CN110526955A - 18 β-enoxolone class the compound of the segment containing hydroxamic acid structure and its application - Google Patents

Abstract

The invention belongs to the technical field of medicine, in particular to 18β-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and their preparation and application, and also to 18β-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and their optical activity Pharmaceutical compositions of isomers and pharmaceutically acceptable salts, and their use in the preparation of medicines for treating and/or preventing various cancers. The general structural formula of the compound is as follows, wherein X and R are as described in the claims and description.

Description

18β-glycyrrhetinic acid compound containing hydroxamic acid structural fragment and its application

Technical field:

The present invention belongs to the field of medical technology, in particular to 18β-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and their preparation and application, and also to 18β-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and their optical activity Pharmaceutical compositions of isomers and pharmaceutically acceptable salts, and their use in the preparation of medicines for treating and/or preventing various cancers.

Background technique:

18β-glycyrrhetinic acid is a pentacyclic triterpenoid natural product with various sources and various pharmacological activities. Its anti-tumor effect has also attracted people's attention, but its activity is not strong, and it is difficult to meet the requirements of clinical use. In order to improve the antitumor effect of 18β-glycyrrhetinic acid, the researchers combined 18β-glycyrrhetinic acid with other active fragments (such as ferulic acid, cinnamic acid, rhodamine B, etc.) through a hybrid strategy, and obtained multiple A hybrid molecule, its activity has a certain improvement compared with the parent compound.

The hydroxamic acid structure can chelate a variety of transition metals, and this chelating ability makes it widely present in a variety of drugs and drug-like molecules. Among them, the inhibitory activity of hydroxamic acid compounds on metalloproteinases and histone deacetylases has been deeply studied, and several compounds have entered the clinic for the treatment of cancer. By introducing hydroxamic acid into different target ligand molecules or natural product structures through the principle of splicing, it is expected to obtain synergistic inhibitory effects on multiple targets and stronger anti-tumor effects.

The present inventors designed and synthesized a series of 18β-glycyrrhetinic acid analogues containing hydroxamic acid structural fragments, and the synthesized compounds had good tumor cell growth inhibitory activity after cell activity screening.

Invention content:

The technical problem solved by the present invention is to provide a series of 18β-glycyrrhetinic acid analogues containing hydroxamic acid structural fragments, and also provide the preparation process of the 18β-glycyrrhetinic acid analogues containing hydroxamic acid structural fragments. Application in prevention and/or treatment of tumor drugs.

The present invention relates to derivatives represented by general formula I or II, and optical isomers and pharmaceutically acceptable salts thereof:

X is

The left side of X is connected to the glycyrrhetinic acid skeleton, and the right side is connected to the hydroxamic acid fragment;

R is halogen, halogenated C1-C4 alkyl, methylsulfonyl, cyano;

m is an integer of 1-6;

n is an integer of 1-8.

The present invention preferably has the compound with the following structure, and its optically active body and pharmaceutically acceptable salt,

in,

X is

The left side of X is connected to the glycyrrhetinic acid skeleton, and the right side is connected to the hydroxamic acid fragment;

R is iodine, trifluoromethyl, cyano;

m is an integer of 1-6;

n is an integer of 1-8.

The present invention preferably has the compound with the following structure, and its optically active body and pharmaceutically acceptable salt,

in,

X is

The left side of X is connected to the glycyrrhetinic acid skeleton, and the right side is connected to the hydroxamic acid fragment;

R is iodine, trifluoromethyl, cyano;

m is an integer of 2-3;

n is an integer of 3-6.

Particularly preferred compounds include:

4-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxybutyramide (Example 1)

5-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxypentanamide (Example 2)

6-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxycaproamide (Example 3)

7-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxyheptanamide (Example 4)

N ¹ -Hydroxy-N ⁵ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)phenyl) Glutaramide (Example 5)

N ¹ -Hydroxy-N ⁶ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)phenyl) Adipamide (Example 6)

N ¹ -Hydroxy-N ⁷ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)phenyl) Pimelic amide (Example 7)

N ¹ -Hydroxy-N ⁸ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)phenyl) Suberamide (Example 8)

N ¹ -Hydroxy-N ⁵ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)phenyl) Glutaramide (Example 9)

N ¹ -Hydroxy-N ⁶ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)phenyl) Adipamide (Example 10)

N ¹ -Hydroxy-N ⁷ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)phenyl) Pimelic amide (Example 11)

N ¹ -Hydroxy-N ⁸ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)phenyl) Suberamide (Example 12)

4-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido)-N-hydroxy Butanamide (Example 13)

5-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido)-N-hydroxy Valeramide (Example 14)

6-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido)-N-hydroxy Caproamide (Example 15)

7-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido)-N-hydroxy Heptanamide (Example 16)

4-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido)-N-hydroxy Butanamide (Example 17)

5-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido)-N-hydroxy Valeramide (Example 18)

6-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido)-N-hydroxy Caproamide (Example 19)

7-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido)-N-hydroxy Heptanamide (Example 20)

N ¹ -Hydroxy-N ⁵ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl)phenyl) Glutaramide (Example 21)

N ¹ -Hydroxy-N ⁶ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl)phenyl) Adipamide (Example 22)

N ¹ -Hydroxy-N ⁷ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl)phenyl) Pimelic amide (Example 23)

N ¹ -Hydroxy-N ⁸ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl)phenyl) Suberamide (Example 24)

N ¹ -Hydroxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-formyloxy)propane Oxy)phenyl)suberamide (Example 25)

N ¹ -Hydroxy-N ⁸ -(4-(3-(2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-formyloxy )propoxy)phenyl)suberamide (Example 26)

N ¹ -Hydroxy-N ⁸ -(4-(3-(2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-formyloxy)propane Oxy)phenyl)suberamide (Example 27)

N ¹ -Hydroxy-N ⁸ -(4-(4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piperazine-1 -yl)phenyl)suberamide (Example 28)

N ¹ -Hydroxy-N ⁸ -(4-(4-(2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piperazine -1-yl)phenyl)suberamide (Example 29)

N ¹ -Hydroxy-N ⁸ -(4-(4-(2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piperazine-1 -yl)phenyl)suberamide (Example 30)

The invention also includes prodrugs of the compounds of the invention. According to the invention, prodrugs are derivatives of the general formula I or II, which themselves may have weak activity or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis and other means) ) is converted into the corresponding biologically active form.

The present invention includes a pharmaceutical composition, which contains a 18β-glycyrrhetinic acid compound containing a hydroxamic acid structural fragment of the general formula I or II, its optically active body, a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient Formulations. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The compounds of the present invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as Injectable solutions or suspensions, or injectable dry powders for immediate use by adding water for injection prior to injection); topical formulations (such as ointments or solutions).

The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: adhesives for oral preparations, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigments, Flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.

Through in vitro activity screening, we found that the compound of the present invention has anti-tumor activity, so the compound of the present invention can be used for the preparation of drugs for the treatment and/or prevention of various cancers, such as breast cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer , liver, bladder, uterus, pancreas, ovary, lymphoma, ovary, skin and blood.

The active compound of the present invention can be used as the sole anticancer drug, or used in combination with one or more other anticancer drugs. Combination therapy is achieved by simultaneous, sequential or spaced administration of the individual therapeutic components.

The Examples and Preparations provided hereinafter further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations does not in any way limit the scope of the invention.

Synthetic route one:

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

Synthetic route two:

Reagent and conditions: a) IBX, DMSO, 85°C, 6h; b) I ₂ , pyridine, THF, reflux, overnight; c) CuCN, NMP, 130°C, 2h; d) BnBr, K ₂ CO ₃ , dry- DMF, rt, 1h; e) FSO ₂ CF ₂ COOCH ₃ , HMPA, CuI, dry-DMF, 70℃, 3.5h; f) TiCl ₄ , dry-CH ₂ Cl ₂ , rt, 2h.

Synthetic route three:

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, rt , 6h; d) 1,3-dibromopropane, K ₂ CO ₃ , dry-DMF, rt, 1h; e) K ₂ CO ₃ , dry-DMF, 80℃, 2h; e) CF ₃ COOH, dry-DCM, rt, 10min.

Synthetic route four:

Reagent and conditions: a) 1-(4-nitrophenyl) piperazine, EDCI, DMAP, CH ₂ Cl ₂ , rt, 2h; b) Fe, NH ₄ Cl, EtOH/H ₂ O, 80℃, 3h; c) HOBT , EDCI, DIEA, DMF, 60℃, 4h; d) CF ₃ COOH, dry-CH ₂ Cl ₂ , rt, 10min.

Detailed ways:

The examples are intended to illustrate, not limit, the scope of the invention. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

The IR of the compound was measured with a Bruker IR-27G chromatograph, the NMR spectrum was measured with a Bruker ARX-600 NMR spectrometer in CDCl ₃ or DMSO-d ₆ with TMS as the internal standard, and the low-resolution mass spectrometer was measured with an Agilent 1100SL ion trap Mass spectrometry was performed, and high-resolution mass spectrometry was determined by Bruker micro-TOF-Q.

Example 1: Preparation of 4-(3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxybutyramide

Step A: Preparation of methyl 4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)butyrate

Dissolve 0.5g (1.06mmol) of GA, 0.31g (1.60mmol) of EDCI and 0.20g (1.60mmol) of DMAP in 20mL of dichloromethane, and stir at room temperature for 30min. Subsequently, 0.25 g (1.60 mmol) of methyl 4-aminobutyrate hydrochloride was added, and stirring was continued for 6 h. The reaction solution was washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography using cyclohexane: acetone (V/V) = 8:1 as eluent, separated to obtain 0.38 g of white solid, yield: 63%. ¹ H NMR (600MHz, DMSO-d ₆ ) 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[MH] ^- .

Step B: Preparation of 4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxybutyramide

Dissolve 0.3 g (0.53 mmol) of methyl 4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxamido)butanoate in 15 mL of methanol, at 0 °C Add 3 mL of sodium hydroxide solution (1 mol/L) and 3 mL of hydroxylamine aqueous solution (50%) dropwise in turn, and stir for 15 min. Then the reaction solution was transferred to room temperature, and stirring was continued for 2 h. The solvent was evaporated under reduced pressure, 15 mL of water was added, and the pH was adjusted to about 7 with aqueous hydrochloric acid (1 mol/L). Stir for 15 min, filter with suction, and wash with water to obtain 0.18 g of white solid, yield: 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. ¹ H MHz -d ₆ )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). ¹³ CNMR(150MHz,DMSO-d ₆ )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. :568.9[MH] ^- .HRMS m/zcalcd for C ₃₄ H ₅₅ N ₂ O ₅ ⁺ [M+H] ⁺ 571.4105,found 571.4109.

Example 2: Preparation of 5-(3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxypentanamide

According to the preparation method of Example 1, the raw material 4-aminobutyric acid methyl ester hydrochloride was replaced by the raw material 5-aminovaleric acid methyl ester hydrochloride in Example 1 to prepare the title compound. 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. ¹ H NMR (600MHz, DMSO-d ₆₃ ) δ10.3 (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). ¹³ C NMR(150MHz,DMSO-d ₆ )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[MH] ^- .HRMSm /z calcd for C ₃₅ H ₅₅ N ₂ O ₅ ^- [MH] ^- 583.4116, found 583.4100.

Example 3: Preparation of 6-(3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxycaproamide

According to the preparation method of Example 1, the raw material 6-aminocaproic acid methyl ester hydrochloride was used instead of the raw material 4-aminobutyric acid methyl ester hydrochloride in Example 1 to prepare the title compound. 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. ¹ H NMR ( _60d0MHz , )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). ¹³ C NMR(150MHz,DMSO-d ₆ )δ 199.6,175.3,170.3,169.5,127.9,77.0,61.6,54.6,48.2,45.3,43.4 . .LC-MS: 597.0 [MH] ^- .HRMS m/z calcd for C ₃₆ H ₅₇ N ₂ O ₅ ^- [MH] ^- 597.4273,found 597.4278.

Example 4: Preparation of 7-(3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxamido)-N-hydroxyheptanamide

According to the preparation method of Example 1, the raw material 7-aminoheptanoic acid ethyl ester hydrochloride was used instead of the raw material 4-aminobutyric acid methyl ester hydrochloride in Example 1 to prepare the title compound. 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. ¹ H NMR (600MHz, _DMSO -d 61 ) δ10.3 (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, ¹³ C NMR(150MHz,DMSO-d ₆ )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} . for C ₃₇ H ₅₉ N ₂ O ₅ ^- [MH] ^- 611.4429, found 611.4428.

Example 5: N ¹ -Hydroxy-N ⁵ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy ) phenyl) the preparation of glutaramide

Step A: Preparation of (2-bromo)ethyl 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylate

Dissolve 3.0 g (6.4 mmol) of GA in 30 mL of dry DMF, add 2.65 g (19.2 mmol) of K ₂ CO ₃ , and stir at room temperature for 30 min. Then 2.7 mL (32.0 mmol) of 1,2-dibromoethane was added dropwise to the reaction solution, and the reaction solution was transferred to 80° C. and stirred for 40 min. After the reaction solution was cooled to room temperature, the reaction solution was poured into 100 mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 6:1 as the eluent was used to separate 2.69 g of white solid, yield: 73%. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Step B: Preparation of (2-(4-nitrophenoxy))ethyl 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylate

Dissolve 0.90g (6.5mmol) of 4-nitrophenol in 30mL of dry DMF, add 1.78g (12.9mmol) of K ₂ CO ₃ , and stir at 80°C for 30min. 10 mL of DMF-dissolved 3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-bromo)ethyl ester (2.5 g, 4.3 mmol) was then added dropwise to the reaction solution , continue stirring for 3h. After the reaction solution was cooled to room temperature, the reaction solution was poured into 100 mL of water, stirred for 15 min, filtered with suction, washed with water, and dried. Silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 4:1 as the eluent, separated to obtain 3.22 g of white solid, yield: 78%. ¹ H NMR (600MHz, DMSO-d ₆ ) 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] ⁺ .

Step C: Preparation of (2-(4-aminophenoxy))ethyl 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylate

Put 2.1g (39.3mmol) of NH ₄ Cl and 2.2g (39.3mmol) of reduced iron powder in a 50mL eggplant-shaped bottle, add 10mL of water, and stir at 80°C for 30min. Add dropwise 30 mL of 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-nitrophenoxy))ethyl ester dissolved in ethanol into the above solution solution (2.5g, 3.93mmol), stirring was continued for 3h. The reaction solution was filtered while hot to remove iron powder, washed with ethyl acetate, and then evaporated to dryness. Dissolve in dichloromethane, wash with water, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure to obtain 2.1 g of white solid, yield: 88%. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Step D: N ¹ -Hydroxy-N ⁵ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy) Preparation of phenyl) glutaramide

Dissolve 0.09mL (0.75mmol) of monomethyl glutarate, 0.10g (0.75mmol) of HOBT and 0.14g (0.75mmol) of EDCI in 20 mL of dichloromethane, and stir at 0°C for 30min. Then 0.3 g (0.5 mmol) of 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-aminophenoxy))ethyl ester and 0.13 mL (0.75mmol) DIEA, stirred at room temperature for 12h. The reaction solution was washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether:ethyl acetate (V/V)=6:1 as the eluent was used to separate and obtain 0.24 g of white solid. The above-mentioned white solid intermediate was replaced with 4-(3β-hydroxyl-11-oxo-18β-oleanane-12-diene-30-carboxamido)methyl butyrate in Step B of Example 1 to prepare The title compound was 0.12 g, and the two-step yield was 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. ¹ H NMR (600MHz, DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 . ,16.7,16.5.LC-MS:733.5[MH] ^- .HRMS m/z calcd for C ₄₃ H ₆₁ N ₂ O ₈ ^- [MH] ^- 733.4433,found 733.4439.

Example 6: N ¹ -Hydroxy-N ⁶ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy ) phenyl) the preparation of adipamide

According to the preparation method of Example 5, the raw material monomethyl adipate was used instead of the raw material monomethyl glutarate in Example 5 to prepare the title compound. 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. ¹ H NMR (600MHz, DMSO-d ₆ ) 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). ¹³ C NMR(150MHz,DMSO-d ₆ ) 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 C ₄₄ H ₆₅ N ₂ O ₈ ⁺ [M+H] ⁺ 749.4735, fo und 749.4746.

Example 7: N ¹ -Hydroxy-N ⁷ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy ) phenyl) the preparation of pimelic acid

According to the preparation method of Example 5, the raw material monoethyl pimelate was used instead of the raw material monomethyl glutarate in Example 5 to prepare the title compound. 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, 1006.97, 893 600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 C ₄₅ H ₆₇ N ₂ O ₈ ⁺ [M+H] ⁺ 763.4892, found 763.4889.

Example 8: N ¹ -Hydroxy-N ⁸ -(4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy ) phenyl) suberamide preparation

According to the preparation method of Example 5, the raw material monomethyl suberate was used instead of the raw material monomethyl glutarate in Example 5 to prepare the title compound. Mp:110-113℃.IR(KBr): ^{3426.3,2928.8,2865.4,1729.3,1655.9,1542.7,1511.0,1459.1,1386.3,1365.5,1243.6,1211.9,1171.6,1085.8,1047.4,7,999} NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )δ199.7, 176.6,171.5,170.2,154.1,133.4,128.0,121.0,115.3,77.4,70.4 . ,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 C ₄₆ H ₆₉ N ₂ O ₈ ⁺ [M+H ] ⁺ 777.5048, found 777.5048.

Example 9: N ¹ -Hydroxy-N ⁵ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy) Preparation of phenyl) glutaramide

The title compound was prepared according to the preparation method of Example 5, substituting the raw material 1,3-dibromopropane for 1,2-dibromoethane in Example 5. 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, ^799.1.1 H NMR (600MHz, DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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, 37.1, 371.9 ,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[MH] ^- .HRMS m/z calcd for C ₄₄ H ₆₃ N ₂ O ₈ ^- [MH] ^- 747.4590, found 747.4591.

Example 10: N ¹ -Hydroxy-N ⁶ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy) Preparation of phenyl) adipamide

According to the preparation method of Example 5, the raw material 1,3-dibromopropane was used to replace the 1,2-dibromoethane in Example 5, and the raw material glutaric acid in Example 5 was replaced with the raw material monomethyl adipate Monomethyl ester, preparation of the title compound. 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, ^1047.29.8 , 895 H NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 C ₄₅ H ₆₇ N ₂ O ₈ ⁺ [M+H] ⁺ 763.4892,found 763.4889.

Example 11: N ¹ -Hydroxy-N ⁷ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy ) phenyl) the preparation of pimelic acid

According to the preparation method of Example 5, the raw material 1,3-dibromopropane is used to replace the 1,2-dibromoethane in Example 5, and the raw material monoethyl pimelate is used to replace the raw material glutaric acid in Example 5 Monomethyl ester, preparation of the title compound. 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, ^799.3.1 H NMR (600MHz, DMSO-d ₆ ) 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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 C ₄₆ H ₆₉ N ₂ O ₈ ⁺ [M+H ] ⁺ 777.5048, found 777.5051.

Example 12: N ¹ -Hydroxy-N ⁸ -(4-(3-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy ) phenyl) suberamide preparation

According to the preparation method of Example 5, the raw material 1,3-dibromopropane is used to replace the 1,2-dibromoethane in Example 5, and the raw material monomethyl suberate is used to replace the raw material glutaric acid in Example 5 Monomethyl ester, preparation of the title compound. 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, ^1051.30 , 180.3 H NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 C ₄₇ H ₇₁ N ₂ O ₈ ⁺ [M+H] ⁺ 791.5205 ,found 791.5215.

Example 13: 4-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido) Preparation of -N-hydroxybutanamide

Step A: Preparation of methyl 4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzoate

According to the preparation method in Step B of Example 5, the raw material methyl p-hydroxybenzoate was replaced by p-nitrophenol to prepare the title compound. ¹ H NMR (600MHz, DMSO-d ₆ ) 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] ⁺ .

Step B: Preparation of (2-(4-carboxyphenoxy))ethyl 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylate

Dissolve 1.08g (1.63mmol) of 4-(2-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzoate In 20mL of ethanol, add 20mL of potassium hydroxide solution (1mol/L), and stir at reflux for 1.5h. After the reaction solution was cooled to room temperature, 50 mL of water was added, and the pH was adjusted to 2-3 with 10% hydrochloric acid solution. Stir for 15 min, filter with suction, wash with water, and dry to obtain 1.03 g of white solid, yield: 78%. ¹ H NMR (600MHz, DMSO-d ₆ )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 [MH] ^- .

Step C: 4-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido)- Preparation of N-hydroxybutanamide

According to the preparation method of Example 5 step D, the raw material 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-carboxyphenoxy))ethyl Esters replace the raw material monomethyl glutarate in Example 5, and replace the 3β-hydroxyl-11-oxo-18β-oleanane-12 in Example 5 with the raw material 4-aminobutyric acid methyl ester hydrochloride -(2-(4-Aminophenoxy))ethyl diene-30-carboxylate, preparation of the title compound. 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, 1086.2, 1049.6, 1049.5 769.4. ¹ H NMR (600MHz, DMSO-d ₆ ) δ10.37(1H, s), 8.69(1H, s), 8.33 (1H, t, J=5.4Hz), 7.80(2H, d, J=8.4 Hz), 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). ¹³ C NMR(150MHz,DMSO-d ₆ )δ199.5,176.2, 169.8,169.3,166.0,160.8 ,129.4,127.8,127.5,114.4,77.0,66.5,66.2,62.8,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,38.9,37.7,32.5,31.9,30.5,29.4,28.7,24.0, ,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 C ₄₃ H ₆₃ N ₂ O ₈ ⁺ [M +H] ⁺ 735.4579,found735.4592.

Example 14: 5-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido) Preparation of -N-hydroxypentanamide

According to the preparation method of Example 13, the raw material 5-aminovaleric acid methyl ester hydrochloride was used instead of the raw material 4-aminobutyric acid methyl ester hydrochloride in Example 13 to prepare the title compound. 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, 1085.0, ^1047.281 , 96 H NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150 MHz,DMSO-d ₆ )δ199.6,176.2,169.9,165.9,160.7,129.4,127.8,127.5 . ,27.4,26.5, 26.2,23.4,23.3,18.7,17.6,16.7,16.5.LC-MS:747.3[MH] ^- .HRMS m/z calcd for C ₄₄ H ₆₅ N ₂ O ₈ ⁺ [M+H] ⁺ 749.4735,found 749.4757.

Example 15: 6-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido) Preparation of -N-hydroxycaproamide

According to the preparation method of Example 13, the raw material 4-aminobutyric acid methyl ester hydrochloride was replaced by the raw material 6-aminocaproic acid methyl ester hydrochloride in Example 13 to prepare the title compound. 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, 760 H. DMSO-d ₆ )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). ¹³ C NMR(150MHz, DMSO-d ₆ )δ198.5,175.2,168.7,168.4,164.8,159.6,128.3,126.8,126.5,113.3 . ,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 C ₄₅ H ₆₇ N ₂ O ₈ ⁺ [M+H] ⁺ 763.4892,found763.4894.

Example 16: 7-(4-(2-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)ethoxy)benzamido) Preparation of -N-hydroxyheptanamide

According to the preparation method of Example 13, the raw material 7-aminoheptanoic acid ethyl ester hydrochloride was used instead of the raw material 4-aminobutyric acid methyl ester hydrochloride in Example 13 to prepare the title compound. 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. ¹ H NMR, DM ( d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 C ₄₆ H ₆₉ N ₂ O ₈ ⁺ [M+H] ⁺ 777.5048, found 777.5051.

Example 17: 4-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido) Preparation of -N-hydroxybutanamide

According to the preparation method of Example 13, the title compound was prepared by replacing the raw material 1,2-dibromoethane with the raw material 1,3-dibromopropane. 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. ¹ H NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ ) 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, 43.3,40.8,40.5,39.3,39.2,38.9,37.8,37.1,32.5,32.0,30.7,29.3,28.7,2 ,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 C ₄₄ H ₆₃ N ₂ O ₈ ^- [MH ] ^- 747.4590, found 747.4593.

Example 18: 5-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido) Preparation of -N-hydroxypentanamide

According to the preparation method of Example 13, the raw material 1,3-dibromopropane is used to replace the raw material 1,2-dibromoethane, and the raw material 5-aminovaleric acid methyl ester hydrochloride is used to replace the raw material 4-amino in Example 13 Methyl butyrate hydrochloride, to prepare the title compound. 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. ¹ H NMR (600MHz, DMSO-d ₆ ) δ10.39(1H, s), 8.70(1H, s), 8.33(1H, t, J=5.4Hz), 7.80(2H, d, J=8.4 Hz), 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). ¹³ C NMR(150MHz,DMSO-d ₆ )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, ,28.6,28.5,28.1,27.4,26.5,26.2,25.9,23.4,18.8,17.6,16.7,16.5.LC-MS:785.6[M+Na] ⁺ .HRMS m/z calcd for C ₄₅ H ₆₇ N ₂ O ₈ ^- [M+H] ⁺ 763.4892,found763.4903.

Example 19: 6-(4-(3-(3β-Hydroxy-11-oxo-18β-oleanane-12-diene-30-formyloxy)propoxy)benzamido) Preparation of -N-hydroxycaproamide

According to the preparation method of Example 13, the raw material 1,3-dibromopropane was used to replace the raw material 1,2-dibromoethane, and the raw material 6-aminocaproic acid methyl ester hydrochloride was used to replace the raw material 4-amino in Example 13 Methyl butyrate hydrochloride, to prepare the title compound. Mp: 107-110 ℃ .IR (KBR): 3411.9, 2929.3,2865.9,1726.8,1632.8,1549.0,1504.3,1386.4,1310.9,12.5, 1172.7, 1047.8,997.8,99,7.8,997.8,99,7.8,99,7.8,99,7.8,99,99,99,99,99,99,99,97.8,99,99,99,99,99,99997.8,99,99,7.8. ¹ H NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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, 38.37, 7.3, 3, 2 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 C ₄₆ H ₆₇ N ₂ O ₈ ^- [MH] ^- 775.4903,found775.4899.

Example 20: N ¹ -Hydroxy-N ⁵ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl ) phenyl) the preparation of glutaramide

According to the preparation method of Example 13, the raw material 1,3-dibromopropane was used to replace the raw material 1,2-dibromoethane, and the raw material 7-aminoheptanoic acid ethyl ester hydrochloride was used to replace the raw material 4-amino in Example 13 Methyl butyrate hydrochloride, to prepare the title compound. 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 , 948 H.67. NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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, 30.7, 32 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 C ₄₇ H ₇₁ N ₂ O ₈ ⁺ [M+H] ⁺ 791.5211, found 791.5205.

Example 21: N ¹ -Hydroxy-N ⁵ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl ) phenyl) the preparation of glutaramide

Step A: Preparation of 1-(4-nitrophenyl)-4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazine

According to the preparation method in step A of Example 1, the raw material 4-nitrophenylpiperazine was used to replace the raw material 4-aminobutyric acid methyl ester hydrochloride to prepare the title compound. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Step B: Preparation of 1-(4-aminophenyl)-4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazine

According to the preparation method of step C of Example 5, the raw material 1-(4-nitrophenyl)-4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-acyl ) piperazine by substituting the starting material 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-nitrophenoxy))ethyl ester to prepare the title compound. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Step C: N ¹ -Hydroxy-N ⁵ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl) Preparation of phenyl) glutaramide

According to the synthesis procedure of Example 5, Step D, the raw material 1-(4-aminophenyl)-4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-acyl) The title compound was prepared by substituting piperazine for the starting material 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-aminophenoxy))ethyl ester. 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. ¹ H NMR (600MHz, DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )δ199. 6,173.5,170.6,169.2,147.2,132.5,129.1,127.9,120.6,116.6,77.0,67.9,65.5,61.5,54.6,49.9,48.2,45.2,43.8,43.4,40.5,369.2,39.0,370,1 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[MH] ^- .HRMS m/z calcd for C ₄₅ H ₆₅ N ₄ O ₆ ^- [MH] ^- 757.4910, found 757.4900.

Example 22: N ¹ -Hydroxy-N ⁶ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl ) phenyl) the preparation of adipamide

According to the synthesis procedure of Example 21, the raw material monomethyl adipate was used instead of the raw material monomethyl glutarate in Example 21 to prepare the title compound. 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, 1025.0, 845 (NMR.5, 99 600MHz,DMSO-d ₆ )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＝13.2 Hz), 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). ¹³ C NMR(150MHz,DMSO- d ₆ )δ199.6,173.5,170.9,170.4,169.4,147.2,132.5,127.9,120.6, 116.6,77.0,61.6,54.6,49.9,48.2,45.2,45.0,43.8,43.7,43.4,40.5,399.3,2 ,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 C ₄₆ H ₆₇ N ₄ O ₆ ^- [MH] ^- 771.5066,found771.5066.

Example 23: N ¹ -Hydroxy-N ⁶ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl ) phenyl) the preparation of adipamide

According to the synthesis procedure of Example 21, the raw material monoethyl pimelate was used instead of the raw material monomethyl glutarate in Example 21 to prepare the title compound. 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, 1025.8, 892 600MHz,DMSO-d ₆ )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＝13.2 Hz), 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). ¹³ C NMR(150MHz,DMSO-d ₆ )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, 32.6, 36. 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 C ₄₇ H ₆₉ N ₄ O ₆ ^- [MH] ^- 785.5223,found785.5216.

Example 24: N ¹ -Hydroxy-N ⁸ -(4-(4-(3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-yl)piperazin-1-yl ) phenyl) suberamide preparation

The title compound was prepared according to the synthetic procedure of Example 21, substituting the raw material monomethyl suberate for the raw material monomethyl glutarate in Example 21. 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, ^1026.7 , 87.9 H1 NMR(600MHz,DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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 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 C ₄₈ H ₇₁ N ₄ O ₆ ^- [MH] ^- 799.5379,found 799.5375.

Preparation of some intermediates

Preparation of 3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid

Weigh 3.5g (7.48mmol) GA and dissolve it in 150mL DMSO, add 8.37g (30mmol) IBX, and stir at reflux at 85°C for 4h. Cool to room temperature, pour into 300mL 5% NaHCO ₃ solution, a white solid precipitates out. Extracted with ether (150mL×3), combined organic layers, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain 2.65g of white solid, yield: 76%. ¹ H NMR (600MHz, DMSO-d ₆ )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).

Preparation of 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid

Weigh 6.0 g of 3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid (12.9 mmol) into a 500 mL eggplant-shaped bottle, and add 300 mL of anhydrous tetrahydrofuran to dissolve it. Then add 13.3g (51.6mmol) of I ₂ and 6.23mL (77.4mmol) of pyridine, and stir the reaction at 80°C for 12h, then add 6.65g (25.8mmol) of I ₂ and 3.12mL (38.7mmol) of pyridine, and continue stirring for 6h . Cool to room temperature, evaporate THF to dryness, dissolve with ethyl acetate, wash with sodium thiosulfate until golden yellow, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography using cyclohexane: acetone (V/V) = 50:1 as eluent, separated to obtain 5.42 g of white solid, yield: 71%. Mp:286-288℃. ¹ H NMR (600MHz, DMSO-d ₆ )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[MH] ^- .

Preparation of 2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid

Weigh 3.5g (6.8mmol) of 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid and 1.22g (13.6mmol) of CuCN and dissolve in 100mL NMP, stirred at 130°C for 2h. After the reaction solution was cooled to room temperature, the reaction solution was poured into 200 mL of water, stirred for 15 min, filtered with suction, washed with water, and dried. After concentration under reduced pressure, silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 6:1 as the eluent, separated to obtain 1.8 g of light yellow solid, yield: 54%. ¹ H NMR(600MHz,DMSO-d ₆ )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[MH] ^- .

Preparation of Benzyl 3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylate

Weigh 4.0g (6.8mmol) of 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid and dissolve it in 100mL of dry DMSO, add 2.8g (20.3mmol) K ₂ CO ₃ , stirred at room temperature for 0.5h. Then 0.96 mL benzyl bromide (8.1 mmol) was added and stirring was continued for 2 h. The reaction solution was poured into 250 mL of water, stirred for 15 min, filtered with suction, washed with water, and dried to obtain 4.27 g of white solid, yield: 92%. Mp:158-161 ℃. ¹ H NMR (600MHz,DMSO-d ₆ )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).

Preparation of Benzyl 2-Trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylate

4.92g 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylate benzyl ester (7.2mmol) was placed in a 250mL three-necked bottle, and 100mL Dried DMF was dissolved, and 4.12 g CuI (21.63 mmol) was added in the dark. Under nitrogen protection, the temperature was raised to 70°C, and 17.3 mL of methyl fluorosulfonyldifluoroacetate (144.2 mmol) and 25 mL of HMPA (144.2 mmol) were slowly added dropwise, and stirring was continued for 4 h. After the reaction solution was slightly cooled, 20 mL of saturated ammonium chloride solution was added to quench it, cooled to room temperature, washed with sodium sulfite, washed with 2N HCl, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 20:1 as the eluent was used to separate 3.3 g of white solid, yield: 73%. Mp:113-115℃. ¹ H NMR (600MHz,DMSO-d ₆ )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] ⁺ .

Preparation of 2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid

Dissolve 2.9 g of benzyl 2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylate in 20 mL of dry dichloromethane in 32.5 mL of 1N TiCl solution (32.5 mmol) was slowly added dropwise to the above solution at 0° C., and stirred for 15 min. Transfer to room temperature and continue stirring for 2h. The reaction solution was slowly added dropwise to ice water, extracted with dichloromethane, washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 10:1 as the eluent, separated to obtain 2.2 g of white solid, yield: 91%. Mp: 259-261℃. ¹ H NMR (600MHz, DMSO-d ₆ ) 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] ⁺ .

Preparation of 8-((4-hydroxyphenyl)amino)-8-oxoctanoic acid

Dissolve 3.62mL (20.2mmol) of monomethyl suberate, 2.36g (17.5mmol) of HOBT and 3.35g (17.5mmol) of EDCI in 40mL of dry DMF, and stir at room temperature for 30min. Subsequently, 2.0 g (18.4 mmol) of p-aminophenol and 2.73 mL (17.5 mmol) of DIEA were added, and the temperature was raised to 60° C. and stirred for 1.5 h. After the reaction solution was cooled to room temperature, it was poured into 200 mL of cold water, stirred for 10 min, filtered with suction, washed with water, and dried to obtain a brown solid. The above brown solid was dissolved in 20 mL of methanol, stirred at 60° C., then 10 mL of NaOH solution (1 mol/L) was added dropwise, and the stirring was continued for 2 h. After the reaction solution was cooled to room temperature, the reaction solution was poured into 150 mL of water, and the pH was adjusted to 2-3 with 10% hydrochloric acid solution. Stir for 15 min, filter with suction, wash with water, and dry to obtain 2.4 g of white solid with a yield of 49%. ¹ H NMR (600MHz, DMSO-d ₆ ) 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[MH] ^- .

Preparation of N ¹ -(4-hydroxyphenyl)-N ⁸ -((tetrahydro-2H-pyran-2-yl)oxy)succinamide

Dissolve 2.0g (7.5mmol) of 8-((4-hydroxyphenyl)amino)-8-oxoctanoic acid, 1.5g (11.3mmol) of HOBT and 2.2 (11.3mmol) of EDCI in 30mL of dry DMF, and stir at room temperature for 30min . Then 2.65 g (22.6 mmol) of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and 1.86 mL (11.3 mmol) of DIEA were added and stirring was continued for 2 h. The reaction solution was poured into a saturated sodium chloride solution, stirred for 15 min, filtered with suction, washed with water, and dried to obtain 2.35 g of a brown solid with a yield of 86%. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Preparation of 8-oxo-8-(((tetrahydro-2H-pyran-2-yl)oxy)amino)octanoic acid

According to the method of N ¹ -(4-hydroxyphenyl)-N ⁸ -((tetrahydro-2H-pyran-2-yl)oxy)succinamide, the raw material 8-((4 -Hydroxyphenyl)amino)-8-oxoctanoic acid, the title compound was prepared. LC-MS: 272.0[MH] ^- .

Example 25: N ¹ -Hydroxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-formyl Preparation of oxy)propoxy)phenyl)suberamide

Step A: Preparation of (3-bromo)propyl 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylate

Dissolve 2.0 g (3.4 mmol) of 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid in 20 mL of dry DMF, add 2.65 g (10.1 mmol) K ₂ CO ₃ , stirred at room temperature for 30 min. Then 1.7 mL (16.8 mmol) of 1,3-dibromopropane was added dropwise to the reaction liquid, and stirring was continued for 1 h. The reaction solution was poured into 100 mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 7:1 as the eluent, separated to obtain 1.7 g of white solid, yield: 71%. ¹ H NMR (600MHz,DMSO-d ₆ )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] ⁺ .

Step B: N ¹ -(tetrahydro-2H-pyran-2-yl)oxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β-olean Preparation of alkane-1,12-diene-30-formyloxy)propoxy)phenyl)suberamide

Dissolve 0.69 g (1.9 mmol) N ¹ -(4-hydroxyphenyl)-N ⁸ -((tetrahydro-2H-pyran-2-yl)oxy)succinamide in 20 mL of dry DMF, add 0.64 g (4.6 mmol) K ₂ CO ₃ , stirred at 80°C for 30 min. Then add 1.1g (1.5mmol) 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid (3-bromo)propyl ester and continue stirring for 2h . After the reaction solution was cooled to room temperature, it was poured into 100 mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether:ethyl acetate (V/V)=4:1 as the eluent was used to separate a white solid 0.18g, yield: 12%. ¹ H NMR (600MHz,DMSO-d ₆ )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] ⁺ .

Step C: N ¹ -Hydroxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-formyloxy Preparation of base) propoxy) phenyl) suberamide

0.12g (0.12mmol) N ¹ -(tetrahydro-2H-pyran-2-yl)oxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β -Oleanane-1,12-diene-30-formyloxy)propoxy)phenyl)suberamide was dissolved in 10 mL of dry dichloromethane, 1 mL of trifluoroacetic acid was added dropwise, and stirred at room temperature for 20 min. The reaction solution was washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using dichloromethane:methanol (V/V)=15:1 as the eluent was used to separate 27.4 mg of white solid, yield: 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. d ₆ )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) ^.13 CNMR(150MHz,DMSO-d ₆ )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[MH] ^- .HRMS m/z calcd for C ₄₇ H ₆₄ IN ₂ O ₈ ^- [MH] ^- 911.3713,found 911.3716.

Example 26: N ¹ -Hydroxy-N ⁸ -(4-(3-(2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30- Preparation of formyloxy)propoxy)phenyl)suberamide

According to the preparation method of Example 25, the raw material 2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid was used instead of 2 in Example 25 -Iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid, Preparation of the title compound. 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, 979.4.70 600MHz,DMSO-d ₆ )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). ¹³ C NMR (150MHz, DMSO-d ₆ ) 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, 85 ,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 for C ₄₈ H ₆₅ F ₃ N ₂ NaO ₈ ⁺ [M+Na] ⁺ 877.4585,found 877.4603.

Example 27: N ¹ -Hydroxy-N ⁸ -(4-(3-(2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-formyl Preparation of oxy)propoxy)phenyl)suberamide

According to the preparation method of Example 25, the 2-iodo in Example 25 was replaced by the raw material 2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid Dai-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid, to prepare the title compound. 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, ^703.1.1 H NMR d ₆ )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). ¹³ C NMR (150MHz, DMSO- d ₆ ) 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, 53.7,50.5,358.4,495,4,5 ,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 [MH] ^- .HRMS m/z calcd for C ₄₈ H ₆₄ N ₃ O ₈ ^- [MH] ^- 810.4699,found810.4695.

Example 28: N ¹ -Hydroxy-N ⁸ -(4-(4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl) Preparation of piperazin-1-yl)phenyl)suberamide

Step A: 1-(4-Nitrophenyl)-4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piperazine preparation of

According to the preparation method of step A of Example 1, the raw material 2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-carboxylic acid was used to replace the raw material GA, and the raw material 4 -Nitrophenylpiperazine was substituted for the starting material 4-aminobutyric acid methyl ester hydrochloride to prepare the title compound. ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺ .

Step B: 1-(4-Aminophenyl)-4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piperazine preparation

According to the synthesis procedure of step C of Example 5, the raw material 1-(4-nitrophenyl)-4-(2-iodo-3,11-dioxo-18β-oleanane-1,12- Diene-30-acyl)piperazine substitute raw material 3β-hydroxy-11-oxo-18β-oleanane-12-diene-30-carboxylic acid (2-(4-aminophenoxy))ethyl ester , to prepare the title compound. LC-MS: 752.6[M+H] ⁺ .

Step C: N ¹ -(tetrahydro-2H-pyran-2-yl)oxy-N ⁸ -(4-(4-(2-iodo-3,11-dioxo-18β-olean Preparation of alkane-1,12-diene-30-yl)piperazin-1-yl)phenyl)suberamide

0.44g (1.6mmol) 8-oxo-8-(((tetrahydro-2H-pyran-2-yl)oxy) amino) octanoic acid, 0.16g (1.2mmol) HOBT and 0.23g (1.2mmol) EDCI was dissolved in 20 mL of dry DMF and stirred at room temperature for 30 min. Then 0.6 g (0.8 mmol) 1-(4-aminophenyl)-4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30- Acyl)piperazine and 0.2mL (1.2mmol) DIEA, transferred to 60°C and stirred for 4h. After the reaction solution was cooled to room temperature, it was poured into 100 mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure, and silica gel column chromatography using petroleum ether: ethyl acetate (V/V) = 5:1 as the eluent, separated to obtain a light yellow solid 0.36, yield: 45%. ¹ H NMR (600MHz, DMSO-d ₆ ) 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] ⁺ .

Step D: N ¹ -Hydroxy-N ⁸ -(4-(4-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-yl)piper Preparation of oxazin-1-yl)phenyl)suberamide

According to the synthesis procedure of step C of Example 25, starting material N ¹ -(tetrahydro-2H-pyran-2-yl)oxy-N ⁸ -(4-(4-(2-iodo-3,11- Dioxo-18β-oleanane-1,12-dien-30-yl)piperazin-1-yl)phenyl)suberamide instead of raw material N ¹ -(tetrahydro-2H-pyran-2 -yl)oxy-N ⁸ -(4-(3-(2-iodo-3,11-dioxo-18β-oleanane-1,12-diene-30-formyloxy) Propoxy)phenyl)suberamide to prepare the title compound. 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, 7103 H.4 DMSO-d ₆ )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). ¹³ C NMR(150MHz,DMSO-d ₆ )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. ,22.4,20.4, 18.9,18.3,14.4.LC-MS:945.8[M+Na] ⁺ .HRMS m/z calcd for C ₄₈ H ₆₇ IN ₄ NaO ₆ ⁺ [M+Na] ⁺ 945.3997,found 945.4019.

Example 29: N ¹ -Hydroxy-N ⁸ -(4-(4-(2-trifluoromethyl-3,11-dioxo-18β-oleanane-1,12-diene-30- Preparation of acyl)piperazin-1-yl)phenyl)suberamide

According to the preparation method of Example 28, replace the raw material 2-iodo- 3,11-Dioxo-18β-oleanane-1,12-diene-30-carboxylic acid, Preparation of the title compound. 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, 1024.02, 97 600MHz,DMSO-d ₆ )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). ¹³ CNMR (150MHz, DMSO-d ₆ ) 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, 50.48, 39.9, LC- MS:887.7[M+Na] ⁺ .HRMS m/z calcd for C ₄₉ H ₆₇ F ₃ N ₄ NaO ₆ ⁺ [M+Na] ⁺ 887.4905,found 887.4902.

Example 30: N ¹ -Hydroxy-N ⁸ -(4-(4-(2-cyano-3,11-dioxo-18β-oleanane-1,12-diene-30-yl) Preparation of piperazin-1-yl)phenyl)suberamide

According to the preparation method of Example 28, the raw material 2-iodo-3, 11-Dioxo-18β-oleanane-1,12-diene-30-carboxylic acid, Preparation of the title compound. 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. ¹ H NMR (600 MHz, DMSO-d ₆ 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 ). ¹³ C NMR (150MHz, DMSO-d ₆ ) 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. ,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[MH] ^- .HRMS m/z calcd for C ₄₉ H ₆₇ N ₅ NaO ₆ ⁺ [M+Na] ⁺ 844.4984,found 844.4954.

Research on the pharmacological action of the product of the present invention

In vitro anti-tumor activity test

1) Cell culture

Human acute leukemia cells HL-60, prostate cancer cells PC-3, and breast cancer cells MCF-7 were cultured in 10% (v/v) heat-inactivated fetal bovine serum, 100 U/mL penicillin, 100 μg/mL chain Mycin and 2mmol/L glutamine in RPMI 1640 culture fluid or high-glucose DMEM culture fluid. All experimental cells were cultured in a 37°C, 5% _CO2 saturated humidity incubator.

2) Cytostatic activity

The growth inhibitory effect of compounds on HL-60 cells was investigated by cell counting. Inoculate a certain density (1×10 ⁵ cells/mL) of cell suspension in a 24-well culture plate, 2 mL/well, add different concentrations of drugs and incubate together for 72 hours, count under a microscope, and calculate the cell growth inhibition rate according to the following formula , and obtain the half growth inhibitory concentration GI ₅₀ (drug concentration when the cell growth inhibition rate reaches 50%).

The growth inhibitory effect of compounds on solid tumor cells PC-3 and MCF-7 was investigated by MTT method. Inoculate a certain density (2-3×10 ⁴ cells/mL) of cell suspension in a 96-well culture plate, 100 μL/well, add different concentrations of compounds and incubate for 96 hours, then add 50 μL of MTT solution and continue to incubate for 3.5 hours, then Discard all the liquid in the 96-well plate and turn it upside down on the filter paper to fully absorb the residual liquid, then add 200 μL DMSO to each well and shake on the shaker for 10 minutes to dissolve the blue-purple crystals, and finally use a microplate reader to measure the absorbance at 570nm , set A1 (containing 200 μL DMSO) as the blank control well; obtain the cell growth inhibition rate according to the following formula, and obtain the half inhibitory concentration GI ₅₀ (compound concentration when the cell growth inhibition rate reaches 50%).

Table 1 compound is to HL-60, the GI ₅₀ (μmol/L) value list of PC-3 and MCF-7

Claims (9)

1. A compound, optical isomer or pharmaceutically acceptable salt represented by general formula I or II:

x is

The left side of the X is connected with a glycyrrhetinic acid skeleton, and the right side of the X is connected with a hydroxamic acid fragment;

r is halogen, trifluoromethyl, methylsulfonyl or cyano;

m is an integer of 1 to 6;

n is an integer of 1 to 8.

2. The compound, optical isomer or pharmaceutically acceptable salt according to claim 1:

x is

The left side of the X is connected with a glycyrrhetinic acid skeleton, and the right side of the X is connected with a hydroxamic acid fragment;

r is iodine, trifluoromethyl or cyano;

m is an integer of 1 to 6;

n is an integer of 1 to 8.

3. The compound, optical isomer or pharmaceutically acceptable salt according to claim 1 or 2:

x is

The left side of the X is connected with a glycyrrhetinic acid skeleton, and the right side of the X is connected with a hydroxamic acid fragment;

r is iodine, trifluoromethyl or cyano;

m is an integer of 2 to 3;

n is an integer of 3 to 6.

4. The compound, optical isomer or pharmaceutically acceptable salt according to claim 1,

4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxamido) -N-hydroxybutyramide

5- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) -N-hydroxypentanamide

6- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formamido) -N-hydroxyhexanamide

7- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxamido) -N-hydroxyheptanamide

N¹-hydroxy-N⁵- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) glutaramide

N¹-hydroxy-N⁶- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) hexanediamide

N¹-hydroxy-N⁷- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) pimelide

N¹-hydroxy-N⁸- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) phenyl) octanediamide

N¹-hydroxy-N⁵- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) glutaramide

N¹-hydroxy-N⁶- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) adipamide

N¹-hydroxy-N⁷- (4- (3- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-formyloxy) propoxy) phenyl) pimelide

N¹-hydroxy-N⁸- (4- (3- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-formyloxy) propoxy) phenyl) octanediamide

4- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxybutyramide

5- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxypentanamide

6- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyhexanamide

7- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyheptanamide

4- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxybutyramide

5- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxypentanamide

6- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxyhexanamide

7- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxyheptanamide

N¹-hydroxy-N⁵- (4- (4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) glutaramide

N¹-hydroxy-N⁶- (4- (4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) adipamide

N¹-hydroxy-N⁷- (4- (4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) pimelide

N¹-hydroxy-N⁸- (4- (4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (3- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (3- (2-trifluoromethyl-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (3- (2-cyano-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-)Formyloxy) propoxy) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (4- (2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-dien-30-acyl) piperazin-1-yl) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (4- (2-trifluoromethyl-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

N¹-hydroxy-N⁸- (4- (4- (2-cyano-3, 11-dioxy-18 β -oleanane-1, 12-dien-30-acyl) piperazin-1-yl) phenyl) octanediamide.

5. A pharmaceutical composition characterized by: comprising a compound, optical isomer or pharmaceutically acceptable salt of any of claims 1-4 and a pharmaceutically acceptable excipient.

6. A process for producing a compound, an optical isomer or a pharmaceutically acceptable salt according to claim 1,

7. use of a compound, an optical isomer or a pharmaceutically acceptable salt according to any one of claims 1 to 4 for the preparation of a medicament for the treatment and/or prevention of an antitumor agent.

8. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment and/or prevention of an antineoplastic agent.

9. The use of claim 7 or 8, wherein the tumor is breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, liver cancer, bladder cancer, uterine cancer, pancreatic cancer, ovarian cancer, lymphatic cancer, ovarian cancer, skin cancer or hematological cancer.