阅读说明：本技术 含异羟肟酸结构片段的18β-甘草次酸类化合物及其应用 (18 β-enoxolone class the compound of the segment containing hydroxamic acid structure and its application ) 是由 赵临襄 刘丹 黄敏 唐煜 谢晓瑞 景永奎 于 2019-09-10 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其制备和应用,还涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其旋光异构体和药学上可接受的盐的药物组合物,及其它们在制备治疗和/或预防各种癌症的药物中的用途。所述的化合物的结构通式如下,其中X、R如权利要求和说明书所述。<Image he="217" wi="700" file="DDA0002197463790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to pharmaceutical technology fields, more particularly to the 18 β-enoxolone class compound of the segment containing hydroxamic acid structure and its preparation and application, further relate to the 18 β-enoxolone class compound of the segment containing hydroxamic acid structure and its pharmaceutical composition of optical isomer and pharmaceutically acceptable salt and its their purposes in preparation treatment and/or the drug for preventing various cancers.The general structure of the compound is as follows, and wherein X, R are as described in claim and specification.)

含异羟肟酸结构片段的18β-甘草次酸类化合物及其应用

技术领域：

本发明属于医药技术领域，具体涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其制备和应用， 还涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其旋光异构体和药学上可接受的盐的药物组合物， 及其它们在制备治疗和/或预防各种癌症的药物中的用途。

背景技术：

18β-甘草次酸是一种五环三萜类天然产物，来源广泛，具有多种药理活性。它的抗肿瘤作用也备受人 们关注，但是其活性不强，难以达到临床使用的要求。为提高18β-甘草次酸的抗肿瘤效果，研究者通过杂 合策略将18β-甘草次酸与其它活性片段(例如：阿魏酸、肉桂酸、罗丹明B等结构)进行拼合，得到了多 种杂合分子，其活性较母体化合物具有一定提高。

异羟肟酸结构能够螯合多种过渡金属，这种螯合能力使其在多种药物及类药性分子中广泛存在。其中， 异羟肟酸类化合物对金属蛋白酶和组蛋白去乙酰化酶的抑制活性被深入研究，并有数个化合物进入临床用 于癌症的治疗。通过拼合原理在不同靶标配体分子或天然产物结构中引入异羟肟酸，有望得到多个作用靶 标的协同抑制效果和更强的抑瘤作用。

本发明人设计并合成了一系列含异羟肟酸结构片段的18β-甘草次酸类似物，经细胞活性筛选，所合成 的化合物具有较好的肿瘤细胞生长抑制活性。

发明内容

：

本发明所解决的技术问题是提供一系列含异羟肟酸结构片段的18β-甘草次酸类似物，还提供了所述含 异羟肟酸结构片段的18β-甘草次酸类似物的在制备预防和/或***药物中的应用。

本发明涉及通式I或II所示的衍生物，及其旋光异构体和药学上可接受的盐：

X为

X左边连接甘草次酸骨架，右边连接异羟肟酸片段；

R为卤素，卤代C1-C4烷基，甲磺酰基，氰基；

m为1-6的整数；

n为1～8的整数。

本发明优选具有如下结构的化合物，及其旋光体和药学上可接受的盐，

其中，

X为

X左边连接甘草次酸骨架，右边连接异羟肟酸片段；

R为碘，三氟甲基，氰基；

m为1-6的整数；

n为1～8的整数。

本发明优选具有如下结构的化合物，及其旋光体和药学上可接受的盐，

其中，

X为

X左边连接甘草次酸骨架，右边连接异羟肟酸片段；

R为碘，三氟甲基，氰基；

m为2-3的整数；

n为3～6的整数。

特别优选的化合物包括：

4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基丁酰胺(实施例1)

5-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基戊酰胺(实施例2)

6-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基己酰胺(实施例3)

7-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基庚酰胺(实施例4)

N¹-羟基-N⁵-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)戊二酰胺(实施例 5)

N¹-羟基-N⁶-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)己二酰胺(实施例 6)

N¹-羟基-N⁷-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)庚二酰胺(实施例 7)

N¹-羟基-N⁸-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)辛二酰胺(实施例 8)

N¹-羟基-N⁵-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)戊二酰胺(实施例 9)

N¹-羟基-N⁶-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)己二酰胺(实施例 10)

N¹-羟基-N⁷-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)庚二酰胺(实施例 11)

N¹-羟基-N⁸-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)辛二酰胺(实施例 12)

4-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基丁酰胺(实施 例13)

5-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基戊酰胺(实施 例14)

6-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基己酰胺(实施 例15)

7-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基庚酰胺(实施 例16)

4-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基丁酰胺(实施 例17)

5-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基戊酰胺(实施 例18)

6-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基己酰胺(实施 例19)

7-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基庚酰胺(实施 例20)

N¹-羟基-N⁵-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)戊二酰胺(实施例 21)

N¹-羟基-N⁶-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)己二酰胺(实施例 22)

N¹-羟基-N⁷-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)庚二酰胺(实施例 23)

N¹-羟基-N⁸-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰胺(实施例 24)

N¹-羟基-N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基)辛二酰胺(实 施例25)

N¹-羟基-N⁸-(4-(3-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基)辛二酰 胺(实施例26)

N¹-羟基-N⁸-(4-(3-(2-氰基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基)辛二酰胺(实 施例27)

N¹-羟基-N⁸-(4-(4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰胺(实施 例28)

N¹-羟基-N⁸-(4-(4-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰胺 (实施例29)

N¹-羟基-N⁸-(4-(4-(2-氰基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰胺(实施 例30)

本发明还包括本发明化合物的前药。依据本发明，前药是通式I或II的衍生物，它们自身可能具有较 弱的活性或甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解和另外的方式)被转 化成相应的生物活性形式。

本发明包括药物组合物，该组合物含有通式I或II的含异羟肟酸结构片段的18β-甘草次酸化合物，及 其旋光体和药物上可接受的盐和药学上可接受的赋型剂。所述药学上可接受的赋型剂是指任何可用于药物 领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用，只要它们不产生其他不 利的作用，例如过敏反应。

本发明的药物组合物可配制成若干种剂型，其中含有药物领域中常用的一些赋型剂，例如，口服制剂 (如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末， 在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。

用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、 崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂 等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮 下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。

通过体外活性筛选，我们发现本发明化合物具有抗肿瘤活性，因此本发明化合物可以用于制备治疗和 /或预防各种癌症的药物，如乳腺癌、肺癌、结肠癌、直肠癌、胃癌、***癌、肝癌、膀胱癌、子宫癌、 胰腺癌、卵巢癌、淋巴癌、卵巢癌、皮肤癌和血液癌。

本发明活性化合物可作为唯一的抗癌药物使用，或者与一种或多种其它抗肿瘤药物联合使用。联合治 疗通过将各个治疗组分同时、顺序或隔开给药来实现。

下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实 施例和制备例的范围并不以任何方式限制本发明的范围。

合成路线一：

Reagent and conditions:a)1,2-dibromoethane or 1,3-dibromopropane,K₂CO₃,dry-DMF,80℃,40min；b) 4-Nitrophenol or Methylparaben,K₂CO₃,dry-DMF,80℃,1～3h；c)Fe,NH₄Cl,EtOH/H₂O,80℃,3h；d)HOBT, EDCI,DIEA,dry-DCM,r.t.,3～24h；e)1MNaOH(aq),NH₂OH(50％in water),MeOH,0℃～r.t.,2h；f)1M KOH(aq),EtOH,reflux,1.5h；g)substituted amine,EDCI,DMAP,dry-DCM,r.t.,6h.

合成路线二：

Reagent and conditions:a)IBX,DMSO,85℃,6h；b)I₂,pyridine,THF,reflux,overnight；c)CuCN,NMP,130 ℃,2h；d)BnBr,K₂CO₃,dry-DMF,r.t.,1h；e)FSO₂CF₂COOCH₃,HMPA,CuI,dry-DMF,70℃,3.5h；f)TiCl₄, dry-CH₂Cl₂,r.t.,2h.

合成路线三：

Reagent and conditions:a)HOBT,EDCI,DIEA,dry-DMF,60℃,1.5h；b)1M NaOH(aq),MeOH,reflux,0.5h； c)HOBT,EDCI,DIEA,dry-DMF,r.t.,6h；d)1,3-dibromopropane,K₂CO₃,dry-DMF,r.t.,1h；e)K₂CO₃, dry-DMF,80℃,2h；e)CF₃COOH,dry-DCM,r.t.,10min.

合成路线四：

Reagent and conditions:a)1-(4-nitrophenyl)piperazine,EDCI,DMAP,CH₂Cl₂,r.t.,2h；b)Fe,NH₄Cl, EtOH/H₂O,80℃,3h；c)HOBT,EDCI,DIEA,DMF,60℃,4h；d)CF₃COOH,dry-CH₂Cl₂,r.t.,10min.

具体实施方式

：

实施例旨在阐述而不是限制本发明的范围。凡基于本发明上述内容所实现的技术均属于本发明的范 围。

化合物的IR用Bruker IR-27G型色谱仪测定，核磁共振谱用Bruker ARX-600核磁共振波谱仪在CDCl₃或DMSO-d₆中以TMS为内标测定，低分辨质谱用Agilent 1100SL型离子阱质谱仪测定，高分辨质谱用 Bruker micro-TOF-Q测定。

实施例1：4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基丁酰胺的制备

步骤A：4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)丁酸甲酯的制备

将0.5g(1.06mmol)GA、0.31g(1.60mmol)EDCI和0.20g(1.60mmol)DMAP溶于20mL二氯甲烷， 室温搅拌30min。随后加入0.25g(1.60mmol)4-氨基丁酸甲酯盐酸盐，继续搅拌6h。反应液用水洗，饱 和氯化钠洗，无水硫酸钠干燥。减压浓缩后以环己烷：丙酮(V/V)＝8：1为洗脱剂硅胶柱层析，分离得白色 固体0.38g，收率：63％。¹H NMR(600MHz,DMSO-d₆)δ7.60(1H,t,J＝5.4Hz),5.48(1H,s),4.30(1H,d,J ＝4.8Hz),3.58(3H,s),3.17～2.97(3H,m),2.60～2.58(1H,m),2.35～2.26(3H,m),2.13～2.00(2H,m),1.93～1.85 (1H,m),1.84～1.78(1H,m),1.78～1.71(1H,m),1.71～1.57(4H,m),1.57～1.46(2H,m),1.46～1.37(2H,m),1.35 (3H,s),1.32～1.21(3H,m),1.19～1.12(1H,m),1.03(6H,s),1.01(3H,s),0.97～0.93(2H,m),0.91(3H,s),0.72 (3H,s),0.71～0.70(1H,m),0.69(3H,s).LC-MS:568.2[M-H]^-.

步骤B:4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基丁酰胺的制备

将0.3g(0.53mmol)4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)丁酸甲酯溶于15mL甲 醇，在0℃下依次滴加3mL氢氧化钠溶液(1mol/L)和3mL羟胺水溶液(50％)，搅拌15min。随后将反应 液转移至室温，继续搅拌2h。减压蒸除溶剂，加入15mL水，用盐酸水溶液(1mol/L)调节pH至7左右。 搅拌15min，抽滤，水洗，得白色固体0.18g，收率：60％。Mp:200-203℃.IR(KBr):3420.1,2927.5,2868.3, 1632.8,1532.8,1491.6,1453.8,1386.5,1365.4,1329.6,1265.3,1174.0,1089.3,1041.1,966.9.¹H NMR(600 MHz,DMSO-d₆)δ10.37(1H,s),8.67(1H,s),7.60(1H,t,J＝5.4Hz),5.48(1H,s),4.30(1H,d,J＝4.8Hz),3.12～2.99(3H,m),2.60～2.58(1H,m),2.32(1H,s),2.13～2.01(2H,m),1.97～1.91(2H,m),1.91～1.85(1H,m), 1.82～1.69(2H,m),1.69～1.56(4H,m),1.56～1.46(2H,m),1.44～1.36(2H,m),1.35(3H,s),1.32～1.22(3H,m), 1.16～1.12(2H,m),1.03(6H,s),1.01(3H,s),0.97～0.93(2H,m),0.91(3H,s),0.72(3H,s),0.71～0.70(1H,m), 0.69(3H,s).¹³CNMR(150MHz,DMSO-d₆)δ199.6,175.5,170.2,169.4,127.9,77.0,61.6,54.6,48.2,45.3,43.4,43.3,41.2,40.5,39.2,39.0,38.9,37.8,37.1,32.6,31.8,30.9,30.5,29.1,28.9,28.6,27.4,26.5,26.4,26.2, 23.5,18.8,17.6,16.7,16.5.LC-MS:568.9[M-H]^-.HRMS m/zcalcd for C₃₄H₅₅N₂O₅ ⁺[M+H]⁺571.4105,found 571.4109.

实施例2：5-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基戊酰胺的制备

按照实施例1的制备方法，用原料5-氨基戊酸甲酯盐酸盐替代实施例1中的原料4-氨基丁酸甲酯盐酸 盐，制备标题化合物。Mp:156-160℃.IR(KBr):3420.7,2927.8,2867.5,1631.9,1532.4,1455.2,1386.5,1365.5, 1263.3,1173.2,1040.1,998.2.¹H NMR(600MHz,DMSO-d₆)δ10.33(1H,s),8.64(1H,s),7.56(1H,t,J＝5.4 Hz),5.48(1H,s),4.31(1H,s),3.11～2.95(3H,m),2.59(1H,d,J＝13.2Hz),2.31(1H,s),2.12～2.01(2H,m), 1.98～1.92(2H,m),1.92～1.87(1H,m),1.83～1.69(2H,m),1.69～1.55(2H,m),1.55～1.43(4H,m),1.43～1.36(4H, m),1.34(3H,s),1.31～1.22(4H,m),1.16～1.11(1H,m),1.03(6H,s),1.00(3H,s),0.97～0.92(2H,m),0.91(3H, s),0.72(3H,s),0.71～0.70(1H,m),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,175.3,170.3,169.5, 127.9,77.0,61.6,54.6,48.2,45.3,43.4,43.3,41.2,39.2,39.0,38.7,37.8,37.1,32.6,32.4,31.8,30.9,29.4,29.2,28.9,28.6,27.4,26.5,26.4,23.5,23.0,18.8,17.6,16.7,16.5.LC-MS:583.0[M-H]^-.HRMSm/z calcd for C₃₅H₅₅N₂O₅ ^-[M-H]^-583.4116,found 583.4100.

实施例3：6-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基己酰胺的制备

按照实施例1的制备方法，用原料6-氨基己酸甲酯盐酸盐替代实施例1中的原料4-氨基丁酸甲酯盐酸 盐，制备标题化合物。Mp:153-156℃.IR(KBr):3419.4,2929.0,2866.1,1645.9,1535.6,1455.7,1386.7,1364.8, 1261.0,1207.7,1187.0,1173.6,1042.8,996.3.¹H NMR(600MHz,DMSO-d₆)δ10.31(1H,s),8.64(1H,s),7.53 (1H,t,J＝5.4Hz),5.48(1H,s),4.30(1H,d,J＝4.8Hz),3.15～2.96(3H,m),2.59(1H,d,J＝13.2Hz),2.32(1H, s),2.11～2.02(2H,m),1.95～1.90(2H,m),1.90～1.86(1H,m),1.83～1.70(2H,m),1.68～1.56(2H,m),1.54～1.44 (4H,m),1.44～1.36(4H,m),1.34(3H,s),1.31～1.19(6H,m),1.17～1.11(1H,m),1.03(6H,s),1.00(3H,s), 0.97～0.93(2H,m),0.91(3H,s),0.72(3H,s),0.71～0.70(1H,m),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ 199.6,175.3,170.3,169.5,127.9,77.0,61.6,54.6,48.2,45.3,43.4,43.3,41.2,40.5,39.2,39.0,38.9,37.8,37.1, 32.7,32.6,31.8,30.9,29.5,29.1,28.9,28.6,27.4,26.5,26.4,25.4,23.4,18.8,17.6,16.6,16.5.LC-MS:597.0 [M-H]^-.HRMS m/z calcd for C₃₆H₅₇N₂O₅ ^-[M-H]^-597.4273,found 597.4278.

实施例4：7-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氨基)-N-羟基庚酰胺的制备

按照实施例1的制备方法，用原料7-氨基庚酸乙酯盐酸盐替代实施例1中的原料4-氨基丁酸甲酯盐酸 盐，制备标题化合物。Mp:135-140℃.IR(KBr):3396.5,2928.8,2864.2,1645.4,1534.2,1455.8,1386.8,1365.0, 1260.4,1173.9,1046.1,995.5.¹H NMR(600MHz,DMSO-d₆)δ10.31(1H,s),8.64(1H,s),7.52(1H,t,J＝5.4 Hz),5.48(1H,s),4.30(1H,s),3.14～2.96(3H,m),2.59(1H,d,J＝13.2Hz),2.31(1H,s),2.12～2.00(2H,m), 1.95～1.87(3H,m),1.83～1.70(2H,m),1.68～1.53(2H,m),1.56～1.43(4H,m),1.43～1.36(4H,m),1.34(3H,s), 1.31～1.18(8H,m),1.18～1.11(1H,m),1.03(6H,s),1.00(3H,s),0.97～0.92(2H,m),0.91(3H,s),0.72(3H,s), 0.71～0.70(1H,m),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,175.3,170.2,169.5,127.9,77.0,61.6, 54.5,48.2,45.3,43.4,43.3,41.2,40.5,39.2,39.0,38.9,37.8,37.1,32.7,32.6,31.8,30.9,29.7,29.1,28.9,28.8,28.6,27.4,26.6,26.5,26.4,25.6,23.4,18.8,17.6,16.6,16.5.LC-MS:611.0[M-H]^-.HRMSm/z calcd for C₃₇H₅₉N₂O₅ ^-[M-H]^-611.4429,found 611.4428.

实施例5：N¹-羟基-N⁵-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)戊二酰 胺的制备

步骤A：3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-溴)乙酯的制备

将3.0g(6.4mmol)GA溶于30mL干燥的DMF，加入2.65g(19.2mmol)K₂CO₃，室温搅拌30min。 随后向反应液中滴加2.7mL(32.0mmol)1,2-二溴乙烷，并将反应液转移至80℃搅拌40min。待反应液冷 却至室温，将反应液倒入100mL水中，用二氯甲烷萃取，水洗，饱和氯化钠洗，无水硫酸钠干燥。减压 蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝6：1为洗脱剂硅胶柱层析，分离得白色固体2.69g，收率：73％。 ¹H NMR(600MHz,DMSO-d₆)δ5.54(1H,s),4.53～4.29(2H,m),4.01～3.99(1H,m),3.80～3.66(2H,m), 3.09～2.97(1H,m),2.57(1H,d,J＝13.2Hz),2.33(1H,s),2.17～2.04(2H,m),1.89～1.81(1H,m),1.81～1.70(3H, m),1.70～1.60(1H,m),1.58～1.46(3H,m),1.46～1.38(3H,m),1.36(3H,s),1.35～1.22(3H,m),1.20～1.15(1H, m),1.14(3H,s),1.04(3H,s),1.03(3H,s),0.98～0.95(1H,m),0.91(3H,s),0.77(3H,s),0.73～0.70(1H,m),0.69 (3H,s).LC-MS:599.4[M+Na]⁺.

步骤B：3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-硝基苯氧基))乙酯的制备

将0.90g(6.5mmol)4-硝基苯酚溶于30mL干燥的DMF，加入1.78g(12.9mmol)K₂CO₃，于80℃搅 拌30min。随后向反应液中滴加10mL DMF溶解的3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-溴) 乙酯(2.5g,4.3mmol)，继续搅拌3h。待反应液冷却至室温，将反应液倒入100mL水中，搅拌15min，抽 滤，水洗，干燥。以石油醚：乙酸乙酯(V/V)＝4：1为洗脱剂硅胶柱层析，分离得白色固体3.22g，收率： 78％。¹H NMR(600MHz,DMSO-d₆)δ8.18(2H,d,J＝9.0Hz),7.17(2H,d,J＝9.0Hz),5.34(1H,s),4.45～4.36 (4H,m),4.29(1H,d,J＝5.4Hz),3.04～2.96(1H,m),2.57(1H,d,J＝13.2Hz),2.29(1H,s),2.11～1.95(2H,m),1.85～1.77(1H,m),1.75～1.66(3H,m),1.66～1.57(1H,m),1.57～1.45(2H,m),1.45～1.33(5H,m),1.31(3H,s), 1.30～1.19(3H,m),1.15～1.11(1H,m),1.10(3H,s),1.01(3H,s),0.99(3H,s),0.96～0.94(1H,m),0.90(3H,s), 0.69(3H,s),0.68(3H,s).LC-MS:658.4[M+Na]⁺.

步骤C：3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-氨基苯氧基))乙酯的制备

将2.1g(39.3mmol)NH₄Cl和2.2g(39.3mmol)还原铁粉置于50mL茄形瓶，加入10mL水，于80℃ 搅拌30min。向上述溶液中滴入30mL乙醇溶解的3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4- 硝基苯氧基))乙酯溶液(2.5g,3.93mmol)，继续搅拌3h。将反应液趁热过滤除去铁粉，用乙酸乙酯洗，随 后蒸干溶剂。用二氯甲烷溶解，水洗，饱和氯化钠洗，无水硫酸钠干燥。减压蒸干溶剂，得白色固体2.1g， 收率：88％。¹H NMR(600MHz,DMSO-d₆)δ6.66(2H,d,J＝9.0Hz),6.48(2H,d,J＝9.0Hz),5.50(1H,s),4.60 (2H,s),4.43～4.24(3H,m),4.08～3.99(2H,m),3.08～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s), 2.13～2.02(2H,m),1.86～1.80(1H,m),1.77～1.69(3H,m),1.69～1.60(1H,m),1.57～1.46(2H,m),1.45～1.36(4H, m),1.35(3H,s),1.34～1.29(2H,m),1.28～1.19(2H,m),1.16～1.12(1H,m),1.11(3H,s),1.03(3H,s),1.02(3H, s),0.96～0.94(1H,m),0.91(3H,s),0.69(6H,s).LC-MS:606.5[M+H]⁺.

步骤D：N¹-羟基-N⁵-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)戊二酰胺 的制备

将0.09mL(0.75mmol)戊二酸单甲酯、0.10g(0.75mmol)HOBT和0.14g(0.75mmol)EDCI溶于20 mL二氯甲烷，并置于0℃搅拌30min。随后加入0.3g(0.5mmol)3β-羟基-11-氧代-18β-齐墩果烷-12-二烯 -30-羧酸(2-(4-氨基苯氧基))乙酯和0.13mL(0.75mmol)DIEA，室温搅拌12h。反应液用水洗，饱和氯化钠 洗，无水硫酸钠干燥。减压蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝6：1为洗脱剂硅胶柱层析，分离得白色 固体0.24g。将上述白色固体中间体替换实施例1中步骤B的4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30- 甲酰氨基)丁酸甲酯，制备标题化合物0.12g，两步收率为33％。Mp:111-115℃.IR(KBr):3305.3,2951.4,2928.5,2868.5,1729.1,1657.5,1542.6,1511.0,1457.5,1386.7,1364.8,1243.8,1212.2,1170.3,1084.3,1040.4, 994.9,830.5,799.5.¹H NMR(600MHz,DMSO-d₆)δ10.37(1H,s),9.74(1H,s),8.68(1H,s),7.47(2H,d,J＝ 9.0Hz),6.87(2H,d,J＝9.0Hz),5.49(1H,s),4.46～4.31(2H,m),4.30(1H,d,J＝4.8Hz),4.18～4.11(2H,m), 3.06～2.97(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.29～2.22(2H,m),2.12～2.02(2H,m),2.02～1.97(2H,m),1.87～1.67(7H,m),1.67～1.59(1H,m),1.59～1.45(2H,m),1.45～1.36(3H,m),1.34(3H,s),1.32～1.18(4H, m),1.15～1.12(1H,m),1.11(3H,s),1.03(3H,s),1.02(3H,s),0.98～0.94(1H,m),0.91(3H,s),0.69(3H,s),0.68 (3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.3,170.6,169.8,169.2,154.3,133.3,127.9,120.9,115.0, 77.0,66.5,63.0,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,39.2,38.9,37.7,37.1,35.9,32.5,32.1,31.9,30.8, 28.7,28.6,28.1,27.4,26.2,23.4,21.7,18.7,17.6,16.7,16.5.LC-MS:733.5[M-H]^-.HRMS m/z calcd for C₄₃H₆₁N₂O₈ ^-[M-H]^-733.4433,found 733.4439.

实施例6：N¹-羟基-N⁶-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)己二酰 胺的制备

按照实施例5的制备方法，用原料己二酸单甲酯替代实施例5中的原料戊二酸单甲酯，制备标题化合 物。Mp:122-124℃.IR(KBr):3425.5,2951.3,2928.2,2867.9,1728.6,1614.4,1511.0,1492.4,1456.5,1442.8, 1400.9,1386.3,1366.1,1212.0,1172.5,1085.7,1049.0,1006.5,831.3,799.1.¹H NMR(600MHz,DMSO-d₆)δ 10.40(1H,s),9.79(1H,s),8.67(1H,s),7.48(2H,d,J＝9.0Hz),6.87(2H,d,J＝9.0Hz),5.49(1H,s),4.47～4.39(1H,m),4.39～4.28(2H,m),4.19～4.11(2H,m),3.05～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s), 2.29～2.22(2H,m),2.12～2.02(2H,m),2.00～1.95(2H,m),1.86～1.80(1H,m),1.76～1.69(3H,m),1.69～1.59(1H, m),1.59～1.46(6H,m),1.46～1.36(4H,m),1.34(3H,s),1.32～1.19(4H,m),1.17～1.12(1H,m),1.11(3H,s),1.03 (3H,s),1.02(3H,s),0.97～0.94(1H,m),0.91(3H,s),0.69(3H,s),0.68(3H,s).¹³C NMR(150MHz,DMSO-d₆) δ199.6,176.3,171.0,169.9,169.4,154.3,133.5,128.1,121.1,115.3,77.4,70.1,66.9,63.1,61.5,54.8,54.5,50.0, 48.4,48.3,45.3,44.1,43.3,41.9,41.8,41.6,40.9,40.4,39.2,38.9,37.7,37.1,36.5,33.9,32.6,32.5,31.9,30.8, 28.6,28.6,28.1,27.4,26.8,26.5,26.2,25.3,24.6,23.4,18.7,17.6,16.7,16.5.LC-MS:771.4[M+Na]⁺.HRMS m/zcalcd for C₄₄H₆₅N₂O₈ ⁺[M+H]⁺749.4735,found 749.4746.

实施例7：N¹-羟基-N⁷-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)庚二酰 胺的制备

按照实施例5的制备方法，用原料庚二酸单乙酯替代实施例5中的原料戊二酸单甲酯，制备标题化合 物。Mp:140-142℃.IR(KBr):3423.0,2929.3,2866.8,1728.7,1631.7,1544.4,1510.9,1457.3,1386.2,1365.5, 1212.2,1172.3,1086.3,1047.4,1006.1,831.7,798.9.¹H NMR(600MHz,DMSO-d₆)δ10.35(1H,s),9.75(1H, s),8.66(1H,s),7.48(2H,d,J＝9.0Hz),6.87(2H,d,J＝9.0Hz),5.48(1H,s),4.47～4.38(1H,m),4.38～4.28(2H, m),4.18～4.12(2H,m),3.06～3.00(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.27～2.22(2H,m),2.12～2.01 (2H,m),1.98～1.91(2H,m),1.86～1.80(1H,m),1.77～1.68(3H,m),1.68～1.60(1H,m),1.60～1.48(6H,m), 1.44～1.35(4H,m),1.34(3H,s),1.32～1.20(6H,m),1.16～1.12(1H,m),1.11(3H,s),1.03(3H,s),1.02(3H,s), 0.98～0.95(1H,m),0.91(3H,s),0.69(3H,s),0.68(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.7,176.1,170.8, 169.8,169.5,154.2,133.8,127.8,121.1,115.3,77.4,70.4,66.6,63.4,61.8,54.8,48.3,45.3,44.1,43.3,40.9,40.5, 39.2,38.9,37.7,37.1,36.6,32.6,32.5,31.9,30.8,28.7,28.7,28.6,28.1,27.4,26.5,26.2,25.4,25.4,23.4,18.8, 17.6,16.7,16.5.LC-MS:785.4[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ⁺[M+H]⁺763.4892,found 763.4889.

实施例8：N¹-羟基-N⁸-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯基)辛二酰 胺的制备

按照实施例5的制备方法，用原料辛二酸单甲酯替代实施例5中的原料戊二酸单甲酯，制备标题化合 物。Mp:110-113℃.IR(KBr):3426.3,2928.8,2865.4,1729.3,1655.9,1542.7,1511.0,1459.1,1386.3,1365.5, 1243.6,1211.9,1171.6,1085.8,1047.5,997.4,830.7,799.1.¹H NMR(600MHz,DMSO-d₆)δ10.35(1H,s),9.74 (1H,s),8.67(1H,s),7.47(2H,d,J＝9.0Hz),6.87(2H,d,J＝9.0Hz),5.48(1H,s),4.47～4.39(1H,m), 4.39～4.27(2H,m),4.17～4.13(2H,m),3.06～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.27～2.21(2H, m),2.12～2.00(2H,m),1.96～1.90(2H,m),1.86～1.80(1H,m),1.76～1.68(3H,m),1.68～1.59(1H,m),1.59～1.45 (6H,m),1.45～1.36(4H,m),1.34(3H,s),1.30～1.21(8H,m),1.16～1.12(1H,m),1.11(3H,s),1.03(3H,s),1.01 (3H,s),0.98～0.94(1H,m),0.91(3H,s),0.69(3H,s),0.68(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.7, 176.6,171.5,170.2,154.1,133.4,128.0,121.0,115.3,77.4,70.4,66.7,63.4,61.7,55.0,48.3,45.3,44.1,43.3, 40.9,40.5,39.2,38.9,37.7,37.1,36.7,32.7,32.5,31.9,30.8,28.9,28.9,28.7,28.6,28.1,27.4,26.5,26.2,25.6, 25.5,23.4,18.8,17.6,16.7,16.5.LC-MS:799.4[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048, found 777.5048.

实施9：N¹-羟基-N⁵-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)戊二酰胺 的制备

按照实施例5的制备方法，用原料1,3-二溴丙烷替代实施例5中的1,2-二溴乙烷，制备标题化合物。 Mp:112-116℃.IR(KBr):3425.9,2924.8,2854.2,1726.2,1653.3,1614.9,1543.7,1511.5,1492.3,1463.0, 1386.9,1366.4,1240.0,1213.0,1172.0,1084.1,1048.6,1008.1,830.6,799.1.¹H NMR(600MHz,DMSO-d₆)δ 10.37(1H,s),9.72(1H,s),8.68(1H,s),7.47(2H,d,J＝8.4Hz),6.93～6.78(2H,m),5.42(1H,s),4.48～4.26(2H,m),4.26～4.11(2H,m),4.05～3.97(1H,m),3.07～2.96(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.29～2.23 (2H,m),2.15～1.93(6H,m),1.88～1.68(6H,m),1.68～1.56(1H,m),1.56～1.45(2H,m),1.45～1.36(3H,m),1.35 (3H,s),1.33～1.21(4H,m),1.21～1.17(2H,m),1.10(3H,s),1.03(6H,s)0.97～0.94(1H,m),0.91(3H,s),0.71 (3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.2,170.6,169.8,169.2,154.6,133.1,127.9,121.0,114.9,77.0,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.0,32.5,32.1, 32.0,30.7,28.7,28.6,28.2,27.4,26.5,26.2,23.4,21.7,18.8,17.6,16.7,16.5.LC-MS:747.7[M-H]^-.HRMS m/z calcd for C₄₄H₆₃N₂O₈ ^-[M-H]^-747.4590,found 747.4591.

实施10：N¹-羟基-N⁶-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)己二酰 胺的制备

按照实施例5的制备方法，用原料1,3-二溴丙烷替代实施例5中的1,2-二溴乙烷，用原料己二酸单甲 酯替代实施例5中的原料戊二酸单甲酯，制备标题化合物。Mp:115-119℃.IR(KBr):3425.2,2953.0,2868.3, 1727.2,1656.6,1542.8,1511.2,1462.9,1386.8,1365.0,1240.6,1212.8,1171.4,1085.5,1047.8,995.2,831.2, 799.6.¹H NMR(600MHz,DMSO-d₆)δ10.37(1H,s),9.73(1H,s),8.67(1H,s),7.47(2H,d,J＝9.0Hz),6.85 (2H,d,J＝9.0Hz),5.42(1H,s),4.31(1H,d,J＝4.8Hz),4.25～4.15(2H,m),4.04～3.97(2H,m),3.05～2.98(1H, m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.28～2.22(2H,m),2.12～1.93(6H,m),1.87～1.79(1H,m),1.76～1.68 (3H,m),1.68～1.60(1H,m),1.57～1.48(6H,m),1.45～1.36(4H,m),1.35(3H,s),1.30～1.21(2H,m),1.21～1.11 (3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s),0.98～0.95(1H,m),0.91(3H,s),0.71(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.2,171.0,169.8,169.4,154.6,133.2,127.8,120.9,114.8,77.0,70.2, 64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.5,32.6,32.0,30.7,28.7,28.6, 28.2,27.4,26.8,26.5,26.2,25.4,23.4,18.8,17.6,16.7,16.5.LC-MS:785.6[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ⁺[M+H]⁺763.4892,found 763.4889.

实施例11：N¹-羟基-N⁷-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)庚二酰 胺的制备

按照实施例5的制备方法，用原料1,3-二溴丙烷替代实施例5中的1,2-二溴乙烷，用原料庚二酸单乙 酯替代实施例5中的原料戊二酸单甲酯，制备标题化合物。Mp:162-165℃.IR(KBr):3415.8,2951.0,2929.3, 2867.6,1726.3,1652.2,1544.3,1511.3,1492.4,1463.0,1386.9,1366.0,1242.0,1213.2,1172.2,1085.9,1048.5, 1007.3,831.2,799.3.¹H NMR(600MHz,DMSO-d₆)δ10.34(1H,s),9.76(1H,s),8.66(1H,s),7.47(2H,d,J＝8.4Hz),6.84(2H,d,J＝8.4Hz),5.42(1H,s),4.32～4.31(1H,m),4.25～4.16(2H,m),4.03～3.98(2H,m), 3.05～2.97(1H,m),2.58(1H,d,J＝13.2Hz),2.36(1H,s),2.29～2.21(2H,m),2.13～1.97(4H,m),1.97～1.91(2H, m),1.86～1.79(1H,m),1.76～1.68(3H,m),1.68～1.59(1H,m),1.59～1.46(6H,m),1.46～1.36(4H,m),1.35(3H, s),1.30～1.22(4H,m),1.22～1.11(3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s),0.97～0.95(1H,m),0.91(3H,s), 0.71(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.7,176.5,172.0,169.8,169.5,154.5,133.5, 128.1,121.1,115.0,77.1,70.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1, 36.6,32.6,32.5,32.0,30.7,28.7,28.7,28.6,28.2,27.4,26.5,26.2,25.4,23.4,18.8,17.6,16.7,16.5.LC-MS: 799.4[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048,found 777.5051.

实施例12：N¹-羟基-N⁸-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯基)辛二 酰胺的制备

按照实施例5的制备方法，用原料1,3-二溴丙烷替代实施例5中的1,2-二溴乙烷，用原料辛二酸单甲 酯替代实施例5中的原料戊二酸单甲酯，制备标题化合物。Mp:186-190℃.IR(KBr):3411.3,2928.1,2867.8, 1725.4,1633.5,1511.0,1491.4,1468.8,1442.5,1398.8,1367.2,1212.3,1172.0,1085.6,1050.0,1001.0,831.3, 798.6.¹H NMR(600MHz,DMSO-d₆)δ10.37(1H,s),9.77(1H,s),8.65(1H,s),7.48(2H,d,J＝8.4Hz),6.84 (2H,d,J＝8.4Hz),5.42(1H,s),4.40～4.26(1H,m),4.26～4.15(2H,m),4.04～3.97(2H,m),3.06～2.97(1H,m), 2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.28～2.21(2H,m),2.12～1.97(4H,m),1.97～1.90(2H,m),1.85～1.79(1H, m),1.78～1.68(3H,m),1.68～1.59(1H,m),1.59～1.45(6H,m),1.45～1.35(4H,m),1.34(3H,s),1.33～1.21(6H, m),1.21～1.11(3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s),0.96～0.93(1H,m),0.91(3H,s),0.71(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.4,176.5,171.1,169.8,169.5,155.1,133.2,127.8,121.1,115.0, 77.2,70.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.7,32.7,32.5,32.0, 30.7,28.9,28.7,28.6,28.2,27.4,26.5,26.2,25.6,25.5,23.4,18.8,17.6,16.7,16.5.LC-MS:813.4[M+Na]⁺. HRMS m/zcalcd for C₄₇H₇₁N₂O₈ ⁺[M+H]⁺791.5205,found 791.5215.

实施例13：4-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基 丁酰胺的制备

步骤A：4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酸甲酯的制备

按照实施例5步骤B的制备方法，将原料对羟基苯甲酸甲酯替换成对硝基苯酚，制备标题化合物。¹H NMR(600MHz,DMSO-d₆)δ7.88(2H,d,J＝9.0Hz),7.06(2H,d,J＝9.0Hz),5.41(1H,s),4.51～4.36(2H,m), 4.33～4.28(3H,m),3.80(3H,s),3.06～2.97(1H,m),2.57(1H,d,J＝13.2Hz),2.30(1H,s),2.11～1.96(2H,m), 1.85～1.78(1H,m),1.75～1.66(3H,m),1.66～1.59(1H,m),1.57～1.46(2H,m),1.44～1.33(4H,m),1.32(3H,s), 1.31～1.28(2H,m),1.25～1.12(2H,m),1.10(3H,s),1.02(3H,s),1.00(3H,s),0.96～0.93(2H,m),0.91(3H,s), 0.69(3H,s),0.66(3H,s).LC-MS:671.4[M+Na]⁺.

步骤B：3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-羧基苯氧基))乙酯的制备

将1.08g(1.63mmol)4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酸甲酯溶 于20mL乙醇，加入20mL氢氧化钾溶液(1mol/L)，回流搅拌1.5h。待反应液冷却至室温，加入50mL 水，用10％的盐酸溶液调节pH至2～3。搅拌15min，抽滤，水洗，干燥，得白色固体1.03g，收率：78％。 ¹H NMR(600MHz,DMSO-d₆)δ12.62(1H,s),7.85(2H,d,J＝9.0Hz),7.03(2H,d,J＝9.0Hz),5.44(1H,s), 4.52～4.34(2H,m),4.34～4.26(3H,m),3.05～2.99(1H,m),2.57(1H,d,J＝13.2Hz),2.31(1H,s),2.11～1.98(2H, m),1.85～1.78(1H,m),1.75～1.67(3H,m),1.67～1.59(1H,m),1.56～1.47(2H,m),1.44～1.33(4H,m),1.32(3H, s),1.32～1.28(2H,m),1.25～1.20(1H,m),1.15～1.11(1H,m),1.10(3H,s),1.03(3H,s),1.00(3H,s),0.96～0.94 (1H,m),0.91(3H,s),0.69(3H,s),0.68～0.67(1H,m),0.66(3H,s).LC-MS:633.2[M-H]^-.

步骤C：4-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基丁酰 胺的制备

按照实施例5步骤D的制备方法，用原料3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-羧基苯 氧基))乙酯替换实施例5中的原料戊二酸单甲酯，用原料4-氨基丁酸甲酯盐酸盐替换实施例5中的3β-羟基 -11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-氨基苯氧基))乙酯，制备标题化合物。Mp:89-91℃.IR(KBr): 3422.3,2950.5,2929.4,2868.8,1728.4,1631.1,1504.6,1494.0,1455.6,1386.2,1366.4,1255.7,1212.5,1173.0,1086.3,1048.2,1005.7,846.5,798.0,769.4.¹H NMR(600MHz,DMSO-d₆)δ10.37(1H,s),8.69(1H,s),8.33 (1H,t,J＝5.4Hz),7.80(2H,d,J＝8.4Hz),7.00(2H,d,J＝8.4Hz),5.48(1H,s),4.50～4.35(2H,m),4.30(1H,d, J＝5.4Hz),4.29～4.24(2H,m),3.28～3.18(2H,m),3.07～2.97(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s), 2.12～2.02(2H,m),2.02～1.96(2H,m),1.87～1.77(1H,m),1.77～1.68(5H,m),1.68～1.59(1H,m),1.59～1.46(2H, m),1.46～1.36(3H,m),1.34(3H,s),1.29～1.18(5H,m),1.16～1.13(1H,m),1.11(3H,s),1.03(3H,s),1.01(3H, s),0.96～0.93(1H,m),0.91(3H,s),0.69(3H,s),0.67(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.2, 169.8,169.3,166.0,160.8,129.4,127.8,127.5,114.4,77.0,66.5,66.2,62.8,61.6,54.5,48.3,45.3,44.1,43.3, 40.9,40.5,38.9,37.7,32.5,31.9,30.5,29.4,28.7,28.0,27.4,26.2,25.9,24.1,23.4,22.6,18.7,17.6,16.7,16.5, 14.5.LC-MS:757.6[M+Na]⁺.HRMS m/z calcd for C₄₃H₆₃N₂O₈ ⁺[M+H]⁺735.4579,found735.4592.

实施例14：5-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基 戊酰胺的制备

按照实施13的制备方法，用原料5-氨基戊酸甲酯盐酸盐替代实施例13中的原料4-氨基丁酸甲酯盐酸 盐，制备标题化合物。Mp:145-150℃.IR(KBr):3407.5,2949.3,2929.5,2868.9,1728.3,1631.9,1504.9,1457.6, 1386.2,1365.9,1254.1,1212.5,1172.5,1086.0,1047.7,997.2,846.7,768.5.¹H NMR(600MHz,DMSO-d₆)δ 10.38(1H,s),8.67(1H,s),8.33(1H,t,J＝5.4Hz),7.80(2H,d,J＝8.4Hz),7.00(2H,d,J＝8.4Hz),5.48(1H,s),4.50～4.35(2H,m),4.31(1H,d,J＝4.8Hz),4.28～4.24(2H,m),3.26～3.15(2H,m),3.05～2.98(1H,m),2.58(1H, d,J＝13.2Hz),2.32(1H,s),2.14～2.00(2H,m),2.00～1.94(2H,m),1.86～1.77(1H,m),1.77～1.67(3H,m), 1.67～1.60(1H,m),1.54～1.46(6H,m),1.44～1.35(3H,m),1.34(3H,s),1.33～1.17(5H,m),1.17～1.13(1H,m), 1.11(3H,s),1.03(3H,s),1.01(3H,s),0.98～0.95(1H,m),0.91(3H,s),0.69(3H,s),0.67(3H,s).¹³C NMR(150 MHz,DMSO-d₆)δ199.6,176.2,169.9,165.9,160.7,129.4,127.8,127.5,114.4,77.0,70.2,66.5,62.8,61.6,54.5, 48.3,45.3,44.1,43.3,40.9,40.5,39.3,39.2,38.9,37.7,37.1,32.5,31.9,30.8,29.3,28.7,28.6,28.0,27.4,26.5, 26.2,23.4,23.3,18.7,17.6,16.7,16.5.LC-MS:747.3[M-H]^-.HRMS m/z calcd for C₄₄H₆₅N₂O₈ ⁺[M+H]⁺ 749.4735,found749.4757.

实施例15：6-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基 己酰胺的制备

按照实施例13的制备方法，用原料6-氨基己酸甲酯盐酸盐替代实施例13中的原料4-氨基丁酸甲酯盐 酸盐，制备标题化合物。Mp:130-134℃.IR(KBr):3423.9,2929.4,2865.7,1728.7,1632.2,1503.4,1458.9, 1386.5,1365.8,1254.2,1211.8,1172.1,1047.0,999.3,846.7,769.1.¹H NMR(600MHz,DMSO-d₆)δ10.34(1H, s),8.66(1H,s),8.29(1H,t,J＝5.4Hz),7.79(2H,d,J＝8.4Hz),7.00(2H,d,J＝8.4Hz),5.48(1H,s),4.51～4.35(2H,m),4.31(1H,d,J＝4.8Hz),4.29～4.25(1H,m),3.24～3.17(2H,m),3.05～2.97(1H,m),2.58(1H,d,J＝ 13.2Hz),2.32(1H,s),2.13～2.01(2H,m),1.97～1.91(2H,m),1.85～1.79(1H,m),1.76～1.67(3H,m),1.67～1.59 (1H,m),1.56～1.44(6H,m),1.44～1.35(3H,m),1.34(3H,s),1.33～1.20(8H,m),1.15～1.12(1H,m),1.11(3H,s), 1.03(3H,s),1.01(3H,s),0.96～0.93(1H,m),0.91(3H,s),0.69(3H,s),0.67(3H,s).¹³C NMR(150MHz, DMSO-d₆)δ198.5,175.2,168.7,168.4,164.8,159.6,128.3,126.8,126.5,113.3,75.9,65.4,65.1,61.8,60.5,53.4, 47.2,44.2,43.0,42.2,39.8,39.4,38.2,37.9,36.6,36.0,31.6,31.4,30.8,29.7,28.4,27.9,27.6,27.5,27.0,26.3, 25.5,24.3,22.4,17.7,16.5,15.6,15.4.LC-MS:785.6[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ⁺[M+H]⁺ 763.4892,found763.4894.

实施例16：7-(4-(2-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)乙氧基)苯甲酰氨基)-N-羟基 庚酰胺的制备

按照实施例13的制备方法，用原料7-氨基庚酸乙酯盐酸盐替代实施例13中的原料4-氨基丁酸甲酯盐 酸盐，制备标题化合物。Mp:135-138℃.IR(KBr):3422.5,2929.6,2864.7,1728.6,1632.3,1504.2,1459.0, 1386.2,1254.0,1211.9,1172.4,1048.1,998.6,846.4,768.9.¹H NMR(600MHz,DMSO-d₆)δ10.32(1H,s),8.67 (1H,s),8.27(1H,s),7.79(2H,d,J＝8.4Hz),7.00(2H,d,J＝8.4Hz),5.47(1H,s),4.52～4.33(2H,m), 4.33～4.21(2H,m),3.24～3.16(2H,m),3.04～2.97(1H,m),2.58(1H,d,J＝13.2Hz),2.31(1H,s),2.12～2.00(2H, m),1.97～1.90(2H,m),1.87～1.78(1H,m),1.78～1.67(3H,m),1.67～1.59(1H,m),1.55～1.45(6H,m),1.45～1.35 (3H,m),1.34(3H,s),1.32～1.29(2H,m),1.29～1.20(8H,m),1.16～1.13(1H,m),1.11(3H,s),1.03(3H,s),1.01 (3H,s),0.96～0.93(1H,m),0.91(3H,s),0.69(3H,s),0.67(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5, 176.2,169.8,169.6,165.9,160.7,129.4,127.9,127.6,114.4,77.0,66.5,66.2,62.8,61.6,54.5,48.3,45.3,44.1, 43.3,40.9,40.5,39.2,38.9,37.7,37.1,32.7,32.5,31.9,31.8,30.8,29.6,29.4,28.8,28.7,28.6,28.0,27.4,26.7, 26.5,26.2,25.8,25.6,24.1,23.4,22.6,18.7,17.6,16.7,16.5,14.5.LC-MS:799.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048,found 777.5051.

实施例17：4-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基 丁酰胺的制备

按照实施例13的制备方法，用原料1,3-二溴丙烷替代原料1,2-二溴乙烷，制备标题化合物。Mp:130-132 ℃.IR(KBr):3376.2,2928.5,2868.9,1725.7,1652.9,1547.5,1504.6,1466.8,1387.0,1366.4,1311.8,1252.2, 1213.0,1172.7,1085.4,1043.5,994.5,845.0,768.2.¹H NMR(600MHz,DMSO-d₆)δ10.34(1H,s),8.66(1H,s), 8.29(1H,t,J＝5.4Hz),7.79(2H,d,J＝8.4Hz),6.97(2H,d,J＝8.4Hz),5.42(1H,s),4.30(1H,d,J＝5.4Hz), 4.27～4.17(2H,m),4.13～4.07(2H,m),3.24～3.18(2H,m),3.06～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32 (1H,s),2.16～2.03(3H,m),2.03～1.93(3H,m),1.87～1.78(1H,m),1.78～1.67(3H,m),1.67～1.58(1H,m), 1.58～1.44(6H,m),1.46～1.36(3H,m),1.34(3H,s),1.33～1.30(1H,m),1.25～1.11(3H,m),1.10(3H,s),1.03 (3H,s),1.02(3H,s),0.97～0.94(1H,m),0.91(3H,s),0.70(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆) δ199.5,176.2,169.8,169.5,165.9,161.0,129.4,127.8,127.4,114.3,77.0,64.9,61.6,61.4,54.5,48.4,45.3,44.0, 43.3,40.8,40.5,39.3,39.2,38.9,37.8,37.1,32.5,32.0,30.7,29.3,28.7,28.6,28.1,27.4,26.5,26.2,23.4,23.2, 18.8,17.6,16.7,16.5.LC-MS:771.6[M+Na]⁺.HRMS m/z calcd for C₄₄H₆₃N₂O₈ ^-[M-H]^-747.4590,found 747.4593.

实施例18：5-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基 戊酰胺的制备

按照实施例13的制备方法，用原料1,3-二溴丙烷替代原料1,2-二溴乙烷，用原料5-氨基戊酸甲酯盐酸 盐替代实施例13中的原料4-氨基丁酸甲酯盐酸盐，制备标题化合物。Mp:125-129℃.IR(KBr):3377.5, 2929.8,2867.8,1725.7,1651.3,1608.0,1546.8,1504.3,1465.9,1387.1,1364.8,1311.6,1251.5,1212.9,1172.2, 1085.3,1043.6,994.4,845.0,768.1.¹H NMR(600MHz,DMSO-d₆)δ10.39(1H,s),8.70(1H,s),8.33(1H,t,J＝5.4Hz),7.80(2H,d,J＝8.4Hz),6.97(2H,d,J＝8.4Hz),5.42(1H,s),4.31(1H,d,J＝4.8Hz),4.27～4.17(2H, m),4.14～4.08(2H,m),3.26～3.18(2H,m),3.05～2.97(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.14～2.03 (3H,m),2.03～1.96(3H,m),1.87～1.78(1H,m),1.78～1.68(6H,m),1.68～1.58(1H,m),1.58～1.46(2H,m), 1.46～1.36(3H,m),1.34(3H,s),1.33～1.29(2H,m),1.24～1.11(3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s), 0.98～0.92(3H,m),0.91(3H,s),0.70(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.2,169.8, 169.4,166.1,161.1,129.4,127.9,127.3,114.4,77.0,64.9,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.3, 39.2,38.9,37.8,37.1,32.5,32.0,30.7,30.5,28.7,28.6,28.5,28.1,27.4,26.5,26.2,25.9,23.4,18.8,17.6,16.7,16.5.LC-MS:785.6[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ^-[M+H]⁺763.4892,found763.4903.

实施例19：6-(4-(3-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-甲酰氧基)丙氧基)苯甲酰氨基)-N-羟基 己酰胺的制备

按照实施例13的制备方法，用原料1,3-二溴丙烷替代原料1,2-二溴乙烷，用原料6-氨基己酸甲酯盐酸 盐替代实施例13中的原料4-氨基丁酸甲酯盐酸盐，制备标题化合物。Mp:107-110℃.IR(KBr):3411.9, 2929.3,2865.9,1726.8,1632.8,1549.0,1504.3,1464.0,1386.4,1366.2,1310.9,1252.5,1212.4,1172.7,1085.3, 1047.8,997.3,845.2,769.7.¹H NMR(600MHz,DMSO-d₆)δ10.34(1H,s),8.65(1H,s),8.27(1H,t,J＝5.4Hz), 7.79(2H,d,J＝9.0Hz),6.97(2H,d,J＝9.0Hz),5.42(1H,s),4.31(1H,d,J＝4.8Hz),4.26～4.18(2H,m), 4.15～4.07(2H,m),3.25～3.14(2H,m),3.05～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.12～2.02(2H, m),2.02～1.97(1H,m),1.97～1.91(2H,m),1.86～1.79(1H,m),1.77～1.69(3H,m),1.68～1.59(1H,m),1.57～1.45 (6H,m),1.45～1.36(3H,m),1.34(3H,s),1.30～1.21(6H,m),1.21～1.11(3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s),0.97～0.94(1H,m),0.91(3H,s),0.70(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5, 176.3,169.8,169.5,165.9,161.0,129.4,127.9,127.4,114.3,77.0,66.2,64.9,61.6,61.4,54.5,48.4,45.3,44.0, 43.3,40.8,39.2,38.9,37.8,37.1,32.7,32.0,30.7,29.5,28.7,28.6,28.1,27.4,26.6,26.2,25.8,25.4,24.1,23.4, 22.6,18.8,17.6,16.7,16.5.LC-MS:799.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₇N₂O₈ ^-[M-H]^-775.4903,found775.4899.

实施例20：N¹-羟基-N⁵-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)戊二酰 胺的制备

按照实施例13的制备方法，用原料1,3-二溴丙烷替代原料1,2-二溴乙烷，用原料7-氨基庚酸乙酯盐酸 盐替代实施例13中的原料4-氨基丁酸甲酯盐酸盐，制备标题化合物。Mp:85-89℃.IR(KBr):3408.7,2929.2, 2862.9,1726.9,1634.6,1608.3,1547.7,1504.1,1464.2,1386.6,1366.0,1252.0,1212.4,1173.1,1047.7,996.6, 845.3,787.7.¹H NMR(600MHz,DMSO-d₆)δ10.33(1H,s),8.65(1H,s),8.26(1H,t,J＝5.4Hz),7.79(2H,d,J ＝8.4Hz),6.97(2H,d,J＝8.4Hz),5.42(1H,s),4.31(1H,d,J＝5.4Hz),4.26～4.17(2H,m),4.14～4.07(2H,m), 3.24～3.17(2H,m),3.06～2.98(1H,m),2.58(1H,d,J＝13.2Hz),2.32(1H,s),2.13～2.02(2H,m),2.02～1.96(1H, m),1.96～1.91(2H,m),1.86～1.79(1H,m),1.76～1.68(3H,m),1.68～1.59(1H,m),1.57～1.44(6H,m),1.44～1.36 (3H,m),1.34(3H,s),1.29～1.21(8H,m),1.20～1.11(3H,m),1.10(3H,s),1.03(3H,s),1.02(3H,s),0.97～0.94 (1H,m),0.91(3H,s),0.70(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.5,176.3,169.8,169.5, 165.9,161.0,129.4,127.9,127.5,114.3,77.0,66.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2, 37.8,37.1,32.7,32.0,30.7,29.6,29.4,28.8,28.7,28.6,28.1,27.4,26.7,25.8,25.6,24.1,23.4,22.6,18.8,17.6, 16.7,16.5.LC-MS:813.6[M+Na]⁺.HRMS m/z calcd for C₄₇H₇₁N₂O₈ ⁺[M+H]⁺791.5211,found791.5205.

实施例21：N¹-羟基-N⁵-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)戊二酰 胺的制备

步骤A：1-(4-硝基苯基)-4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪的制备

按照实施例1步骤A的制备方法，用原料4-硝基苯基哌嗪替换原料4-氨基丁酸甲酯盐酸盐，制备标题 化合物。¹H NMR(600MHz,DMSO-d₆)δ8.09(2H,d,J＝9.6Hz),7.00(2H,d,J＝9.6Hz),5.50(1H,s), 4.35～4.20(1H,m),3.81～3.66(4H,m),3.56～3.42(4H,m),3.08～2.99(1H,m),2.57(1H,d,J＝13.2Hz),2.33 (1H,s),2.24～2.17(1H,m),2.17～2.08(1H,m),2.03～1.96(1H,m),1.91～1.86(1H,m),1.80～1.60(3H,m), 1.57～1.36(6H,m),1.35(3H,s),1.34～1.28(2H,m),1.19(3H,s),1.17～1.12(1H,m),1.02(6H,s),0.98～0.93(2H,m),0.91(3H,s),0.74(3H,s),0.71～0.70(1H,m),0.69(3H,s).LC-MS:682.5[M+Na]⁺.

步骤B：1-(4-氨基苯基)-4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪的制备

按照实施例5步骤C的制备方法，用原料1-(4-硝基苯基)-4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30- 酰基)哌嗪替换原料3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-硝基苯氧基))乙酯，制备标题化合 物。¹H NMR(600MHz,DMSO-d₆)δ6.78(2H,d,J＝8.4Hz),6.68(2H,d,J＝9.6Hz),5.49(1H,s),4.35(1H,d, J＝4.8Hz),3.72～3.63(4H,m),3.07～2.97(1H,m),2.97～2.87(4H,m),2.57(1H,d,J＝13.2Hz),2.33(1H,s),2.24～2.17(1H,m),2.17～2.08(1H,m),2.02～1.95(1H,m),1.90～1.84(1H,m),1.78～1.60(3H,m),1.56～1.36(7H, m),1.35(3H,s),1.34～1.30(2H,m),1.19(3H,s),1.17～1.13(1H,m),1.03(6H,s),0.98～0.96(1H,m),0.91(3H, s),0.73(3H,s),0.72～0.69(1H,m),0.69(3H,s).LC-MS:630.6[M+H]⁺.

步骤C：N¹-羟基-N⁵-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)戊二酰胺的 制备

按照实施例5步骤D的合成步骤，用原料1-(4-氨基苯基)-4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30- 酰基)哌嗪替换原料3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-氨基苯氧基))乙酯，制备标题化合 物。Mp:155-158℃.IR(KBr):3430.9,2924.9,2854.8,1723.0,1613.2,1515.0,1492.5,1457.7,1411.1,1386.4, 1366.5,1328.2,1275.2,1210.9,1174.1,1078.6,1024.5,826.8,799.2.¹H NMR(600MHz,DMSO-d₆)δ10.38 (1H,s),9.69(1H,s),8.68(1H,s),7.45(2H,d,J＝9.0Hz),6.88(2H,d,J＝9.0Hz),5.49(1H,s),4.30(1H,d,J＝ 5.4Hz),3.75～3.60(4H,m),3.08～2.95(5H,m),2.58(1H,d,J＝13.2Hz),2.33(1H,s),2.30～2.16(3H,m), 2.16～2.07(1H,m),2.03～1.95(3H,m),1.92～1.83(1H,m),1.83～1.58(6H,m),1.56～1.38(5H,m),1.35(3H,s), 1.34～1.22(4H,m),1.19(3H,s),1.17～1.13(1H,m),1.03(6H,s),0.97～0.94(1H,m),0.91(3H,s),0.73(3H,s), 0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,173.5,170.6,169.2,147.2,132.5,129.1,127.9,120.6, 116.6,77.0,67.9,65.5,61.5,54.6,49.9,48.2,45.2,43.8,43.4,40.5,39.2,39.0,37.9,37.1,36.0,32.6,32.1,31.9, 30.5,28.8,28.6,27.4,26.7,23.7,23.2,22.9,21.7,19.1,18.8,17.6,16.7,16.5.LC-MS:757.6[M-H]^-.HRMS m/z calcd forC₄₅H₆₅N₄O₆ ^-[M-H]^-757.4910,found 757.4900.

实施例22：N¹-羟基-N⁶-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)己二酰 胺的制备

按照实施例21的合成步骤，用原料己二酸单甲酯替代实施例21中的原料戊二酸单甲酯，制备标题化 合物。Mp:204-208℃.IR(KBr):3425.8,2928.6,2866.7,1652.5,1515.6,1455.8,1415.3,1387.0,1365.7,1327.1, 1275.9,1210.2,1175.5,1085.5,1025.5,995.0,824.0.¹H NMR(600MHz,DMSO-d₆)δ10.34(1H,s),9.67(1H, s),8.67(1H,s),7.45(2H,d,J＝9.0Hz),6.88(2H,d,J＝9.0Hz),5.49(1H,s),4.30(1H,d,J＝4.8Hz), 3.75～3.60(4H,m),3.09～2.93(5H,m),2.58(1H,d,J＝13.2Hz),2.33(1H,s),2.29～2.16(3H,m),2.16～2.06(1H, m),2.02～1.92(3H,m),1.92～1.82(1H,m),1.79～1.59(3H,m),1.59～1.44(8H,m),1.44～1.36(3H,m),1.35(3H, s),1.34～1.22(3H,m),1.19(3H,s),1.18～1.13(1H,m),1.03(6H,s),0.98～0.94(1H,m),0.91(3H,s),0.73(3H,s), 0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,173.5,170.9,170.4,169.4,147.2,132.5,127.9,120.6, 116.6,77.0,61.6,54.6,49.9,48.2,45.2,45.0,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.6,32.6,31.9,28.8, 28.6,27.4,26.7,26.5,26.0,25.6,25.4,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:795.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₇N₄O₆ ^-[M-H]^-771.5066,found771.5066.

实施例23：N¹-羟基-N⁶-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)己二酰 胺的制备

按照实施例21的合成步骤，用原料庚二酸单乙酯替代实施例21中的原料戊二酸单甲酯，制备标题化 合物。Mp:147-151℃.IR(KBr):3429.1,2926.4,2861.2,1612.8,1515.0,1492.7,1458.0,1413.5,1366.1,1328.8, 1274.9,1210.4,1174.5,1088.8,1025.5,826.8,799.4.¹H NMR(600MHz,DMSO-d₆)δ10.33(1H,s),9.67(1H, s),8.66(1H,s),7.45(2H,d,J＝8.4Hz),6.88(2H,d,J＝9.0Hz),5.49(1H,s),4.30(1H,d,J＝4.8Hz), 3.77～3.60(4H,m),3.14～2.94(5H,m),2.58(1H,d,J＝13.2Hz),2.33(1H,s),2.30～2.17(3H,m),2.17～2.06(1H, m),2.06～1.84(4H,m),1.80～1.60(3H,m),1.59～1.43(8H,m),1.43～1.37(3H,m),1.35(3H,s),1.32～1.21(5H, m),1.19(3H,s),1.17～1.12(1H,m),1.03(6H,s),0.98～0.94(1H,m),0.91(3H,s),0.73(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,173.5,171.0,170.5,169.5,147.2,132.5,127.9,120.5,116.6,77.0,61.5, 55.4,54.6,49.9,48.2,45.2,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.6,35.6,32.6,31.9,31.8,29.5,29.1, 28.8,28.6,27.4,27.0,26.7,26.5,25.4,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:809.6[M+Na]⁺.HRMS m/z calcd for C₄₇H₆₉N₄O₆ ^-[M-H]^-785.5223,found785.5216.

实施例24：N¹-羟基-N⁸-(4-(4-(3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰 胺的制备

按照实施例21的合成步骤，用原料辛二酸单甲酯替代实施例21中的原料戊二酸单甲酯，制备标题化 合物。Mp:205-210℃.IR(KBr):3428.5,2928.6,2862.0,1634.7,1515.4,1492.6,1457.2,1414.3,1387.1,1366.2, 1328.5,1275.9,1210.7,1174.7,1026.2,996.7,826.4,799.5.¹H NMR(600MHz,DMSO-d₆)δ10.33(1H,s),9.66 (1H,s),8.65(1H,s),7.45(2H,d,J＝9.0Hz),6.88(2H,d,J＝9.0Hz),5.49(1H,s),4.30(1H,d,J＝4.8Hz), 3.79～3.60(4H,m),3.10～2.93(5H,m),2.58(1H,d,J＝13.2Hz),2.33(1H,s),2.29～2.17(3H,m),2.17～2.07(1H, m),2.03～1.85(4H,m),1.79～1.59(3H,m),1.59～1.43(8H,m),1.43～1.37(3H,m),1.35(3H,s),1.33～1.21(7H, m),1.19(3H,s),1.17～1.12(1H,m),1.03(6H,s),0.99～0.96(1H,m),0.91(3H,s),0.73(3H,s),0.69(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.6,173.5,171.1,170.5,169.5,147.2,132.5,127.9,120.5,116.6,77.0,61.5, 54.6,49.9,48.2,45.2,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.7,32.7,32.6,31.9,29.5,28.9,28.9,28.8, 28.6,27.4,26.7,26.5,26.0,25.6,25.5,24.1,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:823.7[M+Na]⁺.HRMS m/z calcd for C₄₈H₇₁N₄O₆ ^-[M-H]^-799.5379,found 799.5375.

部分中间体的制备

3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备

称取3.5g(7.48mmol)GA溶于150mL DMSO中，加入8.37g(30mmol)IBX，85℃回流搅拌4h。 冷却至室温，倒入300mL 5％NaHCO₃溶液中，析出白色固体。用***萃取(150mL×3)，合并有机层， 用水洗，饱和氯化钠洗，无水硫酸钠干燥，减压浓缩得白色固体2.65g，收率：76％。¹H NMR(600MHz, DMSO-d₆)δ12.21(1H,s),7.64(1H,d,J＝10.2Hz),5.72(1H,d,J＝10.8Hz),5.52(1H,s),2.73(1H,s), 2.17～2.06(2H,m),1.83～1.65(5H,m),1.60～1.53(3H,m),1.44～1.39(2H,m),1.38(3H,s),1.37～1.34(1H,m), 1.31(3H,s),1.29～1.25(1H,m),1.21～1.16(1H,m),1.11(3H,s),1.10(3H,s),1.07(3H,s),1.02(3H,s), 1.00～0.96(1H,m),0.78(3H,s).

2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备

称取6.0g 3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸(12.9mmol)置于500mL茄形瓶中，加入300mL 无水四氢呋喃溶解。随后加入I₂ 13.3g(51.6mmol)和吡啶6.23mL(77.4mmol)，80℃下搅拌反应12h后， 再补加I₂ 6.65g(25.8mmol)和吡啶3.12mL(38.7mmol)，继续搅拌6h。冷却至室温，蒸干四氢呋喃，用乙 酸乙酯溶解，硫代硫酸钠洗至金黄色，饱和氯化钠洗，无水硫酸钠干燥。减压浓缩后以环己烷：丙酮 (V/V)＝50：1为洗脱剂硅胶柱层析，分离得白色固体5.42g，收率：71％。Mp:286-288℃.¹H NMR(600MHz, DMSO-d₆)δ8.42(1H,s),5.53(1H,s),2.87(1H,s),2.16～2.08(2H,m),1.83～1.65(6H,m),1.59～1.50(3H,m), 1.39(3H,s),1.39～1.34(2H,m),1.31(3H,s),1.29～1.25(1H,m),1.20～1.15(2H,m),1.11(3H,s),1.10(3H,s), 1.08(6H,s),1.01～0.96(1H,m),0.78(3H,s).LC-MS:592.2[M-H]^-.

2-氰基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备

称取3.5g(6.8mmol)2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸和1.22g(13.6mmol)CuCN 溶于100mL NMP，于130℃搅拌2h。待反应液冷却至室温，将反应液倒入200mL水中，搅拌15min， 抽滤，水洗，干燥。减压浓缩后以石油醚：乙酸乙酯(V/V)＝6：1为洗脱剂硅胶柱层析，分离得淡黄色固体 1.8g，收率：54％。¹H NMR(600MHz,DMSO-d₆)δ12.22(1H,s),8.49(1H,s),5.55(1H,s),2.98(1H,s), 2.21～2.16(2H,m),2.16～2.05(2H,m),1.95～1.86(2H,m),1.86～1.62(4H,m),1.62～1.50(2H,m),1.50～1.40(1H, m),1.38(3H,s),1.36(3H,s),1.30～1.16(1H,m),1.14(6H,s),1.10(3H,s),1.07(3H,s),1.02～0.97(1H,m),0.78 (3H,s).LC-MS:490.3[M-H]^-.

3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备

称取4.0g(6.8mmol)2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸溶于100mL干燥的DMSO 中，加入2.8g(20.3mmol)K₂CO₃，室温搅拌0.5h。随后加入0.96mL溴化苄(8.1mmol)，继续搅拌2h。 将反应液倒入250mL水中，搅拌15min，抽滤，水洗，干燥得白色固体4.27g，收率：92％。Mp:158-161 ℃.¹H NMR(600MHz,DMSO-d₆)δ8.40(1H,s),7.45～7.29(5H,m),5.41(1H,s),5.22(1H,d,J＝12.0Hz), 5.08(1H,d,J＝12.0Hz),2.84(1H,s),2.15～2.07(1H,m),2.01～1.96(1H,m),1.88～1.82(1H,m),1.79～1.68(5H, m),1.59～1.49(2H,m),1.46～1.40(1H,m),1.37(3H,s),1.36～1.32(2H,m),1.31(3H,s),1.24～1.16(2H,m),1.14 (3H,s),1.10(3H,s),1.08(3H,s),1.05(3H,s),0.99～0.94(1H,m),0.71(3H,s).

2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯的制备

将4.92g 2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯(7.2mmol)置于250mL三颈瓶中， 用100mL干燥DMF溶解，避光条件下加入4.12g CuI(21.63mmol)。氮气保护，升温至70℃，再缓慢滴 加17.3mL氟磺酰二氟乙酸甲酯(144.2mmol)和25mL HMPA(144.2mmol)，继续搅拌4h。反应液稍冷后 加入20mL饱和氯化铵溶液淬灭，冷却至室温，亚硫酸钠洗，2N HCl洗，水洗，饱和氯化钠洗，无水硫 酸钠干燥。减压蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝20：1为洗脱剂硅胶柱层析，分离得白色固体3.3g，收率：73％。Mp:113-115℃.¹H NMR(600MHz,DMSO-d₆)δ8.20(1H,s),7.45～7.30(5H,m),5.43(1H,s),5.22 (1H,d,J＝12.0Hz),5.08(1H,d,J＝12.0Hz),2.94(1H,s),2.16～2.07(1H,m),2.02～1.97(1H,m),1.88～1.82 (1H,m),1.79～1.65(5H,m),1.61～1.55(2H,m),1.47～1.42(1H,m),1.38(3H,s),1.36～1.32(1H,m),1.31(3H,s), 1.24～1.15(3H,m),1.14(3H,s),1.10(3H,s),1.08(6H,s),1.00～0.95(1H,m),0.72(3H,s).LC-MS:626.0 [M+H]⁺,647.7[M+Na]⁺.

2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸的制备

将2.9g 2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸苄酯溶于20mL的干燥的二氯甲烷 中，在0℃下向上述溶液中缓慢滴加32.5mL 1N TiCl溶液(32.5mmol)，搅拌15min。转移至室温，继续 搅拌2h。将反应液缓慢滴加至冰水中，用二氯甲烷萃取，水洗，饱和氯化钠洗，无水硫酸钠干燥。减压 蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝10：1为洗脱剂硅胶柱层析，分离得白色固体2.2g，收率：91％。 Mp:259-261℃.¹H NMR(600MHz,DMSO-d₆)δ12.21(1H,s),8.22(1H,s),5.55(1H,s),2.97(1H,s), 2.17～2.07(2H,m),1.84～1.78(2H,m),1.78～1.63(5H,m),1.63～1.56(2H,m),1.40(3H,s),1.39～1.34(2H,m), 1.32(3H,s),1.30～1.25(1H,m),1.23～1.16(1H,m),1.11(9H,s),1.09(3H,s),1.02～0.97(1H,m),0.79(3H,s). LC-MS:535.5[M+H]⁺,557.5[M+Na]⁺.

8-((4-羟基苯基)氨基)-8-氧代辛酸的制备

将3.62mL(20.2mmol)辛二酸单甲酯、2.36g(17.5mmol)HOBT和3.35g(17.5mmol)EDCI溶于40mL 干燥的DMF，室温搅拌30min。随后加入2.0g(18.4mmol)对氨基苯酚和2.73mL(17.5mmol)DIEA，升 温至60℃搅拌1.5h。待反应液冷却至室温，倒入200mL冷水中，搅拌10min，抽滤，水洗，干燥，得 棕色固体。将上述棕色固体溶于20mL甲醇，于60℃下搅拌，随后滴加10mL NaOH溶液(1mol/L)，继 续搅拌2h。待反应液冷却至室温，将反应液倒入150mL水中，用10％的盐酸溶液调节pH至2～3。搅拌 15min，抽滤，水洗，干燥，得白色固体2.4g，收率49％。¹H NMR(600MHz,DMSO-d₆)δ11.95(1H,s),9.56 (1H,s),9.11(1H,s),7.34(2H,d,J＝9.0Hz),6.66(2H,d,J＝9.0Hz),2.22(2H,t,J＝7.8Hz),2.19(2H,t,J＝ 7.8Hz),1.60～1.45(4H,m),1.33～1.24(4H,m).LC-MS:264.0[M-H]^-.

N¹-(4-羟基苯基)-N⁸-((四氢-2H-吡喃-2-基)氧基)丁二酰胺的制备

将2.0g(7.5mmol)8-((4-羟基苯基)氨基)-8-氧代辛酸、1.5g(11.3mmol)HOBT和2.2(11.3mmol)EDCI 溶于30mL干燥的DMF，室温搅拌30min。随后加入2.65g(22.6mmol)O-(四氢-2H-吡喃-2-基)羟基胺和 1.86mL(11.3mmol)DIEA，继续搅拌2h。将反应液倒入饱和氯化钠溶液中，搅拌15min，抽滤，水洗， 干燥，得棕色固体2.35g，收率86％。¹H NMR(600MHz,DMSO-d₆)δ10.88(1H,s),9.56(1H,s),9.11(1H,s), 7.34(2H,d,J＝9.0Hz),6.66(2H,d,J＝9.0Hz),4.80(1H,s),3.94～3.87(1H,m),3.54～3.45(1H,m),2.22(2H,t, J＝7.8Hz),1.97(2H,t,J＝7.8Hz),1.75～1.44(10H,m),1.33～1.19(4H,m).LC-MS:387.4[M+Na]⁺.

8-氧代-8-(((四氢-2H-吡喃-2-基)氧基)氨基)辛酸的制备

按照N¹-(4-羟基苯基)-N⁸-((四氢-2H-吡喃-2-基)氧基)丁二酰胺的方法，用原料辛二酸替换原料8-((4-羟 基苯基)氨基)-8-氧代辛酸，制备标题化合物。LC-MS:272.0[M-H]^-.

实施例25：N¹-羟基-N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基) 辛二酰胺的制备

步骤A：2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸(3-溴)丙酯的制备

将2.0g(3.4mmol)2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸溶于20mL干燥的DMF，加入 2.65g(10.1mmol)K₂CO₃，室温搅拌30min。随后向反应液中滴加1.7mL(16.8mmol)1,3-二溴丙烷，继续 搅拌1h。将反应液倒入100mL水中，用二氯甲烷萃取，水洗，饱和氯化钠洗，无水硫酸钠干燥。减压蒸 干溶剂，以石油醚：乙酸乙酯(V/V)＝7：1为洗脱剂硅胶柱层析，分离得白色固体1.7g，收率：71％。¹H NMR (600MHz,DMSO-d₆)δ8.42(1H,s),5.56(1H,s),4.25～4.09(2H,m),3.64～3.53(2H,m),2.87(1H,s),2.18～2.09 (3H,m),2.09～2.02(1H,m),1.87～1.82(1H,m),1.82～1.69(5H,m),1.61～1.41(4H,m),1.40(3H,s),1.39～1.35 (2H,m),1.31(3H,s),1.25～1.15(1H,m),1.13(3H,s),1.11(3H,s),1.08(6H,s),1.01～0.97(1H,m),0.78(3H,s). LC-MS:713.0[M+H]⁺.

步骤B：N¹-(四氢-2H-吡喃-2-基)氧基-N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧 基)丙氧基)苯基)辛二酰胺的制备

将0.69g(1.9mmol)N¹-(4-羟基苯基)-N⁸-((四氢-2H-吡喃-2-基)氧基)丁二酰胺溶于20mL干燥的DMF， 加入0.64g(4.6mmol)K₂CO₃，于80℃搅拌30min。随后加入1.1g(1.5mmol)2-碘代-3,11-二氧代-18β-齐 墩果烷-1,12-二烯-30-羧酸(3-溴)丙酯，继续搅拌2h。待反应液冷却至室温，倒入100mL水中，用二氯甲 烷萃取，水洗，饱和氯化钠洗，无水硫酸钠干燥。减压蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝4：1为洗脱 剂硅胶柱层析，分离得白色固体0.18g，收率：12％。¹H NMR(600MHz,DMSO-d₆)δ9.55(1H,s),9.12(1H, s),8.41(1H,s),7.34(2H,d,J＝9.0Hz),6.65(2H,d,J＝8.4Hz),5.53(1H,s),4.93(1H,s),4.24～4.10(2H,m),4.10～3.96(1H,m),3.96～3.39(3H,m),2.85(1H,s),2.42～2.27(1H,m),2.27～2.15(3H,m),2.15～2.00(2H,m), 2.00～1.91(1H,m),1.91～1.80(2H,m),1.81～1.60(7H,m),1.60～1.52(6H,m),1.52～1.44(5H,m),1.44～1.39(2H, m),1.39(3H,s),1.38～1.33(2H,m),1.30～1.21(6H,m),1.21～1.13(3H,m),1.12(3H,s),1.10(3H,s),1.08(3H, s),1.07(3H,s),1.00～0.95(1H,m),0.77(3H,s).LC-MS:1019.5[M+Na]⁺.

步骤C：N¹-羟基-N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基)辛二 酰胺的制备

将0.12g(0.12mmol)N¹-(四氢-2H-吡喃-2-基)氧基-N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二 烯-30-甲酰氧基)丙氧基)苯基)辛二酰胺溶于10mL干燥的二氯甲烷，滴加1mL三氟乙酸，室温搅拌20min。 反应液用水洗，饱和氯化钠洗，无水硫酸钠干燥。减压蒸干溶剂，以二氯甲烷：甲醇(V/V)＝15：1为洗脱 剂硅胶柱层析，分离得白色固体27.4mg，收率：25％。Mp:93-96℃.IR(KBr):3440.8,2928.3,2620.9,2345.1, 1652.5,1631.4,1512.9,1401.7,1269.3,1216.6,1152.0,1007.8,978.4,831.7,703.2.¹H NMR(600MHz, DMSO-d₆)δ9.55(1H,s),9.32(1H,s),9.10(1H,s),8.42(1H,s),7.34(2H,d,J＝8.4Hz),6.66(2H,d,J＝8.4 Hz),5.57(1H,s),4.20～3.55(4H,m),2.86(1H,s),2.40～2.26(2H,m),2.26～2.18(2H,m),2.17～2.00(2H,m), 2.00～1.88(1H,m),1.88～1.68(6H,m),1.60～1.41(7H,m),1.39(3H,s),1.38～1.32(2H,m),1.31(3H,s), 1.30～1.14(7H,m),1.12(3H,s),1.10(3H,s),1.08(3H,s),1.07(3H,s),1.00～0.95(1H,m),0.77(3H,s).¹³CNMR(150MHz,DMSO-d₆)δ198.7,197.8,176.2,172.0,170.9,170.7,155.0,153.5,131.5,127.4,121.2,115.4, 100.5,65.4,62.1,61.2,54.7,51.5,48.7,45.5,44.0,43.8,43.4,40.8,37.7,36.7,32.0,31.4,30.7,29.1,28.6,28.2, 28.2,26.8,26.6,25.9,25.7,24.6,23.3,23.0,22.4,20.4,18.9,18.3,14.5.LC-MS:911.3[M-H]^-.HRMS m/z calcd forC₄₇H₆₄IN₂O₈ ^-[M-H]^-911.3713,found 911.3716.

实施例26：N¹-羟基-N⁸-(4-(3-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯 基)辛二酰胺的制备

按照实施例25的制备方法，用原料2-三氟甲基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施 例25中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸，制备标题化合物。Mp:100-103℃.IR(KBr): 3420.3,2928.6,2350.5,2321.1,1726.5,1656.9,1511.3,1456.8,1387.4,1297.0,1243.4,1216.4,1163.2,1007.8, 979.3,831.4,704.0.¹H NMR(600MHz,DMSO-d₆)δ10.32(1H,s),9.68(1H,s),8.64(1H,s),8.22(1H,s),7.47(2H,d,J＝8.4Hz),6.86(2H,d,J＝8.4Hz),5.56(1H,s),4.27～4.14(2H,m),4.07～3.97(2H,m),2.96(1H,s), 2.29～2.17(2H,m),2.17～1.99(4H,m),1.99～1.89(2H,m),1.89～1.80(1H,m),1.80～1.68(5H,m),1.63～1.42(7H, m),1.39(3H,s),1.32(3H,s),1.30～1.15(8H,m),1.11(6H,s),1.09(6H,s),1.00～0.95(1H,m),0.73(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ199.1,198.6,176.2,172.0,171.1,169.5,164.3,161.9,154.6,133.2,127.4,123.9, 121.0,114.9,64.8,61.5,55.4,54.1,50.5,48.7,45.4,45.3,44.0,43.9,38.2,37.8,36.7,32.7,32.0,31.2,30.7,28.9, 28.9,28.7,28.7,28.1,28.1,26.6,26.1,25.6,25.5,23.2,21.6,20.1,18.9,18.2.LC-MS:877.7[M+Na]⁺.HRMS m/z calcd forC₄₈H₆₅F₃N₂NaO₈ ⁺[M+Na]⁺877.4585,found 877.4603.

实施例27：N¹-羟基-N⁸-(4-(3-(2-氰基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基) 辛二酰胺的制备

按照实施例25的制备方法，用原料2-氰基-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替代实施例 25中的2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸，制备标题化合物。Mp:123-125℃.IR(KBr): 3413.3,2929.8,2866.9,2621.0,1653.8,1631.6,1513.2,1400.9,1255.4,1217.4,1166.1,1007.7,981.2,832.0, 703.1.¹H NMR(600MHz,DMSO-d₆)δ9.58(1H,s),9.45(1H,s),9.21(1H,s),8.48(1H,s),7.34(2H,d,J＝7.8Hz),6.66(2H,d,J＝7.8Hz),5.59(1H,s),4.25～3.50(4H,m),2.97(1H,s),2.42～2.29(2H,m),2.29～2.18(2H, m),2.18～1.95(3H,m),1.95～1.65(8H,m),1.65～1.44(9H,m),1.38(3H,s),1.35(3H,s),1.32～1.25(6H,m),1.14 (3H,s),1.12(3H,s),1.09(3H,s),1.07(3H,s),1.00～0.94(1H,m),0.78(3H,s).¹³C NMR(150MHz,DMSO-d₆) δ198.4,176.1,174.7,173.3,172.1,170.8,153.5,131.4,130.0,127.2,121.1,115.9,115.3,112.0,65.3,62.0,61.1, 53.7,50.5,48.4,45.5,45.0,43.9,43.8,40.7,37.7,36.6,32.0,31.9,31.2,30.6,29.4,29.0,28.6,28.1,27.4,26.7, 26.5,25.6,24.5,23.2,22.5,21.7,19.6,18.9,17.8.LC-MS:810.4[M-H]^-.HRMS m/z calcd for C₄₈H₆₄N₃O₈ ^- [M-H]^-810.4699,found810.4695.

实施例28：N¹-羟基-N⁸-(4-(4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛 二酰胺的制备

步骤A：1-(4-硝基苯基)-4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪的制备

按照实施例1步骤A的制备方法，用原料2-碘代-3,11-二氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替换原 料GA，用原料4-硝基苯基哌嗪替换原料4-氨基丁酸甲酯盐酸盐，制备标题化合物。¹H NMR(600MHz, DMSO-d₆)δ8.42(1H,s),8.09(2H,d,J＝9.6Hz),7.01(2H,d,J＝9.6Hz),5.64(1H,s),3.78～3.69(4H,m), 3.54～3.42(4H,m),2.87(1H,s),2.31～2.25(1H,m),2.19～2.11(1H,m),2.04～1.98(1H,m),1.92～1.87(1H,m), 1.82～1.67(4H,m),1.61～1.44(3H,m),1.39(3H,s),1.38～1.33(2H,m),1.31(3H,s),1.21(3H,s),1.19～1.15(2H, m),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.02～0.98(1H,m),0.76(3H,s).LC-MS:804.6[M+Na]⁺.

步骤B：1-(4-氨基苯基)-4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪的制备

按照实施例5步骤C的合成步骤，用原料1-(4-硝基苯基)-4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二 烯-30-酰基)哌嗪替换原料3β-羟基-11-氧代-18β-齐墩果烷-12-二烯-30-羧酸(2-(4-氨基苯氧基))乙酯，制备标 题化合物。LC-MS:752.6[M+H]⁺.

步骤C：N¹-(四氢-2H-吡喃-2-基)氧基-N⁸-(4-(4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基) 哌嗪-1-基)苯基)辛二酰胺的制备

将0.44g(1.6mmol)8-氧代-8-(((四氢-2H-吡喃-2-基)氧基)氨基)辛酸、0.16g(1.2mmol)HOBT和0.23g (1.2mmol)EDCI溶于20mL干燥的DMF，室温搅拌30min。随后加入0.6g(0.8mmol)1-(4-氨基苯基)-4-(2- 碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪和0.2mL(1.2mmol)DIEA，转移至60℃搅拌，搅 拌4h。待反应液冷却至室温，倒入100mL水中，二氯甲烷萃取，水洗，饱和氯化钠洗，无水硫酸钠干燥。 减压蒸干溶剂，以石油醚：乙酸乙酯(V/V)＝5：1为洗脱剂硅胶柱层析，分离得淡黄色固体0.36，收率：45％。 ¹HNMR(600MHz,DMSO-d₆)δ10.88(1H,s),9.65(1H,s),8.43(1H,s),7.46(2H,d,J＝8.4Hz),6.89(2H,d,J ＝8.4Hz),5.62(1H,s),4.80(1H,s),3.96～3.87(1H,m),3.75～3.65(4H,m),3.52～3.46(1H,m),3.08～2.98(4H, m),2.87(1H,s),2.32～2.26(1H,m),2.26～2.21(2H,m),2.21～2.10(2H,m),2.03～1.92(4H,m),1.92～1.86(1H, m),1.81～1.68(3H,m),1.68～1.59(3H,m),1.59～1.52(4H,m),1.52～1.45(6H,m),1.39(3H,s),1.36～1.33(1H, m),1.31(3H,s),1.29～1.22(6H,m),1.20(3H,s),1.11(3H,s),1.08(3H,s),1.07(3H,s),1.01～0.97(1H,m),0.75 (3H,s).LC-MS:1030.3[M+Na]⁺.

步骤D：N¹-羟基-N⁸-(4-(4-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰 胺的制备

按照实施例25步骤C的合成步骤，用原料N¹-(四氢-2H-吡喃-2-基)氧基-N⁸-(4-(4-(2-碘代-3,11-双氧代 -18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛二酰胺替换原料N¹-(四氢-2H-吡喃-2-基)氧基 -N⁸-(4-(3-(2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-甲酰氧基)丙氧基)苯基)辛二酰胺，制备标题化合 物。Mp:194-197℃.IR(KBr):3402.4,2923.2,2852.3,1633.9,1544.9,1514.4,1457.2,1408.5,1385.3,1273.3,1213.5,1099.8,1008.6,976.8,831.9,703.4.¹H NMR(600MHz,DMSO-d₆)δ10.45(1H,s),9.89(1H,s),8.68 (1H,s),8.43(1H,s),7.50(2H,d,J＝8.4Hz),6.89(2H,d,J＝8.4Hz),5.62(1H,s),3.77～3.63(4H,m), 3.11～2.98(4H,m),2.87(1H,s),2.34～2.22(3H,m),2.22～2.08(1H,m),2.08～1.92(4H,m),1.92～1.84(1H,m), 1.84～1.63(4H,m),1.63～1.43(8H,m),1.39(3H,s),1.31(3H,s),1.30～1.25(6H,m),1.20(3H,s),1.11(3H,s), 1.08(3H,s),1.07(3H,s),1.01～0.98(1H,m),0.75(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ198.8,197.8,173.6, 172.6,171.3,170.7,169.6,163.5,130.1,127.4,120.5,100.5,70.2,54.7,51.5,48.3,45.5,45.4,43.9,43.4,37.9, 36.7,35.6,32.7,31.9,31.7,31.5,29.5,29.2,28.9,28.8,27.0,26.6,26.6,26.5,25.6,25.5,23.0,22.6,22.4,20.4, 18.9,18.3,14.4.LC-MS:945.8[M+Na]⁺.HRMS m/z calcd for C₄₈H₆₇IN₄NaO₆ ⁺[M+Na]⁺945.3997,found 945.4019.

实施例29：N¹-羟基-N⁸-(4-(4-(2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基) 辛二酰胺的制备

按照实施例28的制备方法，用原料2-三氟甲基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替换原料 2-碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-羧酸，制备标题化合物。Mp:197-200℃.IR(KBr):3386.5, 2928.9,2861.1,1685.8,1655.7,1633.1,1515.3,1457.9,1414.1,1386.8,1369.6,1296.9,1219.0,1138.9,1024.6, 977.2,831.0.¹H NMR(600MHz,DMSO-d₆)δ10.33(1H,s),9.67(1H,s),8.65(1H,s),8.23(1H,s),7.46(2H,d, J＝8.4Hz),6.89(2H,d,J＝8.4Hz),5.65(1H,s),3.77～3.63(4H,m),3.13～2.99(4H,m),2.97(1H,s),2.35～2.28 (1H,m),2.28～2.21(2H,m),2.21～2.09(2H,m),2.04～1.99(1H,m),1.97～1.92(2H,m),1.92～1.86(1H,m), 1.83～1.76(1H,m),1.76～1.65(3H,m),1.65～1.53(5H,m),1.53～1.44(4H,m),1.39(3H,s),1.32(3H,s), 1.30～1.22(5H,m),1.20(3H,s),1.11(3H,s),1.10(3H,s),1.09(3H,s),1.02～0.98(1H,m),0.76(3H,s).¹³CNMR(150MHz,DMSO-d₆)δ199.2,198.7,173.5,172.8,172.5,171.0,169.5,164.3,147.1,132.5,130.1,127.4, 120.6,116.6,55.4,54.1,50.5,49.9,48.3,45.3,44.0,43.8,38.2,37.9,36.7,32.7,32.3,31.9,31.2,28.9,28.9,28.8, 28.0,26.7,26.6,26.5,25.6,25.5,23.0,21.6,21.5,20.2,18.9,18.2.LC-MS:887.7[M+Na]⁺.HRMS m/z calcd forC₄₉H₆₇F₃N₄NaO₆ ⁺[M+Na]⁺887.4905,found 887.4902.

实施例30：N¹-羟基-N⁸-(4-(4-(2-氰基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-酰基)哌嗪-1-基)苯基)辛 二酰胺的制备

按照实施例28的制备方法，用原料2-氰基-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-羧酸替换原料2- 碘代-3,11-双氧代-18β-齐墩果烷-1,12-二烯-30-羧酸，制备标题化合物。Mp:154-156℃.IR(KBr):3427.2, 2928.1,2858.8,1655.4,1515.0,1458.2,1415.1,1386.1,1341.9,1218.0,1025.7,980.9,831.3.¹H NMR(600 MHz,DMSO-d₆)δ10.32(1H,s),9.65(1H,s),8.64(1H,s),8.50(1H,s),7.46(2H,d,J＝8.4Hz),6.89(2H,d,J ＝8.4Hz),5.64(1H,s),3.76～3.64(4H,m),3.09～3.00(4H,m),2.98(1H,s),2.35～2.28(1H,m),2.28～2.20(2H, m),2.20～2.10(1H,m),2.04～1.97(1H,m),1.97～1.91(2H,m),1.91～1.84(1H,m),1.84～1.74(1H,m),1.74～1.65 (3H,m),1.62～1.52(4H,m),1.52～1.44(3H,m),1.38(3H,s),1.36(3H,s),1.35～1.32(2H,m),1.31～1.22(6H,m), 1.21(3H,s),1.14(3H,s),1.09(3H,s),1.07(3H,s),1.02～0.98(1H,m),0.76(3H,s).¹³C NMR(150MHz,DMSO-d₆)δ198.6,198.6,174.9,173.5,172.8,171.0,169.5,147.1,132.5,127.3,120.6,116.6,115.9,112.1,55.4, 53.8,50.6,49.9,48.3,45.5,45.1,44.0,43.8,40.5,37.9,36.7,32.7,32.3,31.9,31.3,28.9,28.9,28.8,27.5,26.7, 26.6,26.5,25.6,25.5,23.0,21.7,19.8,19.0,17.9.LC-MS:820.5[M-H]^-.HRMS m/z calcd for C₄₉H₆₇N₅NaO₆ ⁺ [M+Na]⁺844.4984,found 844.4954.

本发明产物药理作用研究

体外抗肿瘤活性测试

1)细胞培养

人急性白血病细胞HL-60，***癌细胞PC-3，乳腺癌细胞MCF-7，培养于含有10％(v/v)经加热 灭活的胎牛血清、100U/mL青霉素、100μg/mL链霉素及2mmol/L谷氨酰胺的RPMI 1640培养液或高糖 DMEM培养液中。所有实验用细胞均于37℃、5％CO₂饱和湿度培养箱中培养。

2)细胞生长抑制活性

化合物对HL-60细胞的生长抑制作用采用细胞计数法考察。将一定密度(1×10⁵个/mL)的细胞悬液接 种于24孔培养板,2mL/孔，加入不同浓度药物共同孵育72小时后于显微镜下计数，依以下公式求得细胞 生长抑制率，并求得半数生长抑制浓度GI₅₀(使细胞生长抑制率达50％时的药物浓度)。

化合物对实体瘤细胞PC-3和MCF-7的生长抑制作用采用MTT法考察。将一定密度(2～3×10⁴个/mL) 的细胞悬液接种于96孔培养板,100μL/孔，加入不同浓度化合物共同孵育96小时后再加入50μL的MTT 溶液继续孵育3.5h，然后将96孔板内的液体全部弃掉倒扣在滤纸上充分吸干残留液体，之后每孔加入 200μL DMSO于振荡器上震荡10min以溶解蓝紫色结晶物，最后使用酶标仪测570nm处吸光值，设A1 (含200μL DMSO)为空白对照孔；依以下公式求得细胞生长抑制率，并求得半数生长抑制浓度GI₅₀(使 细胞生长抑制率达50％时的化合物浓度)。

表1化合物对HL-60，PC-3和MCF-7的GI₅₀(μmol/L)值列表