CN110526955B

CN110526955B - 18 beta-glycyrrhetinic acid compound containing hydroxamic acid structural fragment and application thereof

Info

Publication number: CN110526955B
Application number: CN201910853112.4A
Authority: CN
Inventors: 赵临襄; 刘丹; 黄敏; 唐煜; 谢晓瑞; 景永奎
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2019-09-10
Filing date: 2019-09-10
Publication date: 2020-12-18
Anticipated expiration: 2039-09-10
Also published as: CN110526955A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to 18 beta-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and preparation and application thereof, as well as pharmaceutical compositions of 18 beta-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments, optical isomers and pharmaceutically acceptable salts thereof, and application thereof in preparation of medicines for treating and/or preventing various cancers. The compound has the following structural general formula, wherein X, R is described in the claims and the specification.

Description

18 beta-glycyrrhetinic acid compound containing hydroxamic acid structural fragment and application thereof

The technical field is as follows:

the invention belongs to the technical field of medicines, and particularly relates to 18 beta-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments and preparation and application thereof, as well as pharmaceutical compositions of 18 beta-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments, optical isomers and pharmaceutically acceptable salts thereof, and application thereof in preparation of medicines for treating and/or preventing various cancers.

Background art:

the 18 beta-glycyrrhetinic acid is a pentacyclic triterpenoid natural product, has wide sources and has various pharmacological activities. Its antineoplastic action is also receiving attention, but its activity is not strong, so that it is difficult to meet the requirements for clinical application. In order to improve the anti-tumor effect of the 18 beta-glycyrrhetinic acid, researchers combine the 18 beta-glycyrrhetinic acid with other active fragments (such as structures of ferulic acid, cinnamic acid, rhodamine B and the like) through a hybrid strategy to obtain various hybrid molecules, and the activity of the hybrid molecules is improved to a certain extent compared with that of a parent compound.

Hydroxamic acid structures are capable of chelating a wide variety of transition metals, the chelating ability of which makes them ubiquitous in a variety of drugs and drug-like molecules. Among them, the inhibitory activity of hydroxamic acid compounds against metalloproteases and histone deacetylases is deeply studied, and several compounds are coming into clinical use for the treatment of cancer. Hydroxamic acid is introduced into different target ligand molecules or natural product structures through a splicing principle, so that the synergistic inhibition effect and stronger tumor inhibition effect of multiple action targets are expected to be obtained.

The inventor designs and synthesizes a series of 18 beta-glycyrrhetinic acid analogues containing hydroxamic acid structural fragments, and after cell activity screening, the synthesized compound has better tumor cell growth inhibition activity.

The invention content is as follows:

the technical problem solved by the invention is to provide a series of 18 beta-glycyrrhetinic acid analogs containing hydroxamic acid structural fragments and application of the 18 beta-glycyrrhetinic acid analogs containing hydroxamic acid structural fragments in preparation of medicines for preventing and/or treating tumors.

The invention relates to derivatives shown in general formula I or II, and optical isomers and pharmaceutically acceptable salts thereof:

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, halogenated C1-C4 alkyl, methylsulfonyl, cyano;

m is an integer of 1 to 6;

n is an integer of 1 to 8.

Preferred compounds of the invention are those having the structure, optically active forms and pharmaceutically acceptable salts thereof,

wherein the content of the first and second substances,

x is

r is iodine, trifluoromethyl or cyano;

m is an integer of 1 to 6;

n is an integer of 1 to 8.

wherein the content of the first and second substances,

x is

r is iodine, trifluoromethyl or cyano;

m is an integer of 2 to 3;

n is an integer of 3 to 6.

Particularly preferred compounds include:

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

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

6- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxamido) -N-hydroxyhexanamide (example 3)

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

N¹-hydroxy-N⁵- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) phenyl) glutaramide (example 5)

N¹-hydroxy-N⁶- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) phenyl) hexanediamide (example 6)

N¹-hydroxy-N⁷- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) phenyl) pimelide (example 7)

N¹-hydroxy-N⁸- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-di)Ene-30-formyloxy) ethoxy) phenyl) octanediamide (example 8)

N¹-hydroxy-N⁵- (4- (3- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) propoxy) phenyl) glutaramide (example 9)

N¹-hydroxy-N⁶- (4- (3- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) propoxy) phenyl) hexanediamide (example 10)

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

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

4- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxybutyramide (example 13)

5- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxypentanamide (example 14)

6- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyhexanamide (example 15)

7- (4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyheptanamide (example 16)

4- (4- (3- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxybutyramide (example 17)

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

6- (4- (3- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxyhexanamide (example 19)

7- (4- (3- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxyheptanamide (example 20)

N¹-hydroxy-N⁵- (4- (4- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) glutaramide (example 21)

N¹-hydroxy-N⁶- (4- (4- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) hexanediamide (example 22)

N¹-hydroxy-N⁷- (4- (4- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) pimelide (example 23)

N¹-hydroxy-N⁸- (4- (4- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide (example 24)

N¹-hydroxy-N⁸- (4- (3- (2-iodo-3, 11-dioxy-18. beta. -oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide (example 25)

N¹-hydroxy-N⁸- (4- (3- (2-trifluoromethyl-3, 11-dioxy-18. beta. -oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide (example 26)

N¹-hydroxy-N⁸- (4- (3- (2-cyano-3, 11-dioxy-18. beta. -oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide (example 27)

N¹-hydroxy-N⁸- (4- (4- (2-iodo-3, 11-dioxy-18. beta. -oleanane-1, 12-dien-30-oyl) piperazin-1-yl) phenyl) octanediamide (example 28)

N¹-hydroxy-N⁸- (4- (4- (2-trifluoromethyl-3, 11-dioxy-18. beta. -oleanane-1, 12-dien-30-oyl) piperazin-1-yl) phenyl) octanediamide (example 29)

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

The invention also includes prodrugs of the compounds of the invention. According to the present invention, prodrugs are derivatives of formula I or II which may themselves have a weak activity or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis and otherwise) to the corresponding biologically active form.

The invention includes pharmaceutical compositions comprising 18 beta-glycyrrhetinic acid compounds containing hydroxamic acid structural fragments of the general formula I or II, as well as optically active forms and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. 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 may be used in combination with other active ingredients as long as 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 formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions).

Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binders, lubricants, disintegrating agents, solubilizing agents, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.

Through in vitro activity screening, the compound disclosed by the invention is found to have antitumor activity, so that the compound disclosed by the invention can be used for preparing medicaments for treating and/or preventing various cancers, such as breast cancer, lung cancer, colon cancer, rectal cancer, stomach cancer, prostatic cancer, liver cancer, bladder cancer, uterine cancer, pancreatic cancer, ovarian cancer, lymph cancer, ovarian cancer, skin cancer and blood cancer.

The active compounds of the present invention may be used as sole anticancer agents or in combination with one or more other antitumor agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.

The first synthetic route is as follows:

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)1M NaOH(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.

the second synthetic route is as follows:

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.

the third synthetic route is as follows:

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.

the synthesis route is four:

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.

the specific implementation mode is as follows:

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

IR of the compound was measured by using a Bruker IR-27G type chromatograph, and nuclear magnetic resonance spectroscopy was performed by using a Bruker ARX-600 nuclear magnetic resonance spectrometer in CDCl₃Or DMSO-d₆TMS is used as an internal standard for determination, the low-resolution mass spectrum is determined by an Agilent 1100SL type ion trap mass spectrometer, and the high-resolution mass spectrum is determined by Bruker micro-TOF-Q.

Example 1: preparation of 4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) -N-hydroxybutyramide

Step A: preparation of methyl 4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) butyrate

0.5g (1.06mmol) of GA, 0.31g (1.60mmol) of EDCI and 0.20g (1.60mmol) of DMAP were dissolved in 20mL of dichloromethane and stirred at room temperature for 30 min. 0.25g (1.60mmol) of methyl 4-aminobutyrate hydrochloride are subsequently added and stirring is continued for 6 h. The reaction mixture was washed with water, saturated sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was concentrated in a ratio of cyclohexane: acetone (V/V) ═ 8: silica gel column chromatography with eluent 1, separating to obtain white solid 0.38g, yield: and 63 percent.¹H NMR(600MHz,DMSO-d₆)7.60(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]^-.

Step B preparation of 4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) -N-hydroxybutyramide

0.3g (0.53mmol) of 4- (3 beta-hydroxy-11-oxo-18 beta-quinoline-carboxylic acid)Methyl oleanane-12-diene-30-formylamino) butyrate was dissolved in 15mL of methanol, and 3mL of a sodium hydroxide solution (1mol/L) and 3mL of a hydroxylamine aqueous solution (50%) were sequentially added dropwise at 0 ℃ and stirred for 15 min. The reaction was then transferred to room temperature and stirring was continued for 2 h. The solvent was evaporated under reduced pressure, 15mL of water was added, and the pH was adjusted to about 7 with an aqueous hydrochloric acid solution (1 mol/L). Stirring for 15min, filtering, washing with water to obtain white solid 0.18g, yield: 60 percent. Mp 200 ℃. 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(600MHz,DMSO-d₆)10.37(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).¹³C NMR(150MHz,DMSO-d₆)199.6,175.5,170.2,169.4,127.9,77.0,61.6,54.6,48.2,45.3,43.4,43.3,41.2,40.5,39.2,39.0,38.9,37.8,37.1,32.6,31.8,30.9,30.5,29.1,28.9,28.6,27.4,26.5,26.4,26.2,23.5,18.8,17.6,16.7,16.5.LC-MS:568.9[M-H]^-.HRMS m/z calcd for C₃₄H₅₅N₂O₅ ⁺[M+H]⁺571.4105,found 571.4109.

Example 2: preparation of 5- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) -N-hydroxypentanamide

The title compound was prepared according to the preparation method of example 1, substituting the starting material methyl 4-aminobutyrate hydrochloride in example 1 with the starting material methyl 5-aminovalerate hydrochloride. Mp 156 ℃. 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)10.33(1H,s),8.64(1H,s),7.56(1H,t,J＝5.4Hz),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)199.6,175.3,170.3,169.5,127.9,77.0,61.6,54.6,48.2,45.3,43.4,43.3,41.2,39.2,39.0,38.7,37.8,37.1,32.6,32.4,31.8,30.9,29.4,29.2,28.9,28.6,27.4,26.5,26.4,23.5,23.0,18.8,17.6,16.7,16.5.LC-MS:583.0[M-H]^-.HRMS m/z calcd for C₃₅H₅₅N₂O₅ ^-[M-H]^-583.4116,found 583.4100.

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

The title compound was prepared according to the preparation method of example 1, substituting the starting material methyl 4-aminobutyrate hydrochloride in example 1 with the starting material methyl 6-aminocaproate hydrochloride. Mp 153 ℃. 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)10.31(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)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.

Example 4: preparation of 7- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formylamino) -N-hydroxyheptanoamide

The procedure of example 1 was followed, substituting the starting material, ethyl 7-aminoheptanoate hydrochloride, for the example1 to yield the title compound. Mp 135 ℃. 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)10.31(1H,s),8.64(1H,s),7.52(1H,t,J＝5.4Hz),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)199.6,175.3,170.2,169.5,127.9,77.0,61.6,54.5,48.2,45.3,43.4,43.3,41.2,40.5,39.2,39.0,38.9,37.8,37.1,32.7,32.6,31.8,30.9,29.7,29.1,28.9,28.8,28.6,27.4,26.6,26.5,26.4,25.6,23.4,18.8,17.6,16.6,16.5.LC-MS:611.0[M-H]^-.HRMS m/z calcd for C₃₇H₅₉N₂O₅ ^-[M-H]^-611.4429,found611.4428.

Example 5: n is a radical of¹-hydroxy-N⁵Preparation of- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) glutaramide

Step A: preparation of 3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxylic acid (2-bromo) ethyl ester

3.0g (6.4mmol) of GA in 30mL of dry DMF was added 2.65g (19.2mmol) of K₂CO₃Then, the mixture was stirred at room temperature for 30 min. Subsequently, 2.7mL (32.0mmol) of 1, 2-dibromoethane was added dropwise to the reaction solution, and the reaction solution was transferred to 80 ℃ and stirred for 40 min. After the reaction solution was cooled to room temperature, the reaction solution was poured into 100mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 6: silica gel column chromatography with eluent 1, separating to obtain white solid 2.69g, yield: 73 percent.¹H NMR(600MHz,DMSO-d₆)5.54(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]⁺.

And B: preparation of 3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxylic acid (2- (4-nitrophenoxy)) ethyl ester

0.90g (6.5mmol) of 4-nitrophenol is dissolved in 30mL of dry DMF and 1.78g (12.9mmol) of K is added₂CO₃Then, the mixture was stirred at 80 ℃ for 30 min. Then, 10ml of 3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxylic acid (2-bromo) ethyl ester (2.5g,4.3mmol) dissolved in the mixed solution was added dropwise to the reaction solution, and the mixture was further stirred for 3 hours. And (3) cooling the reaction solution to room temperature, pouring the reaction solution into 100mL of water, stirring for 15min, carrying out suction filtration, washing with water, and drying. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate (V/V) ═ 4: silica gel column chromatography with eluent 1, separating to obtain white solid 3.22g, yield: 78 percent.¹H NMR(600MHz,DMSO-d₆)8.18(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]⁺.

And C: preparation of 3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxylic acid (2- (4-aminophenoxy)) ethyl ester

2.1g (39.3mmol) NH₄Cl and 2.2g (39.3mmol) of reduced iron powder were put in a 50mL eggplant-shaped bottle, 10mL of water was added thereto, and the mixture was stirred at 80 ℃ for 30 min. To the solution was added dropwise a solution of ethyl 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylate (2.5g,3.93mmol) dissolved in 30mL of ethanol, and the mixture was stirred for 3 hours. The reaction solution was filtered while hot to remove iron powder, washed with ethyl acetate, and then the solvent was evaporated. Dissolving with dichloromethane, washing with water, washing with saturated sodium chloride, and drying with anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure to give 2.1g of a white solid, yield: 88 percent.¹H NMR(600MHz,DMSO-d₆)6.66(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 is a radical of¹-hydroxy-N⁵Preparation of- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) glutaramide

0.09mL (0.75mmol) of monomethyl glutarate, 0.10g (0.75mmol) of HOBT and 0.14g (0.75mmol) of EDCI were dissolved in 20mL of dichloromethane and stirred at 0 ℃ for 30 min. Then 0.3g (0.5mmol) of 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylic acid (2- (4-aminophenoxy)) ethyl ester and 0.13mL (0.75mmol) of DIEA were added and stirred at room temperature for 12 h. The reaction mixture was washed with water, saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 6: silica gel column chromatography with eluent 1, and separating to obtain white solid 0.24 g. The white solid intermediate was substituted for the 4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylic acid, step B, example 1Amino) butyric acid methyl ester, 0.12g of the title compound was prepared in 33% yield in two steps. Mp 111 ℃. 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)10.37(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)199.5,176.3,170.6,169.8,169.2,154.3,133.3,127.9,120.9,115.0,77.0,66.5,63.0,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,39.2,38.9,37.7,37.1,35.9,32.5,32.1,31.9,30.8,28.7,28.6,28.1,27.4,26.2,23.4,21.7,18.7,17.6,16.7,16.5.LC-MS:733.5[M-H]^-.HRMS m/z calcd for C₄₃H₆₁N₂O₈ ^-[M-H]^-733.4433,found 733.4439.

Example 6: n is a radical of¹-hydroxy-N⁶Preparation of- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) hexanediamide

The title compound was prepared according to the procedure for the preparation of example 5 substituting the starting monomethyl adipate for the starting monomethyl glutarate in example 5. Mp 122 ℃. 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)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)199.6,176.3,171.0,169.9,169.4,154.3,133.5,128.1,121.1,115.3,77.4,70.1,66.9,63.1,61.5,54.8,54.5,50.0,48.4,48.3,45.3,44.1,43.3,41.9,41.8,41.6,40.9,40.4,39.2,38.9,37.7,37.1,36.5,33.9,32.6,32.5,31.9,30.8,28.6,28.6,28.1,27.4,26.8,26.5,26.2,25.3,24.6,23.4,18.7,17.6,16.7,16.5.LC-MS:771.4[M+Na]⁺.HRMS m/z calcdfor C₄₄H₆₅N₂O₈ ⁺[M+H]⁺749.4735,found 749.4746.

Example 7: n is a radical of¹-hydroxy-N⁷Preparation of- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) pimelinamide

The title compound was prepared according to the preparation of example 5 substituting the starting material monomethyl glutarate in example 5 with the starting material monoethyl pimelate. Mp 140 ℃. 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)10.35(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)199.7,176.1,170.8,169.8,169.5,154.2,133.8,127.8,121.1,115.3,77.4,70.4,66.6,63.4,61.8,54.8,48.3,45.3,44.1,43.3,40.9,40.5,39.2,38.9,37.7,37.1,36.6,32.6,32.5,31.9,30.8,28.7,28.7,28.6,28.1,27.4,26.5,26.2,25.4,25.4,23.4,18.8,17.6,16.7,16.5.LC-MS:785.4[M+Na]⁺.HRMS m/z calcdfor C₄₅H₆₇N₂O₈ ⁺[M+H]⁺763.4892,found 763.4889.

Example 8: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) phenyl) octanediamide

The title compound was prepared according to the preparation of example 5 substituting the starting monomethyl glutarate in example 5 with the starting monomethyl suberate. Mp 110 ℃. 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)10.35(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)199.7,176.6,171.5,170.2,154.1,133.4,128.0,121.0,115.3,77.4,70.4,66.7,63.4,61.7,55.0,48.3,45.3,44.1,43.3,40.9,40.5,39.2,38.9,37.7,37.1,36.7,32.7,32.5,31.9,30.8,28.9,28.9,28.7,28.6,28.1,27.4,26.5,26.2,25.6,25.5,23.4,18.8,17.6,16.7,16.5.LC-MS:799.4[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048,found 777.5048.

Implementation 9: n is a radical of¹-hydroxy-N⁵Preparation of- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) glutaramide

The title compound was prepared by the procedure for example 5 substituting 1, 3-dibromopropane as the starting material for 1, 2-dibromoethane of example 5. Mp 112 ℃. 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)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)199.5,176.2,170.6,169.8,169.2,154.6,133.1,127.9,121.0,114.9,77.0,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.0,32.5,32.1,32.0,30.7,28.7,28.6,28.2,27.4,26.5,26.2,23.4,21.7,18.8,17.6,16.7,16.5.LC-MS:747.7[M-H]^-.HRMS m/z calcd for C₄₄H₆₃N₂O₈ ^-[M-H]^-747.4590,found 747.4591.

Implementation 10: n is a radical of¹-hydroxy-N⁶Preparation of- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) hexanediamide

The title compound was prepared according to the procedure for the preparation of example 5 substituting the starting material 1, 3-dibromopropane for 1, 2-dibromoethane of example 5 and monomethyl adipate for monomethyl glutarate of example 5. Mp 115 ℃. 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)10.37(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)199.5,176.2,171.0,169.8,169.4,154.6,133.2,127.8,120.9,114.8,77.0,70.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.5,32.6,32.0,30.7,28.7,28.6,28.2,27.4,26.8,26.5,26.2,25.4,23.4,18.8,17.6,16.7,16.5.LC-MS:785.6[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ⁺[M+H]⁺763.4892,found 763.4889.

Example 11: n is a radical of¹-hydroxy-N⁷Preparation of- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) pimelinamide

The title compound was prepared according to the procedure for the preparation of example 5 substituting the starting material 1, 3-dibromopropane for 1, 2-dibromoethane of example 5 and monoethyl pimelate for monomethyl glutarate of example 5. Mp 162 ℃. 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)10.34(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)199.7,176.5,172.0,169.8,169.5,154.5,133.5,128.1,121.1,115.0,77.1,70.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.6,32.6,32.5,32.0,30.7,28.7,28.7,28.6,28.2,27.4,26.5,26.2,25.4,23.4,18.8,17.6,16.7,16.5.LC-MS:799.4[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048,found777.5051.

Example 12: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) phenyl) octanediamide

The preparation method of example 5 is followed, starting from 1The title compound was prepared by substituting 3-dibromopropane for 1, 2-dibromoethane in example 5 and the starting monomethyl glutarate in example 5 with the starting monomethyl suberate. Mp 186 ℃. 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)10.37(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)199.4,176.5,171.1,169.8,169.5,155.1,133.2,127.8,121.1,115.0,77.2,70.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,38.9,37.8,37.1,36.7,32.7,32.5,32.0,30.7,28.9,28.7,28.6,28.2,27.4,26.5,26.2,25.6,25.5,23.4,18.8,17.6,16.7,16.5.LC-MS:813.4[M+Na]⁺.HRMS m/z calcdfor C₄₇H₇₁N₂O₈ ⁺[M+H]⁺791.5205,found 791.5215.

Example 13: preparation of 4- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxybutyramide

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

The title compound was prepared following the procedure for the preparation of example 5, step B, substituting p-nitrophenol with the starting methylparaben.¹H NMR(600MHz,DMSO-d₆)7.88(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]⁺.

And B: preparation of 3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-carboxylic acid (2- (4-carboxyphenoxy)) ethyl ester

1.08g (1.63mmol) of methyl 4- (2- (3. beta. -hydroxy-11-oxo-18. beta. -oleanane-12-diene-30-formyloxy) ethoxy) benzoate was dissolved in 20mL of ethanol, and 20mL of a potassium hydroxide solution (1mol/L) was added thereto, followed by stirring under reflux for 1.5 hours. And (3) cooling the reaction liquid to room temperature, adding 50mL of water, and adjusting the pH value to 2-3 by using a 10% hydrochloric acid solution. Stirring for 15min, suction filtering, water washing and drying to obtain 1.03g of white solid, yield: 78 percent.¹H NMR(600MHz,DMSO-d₆)12.62(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]^-.

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

The procedure is as in step D of example 5, using the starting material 3 beta-hydroxy-11-oxo-18 beta-oxazineThe title compound was prepared by substituting the starting material monomethyl glutarate in example 5 with ethyl 2- (4-carboxyphenoxy) oleanane-12-diene-30-carboxylate and the starting material methyl 4-aminobutyrate hydrochloride for ethyl 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylate (2- (4-aminophenoxy)) in example 5. Mp 89-91 deg.C, 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)10.37(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)199.5,176.2,169.8,169.3,166.0,160.8,129.4,127.8,127.5,114.4,77.0,66.5,66.2,62.8,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,38.9,37.7,32.5,31.9,30.5,29.4,28.7,28.0,27.4,26.2,25.9,24.1,23.4,22.6,18.7,17.6,16.7,16.5,14.5.LC-MS:757.6[M+Na]⁺.HRMS m/z calcdfor C₄₃H₆₃N₂O₈ ⁺[M+H]⁺735.4579,found 735.4592.

Example 14: preparation of 5- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxypentanamide

The title compound was prepared according to the procedure for the preparation of example 13, substituting the starting material methyl 4-aminobutyrate hydrochloride in example 13 with the starting material methyl 5-aminovalerate hydrochloride. Mp 145 ℃. 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)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(150MHz,DMSO-d₆)199.6,176.2,169.9,165.9,160.7,129.4,127.8,127.5,114.4,77.0,70.2,66.5,62.8,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,39.3,39.2,38.9,37.7,37.1,32.5,31.9,30.8,29.3,28.7,28.6,28.0,27.4,26.5,26.2,23.4,23.3,18.7,17.6,16.7,16.5.LC-MS:747.3[M-H]^-.HRMS m/z calcd for C₄₄H₆₅N₂O₈ ⁺[M+H]⁺749.4735,found 749.4757.

Example 15: preparation of 6- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyhexanamide

The title compound was prepared according to the preparation of example 13 substituting the starting material methyl 4-aminobutyrate hydrochloride in example 13 with the starting material methyl 6-aminocaproate hydrochloride. Mp 130 ℃. 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)10.34(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)198.5,175.2,168.7,168.4,164.8,159.6,128.3,126.8,126.5,113.3,75.9,65.4,65.1,61.8,60.5,53.4,47.2,44.2,43.0,42.2,39.8,39.4,38.2,37.9,36.6,36.0,31.6,31.4,30.8,29.7,28.4,27.9,27.6,27.5,27.0,26.3,25.5,24.3,22.4,17.7,16.5,15.6,15.4.LC-MS:785.6[M+Na]⁺.HRMS m/z calcd for C₄₅H₆₇N₂O₈ ⁺[M+H]⁺763.4892,found 763.4894.

Example 16: preparation of 7- (4- (2- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) ethoxy) benzoylamino) -N-hydroxyheptanamide

The title compound was prepared according to the preparation of example 13 substituting the starting material of methyl 4-aminobutyrate hydrochloride in example 13 with ethyl 7-aminoheptanoate hydrochloride. Mp 135 ℃. 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)10.32(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)199.5,176.2,169.8,169.6,165.9,160.7,129.4,127.9,127.6,114.4,77.0,66.5,66.2,62.8,61.6,54.5,48.3,45.3,44.1,43.3,40.9,40.5,39.2,38.9,37.7,37.1,32.7,32.5,31.9,31.8,30.8,29.6,29.4,28.8,28.7,28.6,28.0,27.4,26.7,26.5,26.2,25.8,25.6,24.1,23.4,22.6,18.7,17.6,16.7,16.5,14.5.LC-MS:799.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₉N₂O₈ ⁺[M+H]⁺777.5048,found 777.5051.

Example 17: preparation of 4- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxybutyramide

The title compound was prepared by the procedure for the preparation of example 13 substituting the starting material 1, 3-dibromopropane for the starting material 1, 2-dibromoethane. 130 ℃ Mp, 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)10.34(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)199.5,176.2,169.8,169.5,165.9,161.0,129.4,127.8,127.4,114.3,77.0,64.9,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.3,39.2,38.9,37.8,37.1,32.5,32.0,30.7,29.3,28.7,28.6,28.1,27.4,26.5,26.2,23.4,23.2,18.8,17.6,16.7,16.5.LC-MS:771.6[M+Na]⁺.HRMS m/z calcd for C₄₄H₆₃N₂O₈ ^-[M-H]^-747.4590,found 747.4593.

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

The title compound was prepared according to the preparation method of example 13, substituting the starting material 1, 3-dibromopropane for the starting material 1, 2-dibromoethane and substituting the starting material 5-aminopentanoic acid methyl ester hydrochloride for the starting material 4-aminobutyric acid methyl ester hydrochloride in example 13. Mp 125 ℃. 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)10.39(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)199.5,176.2,169.8,169.4,166.1,161.1,129.4,127.9,127.3,114.4,77.0,64.9,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.3,39.2,38.9,37.8,37.1,32.5,32.0,30.7,30.5,28.7,28.6,28.5,28.1,27.4,26.5,26.2,25.9,23.4,18.8,17.6,16.7,16.5.LC-MS:785.6[M+Na]⁺.HRMS m/z calcdfor C₄₅H₆₇N₂O₈ ^-[M+H]⁺763.4892,found 763.4903.

Example 19: preparation of 6- (4- (3- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-formyloxy) propoxy) benzoylamino) -N-hydroxyhexanamide

The title compound was prepared according to the preparation of example 13 using 1, 3-dibromopropane as the starting material instead of 1, 2-dibromoethane and 6-aminocaproic acid methyl ester hydrochloride as the starting material instead of 4-aminobutyric acid methyl ester hydrochloride as in example 13. Mp 107 ℃. IR (KBr) 3411.9,2929.3,2865.9,1726.8,1632.8,1549.0,1504.3,1464.0,1386.4,1366.2,1310.9,1252.5,1212.4,1172.7,1085.3,1047.8,997.3,845.2,769.7.¹HNMR(600MHz,DMSO-d₆)10.34(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)199.5,176.3,169.8,169.5,165.9,161.0,129.4,127.9,127.4,114.3,77.0,66.2,64.9,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,39.2,38.9,37.8,37.1,32.7,32.0,30.7,29.5,28.7,28.6,28.1,27.4,26.6,26.2,25.8,25.4,24.1,23.4,22.6,18.8,17.6,16.7,16.5.LC-MS:799.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₇N₂O₈ ^-[M-H]^-775.4903,found 775.4899.

Example 20: n is a radical of¹-hydroxy-N⁵Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) glutaramide

The title compound was prepared according to the preparation of example 13 using 1, 3-dibromopropane as the starting material instead of 1, 2-dibromoethane and 7-aminoheptanoic acid ethyl ester hydrochloride as the starting material instead of 4-aminobutanoic acid methyl ester hydrochloride as in example 13. Mp 85-89 deg.C, 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)10.33(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)199.5,176.3,169.8,169.5,165.9,161.0,129.4,127.9,127.5,114.3,77.0,66.2,64.8,61.6,61.4,54.5,48.4,45.3,44.0,43.3,40.8,40.5,39.2,37.8,37.1,32.7,32.0,30.7,29.6,29.4,28.8,28.7,28.6,28.1,27.4,26.7,25.8,25.6,24.1,23.4,22.6,18.8,17.6,16.7,16.5.LC-MS:813.6[M+Na]⁺.HRMS m/z calcd for C₄₇H₇₁N₂O₈ ⁺[M+H]⁺791.5211,found 791.5205.

Example 21: n is a radical of¹-hydroxy-N⁵Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) glutaramide

Step A: preparation of 1- (4-nitrophenyl) -4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazine

The title compound was prepared according to the procedure for the preparation of example 1, step a, substituting starting material 4-nitrophenylpiperazine for starting material methyl 4-aminobutyrate hydrochloride.¹H NMR(600MHz,DMSO-d₆)8.09(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]⁺.

And B: preparation of 1- (4-aminophenyl) -4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazine

The title compound was prepared according to the procedure for the preparation of example 5 step C, substituting the starting material 1- (4-nitrophenyl) -4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazine for the starting material 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylic acid (2- (4-nitrophenoxy)) ethyl ester.¹H NMR(600MHz,DMSO-d₆)6.78(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]⁺.

And C: n is a radical of¹-hydroxy-N⁵Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) glutaramide

The title compound was prepared according to the synthetic procedure of example 5 step D substituting the starting material 1- (4-aminophenyl) -4- (3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-acyl) piperazine for the starting material 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylic acid (2- (4-aminophenoxy)) ethyl ester. Mp 155 ℃. 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)10.38(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)199.6,173.5,170.6,169.2,147.2,132.5,129.1,127.9,120.6,116.6,77.0,67.9,65.5,61.5,54.6,49.9,48.2,45.2,43.8,43.4,40.5,39.2,39.0,37.9,37.1,36.0,32.6,32.1,31.9,30.5,28.8,28.6,27.4,26.7,23.7,23.2,22.9,21.7,19.1,18.8,17.6,16.7,16.5.LC-MS:757.6[M-H]^-.HRMS m/z calcd for C₄₅H₆₅N₄O₆ ^-[M-H]^-757.4910,found 757.4900.

Example 22: n is a radical of¹-hydroxy-N⁶Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) hexanediamide

The title compound was prepared according to the procedure for the synthesis of example 21 substituting the starting monomethyl adipate for the starting monomethyl glutarate in example 21. Mp 204 ℃. 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)10.34(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)199.6,173.5,170.9,170.4,169.4,147.2,132.5,127.9,120.6,116.6,77.0,61.6,54.6,49.9,48.2,45.2,45.0,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.6,32.6,31.9,28.8,28.6,27.4,26.7,26.5,26.0,25.6,25.4,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:795.6[M+Na]⁺.HRMS m/z calcd for C₄₆H₆₇N₄O₆ ^-[M-H]^-771.5066,found 771.5066.

Example 23: n is a radical of¹-hydroxy-N⁶Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) hexanediamide

The title compound was prepared according to the procedure for the synthesis of example 21 substituting the starting material monomethyl glutarate in example 21 with monoethyl pimelate. Mp 147 ℃. 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)10.33(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)199.6,173.5,171.0,170.5,169.5,147.2,132.5,127.9,120.5,116.6,77.0,61.5,55.4,54.6,49.9,48.2,45.2,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.6,35.6,32.6,31.9,31.8,29.5,29.1,28.8,28.6,27.4,27.0,26.7,26.5,25.4,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:809.6[M+Na]⁺.HRMS m/z calcd for C₄₇H₆₉N₄O₆ ^-[M-H]^-785.5223,found 785.5216.

Example 24: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (4- (3 beta-hydroxy-11-oxo-18 beta-oleanane-12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

The title compound was prepared according to the procedure for the synthesis of example 21 substituting the starting monomethyl glutarate in example 21 with the starting monomethyl suberate. Mp 205 ℃. 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)10.33(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)199.6,173.5,171.1,170.5,169.5,147.2,132.5,127.9,120.5,116.6,77.0,61.5,54.6,49.9,48.2,45.2,43.8,43.7,43.4,40.5,39.2,39.0,37.9,37.1,36.7,32.7,32.6,31.9,29.5,28.9,28.9,28.8,28.6,27.4,26.7,26.5,26.0,25.6,25.5,24.1,23.2,22.6,18.8,17.6,16.7,16.5.LC-MS:823.7[M+Na]⁺.HRMS m/z calcdfor C₄₈H₇₁N₄O₆ ^-[M-H]^-799.5379,found799.5375.

Preparation of a portion of the intermediate

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

3.5g (7.48mmol) of GA was weighed out and dissolved in 150mL of DMSO, 8.37g (30mmol) of IBX was added, and the mixture was stirred at 85 ℃ under reflux for 4 hours. Cooling downTo room temperature, 300mL of 5% NaHCO was poured₃In the solution, a white solid precipitated. Extraction with ether (150 mL. times.3), combination of organic layers, washing with water, saturated sodium chloride, drying over anhydrous sodium sulfate, and concentration under reduced pressure gave 2.65g of a white solid, yield: 76 percent.¹H NMR(600MHz,DMSO-d₆)12.21(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-18 beta-oleanane-1, 12-diene-30-carboxylic acid

6.0g of 3, 11-dioxo-18 beta-oleanane-1, 12-diene-30-carboxylic acid (12.9mmol) was weighed out and placed in a 500mL eggplant-shaped bottle, and 300mL of anhydrous tetrahydrofuran was added thereto and dissolved. Followed by addition of I₂13.3 g (51.6mmol) of pyridine and 6.23mL (77.4mmol) of pyridine are stirred at 80 ℃ for reaction for 12h, and then I is added₂6.65 g (25.8mmol) and 3.12mL (38.7mmol) of pyridine and stirring was continued for 6 h. Cooling to room temperature, evaporating tetrahydrofuran to dryness, dissolving with ethyl acetate, washing with sodium thiosulfate to golden yellow, washing with saturated sodium chloride, and drying with anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was concentrated in a ratio of cyclohexane: acetone (V/V) ═ 50: silica gel column chromatography with eluent 1, separating to obtain white solid 5.42g, yield: 71 percent. Mp 286-288 ℃.¹H NMR(600MHz,DMSO-d₆)8.42(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]^-.

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

3.5g (6.8mmol) of 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid and 1.22g (13.6mmol) of CuCN were weighed out and dissolved in 100ml of NMP and stirred at 130 ℃ for 2 h. And (3) cooling the reaction solution to room temperature, pouring the reaction solution into 200mL of water, stirring for 15min, carrying out suction filtration, washing with water, and drying. Concentrating under reduced pressure, adding petroleum ether: ethyl acetate (V/V) ═ 6: silica gel column chromatography with eluent 1, separating to obtain light yellow solid 1.8g, yield: 54 percent.¹H NMR(600MHz,DMSO-d₆)12.22(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]^-.

Preparation of 3, 11-dioxo-18 beta-oleanane-1, 12-diene-30-carboxylic acid benzyl ester

Weighing 4.0g (6.8mmol) of 2-iodo-3, 11-dioxo-18 beta-oleanane-1, 12-diene-30-carboxylic acid, dissolving in 100mL of dry DMSO, adding 2.8g (20.3mmol) of K₂CO₃Stirred at room temperature for 0.5 h. 0.96mL of benzyl bromide (8.1mmol) was then added and stirring continued for 2 h. Pouring the reaction solution into 250mL of water, stirring for 15min, performing suction filtration, washing with water, and drying to obtain 4.27g of white solid, wherein the yield is as follows: 92 percent. Mp 158-.¹H NMR(600MHz,DMSO-d₆)8.40(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 2-trifluoromethyl-3, 11-dioxo-18 beta-oleanane-1, 12-diene-30-benzyl carboxylate

4.92g of benzyl 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylate (7.2mmol) are placed in a 250mL three-necked flask, dissolved in 100mL dry DMF and 4.12g of CuI (21.63mmol) are added in the absence of light. Under nitrogen, the temperature was raised to 70 ℃ and 17.3mL of methyl fluorosulfonyldifluoroacetate (144.2mmol) and 25mL of HMPA (144.2mmol) were slowly added dropwise with stirring for 4 h. After the reaction solution is slightly cooled, 20mL of saturated ammonium chloride solution is added for quenching, the reaction solution is cooled to room temperature, washed by sodium sulfite, washed by 2N HCl, washed by water, washed by saturated sodium chloride and dried by anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 20: silica gel column chromatography with eluent 1, separating to obtain white solid 3.3g, yield: 73 percent. Mp 113-115 ℃.¹H NMR(600MHz,DMSO-d₆)8.20(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-18 beta-oleanane-1, 12-diene-30-carboxylic acid

2.9g of benzyl 2-trifluoromethyl-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylate are dissolved in 20mL of dry dichloromethane, 32.5mL of 1N TiCl solution (32.5mmol) are slowly added dropwise to the above solution at 0 ℃ and stirred for 15 min. The mixture was transferred to room temperature and stirring was continued for 2 h. The reaction solution was slowly added dropwise to ice water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 10: silica gel column chromatography with eluent 1, separating to obtain white solid 2.2g, collectingRate: 91 percent. Mp 259-261 ℃.¹H NMR(600MHz,DMSO-d₆)12.21(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-oxooctanoic acid

3.62mL (20.2mmol) of monomethyl suberate, 2.36g (17.5mmol) of HOBT and 3.35g (17.5mmol) of EDCI were dissolved in 40mL of dry DMF and stirred at room temperature for 30 min. 2.0g (18.4mmol) of p-aminophenol and 2.73mL (17.5mmol) of DIEA were then added and the mixture was stirred for 1.5h at 60 ℃. And cooling the reaction liquid to room temperature, pouring the reaction liquid into 200mL of cold water, stirring for 10min, performing suction filtration, washing with water, and drying to obtain a brown solid. The brown solid is dissolved in 20mL of methanol and stirred at 60 ℃ and then a 10mL of NaOH solution (1mol/L) is added dropwise and stirring is continued for 2 h. And (3) after the reaction liquid is cooled to room temperature, pouring the reaction liquid into 150mL of water, and adjusting the pH to 2-3 by using a 10% hydrochloric acid solution. Stirring for 15min, suction filtering, water washing and drying to obtain white solid 2.4g with yield 49%.¹H NMR(600MHz,DMSO-d₆)11.95(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-hydroxyphenyl) -N⁸Preparation of (- (tetrahydro-2H-pyran-2-yl) oxy) butanediamide

2.0g (7.5mmol)8- ((4-hydroxyphenyl) amino) -8-oxooctanoic acid, 1.5g (11.3mmol) HOBT and 2.2(11.3mmol) EDCI are dissolved in 30mL dry DMF and stirred at room temperature for 30 min. 2.65g (22) were then added.6mmol) O- (tetrahydro-2H-pyran-2-yl) -hydroxylamine and 1.86mL (11.3mmol) DIEA and stirring was continued for 2H. And pouring the reaction solution into a saturated sodium chloride solution, stirring for 15min, performing suction filtration, washing with water, and drying to obtain a brown solid 2.35g, wherein the yield is 86%.¹H NMR(600MHz,DMSO-d₆)10.88(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 N¹- (4-hydroxyphenyl) -N⁸- ((tetrahydro-2H-pyran-2-yl) oxy) butanediamide, the starting material 8- ((4-hydroxyphenyl) amino) -8-oxooctanoic acid being replaced by the starting material suberic acid, the title compound being prepared. LC-MS 272.0[ M-H ]]^-.

Example 25: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (3- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

Step A: preparation of 2-iodo-3, 11-dioxo-18 beta-oleanane-1, 12-diene-30-carboxylic acid (3-bromo) propyl ester

2.0g (3.4mmol) 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid was dissolved in 20mL dry DMF and 2.65g (10.1mmol) K was added₂CO₃Then, the mixture was stirred at room temperature for 30 min. Subsequently, 1.7mL (16.8mmol) of 1, 3-dibromopropane was added dropwise to the reaction solution, and stirring was continued for 1 hour. The reaction solution was poured into 100mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 7: 1 is eluent silica gel column layerAfter separation, 1.7g of a white solid was isolated, yield: 71 percent.¹H NMR(600MHz,DMSO-d₆)8.42(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]⁺.

And B: n is a radical of¹- (tetrahydro-2H-pyran-2-yl) oxy-N⁸Preparation of- (4- (3- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

0.69g (1.9mmol) of N¹- (4-hydroxyphenyl) -N⁸- ((tetrahydro-2H-pyran-2-yl) oxy) butanediamide was dissolved in 20mL of dry DMF and 0.64g (4.6mmol) of K was added₂CO₃Then, the mixture was stirred at 80 ℃ for 30 min. Then 1.1g (1.5mmol) 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid (3-bromo) propyl ester is added and stirring is continued for 2 h. After the reaction solution was cooled to room temperature, the reaction solution was poured into 100mL of water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 4: silica gel column chromatography with eluent 1, separating to obtain white solid 0.18g, yield: 12 percent.¹H NMR(600MHz,DMSO-d₆)9.55(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]⁺.

And C: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (3- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

0.12g (0.12mmol) of N¹- (tetrahydro-2H-pyran-2-yl) oxy-N⁸- (4- (3- (2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide was dissolved in 10mL of dry dichloromethane, and 1mL of trifluoroacetic acid was added dropwise thereto, followed by stirring at room temperature for 20 min. The reaction mixture was washed with water, saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with dichloromethane: methanol (V/V) ═ 15: silica gel column chromatography with eluent 1, separating to obtain white solid 27.4mg, yield: 25 percent. Mp 93-96 deg.C, 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)9.55(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＝8.4Hz),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).¹³C NMR(150MHz,DMSO-d₆)198.7,197.8,176.2,172.0,170.9,170.7,155.0,153.5,131.5,127.4,121.2,115.4,100.5,65.4,62.1,61.2,54.7,51.5,48.7,45.5,44.0,43.8,43.4,40.8,37.7,36.7,32.0,31.4,30.7,29.1,28.6,28.2,28.2,26.8,26.6,25.9,25.7,24.6,23.3,23.0,22.4,20.4,18.9,18.3,14.5.LC-MS:911.3[M-H]^-.HRMS m/z calcd for C₄₇H₆₄IN₂O₈ ^-[M-H]^-911.3713,found 911.3716.

Example 26: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (3- (2-trifluoromethyl-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

Preparation according to example 25Method the title compound was prepared by substituting 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid in example 25 with the starting material 2-trifluoromethyl-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid. Mp 100 ℃. 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)10.32(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)199.1,198.6,176.2,172.0,171.1,169.5,164.3,161.9,154.6,133.2,127.4,123.9,121.0,114.9,64.8,61.5,55.4,54.1,50.5,48.7,45.4,45.3,44.0,43.9,38.2,37.8,36.7,32.7,32.0,31.2,30.7,28.9,28.9,28.7,28.7,28.1,28.1,26.6,26.1,25.6,25.5,23.2,21.6,20.1,18.9,18.2.LC-MS:877.7[M+Na]⁺.HRMS m/z calcdfor C₄₈H₆₅F₃N₂NaO₈ ⁺[M+Na]⁺877.4585,found 877.4603.

Example 27: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (3- (2-cyano-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide

The title compound was prepared according to the procedure for the preparation of example 25 substituting the starting material 2-cyano-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid for 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid of example 25. Mp 123 ℃. 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)9.58(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)198.4,176.1,174.7,173.3,172.1,170.8,153.5,131.4,130.0,127.2,121.1,115.9,115.3,112.0,65.3,62.0,61.1,53.7,50.5,48.4,45.5,45.0,43.9,43.8,40.7,37.7,36.6,32.0,31.9,31.2,30.6,29.4,29.0,28.6,28.1,27.4,26.7,26.5,25.6,24.5,23.2,22.5,21.7,19.6,18.9,17.8.LC-MS:810.4[M-H]^-.HRMS m/z calcd for C₄₈H₆₄N₃O₈ ^-[M-H]^-810.4699,found 810.4695.

Example 28: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

Step A: preparation of 1- (4-nitrophenyl) -4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazine

The title compound was prepared according to the procedure for the preparation of step A of example 1, substituting starting material 2-iodo-3, 11-dioxo-18 β -oleanane-1, 12-diene-30-carboxylic acid for starting material GA and starting material 4-nitrophenylpiperazine for starting material methyl 4-aminobutyrate hydrochloride.¹H NMR(600MHz,DMSO-d₆)8.42(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]⁺.

And B: preparation of 1- (4-aminophenyl) -4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazine

The title compound was prepared according to the synthetic procedure of example 5 step C substituting the starting material 1- (4-nitrophenyl) -4- (2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-dien-30-acyl) piperazine for the starting material 3 β -hydroxy-11-oxo-18 β -oleanane-12-diene-30-carboxylic acid (2- (4-aminophenoxy)) ethyl ester. LC-MS 752.6[ M + H ]]⁺.

And C: n is a radical of¹- (tetrahydro-2H-pyran-2-yl) oxy-N⁸Preparation of- (4- (4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

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 are dissolved in 20mL dry DMF and stirred at room temperature for 30 min. Then 0.6g (0.8mmol)1- (4-aminophenyl) -4- (2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-acyl) piperazine and 0.2mL (1.2mmol) DIEA were added, transferred to 60 ℃ and stirred for 4 h. And (3) after the reaction solution is cooled to room temperature, pouring the reaction solution into 100mL of water, extracting with dichloromethane, washing with water, washing with saturated sodium chloride, and drying with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, with petroleum ether: ethyl acetate (V/V) ═ 5: silica gel column chromatography with eluent 1, separating to obtain light yellow solid 0.36, yield: 45 percent.¹H NMR(600MHz,DMSO-d₆)10.88(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 is a radical of¹-hydroxy-N⁸Preparation of- (4- (4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazin-1-yl) phenyl) octanediamide

Synthesis procedure as in step C of example 25, starting with material N¹- (tetrahydro-2H-pyran-2-yl) oxy-N⁸Replacement of raw material N by- (4- (4- (2-iodo-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazine-1-yl) phenyl) octanediamide¹- (tetrahydro-2H-pyran-2-yl) oxy-N⁸- (4- (3- (2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-formyloxy) propoxy) phenyl) octanediamide, the title compound was prepared. Mp 194 ℃ and 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)10.45(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)198.8,197.8,173.6,172.6,171.3,170.7,169.6,163.5,130.1,127.4,120.5,100.5,70.2,54.7,51.5,48.3,45.5,45.4,43.9,43.4,37.9,36.7,35.6,32.7,31.9,31.7,31.5,29.5,29.2,28.9,28.8,27.0,26.6,26.6,26.5,25.6,25.5,23.0,22.6,22.4,20.4,18.9,18.3,14.4.LC-MS:945.8[M+Na]⁺.HRMS m/z calcd for C₄₈H₆₇IN₄NaO₆ ⁺[M+Na]⁺945.3997,found 945.4019.

Example 29: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (4- (2-trifluoromethyl-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazine-1-yl) phenyl) octanediamide

The title compound was prepared according to the procedure for the preparation of example 28 substituting starting material 2-trifluoromethyl-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-carboxylic acid for starting material 2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-carboxylic acid. 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)10.33(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).¹³C NMR(150MHz,DMSO-d₆)199.2,198.7,173.5,172.8,172.5,171.0,169.5,164.3,147.1,132.5,130.1,127.4,120.6,116.6,55.4,54.1,50.5,49.9,48.3,45.3,44.0,43.8,38.2,37.9,36.7,32.7,32.3,31.9,31.2,28.9,28.9,28.8,28.0,26.7,26.6,26.5,25.6,25.5,23.0,21.6,21.5,20.2,18.9,18.2.LC-MS:887.7[M+Na]⁺.HRMS m/z calcd for C₄₉H₆₇F₃N₄NaO₆ ⁺[M+Na]⁺887.4905,found 887.4902.

example 30: n is a radical of¹-hydroxy-N⁸Preparation of- (4- (4- (2-cyano-3, 11-dioxy-18 beta-oleanane-1, 12-diene-30-acyl) piperazine-1-yl) phenyl) octanediamide

The title compound was prepared according to the procedure for the preparation of example 28 substituting the starting material 2-cyano-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-carboxylic acid for the starting material 2-iodo-3, 11-dioxy-18 β -oleanane-1, 12-diene-30-carboxylic acid. Mp 154 ℃. 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(600MHz,DMSO-d₆)10.32(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)198.6,198.6,174.9,173.5,172.8,171.0,169.5,147.1,132.5,127.3,120.6,116.6,115.9,112.1,55.4,53.8,50.6,49.9,48.3,45.5,45.1,44.0,43.8,40.5,37.9,36.7,32.7,32.3,31.9,31.3,28.9,28.9,28.8,27.5,26.7,26.6,26.5,25.6,25.5,23.0,21.7,19.8,19.0,17.9.LC-MS:820.5[M-H]^-.HRMS m/z calcd for C₄₉H₆₇N₅NaO₆ ⁺[M+Na]⁺844.4984,found 844.4954.

Research on pharmacological action of product of the invention

In vitro antitumor Activity test

1) Cell culture

Human acute leukemia cell HL-60, prostate cancer cell PC-3, breast cancer cell MCF-7, cultured in RPMI 1640 culture solution or high sugar DMEM culture solution containing 10% (v/v) heat inactivated fetal bovine serum, 100U/mL penicillin, 100. mu.g/mL streptomycin and 2mmol/L glutamine. All cells used in the experiment were incubated at 37 ℃ with 5% CO₂Culturing in a saturated humidity incubator.

2) Cell growth inhibitory Activity

The growth inhibition effect of the compound on HL-60 cells is examined by a cell counting method. A certain density (1 is multiplied by 10)⁵cell/mL) was inoculated in a 24-well plate, 2 mL/well, incubated with different concentrations of the drug for 72 hours and counted under a microscope, the cell growth inhibition rate was calculated according to the following formula, and the half growth inhibition concentration GI was calculated₅₀(drug concentration at which the cell growth inhibition rate reached 50%).

The growth inhibition effect of the compound on solid tumor cells PC-3 and MCF-7 is examined by adopting an MTT method. A certain density (2-3X 10)⁴one/mL) of the cell suspension is inoculated on a 96-well culture plate, 100 mu L/well of the cell suspension is added, compounds with different concentrations are added for incubation for 96 hours, then 50 mu L of MTT solution is added for continuous incubation for 3.5 hours, and then all liquid in the 96-well plate is discarded and invertedFully absorbing residual liquid on filter paper, adding 200 mu L DMSO into each hole, oscillating for 10min on an oscillator to dissolve a blue-violet crystal, finally measuring the light absorption value at 570nm by using an enzyme-labeling instrument, and setting A1 (containing 200 mu LDMSO) as a blank control hole; the cell growth inhibition rate was determined according to the following formula, and the half growth inhibition concentration GI was determined₅₀(concentration of the compound at which the cell growth inhibition rate reached 50%).

GI of the compounds of Table 1 for HL-60, PC-3 and MCF-7₅₀List of (μmol/L) values

Claims

1. A compound or pharmaceutically acceptable salt represented by formula I or II:

in the general formula I, X is

In the general formula II, X is

r is halogen, trifluoromethyl, cyano;

m is an integer of 1 to 6;

n is an integer of 1 to 8.

2. A pharmaceutically acceptable salt of the compound of claim 1:

in the general formula I, X is

In the general formula II, X is

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 or pharmaceutically acceptable salt of claim 1 or 2:

in the general formula I, X is

In the general formula II, X is

r is iodine, trifluoromethyl or cyano;

m is an integer of 2 to 3;

n is an integer of 3 to 6.

4. A compound or pharmaceutically acceptable salt as described below,

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 beta-oleanane-1, 12-diene-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 or pharmaceutically acceptable salt of any one of claims 1-4 and a pharmaceutically acceptable excipient.

6. A process for the preparation of a compound according to claim 1,

m is an integer of 1 to 6;

n is an integer of 1-8;

or

R is halogen, trifluoromethyl, cyano;

or

R is halogen, trifluoromethyl or cyano.

7. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment and/or prophylaxis of anti-tumour agents.

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, lymphatic cancer, ovarian cancer, skin cancer or hematological cancer.