CN110903341B - 黄体酮骈吡嗪酰胺化合物及其制备方法与抗癌应用 - Google Patents

黄体酮骈吡嗪酰胺化合物及其制备方法与抗癌应用 Download PDF

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CN110903341B
CN110903341B CN201911234480.7A CN201911234480A CN110903341B CN 110903341 B CN110903341 B CN 110903341B CN 201911234480 A CN201911234480 A CN 201911234480A CN 110903341 B CN110903341 B CN 110903341B
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王俊儒
王世军
原肖荣
钱浩
林晓宇
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Abstract

本发明公开了一类黄体酮骈吡嗪酰胺化合物及其制备方法与抗癌应用。所涉及的化合物结构通式如式(I)所示。所公开的制备方法为通过Boc氨基保护、成酰胺、脱Boc反应得到氨基酸分子片段3a‑o；通过黄体酮C‑20羰基保护、A环C‑4位双甲基引入、C‑2氧化，合成含2,3‑邻二羰基的中间物6；最后利用氨基酸片段的二氨基与甾体A环邻二羰基构建吡嗪环，得到目标分子。本发明提供的黄体酮骈吡嗪酰胺化合物对乳腺癌、肝癌和前列腺癌均具抑制活性，尤其对前列腺癌细胞抑制活性更为显著。

Description

黄体酮骈吡嗪酰胺化合物及其制备方法与抗癌应用
技术领域
本发明涉及一类黄体酮骈吡嗪酰胺化合物，及其在制备抗前列腺癌药物中的应用。
背景技术
恶性肿瘤严重威胁着人类健康。根据Freddie Bray等人于2018年9月在全球领先期刊《CA:A Cancer Journal for Clinicians》发表的最新全球癌症统计数据显示2018年全球新增1810万癌症病例，其中970万癌症患者死亡。预计到2020年，全世界每年将新发生2000万例肿瘤，其中1400万例在亚洲、非洲和拉丁美洲的发展中国家。因此，发现新结构类型、新作用机制、高活性且低毒副作用的抗癌药物已成为当务之急。
发明内容
发明人发现了一类黄体酮骈吡嗪酰胺化合物，并且研究发现其具有抗癌细胞活性。
基于此，本发明提供了一类黄体酮骈吡嗪酰胺化合物，该化合物的结构通式如式(I)所示：
Figure BDA0002304514720000011
其中：
R1为氟原子、氯原子、甲基或甲氧基取代的苯基或者环己胺基、β-苯乙胺基或非取代苯基。
具体的，本发明化合物结构选择以下结构式之一：
Figure BDA0002304514720000012
Figure BDA0002304514720000021
本发明同时提供上述化合物在药学上可接受的盐或溶剂。
本发明还提供了上述化合物的制备方法。为此，本发明所提供的制备方法包括：
1)以DL-二氨基丙酸盐酸盐为原料，依次进行Boc氨基保护、成酰胺、脱Boc反应得到氨基酸分子片段3a-o；
2)以黄体酮为原料，依次通过C-20羰基保护、A环C-4位双甲基引入、C-2氧化，合成含2,3-邻二羰基的中间体6；
3)利用氨基酸片段的二氨基与中间体6的A环邻二羰基构建吡嗪环。
同时，本发明提供了一种制备本发明化合物的中间体之一，该中间体的结构式如式(Ⅱ)所示：
Figure BDA0002304514720000031
本发明还提供一种制备本发明化合物的中间体之二，该中间体的结构式如式(Ⅲ)所示：
Figure BDA0002304514720000032
其中：R1为氟原子、氯原子、甲基或甲氧基取代的苯基或者环己胺基、β-苯乙胺基或非取代苯基。
具体，上述式(Ⅲ)中间体结构选择以下结构式之一：
Figure BDA0002304514720000033
Figure BDA0002304514720000041
本发明提供的黄体酮骈吡嗪酰胺化合物对乳腺癌、肝癌和前列腺癌具有一定的抑制活性，尤其是对前列腺细胞具有显著的抑制活性，明显高于抗其他肿瘤细胞的活性，且优于阳性对照5-氟尿嘧啶。
本发明制备方法优势在于制备过程更加容易、更加高效。通过两分子片段构建吡嗪环获得最终目标分子，相比传统路线的将大位阻苯胺基团引入甾体骨架中，反应更加容易；两种分子片段(化合物3a-o，关键中间体6)各自的合成中，均不涉及色谱柱分离，更加高效。
附图说明
图1-图9为本发明化合物的核磁图谱；各图对应的化合物如表3所示。
表3
Figure BDA0002304514720000042
Figure BDA0002304514720000051
具体实施方式
以下通过合成黄体酮骈吡嗪酰胺类化合物实例具体说明本发明的各个方面和特征。本领域的技术人员应该理解，这些实施例只是用于说明目的，而不限制本发明的范围。本发明的保护范围只受权利要求书的限制。在不背离权利要求书范围的条件下，本领域的技术人员可以对发明的各个方面进行各种修改和改进，这些修改和改进也属于本发明的保护范围。
另外，需要注意的是，除非特别指明，下面实施例中所用的各种材料和试剂都是本领域中常用的材料和试剂，可以通过常规的商业途径获得；所用的中间体可以通过常规方法制备；所用方法均为本领域技术人员公知的常规方法。
本发明所述化合物的合成可采用以下方法：
1)通过Boc氨基保护、成酰胺、脱Boc反应得到氨基酸分子片段；2)通过C-20羰基保护、A环C-4位双甲基引入、C-2氧化，合成含2,3-邻二羰基的关键中间物6；3)利用氨基酸片段的二氨基与甾体A环邻二羰基构建吡嗪环。具体合成示例如下：
(一)相关中间体的合成可参考以下方法(所用取代基如表1所示)：
Figure BDA0002304514720000052
表1
Figure BDA0002304514720000053
DL-2,3-二(叔丁氧羰基)氨基丙酸(中间目标物1)的合成：
将二氨基丙酸盐酸盐(0.60g，4.27mmol)溶于1M碳酸氢钠溶液，再加入含二碳酸二叔丁酯(10.63mmol)的二氧六环溶液10.6mL，室温反应12小时。之后在冰浴搅拌下加入3M盐酸溶液调节pH至2.0–3.0，加入饱和食盐水50mL，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，浓缩，得中间目标物1，白色固体1.57g，产率82.55％。
DL-2,3-二(叔丁氧羰基)氨基丙酰胺(中间目标物2a-o)的合成：
以N-(苯基)-DL-2,3-二(叔丁氧羰基)氨基丙酰胺2a的合成为例：
将中间目标物1(180mg,0.6mmol)溶于无水二氯甲烷5mL(N,N-二甲基甲酰胺10滴助溶)，依次加入HOBt(162.16mg，2eq.),EDCl(230.04mg，2eq.)，Et3N(242.86mg，4eq.)，搅拌活化30分钟后加入苯胺(139.70mg，1.5eq.)，回流12小时。之后降温至室温，加入饱和食盐水20mL，二氯甲烷萃取(30mL×3)，合并有机相，无水硫酸钠干燥，浓缩。用二氯甲烷：甲醇：甲酸＝60:1:10滴快速过柱得到中间目标物2a，产率65.88％。
DL-2,3-二氨基丙酰胺(中间目标物3a-o)的合成：
以N-(苯基)-DL-2,3-二(叔丁氧羰基)氨基丙酰胺3a的合成为例：
将中间目标物2a(180mg，0.43-0.47mmol)溶于二氯甲烷1mL，再加入TFA1.5mL，搅拌1小时后，旋干，用3mL甲醇重溶，加三乙胺2mL中和多余的酸，旋干，直接用于下一步反应。
按照相同的方法，分别用苯胺、取代苯胺、环己胺、β-苯乙胺与叔丁氧羰基保护的二氨基丙酸1反应，得到中间物2a-o(产率44.17-67.86％)，进一步脱保护得到3a-o，可直接用于下一步反应。
(二)中间体的合成可参考以下方法：
中间体6的合成路线:
Figure BDA0002304514720000061
中间体4的合成：将黄体酮(1.01g，3.2mmol)置于乙二醇(25mL)中，再加入硅酸四乙酯(1.43mL，6.4mmol)和催化量的p-TsOH，室温反应5小时。检测反应完毕后加入饱和NaHCO3溶液30mL，乙酸乙酯萃取(30mL×3)，合并萃取液，无水硫酸钠干燥，浓缩得到白色固体中间体化合物4(1.10g，95.52％)。m.p.187-188℃；HRMS(ESI):calcd for C23H34O3[M+H]+359.2581,found[M+H]+359.2585；1H NMR(500MHz,CDCl3)δ5.68(s,1H),4.01–3.74(m,4H),2.44–2.18(m,4H),2.11–1.94(m,3H),1.85–1.74(m,2H),1.73–1.57(m,5H),1.56–1.45(m,2H),1.40(qd,J＝12.9,3.8Hz,1H),1.25(s,3H),1.20–1.10(m,5H),1.06–0.94(m,2H),0.89(td,J＝11.9,4.2Hz,1H),0.77(s,3H).13C NMR(125MHz,CDCl3)δ199.62,171.58,123.78,111.78,65.20,63.21,58.12,55.73,53.77,41.83,39.28,38.61,35.69,35.09,33.99,32.93,31.93,24.57,23.74,22.92,20.82,17.39,12.95.
中间体5的合成：将中间体4(1.8g，4.7mmol)溶解于30mL干燥叔丁醇中，加入叔丁醇钾(2.1g，19.0mmol)，氮气保护，室温下搅拌0.5小时，之后用注射器缓慢加入CH3I(2.9ml，47.0mmol)。室温反应16小时后，加入50mL冰水，乙酸乙酯萃取(3×30mL)，饱和食盐水洗(2×30mL)。合并萃取液，经无水Na2SO4干燥并浓缩，得到中间体5(1.0g，59.90％)，为白色固体。m.p.138-140℃；HRMS(ESI):calcd for C25H38O3[M+H]+387.2893,found[M+H]+387.2898；1H NMR(500MHz,CDCl3)δ5.53(dd,J＝4.8,2.1Hz,1H),4.03–3.80(m,4H),2.61–2.34(m,2H),2.13–2.04(m,2H),2.04–1.95(m,1H),1.82–1.76(m,1H),1.71(dt,J＝11.3,6.4Hz,2H),1.68–1.59(m,3H),1.57–1.46(m,2H),1.40(dd,J＝12.9,3.7Hz,1H),1.28(s,3H),1.25–1.12(m,9H),1.03(ddd,J＝12.2,6.6,3.2Hz,2H),0.83(s,3H),0.76(s,3H).13CNMR(125MHz,CDCl3)δ216.89,149.85,119.89,111.91,65.23,63.23,58.20,56.66,48.91,48.68,41.85,39.42,37.11,33.74,32.10,31.65,30.75,30.27,27.26,24.61,23.76,23.02,21.10,19.37,12.94.
中间体6的合成：将中间体5(4.54g，10.00mmol)溶于30mL叔丁醇/干燥四氢呋喃(20:1，v/v)的混合溶液中，再加入叔丁醇钾(2.50g，25.00mmol)，通入O2，于45℃下反应40分钟，TLC检测反应完毕后，加入饱和食盐水50mL，乙酸乙酯萃取(50mL×3)，饱和氯化钠溶液反萃，合并萃取液，无水硫酸钠干燥，得白色固体中间体6(4.04g，92.21％)。m.p.148-150℃；HRMS(ESI):calcd for C25H36O4[M+H]+401.2686,found[M+H]+401.2688；1H NMR(500MHz,CDCl3)δ6.21(s,1H),5.59(s,1H),4.05–3.79(m,4H),2.15(ddd,J＝27.0,17.6,12.0Hz,3H),1.85–1.56(m,8H),1.37(s,3H),1.33(d,J＝5.4Hz,6H),1.28(s,3H),1.22–1.13(m,3H),1.03(dt,J＝19.8,9.9Hz,1H),0.80(s,3H).13C NMR(125MHz,CDCl3)δ199.40,143.84,142.83,123.11,122.10,111.86,65.19,63.22,58.00,57.06,48.23,47.25,41.75,39.19,38.47,32.08,31.43,30.55,24.59,23.97,23.62,23.20,23.01,20.77,13.01.
(三)最终化合物的合成参考方法：
中间体8a-o和化合物9a-o的合成路线:
Figure BDA0002304514720000081
实施例1:
化合物8a，9a的合成为例：
化合物8a：向化合物6(200mg，0.5mmol，1.1equiv)的无水乙醇(10mL)溶液中，加入N-(苯基)-DL-2,3-二氨基丙酰氨3a，1mL三乙胺，催化量的p-TsOH，并将混合物回流8小时。反应完毕后用100-200目硅胶直接拌样，硅胶柱色谱法纯化(石油醚/乙酸乙酯，5:1，v/v)，得到白色固体7a，不需纯化直接用于下一步反应。
将粗产物7a溶于甲醇/二氯甲烷(5mL，1：1，v/v)中，加入3滴6M盐酸，室温下搅拌10分钟。反应完毕后，用碳酸氢钠固体中和多余盐酸，过滤，滤液浓缩拌样，硅胶柱色谱纯化目标产物8a，得白色固体200.13mg，收率64.43％。m.p.243-245℃；HRMS(ESI)m/z calcd forC32H39N3O2[M+H]+498.3115,found 498.3115；1H NMR(500MHz,Chloroform-d)δ9.67(s,1H),9.21(s,1H),7.74(d,J＝8.0Hz,2H),7.39(t,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),5.84(dd,J＝5.3,2.4Hz,1H),3.23(d,J＝15.9Hz,1H),2.72(d,J＝15.8Hz,1H),2.57(t,J＝9.1Hz,1H),2.27–2.23(m,1H),2.22(d,J＝5.4Hz,2H),2.14(s,3H),2.11(s,2H),1.84–1.73(m,2H),1.69(s,3H),1.59–1.50(m,2H),1.40(d,J＝4.3Hz,2H),1.38(s,3H),1.27(s,1H),1.24(s,1H),0.78(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.41,161.45,157.52,154.87,148.14,142.27,141.01,137.47,129.24,124.70,121.24,119.88,63.67,57.03,48.80,44.05,44.00,41.36,38.84,37.90,33.98,31.82,31.74,31.65,31.48,24.50,22.94,21.22,20.55,13.38.
化合物9a：取上一步产物8a(49.80mg,0.1mmol)溶于干燥甲醇/四氢呋喃(2mL，2：
1，v/v)溶液中，在冰浴条件下分批加入硼氢化钠(80mg)，继续搅拌15分钟。反应完毕后，用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯萃取(20mL×3)，合并有机层，无水硫酸钠干燥，浓缩。硅胶柱色谱法纯化(二氯甲烷/甲醇，20：1)，得到目标化合物9a，白色固体48.00mg，收率96.38％。m.p.168-170℃；HRMS(ESI)m/z calcd for C32H41N3O2[M+H]+500.3271,found500.3235；1H NMR(500MHz,Chloroform-d)δ9.68(s,1H),9.21(s,1H),7.75(d,J＝7.9Hz,2H),7.40(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H),5.84(dd,J＝5.2,2.5Hz,1H),3.75(dd,J＝9.9,5.9Hz,1H),3.25(d,J＝15.9Hz,1H),2.72(d,J＝15.9Hz,1H),2.29–2.16(m,2H),1.70(s,5H),1.59–1.46(m,2H),1.39(s,4H),1.26(d,J＝3.3Hz,6H),1.17(d,J＝6.2Hz,4H),0.80(s,6H).
按照相同的方法，分别用不同苯胺、环己胺、β-苯乙胺取代的DL-2,3-二氨基丙酰氨3a-o和关键中间体6(0.5mmol)反应，得到目标产物8a-o(产率37.33-64.43％)，进一步还原得到目标产物9a-o。
实施例2：
化合物8b:将实施例1中的氨基酸分子片段换为N-(2-氟苯基)-DL-2,3-二氨基丙酰氨，得白色固体155.45mg，收率48.30％。m.p.215-217℃；HRMS(ESI)m/z calcd forC32H38FN3O2[M+H]+516.3021,found516.3012；1H NMR(500MHz,Chloroform-d)δ9.67(s,1H),9.21(s,1H),7.74(d,J＝8.0Hz,2H),7.39(t,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),5.84(dd,J＝5.3,2.4Hz,1H),3.23(d,J＝15.9Hz,1H),2.72(d,J＝15.8Hz,1H),2.57(t,J＝9.1Hz,1H),2.27–2.23(m,1H),2.22(d,J＝5.4Hz,2H),2.14(s,3H),2.11(s,2H),1.84–1.73(m,2H),1.69(s,3H),1.59–1.50(m,2H),1.40(d,J＝4.3Hz,2H),1.38(s,3H),1.27(s,1H),1.24(s,1H),0.78(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.41,161.45,157.52,154.87,148.14,142.27,141.01,137.47,129.24,124.70,121.24,119.88,63.67,57.03,48.80,44.05,44.00,41.36,38.84,37.90,33.98,31.82,31.74,31.65,31.48,24.50,22.94,21.22,20.55,13.38.
化合物9b：白色固体43.48mg，收率84.31％。m.p.180-182℃；HRMS(ESI)m/z calcdfor C32H40FN3O2[M+H]+518.3177,found 518.3142；1H NMR(500MHz,Chloroform-d)δ9.68(s,1H),9.21(s,1H),7.75(d,J＝7.9Hz,2H),7.40(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H),5.84(dd,J＝5.2,2.5Hz,1H),3.75(dd,J＝9.9,5.9Hz,1H),3.25(d,J＝15.9Hz,1H),2.72(d,J＝15.9Hz,1H),2.29–2.16(m,2H),1.70(s,5H),1.59–1.46(m,2H),1.39(s,4H),1.26(d,J＝3.3Hz,6H),1.17(d,J＝6.2Hz,4H),0.80(s,6H).
实施例3：
化合物8c：将实施例1中的氨基酸分子片段换为N-(3-氟苯基)-DL-2,3-二氨基丙酰氨，得白色固体120.13mg，收率37.33％。m.p.278-280℃；HRMS(ESI)m/z calcd forC32H38FN3O2[M+H]+516.3021,found516.3013；1H NMR(500MHz,Chloroform-d)δ9.71(s,1H),9.20(s,1H),7.71(dt,J＝10.8,2.2Hz,1H),7.37(td,J＝7.1,6.2,3.1Hz,1H),7.35–7.30(m,1H),6.86(td,J＝8.3,2.4Hz,1H),5.85(dd,J＝5.2,2.4Hz,1H),3.24(d,J＝15.8Hz,1H),2.73(d,J＝15.8Hz,1H),2.57(t,J＝9.1Hz,1H),2.25(d,J＝5.4Hz,0H),2.14(d,J＝3.0Hz,3H),1.85–1.75(m,3H),1.62(d,J＝12.6Hz,2H),1.54(d,J＝8.6Hz,3H),1.38(s,3H),1.28–1.20(m,4H),0.78(s,3H),0.66(s,3H).13C NMR(126MHz,CDCl3)δ209.40,164.23,161.60,157.69,155.26,148.14,141.95,141.13,139.06,138.98,130.40,130.33,121.35,115.27,115.25,111.56,111.39,107.51,107.30,63.73,57.10,48.88,44.10,44.08,41.42,38.89,37.96,34.04,31.87,31.76,31.67,31.54,24.55,23.01,21.28,20.59,13.42.
化合物9c：白色固体38.83mg，收率75.29％。m.p.130-132℃；HRMS(ESI)m/z calcdfor C32H40FN3O2[M+H]+518.3177,518.3142；1H NMR(500MHz,Chloroform-d)δ9.72(s,1H),9.20(s,1H),7.71(dt,J＝10.8,2.2Hz,1H),7.44–7.31(m,2H),6.93–6.79(m,1H),5.84(dd,J＝5.2,2.5Hz,1H),3.75(ddd,J＝12.3,8.0,4.5Hz,1H),3.25(d,J＝16.0Hz,1H),2.72(d,J＝16.0Hz,1H),2.30–2.12(m,2H),1.82–1.75(m,2H),1.70(s,3H),1.65–1.59(m,2H),1.57–1.50(m,2H),1.38(s,3H),1.34(d,J＝10.1Hz,2H),1.28–1.23(m,3H),1.17(d,J＝6.1Hz,4H),0.79(d,J＝3.8Hz,6H).
实施例4：
化合物8d：将实施例1中的氨基酸分子片段换为N-(4-氟苯基)-DL-2,3-二氨基丙酰氨，得白色固体145.35mg，收率45.16％。m.p.160-162℃；HRMS(ESI)m/z calcd forC32H38FN3O2[M+H]+516.3021,found516.3014；1H NMR(500MHz,Chloroform-d)δ9.13(d,J＝1.3Hz,1H),8.10(t,J＝6.3Hz,1H),7.46–7.29(m,2H),7.02(td,J＝8.6,1.8Hz,2H),6.20–5.21(m,1H),4.65(t,J＝7.2Hz,2H),3.20(d,J＝15.9Hz,1H),2.69(d,J＝15.9Hz,1H),2.56(t,J＝9.0Hz,1H),2.28–2.19(m,1H),2.22–2.16(m,1H),2.13(s,3H),2.14–2.05(m,1H),1.76(td,J＝8.9,7.8,2.9Hz,2H),1.68(ddd,J＝14.4,9.7,5.7Hz,2H),1.62–1.52(m,3H),1.53(td,J＝7.8,3.2Hz,2H),1.37–1.25(m,3H),1.31–1.17(m,4H),0.76(s,3H),0.64(d,J＝1.2Hz,3H).13C NMR(126MHz,CDCl3)δ209.36,163.85,163.30,161.35,157.63,154.58,148.32,142.29,140.87,134.16,134.13,129.50,129.44,121.11,115.78,115.61,63.71,57.08,48.86,44.06,44.02,42.71,41.36,38.87,37.88,33.89,31.84,31.79,31.64,31.50,24.51,22.98,21.23,20.54,13.38.
化合物9d：白色固体41.93mg，收率81.31％。m.p.218-220℃；HRMS(ESI)m/z calcdfor C32H40FN3O2[M+H]+518.3177,found518.3143；1H NMR(500MHz,Chloroform-d)δ9.12(s,1H),8.10(t,J＝6.3Hz,1H),7.42–7.30(m,2H),7.15–6.94(m,2H),5.79(dd,J＝5.3,2.5Hz,1H),3.74(dq,J＝9.7,6.1Hz,1H),3.22(d,J＝15.9Hz,1H),2.67(d,J＝15.9Hz,1H),2.27–2.15(m,2H),1.72–1.65(m,4H),1.59(s,3H),1.51(td,J＝13.1,4.0Hz,2H),1.41–1.34(m,2H),1.31(s,3H),1.25(d,J＝2.1Hz,3H),1.16(d,J＝6.1Hz,4H),0.77(d,J＝4.9Hz,6H).
实施例5：
化合物8e：将实施例1中的氨基酸分子片段换为N-(2-氯苯基)-DL-2,3-二氨基丙酰氨，得白色固体160.81mg，收率48.42％。m.p.235-237℃；HRMS(ESI)m/z calcd forC32H38ClN3O2[M+H]+532.2725,found532.2728；1H NMR(500MHz,Chloroform-d)δ10.58(s,1H),9.18(s,1H),8.66(dd,J＝8.3,1.4Hz,1H),7.42(d,J＝8.0Hz,1H),7.33(t,J＝7.8Hz,1H),7.07(t,J＝7.7Hz,1H),5.84(dd,J＝5.3,2.5Hz,1H),3.23(d,J＝15.9Hz,1H),2.72(d,J＝15.9Hz,1H),2.56(t,J＝9.0Hz,1H),2.25(s,1H),2.21(q,J＝4.7Hz,2H),2.13(s,3H),2.13(s,2H),1.83–1.76(m,2H),1.71(s,3H),1.53(d,J＝8.5Hz,2H),1.39(s,3H),1.33(d,J＝10.6Hz,2H),1.29(s,2H),0.79(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.37,161.51,157.76,155.16,148.07,142.19,140.88,134.64,129.28,128.02,124.80,123.18,121.27,120.84,63.70,57.07,48.90,48.86,44.06,41.46,38.87,37.94,33.98,31.84,31.80,31.64,31.51,24.51,22.98,21.25,20.60,13.39.
化合物9e：白色固体45.4mg，收率85.31％。m.p.242-244℃；HRMS(ESI)m/z calcdfor C32H40ClN3O2[M+H]+534.2882,found 534.2845；1H NMR(500MHz,Chloroform-d)δ10.60(s,1H),9.18(s,1H),8.67(dd,J＝8.2,1.5Hz,1H),7.43(dd,J＝8.0,1.4Hz,1H),7.34(td,J＝7.9,1.4Hz,1H),7.08(td,J＝7.7,1.5Hz,1H),5.84(dd,J＝5.3,2.5Hz,1H),3.74(qd,J＝6.2,3.2Hz,1H),3.26(d,J＝16.0Hz,1H),2.72(d,J＝16.0Hz,1H),2.21(ddd,J＝14.8,8.2,3.9Hz,2H),1.81–1.75(m,1H),1.72(s,3H),1.70–1.66(m,3H),1.65–1.59(m,3H),1.39(s,3H),1.34(s,1H),1.25(d,J＝4.8Hz,3H),1.17(d,J＝6.1Hz,4H),0.80(s,3H),0.79(s,3H).
实施例6：
化合物8f：将实施例1中的氨基酸分子片段换为N-(3-氯苯基)-DL-2,3-二氨基丙酰氨，得白色固体150.83mg，收率45.42％。m.p.180-182℃；HRMS(ESI)m/z calcd forC32H38ClN3O2[M+H]+532.2725,found 532.2728；1H NMR(500MHz,Chloroform-d)δ9.68(s,1H),9.20(s,1H),7.83(d,J＝2.0Hz,1H),7.61(dd,J＝8.0,2.0Hz,1H),7.31(t,J＝8.1Hz,1H),7.13(dd,J＝7.9,1.9Hz,1H),5.85(dd,J＝5.3,2.4Hz,1H),3.24(d,J＝15.9Hz,1H),2.73(d,J＝15.8Hz,1H),2.57(t,J＝9.0Hz,1H),2.28–2.24(m,0H),2.24–2.19(m,1H),2.14(s,3H),2.13–2.08(m,2H),1.79(td,J＝8.6,7.4,2.1Hz,1H),1.76(s,0H),1.70(s,3H),1.65–1.59(m,1H),1.54(td,J＝7.4,6.9,3.0Hz,2H),1.38(s,3H),1.30(dd,J＝11.8,7.0Hz,1H),1.24(q,J＝5.7Hz,3H),0.78(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.43,161.58,157.69,155.27,148.08,141.89,141.11,138.64,134.93,130.28,124.76,121.34,119.96,117.91,63.71,57.06,48.83,44.08,44.06,41.41,38.86,37.93,34.03,31.84,31.77,31.68,31.51,24.53,22.98,21.26,20.58,13.41.
化合物9f：白色固体44.87mg，收率84.32％。m.p.308-310℃；HRMS(ESI)m/z calcdfor C32H40ClN3O2[M+H]+534.2882,found 534.2815；1H NMR(500MHz,Chloroform-d)δ9.69(s,1H),9.21(s,1H),7.84(t,J＝2.0Hz,1H),7.69–7.50(m,1H),7.32(t,J＝8.1Hz,1H),5.85(dd,J＝5.3,2.5Hz,1H),3.75(dt,J＝9.7,6.0Hz,1H),3.25(d,J＝15.9Hz,1H),2.73(d,J＝16.0Hz,1H),2.30–2.11(m,2H),1.78(ddd,J＝18.0,10.5,2.4Hz,1H),1.71(s,3H),1.66–1.59(m,2H),1.58–1.51(m,4H),1.39(s,3H),1.35(d,J＝3.2Hz,1H),1.26(d,J＝3.5Hz,3H),1.15(d,J＝11.3Hz,4H),0.81(s,3H),0.80(s,3H).
实施例7：
化合物8g：将实施例1中的氨基酸分子片段换为N-(4-氯苯基)-DL-2,3-二氨基丙酰氨，得白色固体145.54mg，收率43.82％。m.p.239-240℃；HRMS(ESI)m/z calcd forC32H38ClN3O2[M+H]+532.2725,found 532.2728；1H NMR(500MHz,Chloroform-d)δ9.66(s,1H),9.18(s,1H),7.69(d,J＝8.4Hz,2H),7.41–7.28(m,2H),5.83(dd,J＝5.2,2.4Hz,1H),3.23(d,J＝15.8Hz,1H),2.72(d,J＝15.9Hz,1H),2.56(t,J＝9.0Hz,1H),2.25(d,J＝5.3Hz,1H),2.23–2.18(m,1H),2.13(s,3H),2.11(d,J＝5.3Hz,1H),1.79(dd,J＝10.2,2.6Hz,1H),1.74(d,J＝3.0Hz,1H),1.68(s,3H),1.53(d,J＝7.6Hz,2H),1.37(s,3H),1.26(dq,J＝21.6,6.2,5.5Hz,4H),0.77(s,3H),0.64(s,3H).13C NMR(126MHz,CDCl3)δ209.34,161.49,157.64,155.14,148.09,141.98,141.04,136.10,129.65,129.26,121.30,121.11,63.68,57.04,48.82,44.05,44.03,41.38,38.84,37.91,33.99,31.82,31.74,31.64,31.49,24.51,22.97,21.24,20.55,13.38.
化合物9g：白色固体47.08mg，收率88.33％。m.p.276-277℃℃；HRMS(ESI)m/zcalcd for C32H40ClN3O2[M+H]+534.2882,found534.2853；1H NMR(500MHz,Chloroform-d)δ9.67(s,1H),9.18(s,1H),7.91–7.62(m,2H),7.35(d,J＝8.8Hz,2H),5.84(dd,J＝5.3,2.5Hz,1H),3.84–3.63(m,1H),3.25(d,J＝15.9Hz,1H),2.71(d,J＝15.9Hz,1H),2.21(dt,J＝18.0,5.4Hz,2H),1.82–1.73(m,2H),1.69(s,3H),1.62(dd,J＝10.6,5.5Hz,1H),1.57–1.45(m,2H),1.38(s,3H),1.34(d,J＝4.1Hz,1H),1.30(dd,J＝12.4,7.7Hz,1H),1.25(d,J＝3.4Hz,3H),1.16(d,J＝6.1Hz,4H),0.78(d,J＝2.5Hz,6H).
实施例8：
化合物8h：将实施例1中的氨基酸分子片段换为N-(2-甲基苯基)-DL-2,3-二氨基丙酰氨，得白色固体190.67mg，收率59.70％。m.p.180-182℃；HRMS(ESI)m/z calcd forC33H41N3O2[M+H]+512.3272,found 512.3243；1H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.21(d,J＝2.0Hz,1H),7.58(s,1H),7.54(d,J＝8.3Hz,1H),7.39–7.21(m,1H),6.98(d,J＝7.6Hz,1H),5.84(dd,J＝5.2,2.5Hz,1H),3.23(d,J＝15.9Hz,1H),2.73(d,J＝15.9Hz,1H),2.57(t,J＝9.1Hz,1H),2.39(s,3H),2.26(t,J＝4.8Hz,0H),2.25–2.18(m,1H),2.14(d,J＝2.0Hz,4H),2.12(d,J＝2.3Hz,1H),1.80(dt,J＝10.0,4.8Hz,1H),1.70(d,J＝1.9Hz,3H),1.54(d,J＝8.8Hz,2H),1.38(s,3H),1.28(ddd,J＝16.0,11.6,5.0Hz,3H),0.79(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.49,161.44,157.53,154.83,148.20,142.36,141.02,139.21,137.39,129.10,125.58,121.25,120.51,117.02,63.71,57.07,48.83,44.08,44.02,41.38,38.86,37.92,34.00,31.84,31.79,31.68,31.50,24.52,22.96,21.65,21.24,20.57,13.41.
化合物9h：白色固体48.8mg，收率95.37％。m.p.110-111；HRMS(ESI)m/z calcdfor C33H43N3O2[M+H]+514.34280,found514.3395；1H NMR(500MHz,Chloroform-d)δ9.91(s,1H),9.21(d,J＝3.3Hz,1H),8.35(d,J＝8.1Hz,1H),7.29(t,J＝7.8Hz,1H),7.23(d,J＝7.6Hz,1H),7.09(t,J＝7.5Hz,1H),5.84(dd,J＝5.3,2.6Hz,1H),3.75(dt,J＝12.3,6.1Hz,1H),3.26(d,J＝15.9Hz,1H),2.72(d,J＝16.0Hz,1H),2.43(s,3H),2.31–2.15(m,2H),1.83–1.75(m,2H),1.70(d,J＝8.0Hz,3H),1.63(dd,J＝10.5,5.7Hz,1H),1.58–1.51(m,2H),1.46(d,J＝11.4Hz,3H),1.39(s,3H),1.31–1.22(m,3H),1.20–1.12(m,4H),0.81(d,J＝5.9Hz,6H).
实施例9：
化合物8i：将实施例1中的氨基酸分子片段换为N-(3-甲基苯基)-DL-2,3-二氨基丙酰氨，得白色固体180.78mg，收率56.6％。m.p.230-232℃；HRMS(ESI)m/z calcd forC33H41N3O2[M+H]+512.3272,found512.3245；1H NMR(500MHz,Chloroform-d)δ9.62(s,1H),9.21(s,1H),7.59(d,J＝1.9Hz,1H),7.54(dd,J＝8.1,2.0Hz,1H),7.28(d,J＝7.8Hz,1H),6.98(d,J＝7.5Hz,1H),5.85(dd,J＝5.2,2.5Hz,1H),3.24(d,J＝15.8Hz,1H),2.73(d,J＝15.9Hz,1H),2.58(t,J＝9.1Hz,1H),2.39(s,3H),2.25(dd,J＝11.7,6.3Hz,1H),2.22(s,2H),2.14(s,3H),2.13(d,J＝4.9Hz,2H),1.86–1.77(m,2H),1.70(s,3H),1.60–1.50(m,2H),1.39(s,3H),1.33–1.20(m,4H),0.79(s,3H),0.66(s,3H).13C NMR(126MHz,CDCl3)δ209.43,161.45,157.53,154.84,148.24,142.39,141.04,139.22,137.41,129.10,125.58,121.26,120.53,117.04,63.73,57.10,48.87,44.10,44.05,41.41,38.89,37.95,34.01,31.87,31.80,31.68,31.53,24.54,22.99,21.66,21.27,20.59,13.42.
化合物9i：白色固体48.29mg，收率94.37％。m.p.170-172；HRMS(ESI)m/z calcdfor C33H43N3O2[M+H]+514.34280,found514.3398；1H NMR(500MHz,DMSO-d6)δ10.17(s,1H),9.00(s,1H),7.67(s,1H),7.63(s,1H),7.28(t,J＝7.8Hz,1H),6.98(d,J＝7.5Hz,1H),5.91–5.82(m,1H),4.12(d,J＝5.5Hz,1H),3.50(dt,J＝9.5,5.8Hz,1H),3.10(d,J＝15.9Hz,1H),2.75(d,J＝15.9Hz,1H),2.34(s,3H),2.26–2.20(m,1H),2.19–2.06(m,1H),1.71(s,3H),1.60(d,J＝7.2Hz,3H),1.54(dd,J＝10.5,5.4Hz,1H),1.45(dd,J＝13.0,3.7Hz,1H),1.39(s,3H),1.30–1.20(m,3H),1.14(dt,J＝15.8,7.1Hz,3H),1.01(d,J＝6.0Hz,3H),0.73(d,J＝3.7Hz,6H).
实施例10：
化合物8j：将实施例1中的氨基酸分子片段换为N-(4-甲基苯基)-DL-2,3-二氨基丙酰氨，得白色固体175.29mg，收率54.89％。m.p.240-241℃；HRMS(ESI)m/z calcd forC33H41N3O2[M+H]+512.3272,found 512.3251；1H NMR(500MHz,Chloroform-d)δ9.61(s,1H),9.20(s,1H),7.62(d,J＝8.3Hz,2H),7.19(d,J＝8.1Hz,2H),5.84(dd,J＝5.3,2.4Hz,1H),3.23(d,J＝15.9Hz,1H),2.72(d,J＝15.8Hz,1H),2.57(t,J＝9.0Hz,1H),2.34(s,3H),2.26–2.17(m,2H),2.14(s,3H),2.12(s,2H),1.79(ddd,J＝10.3,7.9,2.6Hz,2H),1.69(s,3H),1.54(d,J＝8.4Hz,2H),1.46(s,2H),1.38(s,3H),1.31–1.19(m,3H),0.78(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.42,161.36,157.49,154.75,148.25,142.42,141.01,134.97,134.39,129.76,129.76,121.23,119.93,119.93,63.72,57.09,48.86,44.09,44.04,41.39,38.88,37.94,33.99,31.86,31.78,31.67,31.52,24.53,22.98,21.26,21.07,20.57,13.41.
化合物9j：白色固体48.29mg，收率94.36％。m.p.223-225℃；HRMS(ESI)m/z calcdforC33H43N3O2[M+H]+514.34280,found 514.3395；1H NMR(500MHz,Chloroform-d)δ9.62(s,1H),9.20(s,1H),7.63(d,J＝8.2Hz,2H),7.20(d,J＝8.1Hz,2H),5.84(dd,J＝5.3,2.5Hz,1H),3.75(dt,J＝11.8,5.9Hz,1H),3.24(d,J＝15.9Hz,1H),2.71(d,J＝15.8Hz,1H),2.35(s,3H),2.21(ddt,J＝16.0,10.9,4.9Hz,2H),1.78(td,J＝8.9,7.6,2.4Hz,1H),1.70(s,3H),1.63(tt,J＝10.6,5.3Hz,2H),1.54(dd,J＝13.1,3.8Hz,2H),1.45(d,J＝12.3Hz,1H),1.38(s,3H),1.35–1.28(m,2H),1.25(s,3H),1.17(d,J＝6.1Hz,4H),0.79(s,6H).
实施例11：
化合物8k：将实施例1中的氨基酸分子片段换为N-(2-甲氧基苯基)-DL-2,3-二氨基丙酰氨，得白色固体190.48mg，收率57.83％。m.p.260-262℃；HRMS(ESI)m/zcalcd forC33H41N3O3[M+H]+528.3221,found528.3185；13C NMR(126MHz,CDCl3)δ209.45,161.34,157.52,154.55,148.72,148.33,142.86,140.78,127.61,124.21,121.43,121.18,119.63,110.32,63.76,57.13,56.15,48.90,44.12,44.02,41.42,38.92,38.02,34.01,31.90,31.69,31.56,31.48,24.56,23.00,21.29,20.61,13.43.1H NMR(500MHz,Chloroform-d)δ10.54(s,1H),9.19(s,1H),8.58(dd,J＝8.0,1.7Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),7.03(td,J＝7.7,1.3Hz,1H),6.94(dd,J＝8.1,1.3Hz,1H),5.85(dd,J＝5.3,2.5Hz,1H),3.96(s,3H),3.23(d,J＝15.8Hz,1H),2.73(d,J＝15.8Hz,1H),2.58(t,J＝9.0Hz,1H),2.27(d,J＝5.4Hz,1H),2.23–2.19(m,1H),2.15(s,3H),2.14–2.08(m,1H),1.85–1.76(m,2H),1.72(s,3H),1.68–1.61(m,2H),1.60–1.49(m,2H),1.39(s,3H),1.33–1.15(m,4H),0.80(s,3H),0.66(s,3H).
化合物9k：白色固体49.26mg，收率93.34％。m.p.257-259℃；；HRMS(ESI)m/zcalcd for C33H43N3O3[M+H]+530.3377,found 530.3327；1H NMR(500MHz,Chloroform-d)δ10.55(s,1H),9.18(t,J＝2.5Hz,1H),8.58(dt,J＝8.0,1.6Hz,1H),7.09(tt,J＝7.7,1.6Hz,1H),7.03(td,J＝7.7,1.6Hz,1H),6.94(dd,J＝8.2,1.5Hz,1H),5.84(dd,J＝5.3,2.5Hz,1H),z.30(td,J＝6.7,1.3Hz,1H),3.96(d,J＝1.3Hz,3H),3.80–3.68(m,1H),3.24(d,J＝15.9Hz,1H),2.72(d,J＝15.9Hz,1H),2.21(dq,J＝16.4,5.2Hz,2H),1.78(td,J＝9.0,7.6,2.3Hz,2H),1.72(s,3H),1.66–1.61(m,2H),1.50–1.43(m,2H),1.39(s,3H),1.35–1.28(m,4H),1.17(d,J＝6.1Hz,4H),0.83–0.75(m,6H).
实施例12：
化合物8l：将实施例1中的氨基酸分子片段换为N-(3-甲氧基苯基)-DL-2,3-二氨基丙酰氨，得白色固体150.82mg，收率45.79％。m.p.213-215℃；HRMS(ESI)m/z calcd forC33H41N3O3[M+H]+528.3221,found528.3220；1H NMR(500MHz,Chloroform-d)δ9.66(s,1H),9.19(s,1H),7.54(t,J＝2.2Hz,1H),7.28(d,J＝8.1Hz,1H),7.17(dd,J＝8.0,1.9Hz,1H),6.71(dd,J＝8.2,2.4Hz,1H),5.84(dd,J＝5.2,2.5Hz,1H),3.84(s,3H),3.23(d,J＝15.9Hz,1H),2.72(d,J＝15.8Hz,1H),2.56(t,J＝9.1Hz,1H),2.30–2.23(m,1H),2.23–2.17(m,2H),2.13(s,3H),2.11(d,J＝2.6Hz,2H),1.83–1.74(m,2H),1.69(s,3H),1.53(d,J＝8.2Hz,2H),1.38(s,3H),1.24(d,J＝3.8Hz,4H),0.78(s,3H),0.65(s,3H).13C NMR(126MHz,CDCl3)δ209.37,161.47,160.41,157.55,154.93,148.16,142.23,141.00,138.69,129.89,121.25,112.09,110.66,105.55,63.69,57.05,55.48,48.83,44.05,44.02,41.38,38.85,37.91,33.98,31.83,31.74,31.64,31.50,24.51,22.97,21.24,20.56,13.38.
化合物9l：白色固体49.79mg，收率94.35％。m.p.217-219℃；HRMS(ESI)m/z calcdfor C33H43N3O3[M+H]+530.3377,found 530.3330；1H NMR(500MHz,Chloroform-d)δ9.68(s,1H),9.20(d,J＝3.6Hz,1H),7.56(t,J＝2.2Hz,1H),7.29(d,J＝8.1Hz,1H),7.18(dd,J＝7.9,1.9Hz,1H),6.73(dd,J＝8.3,2.4Hz,1H),5.84(dd,J＝5.4,2.5Hz,1H),3.86(s,3H),3.75(dt,J＝11.7,5.7Hz,1H),3.25(d,J＝15.9Hz,1H),2.72(d,J＝15.9Hz,1H),2.21(ddt,J＝15.7,10.5,4.9Hz,2H),1.77(ddd,J＝17.8,10.3,2.5Hz,2H),1.70(s,3H),1.61(ddd,J＝13.9,9.8,4.6Hz,2H),1.56(d,J＝3.9Hz,2H),1.38(s,3H),1.35–1.30(m,2H),1.25(t,J＝2.7Hz,3H),1.17(d,J＝6.2Hz,4H),0.79(s,6H).
实施例13：
化合物8m：将实施例1中的氨基酸分子片段换为N-(4-甲氧基苯基)-DL-2,3-二氨基丙酰氨，得白色固体160.73mg，收率30.46％。m.p.270-272℃；HRMS(ESI)m/z calcd forC33H41N3O3[M+H]+528.3220,found 528.3223；1H NMR(500MHz,Chloroform-d)δ9.56(s,1H),9.18(s,1H),7.69–7.57(m,2H),6.95–6.85(m,2H),5.82(dd,J＝5.4,2.5Hz,1H),3.79(s,3H),3.21(d,J＝15.8Hz,1H),2.70(d,J＝15.8Hz,1H),2.55(t,J＝9.1Hz,1H),2.24(d,J＝5.8Hz,1H),2.20–2.16(m,2H),2.12(s,3H),1.84–1.74(m,2H),1.67(s,3H),1.64–1.57(m,2H),1.55–1.47(m,2H),1.36(s,3H),1.31–1.18(m,4H),0.77(s,3H),0.63(s,3H).13C NMR(126MHz,CDCl3)δ209.35,161.18,157.44,156.67,154.63,148.18,142.39,140.87,130.66,121.51,121.17,114.36,63.64,57.00,55.56,48.78,44.01,41.32,38.80,37.86,33.92,31.79,31.72,31.60,31.45,24.47,22.92,21.19,20.51,13.34.
化合物9m：白色固体50.85mg，收率96.35％。m.p.210-212℃；HRMS(ESI)m/z calcdfor C33H43N3O3[M+H]+530.3377,found 530.3370；1H NMR(500MHz,Chloroform-d)δ9.57(s,1H),7.88–7.44(m,2H),6.93(d,J＝8.8Hz,2H),5.83(dd,J＝5.3,2.5Hz,1H),3.82(s,3H),3.75(dq,J＝11.7,5.9Hz,1H),3.24(d,J＝15.9Hz,1H),2.70(d,J＝15.9Hz,1H),2.21(dt,J＝18.2,5.3Hz,2H),1.77(td,J＝9.0,7.6,2.5Hz,2H),1.69(s,3H),1.61(dd,J＝10.6,5.6Hz,2H),1.52(td,J＝13.1,4.1Hz,2H),1.37(s,3H),1.34(d,J＝4.1Hz,1H),1.31–1.28(m,1H),1.25(s,3H),1.17(d,J＝6.1Hz,4H),0.78(s,6H).
实施例14：
化合物8n：将实施例1中的氨基酸分子片段换为N-(环己基)-DL-2,3-二氨基丙酰氨，得白色固体160.53mg，收率51.06％。m.p.110-112℃；HRMS(ESI)m/z calcd forC32H45N3O2[M+Na]+527.3482,found 527.3415；1H NMR(500MHz,Chloroform-d)δ9.04(d,J＝2.8Hz,1H),7.65(d,J＝8.5Hz,1H),5.92–5.54(m,1H),4.03–3.81(m,1H),3.14(dd,J＝15.8,2.6Hz,1H),2.64(d,J＝15.8Hz,1H),2.53(t,J＝9.1Hz,1H),2.26–2.13(m,2H),2.09(s,J＝2.6Hz,5H),1.97(dt,J＝13.0,4.0Hz,2H),1.72(dd,J＝13.7,7.3Hz,5H),1.58(d,J＝2.6Hz,5H),1.49(s,2H),1.45–1.36(m,3H),1.29(d,J＝2.5Hz,4H),1.27–1.17(m,4H),0.72(d,J＝2.4Hz,3H),0.60(d,J＝2.7Hz,3H).13C NMR(125MHz,CDCl3)δ209.28,162.68,157.21,154.00,148.34,142.63,140.61,120.96,63.62,57.00,48.77,47.95,43.99,43.89,41.22,38.80,37.81,33.84,33.02,31.78,31.67,31.58,31.44,25.62,24.78,24.45,22.89,21.15,20.45,13.32.
化合物9n：白色固体46.02mg，收率91.35％。m.p.201-203℃；HRMS(ESI)m/z calcdfor C32H47N3O2[M+H]+506.3741,found506.3723；1H NMR(500MHz,Chloroform-d)δ9.04(s,1H),7.67(d,J＝8.5Hz,1H),5.78(dd,J＝5.2,2.5Hz,1H),3.97(dt,J＝8.3,3.7Hz,1H),3.72(dd,J＝10.1,5.9Hz,1H),3.20(d,J＝16.0Hz,1H),2.64(d,J＝15.9Hz,1H),2.29–2.10(m,3H),1.99(dq,J＝13.7,4.5Hz,2H),1.78–1.64(m,7H),1.60(s,5H),1.52–1.40(m,3H),1.31(s,5H),1.23(d,J＝3.1Hz,3H),1.15(d,J＝6.1Hz,4H),0.75(s,6H).
实施例15：
化合物8o：将实施例1中的氨基酸分子片段换为N-(β苯乙基)-DL-2,3-二氨基丙酰氨，得白色固体130.51mg，收率49.72％。m.p.165-167℃；HRMS(ESI)m/z calcd forC34H43N3O2[M+H]+526.3428,found 526.3414；1H NMR(500MHz,Chloroform-d)δ9.08(d,J＝1.9Hz,1H),7.85(t,J＝5.9Hz,1H),7.33(d,J＝7.6Hz,2H),7.28–7.22(m,3H),5.80(dd,J＝5.2,2.5Hz,1H),3.74(q,J＝6.6Hz,2H),3.18(d,J＝15.9Hz,1H),2.94(t,J＝6.8Hz,2H),2.67(d,J＝15.8Hz,1H),2.57(t,J＝9.0Hz,1H),2.22(dt,J＝18.1,5.7Hz,2H),2.14(d,J＝2.0Hz,3H),1.76(q,J＝8.9,7.5Hz,4H),1.53(s,3H),1.26(d,J＝19.5Hz,10H),0.75(s,3H),0.65(d,J＝2.0Hz,3H).13C NMR(126MHz,CDCl3)δ209.53,163.64,157.45,154.29,148.34,142.43,140.61,138.90,128.99,128.99,128.87,128.87,126.76,121.06,63.72,57.08,48.82,44.08,43.97,41.29,40.49,38.87,37.87,35.91,33.79,31.85,31.76,31.69,31.49,24.52,22.94,21.22,20.55,13.40.
化合物9o：白色固体47.5mg，收率90.34％。m.p.203-205℃；HRMS(ESI)m/z calcdfor C34H45N3O2[M+Na]+551.3482,found 551.3415；1H NMR(500MHz,Chloroform-d)δ9.08(d,J＝2.7Hz,1H),7.85(t,J＝6.2Hz,1H),7.33(t,J＝7.5Hz,2H),7.28(d,J＝1.7Hz,2H),7.24(d,J＝7.6Hz,1H),5.80(dd,J＝5.3,2.5Hz,1H),3.75(q,J＝6.6Hz,3H),3.20(d,J＝15.9Hz,1H),2.95(t,J＝6.9Hz,2H),2.66(d,J＝15.8Hz,1H),2.34–2.08(m,2H),1.70(dd,J＝9.8,6.7Hz,4H),1.54(s,3H),1.29(s,3H),1.26(s,8H),1.16(d,J＝6.2Hz,4H),0.79(s,3H),0.77(s,3H).
本发明部分化合物的体外抗肿瘤实验:
分别选用人乳腺癌细胞(MCF-7)、人前列腺癌细胞(PC-3)、人肝癌细胞(HepG2)三种肿瘤细胞。采用CCK8法进行IC50值测试，5-氟尿嘧啶(5-FU)作为阳性对照，每个处理重复三次。以肿瘤细胞PC-3为例，具体方法如下：
将前列腺肿瘤细胞PC-3按3000细胞/孔的密度接种于96孔细胞板中，每孔接种80μL细胞悬液，细胞板置于37℃，5％CO2培养箱，培养24小时。然后实验组每孔加入20μM的化合物工作液20μL，37℃，5％CO2培养箱，避光孵育72小时。结束孵育后，更换新鲜培养基，加入CCK8 10μL/孔，置于37℃，5％CO2培养箱中孵育2小时。在酶标仪上测定450nm处的吸光值，肿瘤细胞抑制率实验结果见表2。细胞抑制率的计算公式如下：
细胞抑制率(％)＝1-[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100
注：A(加药)：具有细胞、CCK8溶液和药物溶液的孔之吸光值；
A(0加药)：具有细胞、CCK8溶液，0.5％DMSO代替药物溶液的孔之吸光值；
A(空白)：具有培养基及CCK8溶液而没有细胞的孔之吸光值。
表2 化合物9a-o对MCF-7、PC-3及HepG2三种肿瘤细胞的抑制活性a
Figure BDA0002304514720000181
a结果以抑制率±标准误表示；
b化合物没有抑制活性。

Claims (8)

1.黄体酮骈吡嗪酰胺化合物，该化合物的结构如式(I)所示：
Figure FDA0003401168460000011
其中：
R1为氟原子、氯原子、甲基或甲氧基取代的苯基或者环己基、苯乙基或非取代苯基。
2.如权利要求1所述的黄体酮骈吡嗪酰胺化合物结构选择以下结构式之一：
Figure FDA0003401168460000012
Figure FDA0003401168460000021
3.权利要求1所述化合物的 在药学上可接受的盐。
4.权利要求1所述化合物的制备方法包括：
1)以DL-二氨基丙酸盐酸盐为原料，依次进行Boc氨基保护、成酰胺、脱Boc反应得到氨基酸分子片段3a-o；
2)以黄体酮为原料，依次通过C-20羰基保护、A环C-4位双甲基引入、C-2氧化，合成含2,3-邻二羰基的中间体6；
3)利用氨基酸片段的二氨基与中间体6的A环邻二羰基构建吡嗪环。
5.制备权利要求1所述化合物的中间体，其结构通式如式(Ⅲ)所示：
Figure FDA0003401168460000022
其中：R1为氟原子、氯原子、甲基或甲氧基取代的苯基或者环己基、苯乙基或非取代苯基。
6.权利要求5所述的中间体结构选择以下结构式之一：
Figure FDA0003401168460000031
7.权利要求5或6所述中间体用于制备权利要求1所述化合物的应用。
8.权利要求1所述黄体酮骈吡嗪酰胺化合物在制备治疗癌症药物中的应用，所述癌症为：乳腺癌、肝癌及前列腺癌。
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