Cyclovirobuxine D derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a cyclovirobuxine D derivative compound shown as a structural formula (I) or a structural formula (Ia), a preparation method and application, experimental results show that the compound shown as the structural formula (I) or the structural formula (Ia) has different degrees of hypoxia and ischemia resistance, so that the compound can be used as a medicine for preventing or treating cardiovascular and cerebrovascular diseases and can be used for preparing medicines for preventing or treating cardiovascular and cerebrovascular diseases. The polypeptide has the potential of treating cardiovascular and cerebrovascular diseases. The cardiovascular and cerebrovascular diseases include but are not limited to angina pectoris, arrhythmia, hypertension, hyperlipidemia and cerebral arterial thrombosis. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of cyclovirobuxine D derivatives and a preparation method and application thereof. Background Art

[0002] Cyclovirobuxine D (CVB-D) is an effective monomer alkaloid extracted from the Buxus microphylla plant. It is a drug for the treatment of cardiovascular and cerebrovascular diseases or a precursor for the development of new drugs and can be widely used in the medical field. Pharmacological activity studies have shown that cyclovirobuxine D has the effect of treating angina pectoris, arrhythmia, and ischemic stroke. The structural formula of cyclovirobuxine D is as follows:

[0003]

[0004] Pharmacological experiments have shown that cyclovirobuxine D can play a role in treating ischemic stroke through multiple pathways such as inhibiting the production of inflammatory factors and protecting nerve cells from peroxidative damage. It is a multi-target and multi-mechanism therapeutic drug.

[0005] In recent years, the existing technology has made a variety of improvements on the structure of cyclovirobuxine D to improve its hypoxia resistance activity, water solubility or bioavailability. For example, the literature "Xiang Tao et al. Synthesis of 3-C monosubstituted cyclovirobuxine D derivatives and study of their anti-hypoxia resistance activity [J]. Organic Chemistry, 2016, 36 (2): 5. DOI: 10.6023 / cjoc201508030" reported a series of 3-amino monosubstituted compounds, and conducted hypoxia resistance experiments, showing good activity. Although the existing research has further improved the physiological activity of cyclovirobuxine D derivatives, its structure is still possible to be further modified, especially the modification of the steroidal core structure. Summary of the invention

[0006] The present invention discloses a new structure of a class of cyclovirobuxine D derivatives with hypoxia-resistant physiological activity, which can still maintain good activity mainly by modifying the mother nucleus and then introducing new metabolic sites based on the modified four-ring structure mother nucleus. In clinical treatment of ischemic stroke, combined administration is often used to exert multi-mechanism therapeutic effects. Based on the above ideas, after obtaining a series of new mother nuclei, a molecular hybridization strategy is adopted to introduce similar structures of marketed drugs edaravone, aspirin and ferulic acid into cyclovirobuxine D to further improve its activity.

[0007] The present invention provides a class of cyclovirobuxine D derivatives, which are obtained by modifying the parent core structure or the 20-amino structure thereof to obtain a class of new compounds with good activity for preventing or treating cardiovascular and cerebrovascular diseases.

[0008] The structural formula of the cyclovirobuxine D derivative is as follows:

[0009]

[0010] In formula (I), there is a single bond or a double bond between carbon atoms No. 8 and No. 9, and there is a single bond or a double bond between carbon atoms No. 9 and No. 11; in formula (I), R1 is H or F; R2 is H or a carbonyl group; R3 is H, a carbonyl group, or -OH; R5 is H or any one of the following structures, Indicates the connection site:

[0011]

[0012] In formula (Ia), R6 is any one of the following structures, Indicates the connection site:

[0013]

[0014] Furthermore, formula (I) is preferably the following structures:

[0015]

[0016] The compound of the present invention of structural formula (I) or formula (Ia) forms pharmaceutically acceptable salts with various organic acids and inorganic acids, such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, nitric acid, phosphoric acid, boric acid, tartaric acid, citric acid, succinic acid, benzoic acid, ascorbic acid or salicylic acid. The compound of the present invention of structural formula (I) or formula (Ia) can also form salts with alkali metals such as sodium, potassium or lithium, can form salts with alkaline earth metals such as calcium or magnesium, can form salts with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine and lysine. It should be understood that solvates such as hydrates of the compound of (I) or formula (Ia) are also within the scope of the present invention. Solvation methods are generally known in the art. The compounds of the present invention can exist in the form of various optical isomers, geometric isomers and stereoisomers. All these isomers and mixtures of their racemic forms are included within the scope of the present invention.

[0017] The present invention also provides a method for preparing compound b in formula (I), wherein cyclovirobuxine D is subjected to ring opening by heating in a hydrochloric acid solution to obtain the compound. The synthetic route of compound b is as follows:

[0018]

[0019] The present invention also provides a method for preparing compound Ib in formula (I), wherein compound b is reacted with a series of derivative acyl chlorides using DCM as a solvent to obtain the compound. The synthetic route of compound Ib is as follows:

[0020]

[0021] The present invention also provides a method for preparing compounds Ⅰc and Ⅰd in formula (Ⅰ), wherein compound b is trifluoroacetylated, oxidized, detrifluoroacetylated, and reduced to obtain compounds c and d, respectively, and then reacted with corresponding acyl chlorides to obtain the compounds. The synthetic routes of compounds Ⅰc and Ⅰd are as follows:

[0022]

[0023] The present invention also provides a method for preparing compound IF in formula (I), wherein compound b is trifluoroacetylated, peroxidized, fluorinated, deacetylated, and then combined with the corresponding acyl chloride to obtain the compound. The synthetic route of compound IF is as follows:

[0024]

[0025] The present invention also provides a method for preparing compound Ⅰh in formula (Ⅰ), wherein cyclovirobuxine D is heated and ring-opened in a hydrochloric acid solution to obtain compound g, which is then acetylated, oxidized, deacetylated, and combined with a corresponding acyl chloride to obtain a compound. The synthetic route of compound Ⅰh is as follows:

[0026]

[0027] The present invention also provides a method for preparing compound i of formula (I), wherein the compound i is obtained by deacetylation of compound g-1 and reduction. The synthetic route of compound i is as follows:

[0028]

[0029] The compound of the structural formula (I) or formula (Ia) of the present invention is mixed with a pharmaceutically acceptable carrier to prepare various preparations. The compound of the structural formula (I) or formula (Ia) is mixed with commonly used auxiliary additives such as disintegrants, excipients, lubricants, adhesives, fillers, etc. that are acceptable in oral preparations, and can be prepared into tablets, pills, capsules or various corresponding sustained-release agents, controlled-release agents and other solid dosage forms of cardiovascular and cerebrovascular disease prevention and treatment drugs according to conventional methods; it is mixed with commonly used solubilizers, emulsifiers, wetting agents, foaming or defoaming agents and other surfactants, diluents, preservatives, stabilizers, flavoring agents, thickeners, etc., and can be prepared into liquid preparations such as aqueous solutions and syrups according to corresponding conventional methods; it can also be prepared into corresponding intramuscular or intravenous injection dosage forms of cardiovascular and cerebrovascular disease prevention and treatment drugs by combining and operating with appropriate solvents and additives commonly used in injections.

[0030] Beneficial effects: Animal experimental results show that the new compound, i.e., the compound of formula (I) or formula (Ia), has different degrees of tolerance to hypoxia and ischemia, so the above compound can be used as a drug for preventing or treating cardiovascular and cerebrovascular diseases, and has the potential to treat cardiovascular and cerebrovascular diseases. Cardiovascular and cerebrovascular diseases include but are not limited to angina pectoris, arrhythmia, hypertension, hyperlipidemia and ischemic stroke. DETAILED DESCRIPTION

[0031] Example 1 Preparation of Compound Ⅰa1

[0032] Compound Ia1 is 3-methyl-1-phenyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and has the following structural formula:

[0033]

[0034] Preparation steps: Take CVB-D (0.5 g, 1.24 mmol) and add it to 20 mL of dry dichloromethane, put it in an ice bath, protect it with nitrogen, add triethylamine (0.127 g, 1.24 mmol), stir it thoroughly to dissolve it, slowly drop edaravone chloride (0.22 g, 1.24 mmol) dissolved in dry dichloromethane, stir until the reaction is completed, TLC detection reaction reaches the end point, the reaction solution is washed with saturated NaHCO3 and saturated NaCl solution, dried over anhydrous sodium sulfate to obtain a crude product, and purified by column chromatography (DCM: MeOH = 35: 1) to obtain 0.24 g of a light yellow solid with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.59(d,J=7.9Hz,2H),7.44(d,J=7.7Hz,2H),7.33(t,J=7.5Hz,1H),6.07(s,1H),4.46(dd,J=11.5,6.5Hz,1H),4.07( t,J=7.4Hz,1H),2.91(d,J=2.1Hz,3H),2.48(s,3H),2.34(s,3H),2.07(d ,J=5.5Hz,1H),2.04(d,J=6.5Hz,1H),2.02–1.99(m,2H),1.99–1.94(m,2H ),1.85(dd,J=13.8,8.8Hz,1H),1.69(d,J=12.1Hz,2H),1.64(d,J=9.0Hz ,2H),1.52(s,2H),1.45(dd,J=12.2,4.7Hz,2H),1.40(s,1H),1.34(d,J=4 .5Hz,1H),1.32(d,J=3.7Hz,2H),1.29(s,3H),1.27(d,J=4.4Hz,2H),1.17 (s,3H),1.16(s,3H),1.15(s,3H),1.05(s,3H).MS(ESI):m / z603.43[M+H] + .

[0035] Example 2 Preparation of Compound Ⅰa2

[0036] Compound Ia2 is 4-1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and has the following structural formula:

[0037]

[0038] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by 4-chloro-edaravone chloride to obtain 0.3 g of a light brown solid with a yield of 36%. 1H NMR(500MHz,Chloroform-d)δ7.51(d,J=8.4Hz,2H),7.37(d,J=8.3Hz,2H),6.04(s,1H),4.45(d,J=4.6Hz ,1H),4.11(t,J=7.5Hz,1H),2.89(d,J=3.1Hz,3H),2.48(s,3H),2.29(s,3H),1.94(d,J=13.0Hz,2H),1.86 (dd,J=14.0,8.9Hz,2H),1.72–1.67(m,2H),1.62(d,J=11.4Hz,2H),1.50(s,3H),1.44–1.40(m,2H),1.35 –1.33(m,2H),1.30(s,2H),1.27(s,2H),1.25(s,2H),1.16(s,3H),1.03(s,3H),0.99(s,3H).MS(ESI):m / z 637.39[M+H] + .

[0039] Example 3 Preparation of Compound Ia3

[0040] Compound Ia3 is 5-1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and has the following structural formula:

[0041]

[0042] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by 4-fluoro-edaravone chloride to obtain 0.25 g of a pale white solid with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.51(dd,J=8.8,4.8Hz,2H),7.10(d,J=8.4Hz,2H),6.03(s,1H),4.44(dd,J=11.5,6.7Hz,1H),4.10(t,J=7. 2Hz,1H),2.86(s,3H),2.74(s,3H),2.50(d,J=7.5Hz,1H),2.30(d,J=2.2Hz,3H),2.03(d,J=16.8Hz,2H),1.98(d,J=3.8Hz,2H),1.94(d,J= 12.7Hz,1H),1.84(dd,J=13.9,8.9Hz,1H),1.66(s,2H),1.54–1.51(m,1H),1.48(dd,J=13.1,4.3Hz,2H),1.45–1.40(m,2H),1.38–1.35(m, 2H),1.34–1.32(m,2H),1.30(d,J=5.1Hz,2H),1.24(s,3H),1.14(s,2H),1.13(s,3H),1.11(s,3H),1.04(s,3H),1.02(s,3H).MS(ESI):m / z 621.42[M+H] + .

[0043] Example 4 Preparation of Compound Ia4

[0044] Compound Ia4 is 4-3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and has the following structural formula:

[0045]

[0046] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by 4-trifluoromethyl-edaravone chloride to obtain 0.30 g of a pale white solid with a yield of 36%. 1HNMR(500MHz,Chloroform-d)δ7.74(d,J=8.5Hz,2H),7.66(d,J=8.4Hz,2H),6.07(s,1H),4.45(dd,J=11.3,6.9Hz,1H),4.12 (d,J=7.1Hz,1H),2.93(s,3H),2.89(s,1H),2.76(s,3H),2.54(d,J=8.1Hz,1H),2.31(s,3H),2.02(d,J=5.3Hz,2H),2.00–1. 99(m,1H),1.86(d,J=5.1Hz,1H),1.67(s,2H),1.54–1.50(m,2H),1.38(d,J=3.9Hz,1H),1.36(d,J=4.0Hz,2H),1.34(d,J=5. 5Hz,2H),1.27(s,3H),1.25(d,J=1.7Hz,2H),1.17(s,2H),1.16(s,2H),1.13(s,3H),1.07(s,3H),1.02(s,3H).MS(ESI):m / z 671.42[M+H] + .

[0047] Example 5 Preparation of Compound Ia5

[0048] Compound Ia5 is 3-methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and has the following structural formula:

[0049]

[0050] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by 4-nitro-edaravone chloride to obtain 0.20 g of a brown-yellow solid with a yield of 25%. 1HNMR(500MHz,Chloroform-d)δ8.28–8.26(m,2H),7.85–7.82(m,2H),6.10(s,1H),4.47(dd,J=11.4,6.5Hz,1H),4.16(t,J=7.5Hz,1H),2.97(s,3H),2.92 (d,J=4.0Hz,1H),2.62(s,3H),2.31(s,3H),2.07(t,J=5.8Hz,2H),1.99–1.9 5(m,2H),1.91–1.87(m,1H),1.72(d,J=12.1Hz,2H),1.64(d,J=13.1Hz,2H),

[0051] 1.53–1.49(m,2H),1.43(t,J=6.3Hz,2H),1.34–1.32(m,2H),1.25(s,3H),1.20(s,2H),1.18 (s,2H),1.15(s,3H),1.13(s,3H),1.11–1.08(m,2H),1.03(s,3H),0.93(s,3H).MS(ESI):m / z

[0052] 648.41[M+H] + .

[0053] Example 6 Compound Ⅰa 10 preparation

[0054] Compound Ⅰa 10 It is 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)carbamate, and the structural formula is as follows:

[0055]

[0056] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by trifluoromethyl edaravone chloride to obtain 0.22 g of a white solid with a yield of 27%. 1H NMR(500MHz,Chloroform-d)δ7.58(dd,J=7.6,1.8Hz,2H),7.46(d,J=7.8Hz,2H),6.53(s,1H),4.41(dd,J=11.4,6.5Hz,1H),4.0 4(t,J=7.4Hz,1H),2.93(s,1H),2.85(s,3H),2.75(s,3H),2.53(s,1H),2.05(s,1H),1.99(s,2H),1.82(d,J=4.8Hz,1H),1.66(s, 2H),1.53(s,2H),1.50(s,2H),1.43(dd,J=12.5,4.3Hz,2H),1.38(t,J=4.8Hz,2H),1.36(d,J=3.4Hz,2H),1.33(s,2H),1.27(s, 3H),1.26(s,3H),1.24–1.19(m,2H),1.13(s,2H),1.12(s,2H),1.10(s,3H),1.06(s,3H),1.01(s,3H).MS(ESI):m / z657.39[M+H] + .

[0057] Example 7 Compound Ⅰa 11 preparation

[0058] Compound Ⅰa 11 It is 2-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopenta[a]cyclopropene[e]phenanthrene-3-yl)ethyl)(methyl)carbamoyl)phenyl acetate, and the structural formula is as follows:

[0059]

[0060] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by aspirin chloride to obtain 0.15 g of a white solid with a yield of 21%. 1H NMR(500MHz,Chloroform-d)δ7.52–7.48(m,1H),7.42(s,1H),7.22(d,J=8.2Hz,1H),6.92–6.90(m,1H),4.68(d,J=12.9Hz,1H) ,3.09(d,J=9.0Hz,2H),3.01(d,J=10.3Hz,2H),2.96–2.92(m,1H),2.86(d,J=10.9Hz,2H),2.82(s,3H),2.33–2.30(m,3H),2.29 (d,J=8.6Hz,3H),2.18(d,J=7.6Hz,2H),2.14(d,J=6.1Hz,2H),2.06–2.02(m,2H),1.80(d,J=12.7Hz,2H),1.53(s,2H),1.37(d, J=3.7Hz,2H),1.29(s,2H),1.22(s,3H),1.18(s,3H),1.16(s,3H),1.06(d,J=2.6Hz,3H),0.96(s,3H).MS(ESI):m / z563.39[MH] + .

[0061] Example 8 Compound Ⅰa 12 preparation

[0062] Compound Ⅰa 12 It is N-(1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, and its structural formula is as follows:

[0063]

[0064] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by 3,4-dimethoxybenzoyl chloride to obtain 0.13 g of a white solid with a yield of 43%. 1H NMR(500MHz,Chloroform-d)δ7.02(s,1H),6.96(s,1H),6.85(t,J=7.0Hz,1H),3.89(s,3H),3.88(s,3H),2.49(d, J=5.4Hz,3H),2.47(s,3H),2.20(s,2H),2.17–2.14(m,2H),2.04(d,J=10.2Hz,2H),1.93(d,J=12.7Hz,1H),1.85– 1.79(m,1H),1.69(d,J=11.8Hz,2H),1.62(d,J=12.9Hz,2H),1.49–1.43(m,2H),1.34(s,2H),1.33–1.30(m,2H),1 .25(s,2H),1.15(s,3H),1.14(s,3H),1.12(s,3H),1.08(d,J=8.5Hz,2H),0.98(s,3H),0.78(s,3H).MS(ESI):m / z 567.41[M+H] + .

[0065] Example 9 Compound Ⅰa 13 Preparation

[0066] Compound Ⅰa 13 (E)-4-(3-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate

[0067]

[0068] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by ferulic acid chloride to obtain 0.14 g of a yellow solid with a yield of 18%. 1H NMR(500MHz,Chloroform-d)δ7.63(dd,J=15.4,9.4Hz,1H),7.16–7.08(m,2H),7.06–7.01(m,2H),6.91–6.78(m,1H),4.19(d,J=7.6Hz,1H),3 .87(d,J=4.2Hz,3H),3.86(s,3H),3.06(d,J=13.4Hz,2H),2.96(d,J=5.6Hz,1H),2.75(s,3H),2.70(d,J=2.0Hz,1H),2.52(dd,J=12.3,4.2Hz, 1H),2.31(s,3H),2.20–2.15(m,1H),2.09–2.04(m,2H),1.93–1.87(m,2H),1.73(d,J=11.6Hz,2H),1.61(d,J=8.8Hz,2H),1.49(d,J=15.0Hz, 2H),1.36(d,J=6.7Hz,2H),1.32(s,2H),1.29(d,J=4.7Hz,2H),1.24(s,3H),1.15(s,3H),1.14(s,3H),1.11(s,3H),1.05(s,3H).MS(ESI):m / z 621.41[M+H] + .

[0069] Example 10 Compound Ⅰa 14 Preparation

[0070] Compound Ⅰa 14 It is (E)-4-(3-((1-(4-hydroxy-2a,5a,8,8-tetramethyl-9-(methylamino)tetradecahydro-1H,12H-cyclopentadien[a]cyclopropen[e]phenanthrene-3-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate, and the structural formula is as follows:

[0071]

[0072] The preparation process is the same as the preparation steps of compound Ⅰa1, except that edaravone chloride is replaced by (E)-3-(4-acetoxyphenyl)acryloyl chloride to obtain 0.20 g of a yellow solid with a yield of 27%. 1H NMR(500MHz,Chloroform-d)δ7.66(d,J=15.6Hz,1H),7.52(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.83(d,J=15.3Hz,1H),5.15(dd,J=11.2,6. 8Hz,1H),4.19(t,J=7.3Hz,1H),3.05(s,2H),2.48(s,3H),2.31(d,J=3. 3Hz,3H),2.20(s,1H),2.13(d,J=22.6Hz,2H),2.07(s,2H),2.05(d,J=4 .2Hz,2H),1.97–1.90(m,2H),1.88(d,J=5.4Hz,1H),1.72(d,J=5.7Hz,1 H),1.60(t,J=14.2Hz,2H),1.50–1.44(m,2H),1.38–1.33(m,2H),1.31( s,2H),1.29(d,J=3.0Hz,2H),1.26(t,J=3.8Hz,2H),1.15(s,3H),1.14( s,3H),1.12(s,3H),0.98(s,3H),0.79(s,3H).MS(ESI):m / z591.41[M+H] + .

[0073] Example 11 Preparation of Compound b

[0074] Compound b is 4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl

[0075] 1H-cyclopenta[a]phenanthrene-16-ol, the structural formula is as follows:

[0076]

[0077] Take CVB-D (15 g, 37.3 mmol) in a 1L three-necked flask, add 540 mL of 3 mol / L hydrochloric acid, control the temperature at 90 ° C, react for 7-8 h, stop heating, cool naturally to room temperature, filter to obtain a crude hydrochloride, dissolve the filtered product in water, adjust the pH>8, pour into 1000 mL of dichloromethane three times to fully extract, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 13 g of crude compound b, which was recrystallized from a mixed solvent of ethyl acetate / methanol to obtain compound b, 4 g, with a yield of 27% (HPLC purity 91%).

[0078] 1 H NMR(500MHz,Chloroform-d)δ5.25(d,J=6.0Hz,1H),4.16(ddd,J=9.7,6.9,2.5Hz,1H),2.51(dd,J=10.7,6.0Hz,1H),2.47(s,3H),2.47(s, 3H),2.19–2.14(m,2H),2.00–1.93(m,2H),1.94–1.89(m,2H),1.85–1.77(m,2H),1.74(dq,J=12.1,2.9,2.4Hz,1H),1.69(ddt,J=11.8,5.7 ,2.7Hz,1H),1.63(dd,J=10.4,6.9Hz,1H),1.55–1.48(m,1H),1.45(dd,J=13.6,2.7Hz,2H),1.40(dt,J=12.9,3.2Hz,2H),1.32(q,J=10.6H z,1H),1.13(d,J=6.1Hz,2H),1.06(s,3H),1.00(s,3H),0.98(s,3H),0.93(dd,J=11.9,2.2Hz,1H),0.79(s,3H),0.66(s,3H).MS(ESI):m / z 402.36[M+H] + .

[0079] Example 12 Preparation of Compound b-1

[0080] Compound b-1 is 4,4,10,13,14-pentamethyl-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, and has the following structural formula:

[0081]

[0082] Compound b (3 g, 7.48 mmol) was placed in a round-bottom flask and added with 60 mL of dichloromethane. DMAP (91.38 mg, 0.748 mmol) and triethylamine (3.0 g, 29.9 mmol) were added in sequence. The mixture was placed in an ice bath and stirred to fully dissolve. Trifluoroacetic anhydride (7.9 g, 37.4 mmol) was slowly added dropwise. The reaction was allowed to proceed for 5 h after the addition was completed. The reaction was observed to be complete after the plate was tapped. 60 mL of dichloromethane was added. The mixture was washed with 1 M HCl, saturated NaHCO3, and saturated brine in sequence. The mixture was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to obtain 14.89 g of a light yellow solid b with a yield of 95%.

[0083] Example 13 Preparation of Compound b-2

[0084] Compound b-2 is 4,4,10,13,14-pentamethyl-12-oxo-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, and has the following structural formula:

[0085]

[0086] CrO3 (2.9 g, 29 mmol) was placed in 100 mL of acetic acid and stirred. The temperature was raised to 80°C. Compound b1 (5 g, 7.24 mmol) was added to the reaction bottle and reacted for 2 h. The reaction was completed after observation by plate tapping. The reaction mixture was poured into ice water for precipitation. The solid was filtered and dissolved in dichloromethane. The solid was washed with saturated NaHCO3 and saturated NaCl in turn. The water was removed with anhydrous sodium sulfate. The dichloromethane was removed by rotary evaporation to obtain 4.5 g of a white solid with a yield of 88.2%.

[0087] Example 14 Preparation of Compound C

[0088] Compound c is 16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,2,3,4,5,6,7,8,10,13,14,15,16,17-tetradecahydro-12H-cyclopenta[a]phenanthrene-12-one, and has the following structural formula:

[0089]

[0090] Compound b-2 (1 g, 1.4 mmol) was placed in a round-bottom flask, 20 mL of MeOH was added, the mixture was stirred, and 15 mL of saturated KOH solution was added. The mixture was heated to reflux overnight. The reaction was detected to be complete by TLC. MeOH was removed by rotary evaporation. 30 mL of dichloromethane was added to the reaction flask, the mixture was fully extracted, and the mixture was washed with saturated NaCl solution. Water was removed with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 0.57 g of white solid compound c. The yield was 96%. 1H NMR(500MHz,Chloroform-d)δ4.17(dt,J=48.5,8.2Hz,1H),2.50(d,J=6.7Hz,3H),2.46(d,J=10.1Hz,3H),2.16(s,1H),2. 09(s,1H),2.01(s,1H),1.92(s,2H),1.83(s,1H),1.81(d,J=12.2Hz,2H),1.70(s,2H),1.62(s,3H),1.50(s,2H),1.38(s,3 H),1.33(s,2H),1.28(d,J=7.0Hz,3H),1.19(d,J=16.6Hz,3H),1.13(s,2H),1.11(d,J=6.1Hz,2H),1.07(d,J=12.2Hz,1H) ,1.04(s,2H),1.02(s,1H),1.01(d,J=1.8Hz,3H),0.91s,1H),0.83(d,J=9.3Hz,3H),0.78(s,1H).MS(ESI):m / z417.3[M+H] + .

[0091] Example 15 Preparation of Compound d

[0092] Compound d is 4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl

[0093] (2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-12,16-diol) has the following structural formula:

[0094]

[0095] Compound c (1 g, 2.4 mmol) was placed in a round-bottom flask, 20 mL of MeOH was added, CeCl3·7H2O (1.34 g, 3.6 mmol) was added, and NaBH4 (0.136 g, 3.6 mmol) was added in batches. The mixture was heated to reflux overnight. The reaction was completed by plate spot detection. The remaining MeOH was dried by rotary evaporation. 30 mL of dichloromethane was added to the reaction flask to dissolve the solid, which was washed with saturated NaCl solution and dehydrated with anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain 0.92 g of white solid compound c with a yield of 92%. 1HNMR(500MHz,Chloroform-d)δ5.98(d,J=6.7Hz,1H),5.59(s,1H),4.17(d,J=29.0Hz,2H),3.48(s,2H),2 .93(d,J=14.9Hz,1H),2.48(s,3H),2.46(s,3H),2.36(s,2H),2.23(d,J=33.3Hz,2H),1.97–1.95(m,2H),1 .90(d,J=12.2Hz,2H),1.78(s,2H),1.65(s,2H),1.56(d,J=14.2Hz,2H),1.42(d,J=10.4Hz,2H),1.25(s, 3H),1.20(d,J=5.3Hz,2H),1.14(s,3H),1.02(s,3H),0.97(s,3H),0.80(s,3H).MS(ESI):m / z419.36[M+H] + .

[0096] Example 16 Preparation of Compound Ib1

[0097] 3-Methyl-1-phenyl-1H-pyrazol-5-yl (1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl) (methyl) carbamate, the structural formula is as follows:

[0098]

[0099] Compound b (0.5 g, 1.24 mmol) was placed in a round-bottom flask, 30 mL of dry dichloromethane was added, and triethylamine (0.13 g, 1.24 mmol) was added, stirred to fully dissolve, and edaravone chloride (0.22 g, 1.24 mmol) was slowly added dropwise under ice bath conditions, and nitrogen was protected. The reaction was completed by spot plate detection, and the mixture was washed with saturated NaHCO3 and saturated brine in turn, and water was removed by anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and purified by column chromatography (DCM: MeOH = 35: 1). The mixture was dried to obtain 10.24 g of a pale white solid compound Ib, with a yield of 32%. 1H NMR(500MHz,Chloroform-d)δ7.57–7.51(m,2H),7.43–7.38(m,3H),7.25(s,3H),6.05–6.00(m,1H),4.41(s,1H), 4.06(d,J=7.8Hz,1H),3.47(dd,J=4.4,2.3Hz,1H),2.89–2.84(m,5H),2.62(d,J=4.6Hz,5H),2.30(s,5H),2.17(s, 3H),2.13(s,2H),1.93(s,2H),1.87(s,3H),1.73(s,3H),1.46(d,J=12.5Hz,2H),1.37(s,4H),1.28(d,J=3.6Hz,3 H),1.22(d,J=4.9Hz,3H),1.03(s,7H),0.96(s,7H),0.94(s,9H),0.93(s,8H),0.65(d,J=6.2Hz,5H).MS(ESI):m / z 603.43[M+H] + .

[0100] Example 17 Preparation of Compound Ib2

[0101] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0102]

[0103] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by 4-chloro-edaravone chloride to obtain 0.15 g of a light yellow solid with a yield of 19%.

[0104] 1 H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.51(s,1H),7.38(s,1H),7.37(d,J=2.0Hz, 1H),6.04(s,1H),4.44(dd,J=11.1,6.4Hz,1H),4.13(d,J=7.6Hz,1H),3.64(p,J=6.1Hz,

[0105] 1H),2.89(s,3H),2.82(s,1H),2.54(s,3H),2.30(s,3H),2.05(d,J=6.2Hz,2H),1.93(s,2H),

[0106] 1.84(d,J=12.8Hz,2H),1.71(d,J=12.3Hz,2H),1.64(s,2H),1.38(s,2H),1.25(s,2H),1.16(s, 2H),1.13(s,3H),1.12(s,3H),1.06(s,3H),1.03(s,3H),0.96(s,3H),0.86(s,3H).MS(ESI):m / z 637.39[M+H] + .

[0107] Example 18 Preparation of Compound Ib3

[0108] 1-(4-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0109]

[0110] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by 4-fluoro-edaravone chloride to obtain 0.17 g of light yellow solid with a yield of 22%. 1 H NMR(500MHz,Chloroform-d)δ7.57–7.53(m,2H),7.12(d,J=8.7Hz,2H),6.06(s,1H),4.53–4.45(m, 1H),4.16(s,1H),3.76–3.69(m,1H),3.17(s,1H),3.15(s,3H),3.14(s,3H),3.12(s,1H),2.90(s,2 H),2.80(s,3H),2.48(d,J=12.3Hz,2H),2.33(s,3H),2.17(s,2H),2.05(s,2H),1.96(s,1H),1.45( s,2H),1.44(s,3H),1.42(s,2H),1.31(s,3H),1.13(s,3H),1.10(s,3H),1.09(s,3H).MS(ESI):m / z 621.42[M+H] + .

[0111] Example 19 Preparation of Compound Ib4

[0112] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0113]

[0114] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by 4-trifluoromethyl-edaravone chloride to obtain 0.13 g of a white solid with a yield of 16%. 1 H NMR(500MHz,Chloroform-d)δ7.78(s,1H),7.77(s,1H),7.71(s,1H),7.69(s,1H),6.11(s,1H),4.47(d ,J=10.8Hz,1H),4.34(t,J=6.7Hz,1H),4.18(s,1H),2.97(s,3H),2.81(s,3H),2.35(s,3H),2.18(s,2H) ,2.09(s,2H),2.03(s,2H),1.98(d,J=9.0Hz,2H),1.77–1.75(m,2H),1.53(s,2H),1.47(d,J=4.3Hz,2H ),1.32(d,J=3.3Hz,3H),1.31(s,3H),1.29(s,3H),1.14(s,3H),1.09(s,3H),1.00(s,3H).MS(ESI):m / z 641.42[M+H] + .

[0115] Example 20 Preparation of Compound Ib5

[0116] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0117]

[0118] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by 4-nitro-edaravone chloride to obtain 0.13 g of brown solid with a yield of 16%. 1 H NMR(500MHz,Chloroform-d)δ8.28(s,2H),8.26(d,J=1.9Hz,3H),7.84(s,2H),7.83(d,J=1.9Hz,2H),6.10(s,1H),4.46 (dd,J=11.3,6.4Hz,1H),4.17(d,J=7.6Hz,1H),2.97(s,3H),2.93(s,2H),2.76(s,6H),2.31(s,5H),2.20(s,1H),2.15( d,J=12.4Hz,3H),2.07(d,J=5.6Hz,3H),1.99(d,J=10.0Hz,4H),1.74(d,J=12.4Hz,4H),1.39(s,3H),1.28(d,J=2.9Hz, 9H),1.27(s,9H),1.25(s,7H),1.22(d,J=6.1Hz,5H),1.20(s,4H),1.10(s,7H),1.06(s,7H),0.97(s,6H).MS(ESI):m / z 648.41[M+H] + .

[0119] Example 21 Compound Ib 10 Preparation

[0120] 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0121]

[0122] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by trifluoromethyl edaravone chloride to obtain 0.15 g of a white solid with a yield of 18%. 1H NMR(500MHz,Chloroform-d)δ7.59(s,1H),7.58(s,1H),7.47(s,1H),7.45(s,1H ),6.53(s,1H),4.44–4.38(m,1H),4.16(d,J=7.5Hz,1H),4.05(d,J=7.4Hz,1H),2 .86(s,3H),2.66(s,3H),2.65(s,3H),2.26(s,2H),2.13(s,2H),2.02(d,J=6.0Hz ,2H),1.91(s,2H),1.79(s,2H),1.75(d,J=9.2Hz,2H),1.65(s,2H),1.37(s,2H),

[0123] 1.26(d,J=4.8Hz,2H),1.17(s,3H),1.03(s,2H),1.02(s,3H),1.00(s,3H),0.96(s,3H),0.94(s,3H).MS(ESI):m / z 657.40[M+H] + .

[0124] Example 22 Compound Ib 11 Preparation

[0125] 2-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamoyl)phenyl acetate, the structural formula is as follows:

[0126]

[0127] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by aspirin chloride to obtain 0.17 g of a white solid with a yield of 24%. 1H NMR (500MHz, DMSO-d6) δ6.68–6.65(m,2H),6.35(d,J=7.8Hz,2H),4.40(dd,J=10.5,6.6Hz,1H),3.75(t,J=7 .6Hz,1H),3.49(d,J=7.3Hz,1H),2.36(s,3H),2.31(s,3H),1.99(s,1H),1.96(s,3H),1.66(s,2H),1.61(s,2 H),1.44(s,2H),1.32(s,2H),0.87(s,3H),0.74(d,J=4.6Hz,2H),0.69(s,2H),0.65(d,J=6.1Hz,2H),0.55( d,J=6.7Hz,2H),0.51(s,3H),0.48(s,3H),0.45(s,3H),0.43(s,3H),0.26(s,3H).MS(ESI):m / z565.40[M+H] + .

[0128] Example 23 Compound Ib 12 Preparation

[0129] N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, the structural formula is as follows:

[0130]

[0131] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by 3,4-dimethoxybenzoyl chloride to obtain 0.15 g of a white solid with a yield of 21%. 1H NMR(500MHz,Chloroform-d)δ7.40(d,J=15.6Hz,1H),7.34(d,J=8.3Hz,1H),6.91(s,1H),4.90(dd,J=11.4,6.5Hz,1H),3.92(t,J=7 .2Hz,1H),2.86(d,J=7.2Hz,3H),2.27(s,3H),2.10(s,3H),1.98(t,J=16.3Hz,2H),1.86(dd,J=11.2,5.8Hz,1H),1.73(s,2H),1.62( dd,J=15.3,8.0Hz,2H),1.52–1.42(m,2H),1.26(d,J=12.4Hz,1H),1.20(s,2H),1.13(d,J=11.7Hz,2H),1.06(d,J=7.8Hz,2H),0.94( d,J=6.8Hz,2H),0.83(s,3H),0.79(s,3H),0.77(s,3H),0.70(d,J=11.6Hz,1H),0.64(s,2H),0.58(s,3H),0.56(s,3H).MS(ESI):m / z 567.42[M+H] + .

[0132] Example 24 Compound Ib 13 Preparation

[0133] (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)-2-methoxyphenyl acetate, the structural formula is as follows:

[0134]

[0135] The preparation process is the same as the preparation steps of compound Ⅰb1, except that edaravone chloride is replaced by ferulic acid chloride to obtain 0.2 g of a light yellow solid with a yield of 26%. 1H NMR(500MHz,Chloroform-d)δ7.13(d,J=3.5Hz,1H),7.08(d,J=1.9Hz,1H),5.15(dd,J=11.5,6.5Hz,1H ),4.56(d,J=12.7Hz,1H),4.23(s,1H),3.09(s,3H),3.06(s,3H),2.98(s,2H),2.23(d,J=16.4Hz,1H),2 .16(d,J=12.5Hz,2H),2.11–2.07(m,1H),1.96(d,J=13.2Hz,2H),1.86–1.81(m,1H),1.69(s,2H),1.50 (t,J=12.3Hz,2H),1.42(s,2H),1.34(d,J=6.5Hz,1H),1.25(s,2H),1.16(d,J=6.8Hz,2H),1.10(s,3H),

[0136] 1.00(s,3H),0.94(d,J=4.9Hz,2H),0.92(s,3H),0.91(s,3H),0.79(s,3H).MS(ESI):m / z

[0137] 621.43[M+H] + .

[0138] Example 25 Compound Ib 14 Preparation of (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate, the structural formula is as follows:

[0139]

[0140] The preparation process is the same as compound Ⅰb1, except that edaravone chloride is replaced by (E)-3-(4-acetoxyphenyl)acryloyl chloride to obtain 0.18 g of light yellow solid with a yield of 24.6%. 1H NMR(500MHz,Chloroform-d)δ7.02(s,2H),6.84(d,J=8.1Hz,2H),5.24(s,1H),4.34(s,1H),3.8 9(s,3H),3.88(s,3H),3.01(s,1H),2.92(s,2H),2.49(s,3H),2.17(d,J=5.9Hz,2H),2.15(d,J=5 .9Hz,2H),1.95(s,2H),1.92(s,2H),1.71(d,J=12.1Hz,2H),1.40(s,2H),1.37(s,2H),1.34(s, 2H),1.25(s,3H),1.23(s,3H),1.01(s,3H),0.99(s,3H),0.80(s,3H).MS(ESI):m / z591.42[M+H] + .

[0141] Example 26 Compound Ic 12 Preparation

[0142] N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-12-oxo-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, the structural formula is as follows:

[0143]

[0144] The preparation process is the same as compound Ⅰb 12 The preparation steps are as follows, except that compound b is replaced by compound c, to obtain 0.18 g of a light yellow solid with a yield of 25.8%. 1 H NMR(500MHz,Chloroform-d)δ6.99(d,J=37.4Hz,2H),6.85(d,J=7.7Hz,1H),3.92(d,J=2.5Hz,1H),3.89(s,3H),3. 89–3.87(m,3H),3.03–2.97(m,2H),2.91(d,J=15.9Hz,2H),2.48(d,J=2.2Hz,3H),2.47–2.44(m,3H),1.96(s,2H),

[0145] 1.80(s,2H),1.56(d,J=5.5Hz,2H),1.46(d,J=11.5Hz,2H),1.35(d,J=6.6Hz,2H),1.30(d,J=7.8Hz,2H),1.2 5(s,3H),1.15(s,3H),1.02(s,3H),1.01(s,3H),0.83(d,J=4.9Hz,3H),0.77(d,J=17.1Hz,3H).MS(ESI):m / z 581.40[M+H] + .

[0146] Example 27 Compound Ic 14 Preparation

[0147] (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-12-oxo

[0148] -2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate, the structural formula is as follows:

[0149]

[0150] The preparation process is the same as compound Ⅰb 14 The preparation steps are as follows, the only difference being that compound b is replaced by compound c, to obtain 0.18 g of a light yellow solid, and 0.13 g of a light yellow solid, with a yield of 17.9%. 1 HNMR(500MHz,Chloroform-d)δ7.39–7.36(m,2H),6.93(d,J=8.1Hz,2H),4.11(t,J=6.7Hz,1H),3.96(d,J= 25.1Hz,1H),2.94(s,1H),2.86(t,J=8.8Hz,2H),2.77(d,J=5.1Hz,2H),2.41(t,J=1.9Hz,3H),2.13(s,3H),

[0151] 1.97–1.89(m,2H),1.63(d,J=15.1Hz,2H),1.56–1.52(m,1H),1.42–1.37(m,2H),1.27(t,J=4.0Hz,2H),1.12(d,J=7.1Hz,2 H),1.03(d,J=2.8Hz,3H),0.99(d,J=5.0Hz,3H),0.92(s,3H),0.81(d,J=3.7Hz,3H),0.73(s,3H),0.71(s,3H).MS(ESI):m / z 605.40[M+H] + .

[0152] Example 28 Preparation of Compound Id3

[0153] 1-(4-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl (1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl) (methyl) carbamate, the structural formula is as follows:

[0154]

[0155] The preparation process is the same as the preparation steps of compound Ⅰb3, except that compound b is replaced by compound d, and 0.13 g of light white solid is obtained, with a yield of 17.1%. 1 H NMR(500MHz,Chloroform-d)δ7.55(dd,J=6.3,3.2Hz,2H),7.14–7.12(m,2H),6.05(d,J=4.3Hz,1H),5.62 (d,J=8.2Hz,1H),4.34(dd,J=11.7,7.0Hz,1H),4.19(s,1H),3.74(s,1H),3.51(s,2H),2.96(d,J=4.1Hz,3 H),2.87(s,3H),2.80(s,3H),2.62–2.55(m,2H),2.46(dd,J=23.1,12.9Hz,2H),2.07(s,2H),1.87(s,2H) ,1.33(s,3H),1.30(s,3H),1.23(s,3H),1.17(s,3H),1.10(s,3H),1.04(s,3H),0.86(s,3H).MS(ESI):m / z

[0156] 637.41[M+H] + .

[0157] Example 29 Preparation of Compound Id4

[0158] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0159]

[0160] The preparation process is the same as the preparation steps of compound Ⅰb4, except that compound b is replaced by compound d, and 0.18 g of white solid is obtained with a yield of 21.9%.

[0161] 1 H NMR(500MHz,Chloroform-d)δ7.66–7.62(m,2H),7.55(d,J=4.3Hz,2H),5.97(d,J=8.2Hz,1H),5.48–5.40(m,1H),4.0 5(s,1H),3.55(d,J=3.5Hz,1H),2.99–2.95(m,1H),2.84(d,J=15.0Hz,2H),2.76(d,J=16.5Hz,2H),2.61(s,3H),2.57 (s,3H),2.17(s,3H),1.91(s,2H),1.69(d,J=13.3Hz,2H),1.45(s,2H),1.27(t,J=7.5Hz,2H),1.17(d,J=5.1Hz,2H), 1.14(s,3H),1.12(s,2H),1.09(s,3H),1.07(s,2H),1.04(s,3H),1.03(s,2H),0.97(s,3H),0.90(s,3H).MS(ESI):m / z 687.41[M+H] + .

[0162] Example 30 Preparation of Compound Id5

[0163] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0164]

[0165] The preparation process is the same as the preparation steps of compound Ⅰb5, except that compound b is replaced by compound d, and 0.16 g of white solid is obtained with a yield of 20.2%.

[0166] 1 H NMR(500MHz,Chloroform-d)δ8.28(dd,J=6.8,2.5Hz,2H),7.82(d,J=8.7Hz,2H),6.09(d,J=5.5Hz,1H),5.59(s,1H),4.30 (t,J=6.7Hz,1H),3.70(s,1H),3.64(p,J=6.1Hz,1H),3.10(q,J=7.4Hz,2H),3.03(s,1H),2.95(s,1H),2.75(s,3H),2.72(s ,3H),2.44–2.40(m,1H),2.32(s,3H),2.04(s,2H),1.94(d,J=13.0Hz,2H),1.84(s,2H),1.71(t,J=7.3Hz,2H),1.39(d,J= 7.3Hz,2H),1.28(d,J=2.5Hz,3H),1.26(s,3H),1.19(s,3H),1.17(d,J=4.6Hz,3H),1.13(s,3H),1.12(s,3H).MS(ESI):m / z 664.41[M+H] + .

[0167] Example 31 Compound Id 10 Preparation

[0168] 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(12,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0169]

[0170] The preparation process is the same as compound Ⅰb 10 The preparation steps are as follows, except that compound b is replaced by compound d, to obtain 0.14 g of a white solid with a yield of 17.4%. 1H NMR(500MHz,Chloroform-d)δ7.63–7.60(m,2H),7.52–7.49(m,2H),7.47(dd,J=11.0,3.9Hz,1H),6.56(d,J=5.7Hz,1H),5.6 3(s,1H),4.32(s,1H),4.14(s,1H),2.97(dd,J=9.8,4.7Hz,3H),2.88(d,J=6.7Hz,2H),2.77(d,J=6.9Hz,3H),2.45(d,J=17. 3Hz,2H),2.16(d,J=13.2Hz,2H),1.98(t,J=14.2Hz,2H),1.86(d,J=12.8Hz,2H),1.79–1.72(m,2H),1.49(d,J=10.4Hz,2H), 1.34(s,3H),1.29(s,3H),1.27(s,2H),1.23(s,2H),1.20(d,J=3.8Hz,3H),1.18(d,J=3.0Hz,3H),1.15(s,3H).MS(ESI):m / z 673.39[M+H] + .

[0171] Example 32 Preparation of Compound b-3

[0172] 1,1,4a,6a,9a-pentamethyl-2-(2,2,2-trifluoro-N-methylacetylamino)-7-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-8-yl 2,2,2-trifluoroacetate, the structural formula is as follows:

[0173]

[0174] Compound b-1 (3 g, 4.34 mmol) was placed in a round-bottom flask, 50 mL of dichloromethane was added and stirred to fully dissolve, m-CPBA (1.5 g, 8.69 mmol) was slowly added under ice bath conditions, and stirred until the reaction was complete. A saturated solution of Na2S2O3 was added to the reaction flask, excess m-CPBA was removed, the organic phase was separated and washed with NaHCO3 and saturated brine in turn, dehydrated with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 32.55 g of white solid compound b. ， The yield was 83.1%.

[0175] Example 33 Preparation of Compound b-4

[0176] 9-Fluoro-4,4,10,13,14-pentamethyl-11-oxo-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl 2,2,2-trifluoroacetate, the structural formula is as follows:

[0177]

[0178] Compound b-3 (3 g, 4.14 mmol) was placed in a round-bottom flask, 50 mL of dichloromethane was added, and the temperature was maintained below 0°C in an ice bath. BF3·ET2O (5.88 g, 41.4 mmol) was slowly added to react until completion. The reaction was detected to be complete by TLC. 50 mL of dichloromethane was added to the reaction flask, and the mixture was washed with water, saturated NaHCO3, and saturated NaCl solution in sequence. Water was removed by anhydrous sodium sulfate, and excess solvent was removed by rotary evaporation. The mixture was purified by column chromatography (DCM:MeOH=100:1) and dried to obtain 2.28 g of a white solid with a yield of 76.1%.

[0179] Example 34 Preparation of Compound e

[0180] 9-Fluoro-16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)hexahydro-11H-cyclopenta[a]phenanthrene-11-one, the structural formula is as follows:

[0181]

[0182] The preparation process is the same as the preparation steps of compound c, except that compound b-2 is replaced by compound b-4, and 1.16 g of white solid is obtained with a yield of 96%.

[0183] 1 H NMR(500MHz,Chloroform-d)δ3.63(t,J=7.6Hz,1H),2.29(d,J=13.5Hz,1H),2.12–

[0184] 2.10(m,4H),1.93(s,3H),1.93(s,3H),1.68(d,J=13.6Hz,1H),1.46–1.40(m,2H),1.36(dd,J=11.9,4 .0Hz,1H),1.29(d,J=11.2Hz,2H),1.22–1.14(m,2H),0.95–0.92(m,1H),0.86(d,J=12.2Hz,1H),0.81 (s,3H),0.78(s,2H),0.74(d,J=13.7Hz,1H),0.57(d,J=6.2Hz,2H),0.55(s,3H),0.48(s,3H),0.45–0 .40(m,1H),0.37(s,2H),0.29(d,J=11.0Hz,1H),0.24(s,3H),0.20(s,3H).MS(ESI):m / z419.37[M+H] + .

[0185] Example 35 Preparation of Compound If1

[0186] 3-Methyl-1-phenyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0187]

[0188] The preparation process is the same as the preparation steps of compound Ⅰb1, except that compound b is replaced by compound f, and 0.14 g of white solid is obtained with a yield of 16.8%. 1H NMR(500MHz,Chloroform-d)δ7.54(d,J=7.7Hz,2H),7.41(d,J=8.0Hz,2H),7.31(t,J=7.4Hz,1H),6.02(d,J=5.4Hz,1H),4.3 7(s,1H),4.09(t,J=7.2Hz,1H),2.92(d,J=4.4Hz,1H),2.87(d,J=6.1Hz,3H),2.60(d,J=3.1Hz,3H),2.31(s,3H),2.15(s,2H ),2.11(d,J=16.0Hz,2H),1.87(d,J=10.0Hz,2H),1.82(d,J=10.8Hz,2H),1.68(s,2H),1.34(s,2H),1.31(d,J=7.7Hz,2H),1 .27(s,3H),1.13(s,3H),1.12(s,3H),1.09(s,2H),1.05(d,J=3.0Hz,3H),0.92(s,3H),0.72(s,3H).(ESI):m / z619.42[M+H] + .

[0189] Example 36 Preparation of Compound If2

[0190] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0191]

[0192] The preparation process is the same as the preparation steps of compound Ⅰb2, except that compound b is replaced by compound f, and 0.15 g of white solid is obtained with a yield of 18.9%. 1H NMR(500MHz,Chloroform-d)δ7.52–7.49(m,2H),7.38(d,J=8.7Hz,2H),6.03(d,J=4.0Hz,1H),4.40(s,1H),4.1 8(s,1H),2.96–2.93(m,1H),2.88(d,J=6.1Hz,3H),2.68(s,3H),2.29(s,3H),2.16(d,J=13.9Hz,2H),1.89(s,2H ),1.84(s,2H),1.72(s,2H),1.33(s,2H),1.29(s,3H),1.25(s,3H),1.20(s,3H),1.13(d,J=5.5Hz,2H),1.07(s ,3H),1.01(s,3H),0.96(t,J=7.4Hz,2H),0.87(d,J=5.6Hz,2H),0.83(d,J=11.7Hz,2H),0.73(s,3H).(ESI):m / z 653.39[M+H] + .

[0193] Example 37 Preparation of Compound If3

[0194] 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0195]

[0196] The preparation process is the same as the preparation steps of compound Ⅰb3, except that compound b is replaced by compound f, and 0.2 g of white solid is obtained with a yield of 26.3%. 1H NMR(500MHz,Chloroform-d)δ7.57–7.52(m,2H),7.14(d,J=8.2Hz,2H),6.05(s,1H),4.49–4.46( m,1H),4.33(d,J=7.0Hz,1H),4.20(s,1H),3.73(d,J=8.2Hz,1H),2.75(s,3H),2.68(s,3H),2.33( s,3H),2.21(s,2H),1.93(s,2H),1.89(s,2H),1.75(s,2H),1.57(d,J=13.6Hz,2H),1.32(s,3H),1 .26(s,3H),1.11(s,3H),1.10(s,3H),1.07(s,3H),0.99(t,J=7.4Hz,2H),0.73(s,3H).(ESI):m / z 637.42[M+H] + .

[0197] Example 38 Preparation of Compound If4

[0198] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0199]

[0200] The preparation process is the same as the preparation steps of compound Ⅰb4, except that compound b is replaced by compound f, and 0.18 g of white solid is obtained with a yield of 21.9%. 1H NMR(500MHz,Chloroform-d)δ7.67(d,J=8.4Hz,2H),7.58(d,J=7.6Hz,2H),6.01(s,1H),4.31(s,1H),4.20(t, J=6.7Hz,1H),4.10(d,J=8.5Hz,1H),3.55(dd,J=12.1,5.9Hz,1H),2.82(d,J=3.5Hz,3H),2.63(s,3H),2.20(s ,3H),2.06(d,J=13.1Hz,2H),1.80(s,2H),1.73(d,J=11.4Hz,2H),1.37–1.33(m,1H),1.31(d,J=4.5Hz,2H),1 .21(d,J=7.1Hz,4H),1.14(s,3H),1.03(s,3H),1.02(s,3H),0.97(s,3H),0.94(s,3H),0.64(s,3H).(ESI):m / z 687.41[M+H] + .

[0201] Example 39 Preparation of Compound If5

[0202] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0203]

[0204] The preparation process is the same as the preparation steps of compound Ⅰb5, except that compound b is replaced by compound f, and 0.1 g of brown solid is obtained with a yield of 12.6%. 1H NMR(500MHz,Chloroform-d)δ8.02–8.00(m,2H),7.61–7.57(m,2H),5.82(d,J=20.1Hz,1H),4.12(s,1H) ,3.91(d,J=18.5Hz,1H),2.87–2.80(m,1H),2.41(s,3H),2.29(dt,J=4.0,1.9Hz,3H),2.01(s,3H),1.89– 1.84(m,2H),1.41(s,2H),1.35(s,2H),1.11(t,J=7.4Hz,2H),1.04(s,2H),1.01(s,2H),0.92(s,3H),0.9 2(s,3H),0.78(s,3H),0.72(s,3H),0.67–0.60(m,2H),0.51(s,2H),0.45(s,3H).(ESI):m / z664.41[M+H] + .

[0205] Example 40 Compound If 10 Preparation

[0206] 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0207]

[0208] The preparation process is the same as compound Ⅰb 10 The preparation steps are as follows, except that compound b is replaced by compound f, to obtain 0.18 g of a brown solid with a yield of 22.4%. 1H NMR(500MHz,Chloroform-d)δ7.57(d,J=7.7Hz,2H),7.47(d,J=7.0Hz,2H),7.42(t,J=7.2Hz,1H),6.52(s,1H),4.36(s,1H),4.13–4 .09(m,1H),3.13–3.09(m,1H),2.98(d,J=13.5Hz,1H),2.84(d,J=6.4Hz,3H),2.74(s,3H),2.59(d,J=13.6Hz,1H),2.45(d,J=11.5H z,1H),2.15(d,J=13.7Hz,1H),2.10(d,J=12.4Hz,1H),2.03–1.96(m,2H),1.89(s,2H),1.85(s,2H),1.70(s,2H),1.41(d,J=7.3Hz, 2H),1.33(s,2H),1.27(s,3H),1.25(s,3H),1.08(s,3H),1.07(s,3H),0.89(d,J=12.5Hz,2H),0.72(s,3H).(ESI):m / z673.40[M+H] + .

[0209] Example 41 Compound If 12 Preparation

[0210] N-(1-(8-hydroxy-1,1,4a,6a,9a-pentamethyl-2-(methylamino)hexahydrocyclopenta[1,2]phenanthro[4,4a-b]oxiran-7-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, the structural formula is as follows:

[0211]

[0212] The preparation process is the same as compound Ⅰb 12 The preparation steps are as follows, except that compound b is replaced by compound f, to obtain 0.11 g of a brown solid with a yield of 15.8%. 1H NMR(500MHz,Chloroform-d)δ7.01(s,1H),6.94(d,J=6.8Hz,1H),6.84(d,J=7.8Hz,1H),4.19(s,1H),3.89 (s,3H),3.88(d,J=2.7Hz,3H),2.91(d,J=9.8Hz,3H),2.47(d,J=6.2Hz,3H),2.15(s,2H),1.91(d,J=11.2Hz ,2H),1.81(d,J=12.5Hz,2H),1.66(d,J=11.8Hz,2H),1.57–1.50(m,2H),1.44(d,J=15.3Hz,2H),1.31(s,2H ),1.25(s,3H),1.11(d,J=4.6Hz,3H),1.05(d,J=5.9Hz,3H),0.81(s,3H),0.68(d,J=3.4Hz,3H).(ESI):m / z 583.41[M+H] + .

[0213] Example 42 Preparation of Compound g

[0214] 4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl

[0215] 1H-cyclopenta[a]phenanthrene-16-ol, the structural formula is as follows:

[0216]

[0217] Take a 1L three-necked flask, add 550mL of 2mol / L hydrochloric acid, heat to reflux, add CVB-D (10g, 24.9mmol) and react for 12h, stop heating, cool naturally to room temperature, filter to obtain a crude hydrochloride, dissolve the filtered product in water, adjust pH>8, pour into 1000mL of dichloromethane three times for full extraction, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain 8.4g of a crude compound b. The purity detected by HPLC was 49%, and the yield was 41%.

[0218] Example 43 Preparation of Compound g-1

[0219] 4,4,10,13,14-pentamethyl-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, the structural formula is as follows:

[0220]

[0221] The preparation process is the same as the preparation steps of compound b-1, except that compound b is replaced by compound g, and 4.8 g of light white solid is obtained, with a yield of 93.2%.

[0222] Example 44 Preparation of Compound g-2

[0223] 4,4,10,13,14-pentamethyl-7,11-dioxo-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16-yl 2,2,2-trifluoroacetate, the structural formula is as follows:

[0224]

[0225] The preparation process is the same as compound b-2, except that compound b-1 is replaced by compound g-1, to obtain 4.3 g of yellow solid with a yield of 83%.

[0226] Example 45 Preparation of Compound g-3

[0227] 7-Hydroxy-4,4,10,13,14-pentamethyl-11-oxo-3-(2,2,2-trifluoro-N-methylacetylamino)-17-(1-(2,2,2-trifluoro-N-methylacetylamino)ethyl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-yl 2,2,2-trifluoroacetate, the structural formula is as follows:

[0228]

[0229] The preparation process is the same as compound d, except that compound c is replaced by compound g-2, to obtain 0.9 g of a yellow solid with a yield of 90%.

[0230] Example 46 Preparation of Compound i

[0231] 7,16-dihydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,2,3,4,5,6,7,10,12,13,14,15,16,17-tetradecahydro-11H-cyclopenta[a]phenanthrene-11-one, the structural formula is as follows:

[0232]

[0233] The preparation process is the same as the preparation steps of compound c, except that compound b-2 is replaced by compound g-3, and 0.57 g of light yellow solid is obtained, with a yield of 95%. 1 H NMR(500MHz,Chloroform-d)δ4.58(dd,J=9.7,5.2Hz,1H),4.27(dd,J=9.8,4.4Hz,1H),3.70(td,J=10.1,5.0H z,1H),3.00–2.93(m,1H),2.87–2.82(m,2H),2.55–2.52(m,2H),2.50(d,J=3.0Hz,2H),2.48(s,3H),2.40(s,3H ),2.10(t,J=9.5Hz,1H),2.06–2.02(m,1H),1.61–1.57(m,1H),1.44(s,2H),1.41(d,J=3.0Hz,2H),1.31(d,J= 2.4Hz,3H),1.29(s,3H),1.15(s,2H),1.14(s,2H),1.04(s,3H),0.85(s,3H),0.81(d,J=8.5Hz,3H).(ESI):m / z 433.34[M+H] + .

[0234] Example 47 Preparation of Compound H

[0235] 16-Hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-17-(1-(methylamino)ethyl)-1,3,4,5,6,10,12,13,14,15,16,17-dodecahydro-7H-cyclopenta[a]phenanthrene-7,11(2H)-dione, the structural formula is as follows:

[0236]

[0237] The preparation process is the same as the preparation steps of compound c, except that compound b-2 is replaced by compound g-2, and 0.56 g of light yellow solid is obtained, and the yield is 95%. 1H NMR(500MHz,Chloroform-d)δ3.99(t,J=8.0Hz,1H),2.72(t,J=15.2Hz,2H),2.48(s,2H),2.38(d,J=5.8Hz, 2H),2.36–2.35(m,2H),2.34(s,2H),2.31(s,3H),2.30(s,3H),2.20(dd,J=14.6,9.4Hz,2H),2.04–2.00(m,1 H),1.83–1.77(m,2H),1.58(dd,J=10.5,6.5Hz,1H),1.41(dd,J=10.0,7.2Hz,1H),1.26(s,3H),1.14(s,3H), 1.00(t,J=5.0Hz,1H),0.97(d,J=6.2Hz,2H),0.87(s,3H),0.68(s,3H),0.65(s,3H).(ESI):m / z430.32[M+H] + .

[0238] Example 48 Preparation of Compound Ih1

[0239] 1-phenyl-1H-pyrazol-5-yl (1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl) (methyl) carbamate, the structural formula is as follows:

[0240]

[0241] The preparation process is the same as the preparation steps of compound Ⅰb1, except that compound b is replaced by compound h, and 0.13 g of white solid is obtained with a yield of 13%. 1H NMR(500MHz,Chloroform-d)δ7.54(d,J=8.1Hz,2H),7.42(d,J=7.8Hz,2H),7.34(d,J=7.6Hz,1H),6.02(s,1H ),4.40(s,1H),4.03(t,J=7.1Hz,1H),2.89(s,2H),2.47(d,J=3.7Hz,1H),2.44(s,3H),2.31(s,3H),1.55(s, 2H),1.54(d,J=4.7Hz,2H),1.39(s,3H),1.35–1.31(m,2H),1.27(s,3H),1.25(s,3H),1.15(s,2H),1.14(d,J =3.2Hz,2H),1.00(s,3H),0.96(t,J=7.3Hz,1H),0.83(s,3H),0.81(d,J=3.1Hz,3H).(ESI):m / z631.39[M+H] + .

[0242] Example 49 Preparation of Compound Ih2

[0243] 1-(4-chlorophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0244]

[0245] The preparation process is the same as the preparation steps of compound Ⅰb2, except that compound b is replaced by compound h, and 0.13 g of white solid is obtained with a yield of 17.2%. 1H NMR(500MHz,Chloroform-d)δ7.23(dd,J=8.8,1.5Hz,2H),7.10–7.07(m,2H),5.73(d,J=15.8Hz,1H),4.06( s,1H),3.91(s,1H),3.80(s,1H),3.34(s,1H),2.81–2.78(m,2H),2.39(s,3H),2.25(q,J=1.8Hz,3H),2.16(s ,2H),2.11(d,J=16.5Hz,2H),1.94(d,J=1.5Hz,3H),1.85–1.79(m,2H),1.26(d,J=12.8Hz,2H),1.08(d,J=1. 5Hz,3H),1.07(d,J=1.4Hz,3H),0.98(s,3H),0.94(s,3H),0.85(s,2H),0.78(s,3H),0.52(s,3H).(ESI):m / z 665.35[M+H] + .

[0246] Example 50 Preparation of Compound Ih3

[0247] 1-(4-Fluorophenyl)-3-methyl-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0248]

[0249] The preparation process is the same as the preparation steps of compound Ⅰb3, except that compound b is replaced by compound h, and 0.11 g of light white solid is obtained, with a yield of 14.6%. 1H NMR(500MHz,Chloroform-d)δ7.26–7.20(m,2H),6.83–6.80(m,2H),5.73(d,J=18.6Hz,1H),4.08(s,1H),3.80(t,J= 7.1Hz,1H),3.35(s,1H),2.71(d,J=13.8Hz,2H),2.56(s,3H),2.51(d,J=25.2Hz,2H),2.39(s,3H),2.26(p,J=1.9Hz, 3H),2.17(d,J=3.0Hz,2H),1.91(d,J=9.7Hz,1H),1.85–1.79(m,2H),1.67(s,2H),1.10(s,2H),1.09–1.08(m,2H),0 .99(s,3H),0.94(s,3H),0.93(s,2H),0.85(d,J=2.4Hz,2H),0.85–0.83(m,2H),0.79(s,3H),0.53(s,3H).(ESI):m / z 649.38[M+H] + .

[0250] Example 51 Preparation of Compound Ih4

[0251] 3-Methyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0252]

[0253] The preparation process is the same as the preparation steps of compound Ⅰb4, except that compound b is replaced by compound h, and 0.13 g of white solid is obtained with a yield of 16%. 1H NMR(500MHz,Chloroform-d)δ7.58(d,J=8.4Hz,2H),7.50(d,J=8.3Hz,2H),5.90(d,J=6.6Hz,1H),3.94(s,1H),3.4 8(s,1H),2.84(d,J=13.6Hz,1H),2.75(s,2H),2.71(s,1H),2.53(s,3H),2.38(p,J=1.9Hz,3H),2.30(d,J=4.8Hz,2H ),2.25(d,J=15.9Hz,1H),2.09(s,3H),1.97(d,J=14.3Hz,2H),1.83–1.77(m,2H),1.38(d,J=6.7Hz,1H),1.24(s,3 (ESI): m / z 699.37[M+H] + .

[0254] Example 52 Preparation of Compound Ih5

[0255] 3-Methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0256]

[0257] The preparation process is the same as the preparation steps of compound Ⅰb5, except that compound b is replaced by compound h, and 0.12 g of brown solid is obtained with a yield of 12.7%. 1H NMR(500MHz,Chloroform-d)δ8.22(d,J=9.1Hz,2H),7.77(d,J=9.1Hz,2H),6.03(s,1H),4.10(s,1H),3 .46(s,1H),3.04(d,J=7.3Hz,3H),3.01(d,J=7.3Hz,3H),2.89(s,2H),2.49–2.45(m,2H),2.41(s,2H),2 .22(s,3H),2.09(d,J=14.4Hz,2H),1.98(q,J=12.5,11.6Hz,2H),1.35(s,2H),1.34(s,2H),1.32(s,3H) ,1.31(s,2H),1.23(s,2H),1.21(s,3H),1.20(s,2H),1.16(s,3H),1.06(s,3H),0.77(s,3H).(ESI):m / z 676.37[M+H] + .

[0258] Example 53 Compound Ih 10 Preparation

[0259] 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamate, the structural formula is as follows:

[0260]

[0261] The preparation process is the same as compound Ⅰb 10 The preparation steps are as follows, except that compound b is replaced by compound h, to obtain 0.16 g of a yellow solid with a yield of 12.7%. 1H NMR(500MHz,Chloroform-d)δ7.43(d,J=8.3Hz,2H),7.31–7.29(m,2H),7.25–7.21(m,1H),6.44(s,1H),3.94 (s,1H),3.64(s,1H),2.86(d,J=13.1Hz,1H),2.70(d,J=9.7Hz,3H),2.67(s,3H),2.40(q,J=2.0Hz,2H),2.32 (d,J=7.1Hz,2H),2.22(dd,J=30.7,16.0Hz,2H),1.95(d,J=17.5Hz,2H),1.80(d,J=19.2Hz,2H),1.44–1.34( m / z 685.36[M+H] + .

[0262] Example 54 Compound Ih 11 Preparation

[0263] 2-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)carbamoyl)phenyl acetate, the structural formula is as follows:

[0264]

[0265] The preparation process is the same as compound Ⅰb 11 The preparation steps are as follows, except that compound b is replaced by compound h, to obtain 0.10 g of a yellow solid with a yield of 14.5%. 1H NMR(500MHz,Chloroform-d)δ7.01(s,2H),6.69(d,J=8.1Hz,2H),2.69(s,2H),2 .39(p,J=2.0Hz,3H),2.15(t,J=8.7Hz,2H),2.06(d,J=11.4Hz,2H),1.88(s,2H), 1.17(s,2H),1.11(s,2H),1.09(s,2H),1.06(s,3H),1.01(s,2H),0.93(s,3H),0 .92(s,3H),0.89(d,J=6.1Hz,2H),0.85(d,J=3.3Hz,3H),0.66(s,3H).(ESI):m / z 593.36[M+H] + .

[0266] Example 55 Compound Ih 12 Preparation

[0267] Compound Ⅰh 12 It is N-(1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)-3,4-dimethoxy-N-methylbenzamide, and its structural formula is as follows:

[0268]

[0269] The preparation process is the same as compound Ⅰb 12 The preparation steps are as follows, except that compound b is replaced by compound h, to obtain 0.12 g of a yellow solid with a yield of 17.4%. 1 H NMR(500MHz,Chloroform-d)δ7.03(s,2H),6.84(d,J=8.1Hz,1H),3.89(s,3H),3.87 (s,3H),3.01–2.93(m,3H),2.87(s,3H),2.51–2.47(m,2H),2.25–2.12(m,2H),1.94( t,J=10.4Hz,2H),1.45(s,3H),1.38(d,J=12.4Hz,2H),1.29(s,2H),1.25(s,3H),1. 17(d,J=12.8Hz,2H),1.01(s,3H),0.95(s,2H),0.82(s,3H).(ESI):m / z595.38[M+H] + .

[0270] Example 56 Compound Ih 14 Preparation

[0271] Compound Ⅰh 14 It is (E)-4-(3-((1-(16-hydroxy-4,4,10,13,14-pentamethyl-3-(methylamino)-7,11-dioxo-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)(methyl)amino)-3-oxoprop-1-en-1-yl)phenyl acetate, and the structural formula is as follows:

[0272]

[0273] The preparation process is the same as compound Ⅰb 14 The preparation steps are as follows, except that compound b is replaced by compound h, to obtain 0.16 g of a yellow solid with a yield of 22.3%. 1 H NMR (500MHz, Chloroform-d) δ7.54(s,1H),7.53(s,1H),7.11(s,1H),7.10(s,1H),5.15(s,1H),4.63(d,J=12. 5Hz,1H),4.25(s,1H),3.09(s,3H),3.06(s,3H),2.98(s,2H),2.52–2.46(m,3H),2.10(dd,J=28.6,14.5Hz,2H ),1.87–1.81(m,1H),1.75–1.66(m,1H),1.46(s,2H),1.42(t,J=7.3Hz,2H),1.36(s,3H),1.27(d,J=14.2Hz,2 (ESI): m / z 618.37[M+H] + .

[0274] Test example: Mouse hypoxia tolerance experiment

[0275] The following is an animal experiment of the above compounds, namely a mouse hypoxia tolerance experiment. The specific operation and results are as follows:

[0276] Animals used: ICR mice, male, 25g±2g; Grouping: blank control group, CVB-D positive control group, and test compound group were set up and randomly divided into groups, with 6 mice in each group; the CVB-D positive control group and the test compound group were both given 7.5 mg / kg, and the blank control group was given the same equivalent of normal saline.

[0277] Experimental method: The drug was dissolved in saline and administered by gavage. 2 hours after administration, the mice in each group were placed in a 250 mL ground-mouth bottle containing 15 g of soda lime, sealed with vaseline, and tightly covered to prevent air leakage. The time was counted, and the death time of the mice due to hypoxia was observed and recorded using respiratory arrest as an indicator. The time was compared with the blank group and CVB-D group, and the T test was performed to calculate the P value.

[0278] Results: As shown in Table 1, there was a significant difference between the CVB-D group and the blank control group in the above hypoxia tolerance experiment (p≤0.05), indicating that CVB-D can significantly enhance hypoxia tolerance.

[0279] Table 1 Comparison table of animal experiment results:

[0280]

[0281] Among them, p1 represents the difference with the blank control group, and p2 represents the difference with the CVB-D positive control group;

[0282] *Indicates that the tested compound has significant difference with the blank control group, i.e. p≤0.05;

[0283] **Indicates that the tested compound has significant difference with both the blank control group and the CVB-D group, i.e., p≤0.05;

[0284] In Table 1 above, compounds b, e, i, Ⅰa3, Ⅰa4, Ⅰa5, Ⅰa 11 , Ⅰa 12 , Ⅰa 13 , Ⅰa 14 , Ⅰb2, Ⅰb3, Ⅰb4, Ⅰb 11 , Ⅰb 12 Ⅰb 13 Ⅰb 14 , Ⅰc 12 , Ⅰd3, Ⅰh5, Ⅰh 10 , Ⅰh 14 Compared with the blank control group, there were significant differences (p≤0.05), among which Ⅰa 12 , Ⅰb2, Ⅰb3, Ⅰb 12 Ⅰb 13 Compared with the blank control group and the CVB-D positive control group, there were significant differences, demonstrating excellent hypoxia tolerance.

Claims

1. A cyclovirobuxine D derivative, characterized in that: The structural formula of the cyclovirobuxine D derivative is shown in (I) or (Ia): In formula (I), there is a single bond or a double bond between carbon atoms No. 8 and No. 9, and there is a single bond or a double bond between carbon atoms No. 9 and No. 11; in formula (I), R1 is H or F; R2 is H or a carbonyl group; R3 is H, a carbonyl group, or -OH; R5 is H or any one of the following structures, Indicates the connection site: In formula (Ia), R6 is any one of the following structures, Indicates the connection site:

2. A cyclovirobuxine D derivative according to claim 1, characterized in that: The structural formula of the cyclovirobuxine D derivative is as follows:

3. The cyclovirobuxine D derivative according to claim 1, characterized in that: The structural formula of the cyclovirobuxine D derivative is as follows:

4. The pharmaceutically acceptable salt of the cyclovirobuxine D derivative according to claim 1.

5. A pharmaceutical composition comprising the cyclovirobuxine D derivative or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

6. Use of the cyclovirobuxine D derivative or a pharmaceutically acceptable salt thereof according to claim 1 for preparing a drug for preventing or treating cardiovascular and cerebrovascular diseases.

7. The use of claim 6, wherein the cardiovascular disease is angina pectoris, arrhythmia, hypertension, hyperlipidemia and ischemic stroke.

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