7.0Hz,1H),3.45(s,3H),2.71(dt,J＝14.8,5.0Hz,1H),2.60–2.48(m,2H),2.48–2.28(m,4H),2.27–2.12(m,4H),2.05–1.92(m,3H),1.86(s,3H),1.76–1.62(m,2H),1.51–1.38(m,1H),1.35–1.24(m,1H),0.36(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,167.01,156.48,152.17,150.02,144.90,144.55,141.54,138.75,130.63,129.88,128.35,127.28,123.30,123.20,82.69,82.20,80.03,49.69,46.97,40.04,39.29,39.06,38.96,38.28,36.77,31.11,27.34,25.88,23.36,13.85,3.93.

HRMS(ESI-TOF):calcd for C₃₄H₃₆ClN₂O₃[M+H]⁺555.2409；found 555.2401.

实施例12

2-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylisonicotinamide(FZU-0010-014)

与实施例9不同之处在于：将5-氯烟酸替换为2-氯烟酸，得到100mg产物，产率为90％，PE/EtOAc＝2：3。产物为白色固体，mp:117.5–118.6℃。

¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),7.44(d,J＝7.9Hz,1H),7.11(d,J＝6.9Hz,2H),7.06(d,J＝7.4Hz,1H),6.96(d,J＝6.8Hz,2H),5.78(s,1H),4.38(d,J＝5.4Hz,1H),3.49(s,3H),2.81–2.68(m,1H),2.64–2.54(m,2H),2.52–2.30(m,4H),2.29–2.17(m,4H),2.09–1.94(m,3H),1.90(s,3H),1.79–1.65(m,2H),1.53–1.41(m,1H),1.40–1.29(m,1H),0.36(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.38,167.01,156.46,152.17,150.04,144.89,144.54,141.55,138.74,130.63,129.88,128.35,127.29,123.31,123.19,82.70,82.20,80.03,49.70,46.97,40.04,39.28,39.06,38.96,38.28,36.78,31.11,27.34,25.88,23.36,13.84,3.93.

HRMS(ESI-TOF):calcd for C₃₄H₃₆ClN₂O₃[M+H]⁺555.2409；found 555.2401.

实施例13

Following the General Procedure C:

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpicolinamide(FZU-0002-018)

将37mg,0.3mmol的吡啶甲酸，84mg,0.2mmol的美她司酮，115mg,0.6mmol的EDCI加入到2.0mL CH₂Cl₂中，按方法C制备得到102mg的产物，得率为98％，PE/EtOAc＝1:3，产物为黄色固体，mp:116.3–117.4℃。

¹H NMR(400MHz,CDCl₃)δ8.36–8.15(m,1H),7.60–7.44(m,1H),7.41–7.28(m,1H),7.17–6.74(m,5H),5.73(s,1H),4.31(d,J＝6.6Hz,1H),3.47(s,3H),2.74–2.62(m,1H),2.60–2.49(m,2H),2.46–2.25(m,4H),2.23–2.08(m,5H),2.06–1.91(m,2H),1.85(s,3H),1.76–1.59(m,2H),1.51–1.35(m,1H),1.33–1.21(m,1H),0.34(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.49,168.79,156.64,154.21,148.37,145.42,143.41,141.99,136.19,129.65,127.65,126.87,123.93,123.75,123.12,82.69,82.25,80.03,49.65,46.89,40.07,39.27,39.16,38.87,37.79,36.81,31.12,27.35,25.80,23.38,13.66,3.90.

HRMS(ESI-TOF):calcd for C₃₄H₃₅N₂O₃[M-H]^-519.2653；found 519.2623.

实施例14

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzamide(FZU-0002-006)

将44mg,0.36mmol的吡啶甲酸，125mg,0.3mmol的美她司酮，173mg,0.9mmol的EDCI加入到3.0mL CH₂Cl₂中，按方法C制备得到120mg的产物，得率为77％，PE/EtOAc＝1:1，产物为白色固体，mp:126.5–127.9℃。

¹H NMR(400MHz,CDCl₃)δ7.24(d,J＝7.8Hz,2H),7.20(d,J＝7.1Hz,1H),7.10(t,J＝7.4Hz,2H),7.03(d,J＝8.0Hz,2H),6.93(d,J＝7.9Hz,2H),5.76(s,1H),4.35(d,J＝7.1Hz,1H),3.49(s,3H),2.71(dt,J＝10.8,5.1Hz,1H),2.63–2.52(m,2H),2.51–2.30(m,4H),2.29–2.16(m,4H),2.07–1.93(m,3H),1.90(s,3H),1.79–1.66(m,2H),1.51–1.41(m,1H),1.37–1.28(m,1H),0.40(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.44,170.57,156.56,145.35,143.47,142.60,135.78,129.69,129.67,128.87,127.81,127.61,127.09,123.16,82.66,82.28,80.06,49.67,46.93,40.09,39.34,39.17,38.90,38.22,36.80,31.13,27.38,25.80,23.39,13.75,3.90.

HRMS(ESI-TOF):calcd for C₃₅H₃₆NO₃[M-H]^-518.2701；found 519.2693.

实施例15

3-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpropanamide(FZU-0002-014)

与实施例14不同之处在于：将44mg,0.36mmol的吡啶甲酸替换为39mg,0.36mmol 3-氯丙酸，得到147mg产物，产率为97％，PE/EtOAc＝1:1，产物为白色固体。

¹H NMR(400MHz,CDCl₃)δ7.26(d,J＝8.2Hz,2H),7.11(d,J＝8.4Hz,2H),5.80(s,1H),4.47(d,J＝7.0Hz,1H),3.80–3.67(m,2H),3.27(s,3H),2.81(dt,J＝10.1,5.6Hz,1H),2.65–2.57(m,2H),2.54–2.41(m,5H),2.37–2.22(m,3H),2.09–2.02(m,1H),2.01–1.92(m,1H),1.90(s,3H),1.79–1.71(m,2H),1.52–1.46(m,1H),1.40–1.31(m,1H),0.51(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.33,169.64,156.47,145.11,145.00,141.08,129.91,128.58,127.44,123.32,82.71,82.30,80.06,49.82,47.00,40.21,40.16,39.28,39.18,39.00,37.40,36.96,36.85,31.14,27.39,26.01,23.42,13.95,3.92.

HRMS(ESI-TOF):calcd for C₃₁H₃₅ClNO₃[M-H]^-504.2311；found 504.2322.

实施例16

4-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzamide(FZU-0002-015)

与实施例14不同之处在于：将吡啶甲酸替换为4-氯苯甲酸，得到140mg产物，产率为90％，产物为白色固体，mp:117.4–118.6℃。

¹H NMR(400MHz,CDCl₃)δ7.18(d,J＝8.5Hz,2H),7.12–6.99(m,4H),6.92(d,J＝8.4Hz,2H),5.77(s,1H),4.37(d,J＝7.1Hz,1H),3.46(s,3H),2.73(dt,J＝15.0,5.3Hz,1H),2.63–2.49(m,2H),2.49–2.29(m,4H),2.28–2.17(m,3H),2.09–1.92(m,3H),1.89(s,3H),1.80–1.66(m,2H),1.53–1.39(m,1H),1.37–1.26(m,1H),0.37(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.36,169.41,156.48,145.13,143.82,142.36,135.76,134.23,130.39,129.80,128.01,127.92,127.09,123.27,82.74,82.26,80.09,49.72,46.99,40.10,39.39,39.15,38.98,38.32,36.82,31.15,27.41,25.88,23.41,13.76,3.93.

HRMS(ESI-TOF):calcd for C₃₅H₃₅ClNO₃[M-H]^-552.2311；found 552.2292.

实施例17

3-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N,4-dimethylbenzamide(FZU-0010-021)

与实施例13不同之处在于：将37mg,0.3mmol的吡啶甲酸替换为51mg,0.3mmol4-甲基-3-氯苯甲酸，PE/EtOAc＝3:2，得到产物为70mg,得率为61％。产物为白色固体，mp:116.6–117.8℃。

¹H NMR(400MHz,CDCl₃)δ7.24(s,1H),7.07(d,J＝8.3Hz,2H),7.03(dd,J＝7.9,1.6Hz,1H),7.01–6.87(m,4H),5.77(s,1H),4.37(d,J＝7.3Hz,1H),3.47(s,3H),2.77–2.66(m,1H),2.63–2.53(m,2H),2.49–2.36(m,3H),2.36–2.31(m,1H),2.30–2.25(m,3H),2.23–2.14(m,3H),2.07–1.96(m,2H),1.91(s,3H),1.80–1.68(m,2H),1.53–1.43(m,1H),1.38–1.29(m,1H),0.44(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.40,169.01,156.53,145.29,143.84,142.39,137.95,134.83,133.71,130.12,129.77,129.67,128.03,127.25,127.02,123.21,82.69,82.30,80.09,49.64,46.94,40.18,39.37,39.28,38.94,38.38,36.81,31.18,27.44,25.85,23.42,20.03,13.75,3.90.

实施例18

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-3-methoxy-N-methylbenzamide(FZU-0010-022)

与实施例17不同之处在于：将51mg,0.3mmol4-甲基-3-氯苯甲酸替换为61mg,0.3mmol的3-甲氧基苯甲酸，得到76mg的产物，得率为69％，产物为白色固体，mp:112.6–113.8℃。

¹H NMR(400MHz,CDCl₃)δ7.09–7.01(m,2H),7.00–6.91(m,3H),6.88(s,1H),6.75(d,J＝7.7Hz,2H),5.76(s,1H),4.35(d,J＝6.5Hz,1H),3.67(s,3H),3.48(s,3H),2.78–2.64(m,1H),2.62–2.51(m,2H),2.50–2.30(m,4H),2.28–2.16(m,3H),2.11–1.94(m,3H),1.86(s,3H),1.81–1.65(m,2H),1.53–1.40(m,1H),1.37–1.28(m,1H),0.41(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.42,170.40,158.97,156.56,145.38,143.52,142.61,137.09,129.71,128.60,127.83,126.96,123.17,121.27,115.66,114.12,82.67,82.30,80.08,55.22,49.66,46.91,40.15,39.36,39.25,38.92,38.24,36.81,31.16,27.41,25.82,23.41,13.68,3.89.

HRMS(ESI-TOF):calcd for C₃₆H₄₀NO₄[M+H]⁺550.2952；found 550.2945.

实施例19

4-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methyl-2-nitrobenzamide(FZU-0010-023)

与实施例17不同之处在于：将51mg,0.3mmol的4-甲基-3-氯苯甲酸替换为80mg,0.4mmol的4-氯-2-硝基苯甲酸，PE/EtOAc＝1:1得到81mg的产物，得率为68％，产物为白色固体，mp:128.5–129.6℃。

¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝1.5Hz,1H),7.40(dd,J＝8.2,1.5Hz,1H),7.22(d,J＝8.2Hz,1H),6.95(q,J＝8.4Hz,4H),5.73(s,1H),4.29(d,J＝7.0Hz,1H),3.47(s,3H),2.72–2.61(m,1H),2.57–2.48(m,2H),2.45–2.23(m,6H),2.21–2.05(m,3H),2.05–1.95(m,1H),1.95–1.87(m,1H),1.82(s,3H),1.76–1.60(m,2H),1.49–1.37(m,1H),1.33–1.24(m,1H),0.20(s,3H).¹³C NMR(101MHz,CDCl₃)δ199.22,166.14,156.40,146.22,144.89,144.86,140.11,135.18,133.36,131.65,130.55,129.70,128.00,127.02,124.20,123.13,82.43,82.19,76.84,49.53,46.76,39.97,39.24,38.98,38.81,37.00,36.66,31.00,27.26,25.70,23.28,13.35,3.79.

HRMS(ESI-TOF):calcd for C₃₅H₃₆ClN₂O₅[M+H]⁺599.2307；found 599.2294.

实施例20

3,5-Dichloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzamide(FZU-0010-024)

与实施例19不同之处在于：将80mg,0.4mmol的4-氯-2-硝基苯甲酸替换为76mg,0.4mmol3,5-二氯苯甲酸，得到73mg的产物，得率为61％。产物为白色固体，mp:115.7–116.9℃。

¹H NMR(400MHz,CDCl₃)δ7.19(t,J＝1.8Hz,1H),7.14–7.09(m,2H),7.08(d,J＝8.3Hz,2H),6.92(d,J＝8.4Hz,2H),5.75(s,1H),4.35(d,J＝7.2Hz,1H),3.44(s,3H),2.75–2.62(m,1H),2.59–2.48(m,2H),2.48–2.26(m,4H),2.24–2.07(m,3H),2.07–1.95(m,2H),1.88(s,3H),1.77–1.62(m,2H),1.52–1.39(m,1H),1.37–1.26(m,1H),0.44(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.33,167.50,156.45,145.03,144.32,141.71,138.64,134.49,129.86,129.72,128.24,127.40,126.99,123.30,82.71,82.29,80.11,49.66,46.90,40.16,39.23,38.95,38.39,36.82,31.20,27.45,25.86,23.40,13.79,3.92.

HRMS(ESI-TOF):calcd for C₃₅H₃₆Cl₂NO₃[M+H]⁺588.2067；found 588.2058.

实施例21

N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-2-methoxy-N-methylbenzamide(FZU-0010-026)

与实施例20不同之处在于：将76mg,0.4mmol3,5-二氯苯甲酸替换为61mg,0.3mmol的甲氧基苯甲酸，PE/EtOAc＝2:3，得到75mg的产物，得率为68％。产物为白色固体，mp:124.2–125.3℃。

¹H NMR(400MHz,CDCl₃)δ7.19–7.05(m,2H),7.03–6.87(m,4H),6.74(t,J＝7.1Hz,1H),6.57(d,J＝8.3Hz,1H),5.75(s,1H),4.29(d,J＝6.7Hz,1H),3.61(s,3H),3.46(s,3H),2.77–2.62(m,1H),2.60–2.49(m,2H),2.49–2.27(m,4H),2.27–2.08(m,4H),2.03–1.91(m,2H),1.87(s,3H),1.79–1.61(m,2H),1.51–1.39(m,1H),1.36–1.27(m,1H),0.29(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.42,169.31,156.55,155.11,145.48,143.39,141.69,130.28,129.64,128.72,127.00,126.85,126.59,123.11,120.16,110.48,82.66,82.27,80.06,55.16,49.63,46.81,40.12,39.28,39.21,38.90,36.92,36.82,31.13,27.39,25.80,23.39,13.56,3.87.

HRMS(ESI-TOF):calcd for C₃₆H₄₀NO₄[M+H]⁺550.2952；found 550.2942.

实施例22

4-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methyl-3-nitrobenzamide(FZU-0010-027)

与实施例20不同之处在于：将76mg,0.4mmol3,5-二氯苯甲酸替换为81mg,0.4mmol的4-氯-3-硝基苯甲酸，得到90mg的产物，得率为74％。产物为白色固体，mp:123.3–124.6℃℃℃℃。

¹H NMR(400MHz,CDCl₃)δ7.78(s,1H),7.41(d,J＝8.3Hz,1H),7.30(d,J＝8.7Hz,1H),7.13(d,J＝7.9Hz,2H),6.97(d,J＝7.8Hz,2H),5.78(s,1H),4.38(d,J＝7.0Hz,1H),3.49(s,3H),2.81–2.68(m,1H),2.64–2.53(m,2H),2.51–2.30(m,4H),2.29–2.14(m,3H),2.09–1.98(m,2H),1.98–1.91(m,1H),1.87(s,3H),1.79–1.65(m,2H),1.55–1.41(m,1H),1.38–1.25(m,1H),0.38(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.32,166.68,156.39,147.10,144.73,144.66,141.52,135.61,133.33,131.28,129.95,128.45,128.38,127.08,126.33,123.36,82.74,82.19,80.04,49.68,46.95,40.05,39.25,39.08,38.98,38.55,36.79,31.14,27.39,25.87,23.37,13.69,3.94.

HRMS(ESI-TOF):calcd for C₃₅H₃₅ClN₂NaO₅[M+Na]⁺621.2127；found 621.2166.

实施例23

4-Chloro-3-fluoro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylbenzamide(FZU-0010-028)

与实施例22不同之处在于：81mg,0.4mmol的4-氯-3-硝基苯甲酸为52mg,0.3mmol的3-氯-4-氟苯甲酸，得到75mg的产物，得率为64％。产物为白色固体，mp:121.2–122.2℃。

¹H NMR(400MHz,CDCl₃)δ7.13(d,J＝7.8Hz,1H),7.11–7.06(m,2H),7.04(dd,J＝9.5,1.5Hz,1H),6.95(dd,J＝11.9,9.3Hz,3H),5.77(s,1H),4.37(d,J＝7.1Hz,1H),3.45(d,J＝8.8Hz,3H),2.73(dt,J＝14.9,5.2Hz,1H),2.65–2.53(m,2H),2.52–2.29(m,4H),2.28–2.17(m,3H),2.17–2.08(m,1H),2.08–1.93(m,2H),1.89(s,3H),1.80–1.64(m,2H),1.53–1.41(m,1H),1.38–1.29(m,1H),0.37(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.27,168.00,158.48,156.41,155.99,145.02,144.21,141.96,136.17,136.11,129.89,129.81,128.16,127.00,125.47,125.43,123.26,122.71,122.53,117.44,117.21,82.63,82.27,80.04,49.68,46.94,40.10,39.35,39.13,38.97,38.34,36.78,31.13,27.39,25.85,23.38,13.62,3.90.

HRMS(ESI-TOF):calcd for C₃₅H₃₆ClFNO₃[M+H]⁺572.2362；found 572.2355.

实施例24

3-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methyl-2-nitrobenzamide(FZU-0010-029)

与实施例22不同之处在于：4-氯-3-硝基苯甲酸为60mg,0.3mmol，得到74mg的产物，得率为61％。产物为白色固体，mp:121.8–123.0℃。

¹H NMR(400MHz,CDCl₃)δ7.34(d,J＝8.0Hz,1H),7.15(d,J＝7.9Hz,2H),7.11–6.95(m,3H),6.87(d,J＝7.6Hz,1H),5.77(s,1H),4.36(d,J＝7.0Hz,1H),3.46(s,3H),2.82–2.66(m,1H),2.65–2.53(m,2H),2.50–2.28(m,4H),2.26–2.11(m,3H),2.09–1.99(m,2H),1.97–1.91(m,1H),1.89(s,3H),1.80–1.63(m,2H),1.53–1.41(m,1H),1.35–1.20(m,1H),0.31(s,3H).

¹³C NMR(101MHz,CDCl₃)δ199.38,165.01,156.50,147.52,144.98,144.79,140.82,133.13,131.42,130.31,129.85,128.27,127.52,126.75,126.48,123.28,82.84,82.17,80.05,49.65,46.93,40.12,39.42,39.17,38.89,37.57,36.81,31.15,27.40,25.85,23.38,13.68,3.92.

实施例25

3-Chloro-4-fluoro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1

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