CN114195843A

CN114195843A - Split-ring lupane derivative and application thereof in preparation of multi-target inhibitor

Info

Publication number: CN114195843A
Application number: CN202111381929.XA
Authority: CN
Inventors: 赵岩; 王豪豪; 杜锐; 李平亚
Original assignee: Jilin Agricultural University
Current assignee: Jilin Agricultural University
Priority date: 2021-11-19
Filing date: 2021-11-19
Publication date: 2022-03-18
Anticipated expiration: 2041-11-19
Also published as: CN114195843B

Abstract

The invention relates to a lupane schizocyclane derivative and application thereof in preparation of a multi-target inhibitor, belonging to the field of medicines. The split-ring lupane derivatives are compounds for preventing and treating Cyclin D1, PLK1, FASN and GPX4 mediated related diseases. The invention has the advantages that: a series of antagonists of Cyclin D1, PLK1, FASN and GPX4 receptors are obtained by a semisynthesis mode, and can be used for preventing, treating or relieving Cyclin D1, PLK1, FASN and GPX4 mediated related diseases, pharmacological experiments prove that the antagonists of Cyclin D1, PLK1, FASN and GPX4 have the effects, and the compounds can be developed into medicines for preventing, treating or relieving Cyclin D1, PLK1, FASN and GPX4 mediated related diseases such as tumors, cancers, obesity, diabetes, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases by further experiments.

Description

Split-ring lupane derivative and application thereof in preparation of multi-target inhibitor

Technical Field

The invention belongs to the field of medicines, and particularly relates to a 3, 4-secolupane derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof, and application thereof in preparation of medicines for preventing and treating Cyclin D1, PLK1, FASN and GPX 4-mediated related diseases.

Background

G1/S-specific Cyclin-D1 (Cyclin D1), a Cyclin closely associated with cell proliferation. Cyclin D1 phosphorylates retinoblastoma protein Rb by binding with Cyclin-dependent kinase 4/6(CDK4/6), releases transcription factor E2F, thereby promoting deoxyribonucleic acid DNA synthesis, accelerating the transition of cell cycle from G1 phase to S phase, having the property of tumor gene, and the over-expression of Cyclin D1 can cause uncontrolled cell proliferation and malignant growth, finally forming tumor (Lakshminayana S et al, J Carcinog,2018,17(1): 7; Zhenzhain et al, 2011, 9(3): 443): 444.). Polo-like kinase 1(PLK1) is a member of the serine/threonine kinase family, and can regulate the processes of cell mitosis, cytokinesis, DNA damage response and development by interacting with various substrates through the kinase activity, and is closely related to diseases such as cancer, acute leukemia and myelodysplastic syndrome. FASN, also known as fatty acid synthase, has multiple functions and is a key enzyme for the synthesis of fatty acids. FASN is not expressed or is expressed at very low levels in normal cells or tissues, and is mainly used for synthesizing triglycerides for energy storage (Wu X et al, Adv Biol Regul,2014,54: 214-21; Menendez JA et al, Curr Opin Clin Nutr Metab Care,2006,9(4):346-57), and has important significance for controlling the fat deposition of animal bodies. The abnormal fatty acid metabolism is closely related to the occurrence and development of a plurality of diseases, which are mainly reflected in the aspects of obesity, diabetes, cancer and the like. GPX4 is a selenoprotein that can reduce lipid peroxides into corresponding lipid alcohols, inhibit the occurrence of lipid peroxidation, and is closely related to tumors, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases (Jiazhong, et al, J.Zhonghua tumor prevention and treatment, 2019,26(3): 155-161.). Studies have also found that Cyclin D1, PLK1, FASN and GPX4 are overexpressed in a variety of tumors and associated with poor tumor progression and prognosis (poliono-Alcal E et al, cancers (basel),2020,12(5): 308-15; zayteva YY et al, carcinogenisis, 2014,35(6): 1341-51; Liu H et al, Biochemistry,2018,57(14):2059-2060.), and that inhibition of them reduces the tumorigenicity in tumor cells, making Cyclin D1, PLK1, FASN and GPX4 promising targets for anti-tumor therapy.

Lupane type triterpenes and their saponins are mainly distributed in plants of Leguminosae, Araliaceae, Cucurbitaceae, Caryophyllaceae, Umbelliferae, Betulaceae, Oleaceae, and Celastraceae. Modern pharmacological studies show that the compounds have the effects of resisting inflammation, tumors, viruses, oxidation and bacteria, improving immunity (AMIRI S and the like, Biotechnol Adv,2020,38: 107409; Bian X and the like, RSC Adv,7(66): 41640-. In recent years, more and more structurally complex, novel lupane-type triterpenoids have been discovered. The discovery and activity research of novel triterpene compounds with different positions on a framework, such as substitution, ring cleavage, carbon degradation, rearrangement and the like, and complex triterpene saponins connected by a plurality of sugars has become a research hotspot of natural product research.

Disclosure of Invention

The invention provides a lupine schizophyllane derivative and application thereof in preparation of a multi-target inhibitor, in particular to application of the compounds and compositions in preparation of drugs for preventing and treating Cyclin D1, PLK1, FASN and GPX4 mediated related diseases.

The technical scheme adopted by the invention is as follows:

a secolupane derivative of formula i:

wherein R is_aSelected from: -OH, -NH₂、-SH、-F、-Cl。

The cracking ring lupane derivative and Ra are taken as glycosyl compounds as raw materials, and the cracking ring lupane derivative shown as a general formula II is obtained through a series of chemical reactions:

wherein X is selected from: - (CH)₂)₃-、-(CH₂)₄-、-(CH₂)₅-、-(CH₂)₆-、-(CH₂)₁₀-；

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

the cracking ring lupane derivative and Ra which are taken as glycosyl compounds are taken as raw materials, and the cracking ring lupane derivative shown in the general formula III is obtained through a series of chemical reactions:

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

the cracked ring lupane derivative and Ra which are taken as glycosyl compounds are taken as raw materials, and the cracked ring lupane derivative shown as a general formula IV is obtained through a series of chemical reactions:

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

R_cselected from: C1-C9 alkyl.

In the technical scheme of the invention, the optical isomers of the compounds in the general formulas I-IV or pharmaceutically acceptable salts or solvates thereof.

The invention also provides a pharmaceutical composition which contains the secolupane derivative, the optical isomer thereof or the pharmaceutically acceptable salt or solvate thereof and pharmaceutically acceptable carriers and excipients.

The carrier comprises protein, folic acid, antibody, nano material and the like which are commonly used in the field of pharmacy. The term "excipient" refers to an additive other than the principal agent in a pharmaceutical formulation, which may also be referred to as an adjuvant, such as a binder, a filler, a disintegrant, a lubricant in a tablet; wine, vinegar, medicinal juice, etc. in the Chinese medicinal pill; base portion in semisolid formulations ointments, creams; preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid preparations can all be referred to as excipients.

The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field.

The invention also provides the application of the derivative, the optical isomer thereof or the pharmaceutically acceptable salt or solvate thereof and the composition in the preparation of drugs for preventing and treating Cyclin D1, PLK1, FASN and GPX4 mediated related diseases;

the related diseases mediated by Cyclin D1, PLK1, FASN and GPX4 comprise tumors, cancers, obesity, diabetes, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases.

The derivative, the optical isomer thereof or the pharmaceutically acceptable salt or the solvate thereof can be independently administered, can be administered in a composition mode or can be administered in combination of multiple medicines.

The split-ring lupane derivative is a special 3, 4-split-ring 3, 11-ring-closure lupane triterpenoid derivative in the existing lupane triterpenoids. On the basis of the structure, a chemical means is used for carrying out structural modification and reconstruction, and a class of seco-lupane derivatives which can prevent and treat Cyclin D1, PLK1, FASN and GPX4 mediated related diseases are formed.

The invention has the advantages that: a series of antagonists of Cyclin D1, PLK1, FASN and GPX4 are obtained by semisynthesis, and can be used for preventing, treating or relieving Split-ring lupane derivatives of Cyclin D1, PLK1, FASN and GPX4 mediated related diseases. Pharmacological experiments prove that the antagonist-like effects of Cyclin D1, PLK1, FASN and GPX4 of the compounds can be developed into medicines for preventing, treating or relieving Cyclin D1, PLK1, FASN and GPX 4-mediated related diseases through further experiments.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

The compounds encompassed by the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art. Wherein preferred embodiments include, but are not limited to, embodiments of the present invention.

Synthesis of derivatives:

the solvent and the synthetic drug thereof used in the present invention can be commercially available. Abbreviations used herein have the following respective definitions: lawesson, 2, 4-bis (p-methoxyphenyl) -1, 3-dithio-2, 4-diphosphetane-2, 4-disulfide; DAST, diethylaminosulfur trifluoride; SOCl₂Thionyl chloride; THF, tetrahydrofuran; DMF, N-dimethylformamide; DCM, dichloromethane; PA, acetone; MeOH, methanol; EtOH, ethanol; PrOH, propanol; PeOH, amyl alcohol; NoOH, nonanol; NaOH, sodium hydroxide; HCl, hydrochloric acid; TBHP, tert-butyl hydroperoxide; MOPS: 3- (N-morphine) propanesulfonic acid; EGTA: ethylene glycol bis (2-aminoethyl ether) tetraacetic acid; EDTA: ethylene diamine tetraacetic acid; DTT: dithiothreitol(ii) a BSA: bovine serum albumin; MBP: myelin basic protein; DMSO, DMSO: dimethyl sulfoxide; r.t., room temperature; O/N, overnight; reflux, reflux; stir, stirring.

Example 1: preparation of Compound I-1(Chiisanogenin) of general formula I

Chiisanoside (1910.2mg, 2.0mmol) is dissolved in 10% sodium hydroxide methanol, heated and refluxed for 4h, the reaction solution is neutralized by hydrochloric acid to make the pH value between 6 and 7, the solvent is recovered under reduced pressure, solid powder is separated by silica gel column chromatography, and white solid (Chiisanogenin, C-1)363.51mg is obtained after drying, and the yield is 75%. C₃₀H₄₄O₅.MS：[M]⁺484.31969.¹H NMR(300MHz,Chloroform-d)δ5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),3.88(1H),2.80(1H),2.66(1H),2.55(1H),2.02(1H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.73(s,3H),1.67(s,3H),1.08(s,3H),1.02(s,3H),1.01(s,3H)。

Example 2: synthesis of Compounds I-2, I-3, I-4 and I-5 of the general formula I

Compound I-1(484.68mg, 1.0mmol) was dissolved in DMF (10mL) and SOCl was added₂(118.96mg, 1.0mmol), refluxed for 2 hours, and concentrated. Subsequently, ammonia gas was introduced and the reaction was carried out at room temperature for 2 hours. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 305.79mg of a white powder (C-2), yield 63.22%. C₃₀H₄₅NO₄.MS：[M]⁺483.32584.¹H NMR(300MHz,Chloroform-d)δ6.52(s,2H),5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),3.88(1H),2.80(1H),2.66(1H),2.55(1H),2.02(1H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.73(s,3H),1.66(s,3H),1.07(s,3H),1.01(s,3H),0.98(s,3H)。

Compound I-1(484.68mg, 1.0mmol) was dissolved in anhydrous THF (10mL), and Lawesson's reagent was added and stirred at room temperature for 4 hours. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 299.64mg of a pale yellow powder (C-3) in 59.84% yield. C₃₀H₄₄O₄S.MS：[M]⁺500.29626.¹H NMR(300MHz,Chloroform-d)δ8.45(s,1H),5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),3.88(1H),2.80(1H),2.66(1H),2.55(1H),2.02(1H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.75(s,3H),1.65(s,3H),1.08(s,2H),1.02(s,3H),0.97(s,3H)。

Compound I-1(484.68mg, 1.0mmol) was dissolved in DMF (10mL) and SOCl was added₂(118.96mg, 1.0mmol), reflux reaction for 2 hours, recovery of the solvent under reduced pressure to give a solid powder, separation by silica gel column chromatography, and drying to give 350.88mg of (C-4) as a yellow powder with a yield of 69.74%. C₃₀H₄₃ClO₄.MS：[M]⁺502.27726.¹H NMR(300MHz,Chloroform-d)δ5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),3.88(1H),2.80(1H),2.66(1H),2.55(1H),2.02(1H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.74(s,3H),1.67(s,3H),1.07(s,2H),1.00(s,3H),0.95(s,3H)。

Compound I-1(484.68mg, 1.0mmol) was dissolved in DCM (10mL), 600. mu.L of DAST solution was added, and the reaction was carried out at-78 ℃ for 6 hours, followed by gradual warming to room temperature. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 302.27mg of a white powder (C-5) in 62.13% yield. C₃₀H₄₃FO₄.MS：[M]⁺486.30548.¹H NMR(300MHz,Chloroform-d)δ5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),3.88(1H),2.80(1H),2.66(1H),2.55(1H),2.02(1H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.72(s,3H),1.64(s,3H),1.07(s,3H),1.01(s,3H),0.98(s,3H)。

Example 3: synthesis of Compounds of the general formulae II-1-1 and II-1-1-1

Dissolving compound I-1(484.68mg, 1.0mmol) in PA (10mL), adding 1, 3-dibromopropane (605.67 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-1-1) 506.02mg with the yield of 81.85%. C₃₃H₄₉BrO₅.MS：[M]⁺604.27659.¹H NMR (300MHz, Chloroform-d) Δ 5.23(1H),4.83(1H),4.78(2H),4.73(1H), 4.15-4.08 (m,1H),3.88(1H),3.71(1H),3.64(1H),3.45(2H),2.80(1H),2.66(1H),2.55(1H),2.04(1H),2.02(2H), 1.93-1.83 (m,2H), 1.83-1.38 (m,16H),1.73(s,3H),1.67(s,3H),1.08(s,3H),1.02(s,3H),1.01(s, 3H). Dissolving compound II-1-1 (605.65mg,1.0mmol) in CAN (10mL), adding imidazole (136.15mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-1-1-1) 483.61mg with yield of 55.21%. C₃₆H₅₂N₂O₅.MS：[M]⁺592.38328.¹H NMR(300MHz,Chloroform-d)δ7.73(1H),7.15(1H),6.91(1H),5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),4.03(2H),3.88(1H),3.71(1H),3.63(1H),3.54(1H),2.80(1H),2.66(1H),2.55(1H),2.04(1H),2.02(2H),1.93–1.83(m,2H),1.83–1.38(m,16H),1.73(s,3H),1.67(s,3H),1.08(s,3H),1.02(s,3H),1.01(s,3H)。

Example 4: synthesis of Compounds of the general formulae II-1-2 and II-1-2-1

Dissolving compound I-1(484.68mg, 1.0mmol) in PA (10mL), adding 1, 4-dibromobutane (647.73 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-1-2) 496.67mg with the yield of 80.15%. C₃₄H₅₁BrO₅.MS：[M]⁺618.28558.¹H NMR (300MHz, Chloroform-d) Δ 5.25(1H),4.84(1H),4.78(2H),4.74(1H), 4.15-4.08 (m,1H),3.87(1H),3.72(1H),3.65(1H),3.45(2H),2.82(1H),2.66(1H),2.55(1H),2.03(1H),2.01(2H), 1.93-1.83 (m,2H), 1.82-1.38 (m,18H),1.74(s,3H),1.68(s,3H),1.09(s,3H),1.02(s,3H),1.00(s, 3H). Dissolving a compound II-1-2 (605.65mg,1.0mmol) in CAN (10mL), adding 1,2, 4-triazole (138.14mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, carrying out reflux reaction for 12h, recovering the solvent under reduced pressure to obtain solid powder, carrying out silica gel column chromatography separation, and drying to obtain white powder (II-1-2-1) (517.94 mg) with the yield of 71.84%. C₄₀H₆₀N₆O₆.MS：[M]⁺720.45587.¹H NMR(300MHz,Chloroform-d)δ8.18(2H),7.71(2H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.75–3.55(m,4H),3.48–3.40(m,5H),2.50(1H),2.42(1H),2.30(1H),2.13–1.93(m,7H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.43(m,18H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 5: synthesis of Compounds of the general formulae II-1-3 and II-1-3-1

Dissolving the compound I-1(484.68mg, 1.0mmol) in PA (10mL), adding 1, 5-dibromopentane (689.82 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-1-3) 506.02mg with the yield of 79.85%. C₃₅H₅₃BrO₅.MS：[M]⁺632.31659.¹H NMR (300MHz, Chloroform-d) Δ 5.23(1H),4.83(1H),4.78(2H),4.73(1H), 4.15-4.08 (m,1H),3.88(1H),3.71(1H),3.64(1H),3.45(2H),2.80(1H),2.66(1H),2.55(1H),2.04(1H),2.02(2H), 1.93-1.83 (m,2H), 1.83-1.38 (m,20H),1.73(s,3H),1.67(s,3H),1.08(s,3H),1.02(s,3H),1.01(s, 3H). Dissolving the compound II-1-3 (689.82mg,1.0mmol) in CAN (10mL), adding tryptamine (320.43mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, carrying out reflux reaction for 12h, recovering the solvent under reduced pressure to obtain solid powder, carrying out silica gel column chromatography separation, and drying to obtain light yellow powder (II-1-3-1) (464.96 mg) with the yield of 65.21%. C₄₅H₆₄N₂O₅.MS：[M]⁺712.47328.¹H NMR(300MHz,Chloroform-d)δ7.65–7.60(m,1H),7.44(1H),7.31–7.25(m,1H),7.09(1H),6.94(s,1H),5.23(1H),4.83(1H),4.78(2H),4.73(1H),4.15–4.08(m,1H),4.03(2H),3.88(1H),3.71(1H),3.63(1H),3.54(1H),3.04(2H),2.94–2.81(m,2H),2.80(1H),2.66(1H),2.55(1H),2.04(1H),2.02(2H),1.93–1.83(m,2H),1.83–1.38(m,20H),1.73(s,3H),1.67(s,3H),1.56(m,2H),1.08(s,3H),1.02(s,3H),1.01(s,3H)。

Example 6: synthesis of Compounds of the general formulae II-1-5 and II-1-5-1

Dissolving the compound I-1(484.68mg, 1.0mmol) in PA (10mL), adding 1, 10-dibromopentane (900.21 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-1-5) 456.58mg with the yield of 64.87%. C₄₀H₆₃BrO₅.MS：[M]⁺702.38522.¹H NMR (300MHz, Chloroform-d) Δ 5.24(1H),4.83(1H),4.79(2H),4.73(1H), 4.15-4.10 (m,1H),3.88(1H),3.75(1H),3.64(1H),3.45(2H),2.83(1H),2.65(1H),2.54(1H),2.06(1H),2.02(2H), 1.94-1.83 (m,2H), 1.82-1.38 (m,30H),1.73(s,3H),1.66(s,3H),1.08(s,3H),1.01(s,3H),1.00(s, 3H). Compound ii-1-5 (647.74mg,1.0mmol) is dissolved in CAN (10mL), 5-hydroxytryptamine (352.44mg, 2.0mmol) is added, a proper amount of anhydrous potassium carbonate is added, reflux reaction is carried out for 12h, the solvent is recovered under reduced pressure to obtain solid powder, silica gel column chromatography separation is carried out, and light yellow powder (II-1-5-1) 443.13mg is obtained after drying, and the yield is 55.45%. C₅₀H₇₄N₂O₆.MS：[M]⁺798.54576.¹H NMR(300MHz,Chloroform-d)δ8.44(s,1H),7.45(1H),7.30–7.25(m,1H),7.09(1H),6.93(s,1H),5.23(1H),4.83(1H),4.75(2H),4.73(1H),4.16–4.08(m,1H),4.03(2H),3.88(1H),3.72(1H),3.65(1H),3.55(1H),3.04(2H),2.95–2.81(m,2H),2.80(1H),2.66(1H),2.55(1H),2.05(1H),2.01(2H),1.93–1.83(m,2H),1.82–1.38(m,22H),1.75(s,3H),1.69(s,3H),1.54(m,2H),1.08(s,3H),1.04(s,3H),1.00(s,3H)。

Example 7: synthesis of Compounds of the general formulae II-2-1 and II-2-1-1

Dissolving the compound I-2(483.69mg, 1.0mmol) in PA (10mL), adding 1, 3-dibromopropane (605.67 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-2-1) 383.36mg with the yield of 63.40%. C₃₃H₅₀BrNO₄.MS：[M]⁺603.28582.¹H NMR (300MHz, Chloroform-d) Δ 6.53(s,2H),5.23(1H),4.82(1H),4.76(2H),4.73(1H), 4.14-4.08 (m,1H),3.88(1H),3.70(1H),3.65(1H),3.45(2H),2.81(1H),2.66(1H),2.55(1H),2.04(1H),2.00(2H), 1.93-1.83 (m,2H), 1.81-1.38 (m,16H),1.73(s,3H),1.65(s,3H),1.06(s,3H),1.01(s,3H),0.99(s, 3H). Dissolving the compound II-2-1 (604.67mg,1.0mmol) in CAN (10mL), adding 2-ethylimidazole (226.14mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-2-1-1) 320.17mg with the yield of 51.66%. C₃₈H₅₇N₃O₄.MS：[M]⁺619.42336.¹H NMR(300MHz,Chloroform-d)δ7.17(1H),6.99(1H),6.55(s,2H),5.23(1H),4.84(1H),4.78(2H),4.72(1H),4.15–4.08(m,1H),4.05(2H),3.88(1H),3.72(1H),3.63(1H),3.55(1H),2.80(1H),2.73(m,2H),2.66(1H),2.55(1H),2.05(1H),2.02(2H),1.93–1.83(m,2H),1.81–1.38(m,16H),1.73(s,3H),1.67(s,3H),1.26(s,3H),1.08(s,3H),1.01(s,3H),1.01(s,3H)。

Example 8: synthesis of Compounds of the general formulae II-2-3 and II-2-3-1

Dissolving the compound I-2(483.69mg, 1.0mmol) in PA (10mL), adding 1, 5-dibromopentane (689.82 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-2-3) 381.02mg with the yield of 60.22%. C₃₅H₅₄BrNO₄.MS：[M]⁺631.31889.¹H NMR (300MHz, Chloroform-d) Δ 6.54(s,2H),5.25(1H),4.82(1H),4.76(2H),4.72(1H), 4.14-4.06 (m,1H),3.90(1H),3.70(1H),3.63(1H),3.44(2H),2.81(1H),2.65(1H),2.55(1H),2.06(1H),2.01(2H), 1.93-1.84 (m,2H), 1.81-1.38 (m,20H),1.75(s,3H),1.65(s,3H),1.08(s,3H),1.03(s,3H),1.01(s, 3H). Dissolving the compound II-2-3 (632.72mg,1.0mmol) in CAN (10mL), adding 4-methylimidazole (164.2mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain 326.34mg of light yellow powder (II-2-3-1) with the yield of 51.48%. C₃₉H₅₉N₃O₄.MS：[M]⁺633.44288.¹H NMR(300MHz,Chloroform-d)δ7.45(1H),6.83(1H),6.55(s,2H),5.24(1H),4.85(1H),4.78(2H),4.73(1H),4.16–4.08(m,1H),4.06(2H),3.88(1H),3.84(s,3H),3.74(1H),3.65(1H),3.55(1H),2.80(1H),2.66(1H),2.55(1H),2.23(s,3H),2.05(1H),2.02(2H),1.93–1.83(m,2H),1.81–1.36(m,20H),1.75(s,3H),1.68(s,3H),1.56(m,2H),1.08(s,3H),1.01(s,3H),0.98(s,3H)。

Example 9: synthesis of Compounds of the general formulae II-3-1 and II-3-1-1

Dissolving the compound I-3(500.74mg, 1.0mmol) in PA (10mL), adding 1, 4-dibromobutane (647.73 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-3-1) 392.89mg with the yield of 61.80%. C₃₄H₅₁BrO₅.MS：[M]⁺634.26775.¹H NMR (300MHz, Chloroform-d) Δ 8.44(s,1H),5.24(1H),4.84(1H),4.76(2H),4.73(1H), 4.15-4.08 (m,1H),3.88(1H),3.72(1H),3.66(1H),3.45(2H),2.83(1H),2.66(1H),2.55(1H),2.03(1H),2.01(2H), 1.92-1.83 (m,2H), 1.82-1.38 (m,18H),1.75(s,3H),1.68(s,3H),1.09(s,3H),1.03(s,3H),1.01(s, 3H). Dissolving the compound II-3-1 (635.74mg,1.0mmol) in CAN (10mL), adding 7-benzyloxytryptamine (504.64mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain 473.47mg of white powder (II-3-1-1) with the yield of 58.66%. C₅₀H₆₆N₂O₅S.MS：[M]⁺806.46787.¹H NMR(300MHz,Chloroform-d)δ8.45(s,1H),7.51(1H),7.39–7.28(m,3H),7.10(1H),7.05–6.99(m,2H),6.87(2H),5.23(1H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.75–3.55(m,4H),3.48–3.40(m,5H),2.50(1H),2.42(1H),2.30(1H),2.13–1.93(m,7H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.34(m,18H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 10: synthesis of Compounds of the general formulae II-3-4 and II-3-4-1

Compound I-3(500.74mg, 1.0mmol) was dissolved in PA (10mL) and 1, 6-dibromopentane (731) was added.97 mul, 3.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-3-4) 419.39mg with yield of 63.18%. C₃₆H₅₅BrO₄S.MS：[M]⁺662.29645.¹H NMR (300MHz, Chloroform-d) Δ 8.44(s,1H),5.23(1H),4.83(1H),4.78(2H),4.72(1H), 4.14-4.07 (m,1H),3.88(1H),3.72(1H),3.62(1H),3.44(2H),2.80(1H),2.66(1H),2.55(1H),2.06(1H),2.02(2H), 1.95-1.83 (m,2H), 1.80-1.38 (m,22H),1.72(s,3H),1.65(s,3H),1.09(s,3H),1.02(s,3H),1.00(s, 3H). Dissolving the compound II-3-4 (663.80mg,1.0mmol) in CAN (10mL), adding 2-methylimidazole (164.20mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain light yellow powder (II-3-4-1) 371.99mg with the yield of 55.94%. C₄₀H₆₀N₂O₄S.MS：[M]⁺664.42748.¹H NMR(300MHz,Chloroform-d)δ8.42(s,1H),6.98(1H),6.94(1H),5.23(1H),4.85(1H),4.76(2H),4.72(1H),4.15–4.08(m,1H),4.03(2H),3.88(1H),3.73(1H),3.64(1H),3.55(1H),2.80(1H),2.66(1H),2.55(1H),2.05(1H),2.02(2H),1.93–1.84(m,2H),1.83–1.38(m,22H),1.73(s,3H),1.68(s,3H),1.55(m,2H),1.08(s,3H),1.03(s,3H),1.01(s,3H)。

Example 11: synthesis of Compounds of the general formulae II-4-1 and II-4-1-1

Dissolving the compound I-4(486.67mg, 1.0mmol) in PA (10mL), adding 1, 5-dibromopentane (689.82 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-4-1) 370.87mg with the yield of 58.34%. C₃₅H₅₃BrO₅.MS：[M]⁺634.29774.¹H NMR(300MHz,Chloroform-d)δ5.25(1H),4.84(1H),4.78(2H),4.74(1H),4.15–4.08(m,1H),3.90(1H),3.72(1H),3.65(1H) 3.45(2H),2.82(1H),2.66(1H),2.55(1H),2.05(1H),2.02(2H), 1.93-1.83 (m,2H), 1.81-1.38 (m,20H),1.73(s,3H),1.66(s,3H),1.08(s,3H),1.02(s,3H),1.00(s, 3H). Dissolving the compound II-4-1 (635.70mg,1.0mmol) in CAN (10mL), adding 5-methoxytryptamine (380.5mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain light yellow powder (II-4-1-1) 414.24mg with the yield of 55.60%. C₄₆H₆₅FN₂O₅.MS：[M]⁺744.48726.¹H NMR(300MHz,Chloroform-d)δ7.46(1H),7.31–7.25(m,1H),7.10(1H),6.94(s,1H),5.24(1H),4.85(1H),4.78(2H),4.74(1H),4.15–4.08(m,1H),4.05(2H),3.88(1H),3.83(s,3H),3.73(1H),3.63(1H),3.55(1H),3.04(2H),2.95–2.81(m,2H),2.79(1H),2.66(1H),2.55(1H),2.04(1H),2.02(2H),1.93–1.83(m,2H),1.81–1.38(m,20H),1.75(s,3H),1.67(s,3H),1.55(m,2H),1.07(s,3H),1.01(s,3H),0.99(s,3H)。

Example 12: synthesis of Compounds of the general formulae II-5-1 and II-5-1-1

Dissolving the compound I-5(503.12mg, 1.0mmol) in PA (10mL), adding 1, 10-dibromopentane (900.21 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (II-5-1) 435.18mg with the yield of 60.25%. C₄₀H₆₂BrClO₄.MS：[M]⁺720.34632.¹H NMR (300MHz, Chloroform-d) Δ 5.24(1H),4.84(1H),4.80(2H),4.72(1H), 4.16-4.11 (m,1H),3.88(1H),3.76(1H),3.65(1H),3.45(2H),2.84(1H),2.65(1H),2.52(1H),2.08(1H),2.02(2H), 1.94-1.83 (m,2H), 1.80-1.38 (m,30H),1.73(s,3H),1.65(s,3H),1.08(s,3H),1.00(s,3H),0.98(s, 3H). Dissolving compound II-5-1 (722.29mg,1.0mmol) in CAN (10mL), adding 5-fluorotryptamine hydrochloride (429.34mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powderThe residue was subjected to silica gel column chromatography and dried to obtain 469.95mg of a pale yellow powder (II-5-1-1), yield 57.34%. C₅₀H₇₂ClFN₂O₄.MS：[M]⁺819.57674.¹H NMR(300MHz,Chloroform-d)δ7.44(1H),7.31–7.26(m,1H),7.10(1H),6.93(s,1H),5.23(1H),4.85(1H),4.74(2H),4.72(1H),4.16–4.08(m,1H),4.04(2H),3.88(1H),3.71(1H),3.64(1H),3.54(1H),3.06(2H),2.95–2.81(m,2H),2.80(1H),2.66(1H),2.55(1H),2.04(1H),2.00(2H),1.93–1.83(m,2H),1.82–1.38(m,22H),1.75(s,3H),1.66(s,3H),1.53(m,2H),1.07(s,3H),1.02(s,3H),0.97(s,3H)。

Example 13: preparation of Compounds III-1 of general formula III

Compound I-1(484.68mg, 1.0mmol) was dissolved in 10% sodium hydroxide methanol, heated under reflux for 4h, the reaction solution was neutralized with hydrochloric acid to pH 6-7, the solvent was recovered under reduced pressure to give a solid powder, which was separated by silica gel column chromatography and dried to give 319.41mg of (iii-1) as a pale yellow solid with a yield of 63.54%. C₃₀H₄₆O₆.MS：[M]⁺502.32367.¹H NMR(300MHz,Chloroform-d)δ4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.44(1H),2.50(1H),2.42(1H),2.30(1H),2.13–2.05(m,2H),1.97(1H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.43(m,15H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 14: preparation of Compounds III-2, III-3, III-4 and III-5 of general formula III

Compound III-1(502.69mg, 1.0mmol) was dissolved in DMF (10mL) and SOCl was added₂(118.96mg, 1.0mmol), refluxed for 2 hours, and concentrated. Subsequently, ammonia gas was introduced and the reaction was carried out at room temperature for 2 hours. Recovering solvent under reduced pressure to obtain solid powder, separating with silica gel column chromatography, drying302.08mg of (III-2) was obtained as a pale yellow solid with a yield of 60.33%. C₃₀H₄₈N₂O₄.MS：[M]⁺500.35588.¹H NMR(300MHz,Chloroform-d)δ6.97(1H),6.52(1H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.44(1H),2.50(1H),2.42(1H),2.30(1H),2.13–2.05(m,2H),1.97(1H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.43(m,15H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Compound III-1(502.69mg, 1.0mmol) was dissolved in anhydrous THF (10mL), and Lawesson's reagent was added and stirred at room temperature for 4 hours. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 361.10mg of a white solid (III-3), which was obtained in a yield of 67.52%. C₃₀H₄₆O₄S₂.MS：[M]⁺534.27437.¹H NMR(300MHz,Chloroform-d)δ8.74(s,1H),8.45(s,1H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.44(1H),2.50(1H),2.42(1H),2.30(1H),2.13–2.05(m,2H),1.97(1H),1.88–1.79(m,1H),1.79–1.74(m,3H),1.76(s,3H),1.75–1.43(m,15H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Compound III-1(502.69mg, 1.0mmol) was dissolved in DMF (10mL) and SOCl was added₂(118.96mg, 1.0mmol), reflux reaction for 2 hours, recovery of the solvent under reduced pressure to give a solid powder, separation by silica gel column chromatography, and drying to give 351.70mg of (III-4) as a yellow powder with a yield of 65.18%. C₃₀H₄₄Cl₂O₄.MS：[M]⁺538.25774.¹H NMR(300MHz,Chloroform-d)δ4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.44(1H),2.50(1H),2.42(1H),2.30(1H),2.13–2.05(m,2H),1.97(1H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.43(m,15H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Compound III-1(502.69mg, 1.0mmol) was dissolved in DCM (10mL) and 600. mu.L of DAST solution was added and reacted at-78 ℃ for 6 hours, followed by gradual warming to room temperature. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 303.85mg of a white powder (III-5), in a yield of 59.97%. C₃₀H₄₄F₂O₄.MS：[M]⁺506.31589.¹H NMR(300MHz,Chloroform-d)δ4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.44(1H),2.50(1H),2.42(1H),2.30(1H),2.13–2.05(m,2H),1.97(1H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.43(m,15H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 15: preparation of Compounds of the formulae III-1-1 and III-1-1-1

Compound III-1(502.69mg, 1.0mmol) was dissolved in PA (10mL), 1, 3-dibromopropane (605. mu.L, 3.0mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, reflux reaction was carried out for 12h, the solvent was recovered under reduced pressure to give a solid powder, which was separated by silica gel column chromatography and dried to give 522.97mg of (III-1-1) as a white powder with a yield of 70.23%. C₃₆H₅₆Br₂O₆.MS：[M]⁺744.23996.¹H NMR (300MHz, Chloroform-d) Δ 4.83(1H), 4.79-4.73 (m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H), 3.75-3.55 (m,4H), 3.48-3.40 (m,5H),2.50(1H),2.42(1H),2.30(1H), 2.13-1.79 (m,8H),1.76(s,3H), 1.79-1.43 (m,27H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s, 3H). Dissolving compound III-1-1(744.65mg,1.0mmol) in CAN (10mL), adding imidazole (136.15mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-1-1-1)429.09mg with yield of 59.68%. C₄₂H₆₂N₄O₆.MS：[M]⁺718.46428.¹H NMR(300MHz,Chloroform-d)δ7.73(2H),7.15(2H),6.91(2H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.75–3.55(m,4H),3.48–3.40(m,5H),2.50(1H),2.42(1H),2.30(1H),2.13–1.79(m,8H),1.76(s,3H),1.79–1.41(m,27H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 16: preparation of Compounds of the formulae III-1-2 and III-1-2-1

Dissolving the compound III-1(502.69mg, 1.0mmol) in PA (10mL), adding 1, 5-dibromopentane (689.82 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-1-2)534.82mg with the yield of 66.79%. C₄₀H₆₄Br₂O₆.MS：[M]⁺800.29554.¹H NMR (300MHz, Chloroform-d) Δ 4.85(1H), 4.80-4.74 (m,2H),4.72(1H),4.18(1H),4.06(1H),3.90(1H), 3.75-3.54 (m,4H), 3.48-3.41 (m,5H),2.50(1H),2.41(1H),2.30(1H), 2.12-1.78 (m,8H),1.76(s,3H), 1.77-1.39 (m,35H),1.15(s,3H),1.06(s,3H),0.99(s, 3H). Dissolving the compound III-1-2(744.65mg,1.0mmol) in CAN (10mL), adding tryptamine (320.43mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-1-2-1)513.64mg with the yield of 53.58%. C₆₀H₈₆N₄O₆.MS：[M]⁺958.64477。¹H NMR(300MHz,Chloroform-d)δ7.66–7.60(m,2H),7.44(2H),7.28(2H),7.09(2H),6.94(s,2H),4.83(1H),4.79–4.73(m,2H),4.71(1H),4.18(1H),4.06(1H),3.90(1H),3.75–3.40(m,9H),3.04(4H),2.94–2.81(m,4H),2.50(1H),2.42(1H),2.30(1H),2.13–1.93(m,7H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.74(m,3H),1.73(s,3H),1.75–1.40(m,39H),1.12(s,3H),1.03(s,3H),0.97(s,3H)。

Example 17: preparation of Compounds of the formulae III-2-1 and III-2-1-1

Dissolving compound III-2(500.27mg, 1.0mmol) in PA (10mL), adding 1, 4-dibromobutane (647.73 muL, 3.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powderThe residue was subjected to silica gel column chromatography and dried to obtain 481.24mg of a white powder (III-2-1) with a yield of 62.44%. C₃₈H₆₂Br₂N₂O₄.MS：[M]⁺770.30668.¹H NMR (300MHz, Chloroform-d) Δ 6.98(1H),6.53(1H),4.84(1H), 4.79-4.73 (m,2H),4.72(1H),4.18(1H),4.07(1H),3.90(1H), 3.75-3.56 (m,4H), 3.48-3.40 (m,5H),2.50(1H),2.43(1H),2.32(1H), 2.15-1.78 (m,8H),1.77(s,3H), 1.77-1.42 (m,31H),1.73(s,3H),1.12(s,3H),1.02(s,3H),0.97(s, 3H). Dissolving compound III-2-1(744.65mg,1.0mmol) in CAN (10mL), adding 2-ethylimidazole (226.14mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-2-1-1)413.88mg with yield of 51.66%. C₄₈H₇₆N₆O₄.MS：[M]⁺800.58622.¹H NMR(300MHz,Chloroform-d)δ7.08(2H),6.94(2H),4.82(1H),4.79–4.72(m,2H),4.70(1H),4.18(1H),4.09(1H),3.90(1H),3.75–3.54(m,4H),3.48–3.42(m,5H),2.49(1H),2.47(s,3H),2.44(s,3H),2.40(1H),2.32(1H),2.13–1.80(m,8H),1.76(s,3H),1.79–1.43(m,31H),1.73(s,3H),1.13(s,3H),1.05(s,3H),0.98(s,3H)。

Example 18: preparation of Compounds of the formulae III-2-2 and III-2-2-1

Dissolving the compound III-2(500.27mg, 1.0mmol) in PA (10mL), adding 1, 3-dibromopropane (605 uL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain 450.29mg of white powder (III-2-2) with the yield of 60.63%. C₃₆H₅₈Br₂N₂O₄.MS：[M]⁺742.26478.¹H NMR(300MHz,Chloroform-d)δ6.97(1H),6.52(1H),4.83(1H),4.78–4.72(m,2H),4.70(1H),4.16(1H),4.07(1H),3.90(1H),3.74–3.55(m,4H),3.48–3.40(m,5H),2.52(1H),2.41(1H),2.30(1H),2.13–1.79(m,8H) 1.77(s,3H), 1.79-1.42 (m,27H),1.73(s,3H),1.12(s,3H),1.03(s,3H),0.99(s, 3H). Dissolving compound III-2-2(742.68mg,1.0mmol) in CAN (10mL), adding 7-benzyloxytryptamine (504.64mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain a solid powder, separating by silica gel column chromatography, and drying to obtain 538.51mg of white powder (III-2-2-1) with a yield of 49.61%. C₆₈H₈₈N₆O₆.MS：[M]⁺1084.67728.¹H NMR(300MHz,Chloroform-d)δ8.45(s,2H),7.51(2H),7.39–7.28(m,6H),7.10(2H),7.05–6.99(m,4H),6.87(4H),4.83(1H),4.79–4.74(m,2H),4.73(1H),4.18(1H),4.06(1H),3.92(1H),3.75–3.40(m,9H),3.06(4H),2.94–2.82(m,4H),2.50(1H),2.42(1H),2.33(1H),2.13–1.79(m,8H),1.75(s,3H),1.78–1.74(m,3H),1.73(s,3H),1.75–1.40(m,31H),1.13(s,3H),1.03(s,3H),0.96(s,3H)。

Example 19: preparation of Compounds of the formulae III-3-1 and III-3-1-1

Dissolving the compound III-3(534.81mg, 1.0mmol) in PA (10mL), adding 1, 6-dibromopentane (731.91 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-3-1)543.94mg with the yield of 63.18%. C₄₂H₆₈Br₂O₄S₂.MS：[M]⁺860.28755.¹H NMR (300MHz, Chloroform-d) Δ 8.75(s,1H),8.45(s,1H),4.85(1H), 4.79-4.73 (m,2H),4.72(1H),4.20(1H),4.08(1H),3.91(1H), 3.75-3.54 (m,4H), 3.47-3.40 (m,5H),2.52(1H),2.41(1H),2.33(1H), 2.12-1.78 (m,8H),1.76(s,3H), 1.76-1.38 (m,39H),1.16(s,3H),1.08(s,3H),1.00(s, 3H). Dissolving compound III-3-1 (860.93mg,1.0mmol) in CAN (10mL), adding 5-methoxytryptamine (380.5mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-3-1-1)540.67mg, yield 50.08%. C₆₄H₉₄N₄O₆S₂.MS：[M]⁺1078.65887.¹H NMR(300MHz,Chloroform-d)δ8.74(s,1H),8.46(s,1H),7.45(2H),7.30(2H),7.09(2H),6.95(s,2H),4.83(1H),4.80–4.76(m,2H),4.73(1H),4.20(1H),4.06(1H),3.92(1H),3.85(s,3H),3.75–3.41(m,9H),3.05(4H),2.94–2.81(m,4H),2.51(1H),2.43(1H),2.30(1H),2.15–1.95(m,7H),1.88–1.78(m,1H),1.75(s,3H),1.78–1.72(m,3H),1.73(s,3H),1.75–1.38(m,43H),1.15(s,3H),1.08(s,3H),0.99(s,3H)。

Example 20: preparation of Compounds of the formulae III-3-2 and III-3-2-1

Dissolving the compound III-3(534.81mg, 1.0mmol) in PA (10mL), adding 1, 4-dibromobutane (647.73 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-3-2)519.03mg with the yield of 64.49%. C₃₈H₆₀Br₂O₄S₂.MS：[M]⁺804.22377.¹H NMR (300MHz, Chloroform-d) Δ 8.76(s,1H),8.45(s,1H),4.84(1H), 4.80-4.74 (m,2H),4.72(1H),4.20(1H),4.08(1H),3.90(1H), 3.75-3.56 (m,4H), 3.49-3.41 (m,5H),2.50(1H),2.45(1H),2.32(1H), 2.15-1.78 (m,8H),1.74(s,3H), 1.77-1.42 (m,31H),1.73(s,3H),1.12(s,3H),1.02(s,3H),0.98(s, 3H). Dissolving the compound III-3-2 (804.82mg,1.0mmol) in CAN (10mL), adding 2-methylimidazole (164.20mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-3-2-1)465.36mg with the yield of 57.65%. C₄₆H₇₀N₄O₄S₂.MS：[M]⁺806.47326.¹H NMR(300MHz,Chloroform-d)δ7.10(2H),6.94(2H),4.85(1H),4.79–4.72(m,2H),4.70(1H),4.18(1H),4.08(1H),3.90(1H),3.74–3.55(m,4H),3.48–3.40(m,5H),2.50(1H),2.48(s,3H),2.45(s,3H),2.42(1H),2.33(1H),2.13–1.80(m,8H),1.76(s,3H),1.79–1.37(m,31H),1.73(s,3H),1.16(s,3H),1.07(s,3H),1.00(s,3H)。

Example 21: preparation of Compounds of the formulae III-4-1 and III-4-1-1

Compound III-4(539.58mg, 1.0mmol) was dissolved in PA (10mL), 1, 10-dibromodecane (900.21. mu.L, 3.0mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, reflux reaction was carried out for 12 hours, the solvent was recovered under reduced pressure to give a solid powder, which was separated by silica gel column chromatography and dried to give 491.20mg of a white powder (III-4-1) with a yield of 50.23%. C₅₀H₈₂Br₂Cl₂O₄.MS：[M]⁺976.38489.¹H NMR (300MHz, Chloroform-d) Δ 4.85(1H), 4.79-4.74 (m,2H),4.72(1H),4.23(1H),4.08(1H),3.90(1H), 3.75-3.54 (m,4H), 3.48-3.40 (m,5H),2.55(1H),2.43(1H),2.35(1H), 2.13-1.78 (m,8H),1.76(s,3H), 1.75-1.38 (m,50H),1.14(s,3H),1.07(s,3H),1.01(s, 3H). Dissolving the compound III-4-1(977.91mg,1.0mmol) in CAN (10mL), adding 5-hydroxytryptamine (352.44mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-4-1-1)622.36mg with the yield of 54.76%. C₇₀H₁₀₄Cl₂N₄O₄.MS：[M]⁺1134.73388.¹H NMR(300MHz,Chloroform-d)δ7.67–7.62(m,2H),7.45(2H),7.28(2H),7.09(2H),6.95(s,2H),4.83(1H),4.78–4.72(m,2H),4.70(1H),4.18(1H),4.06(1H),3.92(1H),3.76–3.55(m,4H),3.48–3.40(m,5H),3.05(4H),2.95–2.82(m,4H),2.52(1H),2.42(1H),2.30(1H),2.13–1.79(m,8H),1.76(s,3H),1.79–1.39(m,54H),1.12(s,3H),1.04(s,3H),0.99(s,3H)。

Example 22: preparation of Compounds of the formulae III-4-2 and III-4-2-1

Dissolving the compound III-4(539.58mg, 1.0mmol) in PA (10mL), adding 1, 6-dibromopentane (731.91 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain 526.17mg of white powder (III-4-2) with the yield of 60.78%. C₄₂H₆₆Br₂Cl₂O₄.MS：[M]⁺864.26655.¹H NMR (300MHz, Chloroform-d) Δ 4.82(1H), 4.79-4.73 (m,2H),4.73(1H),4.20(1H),4.08(1H),3.89(1H), 3.75-3.53 (m,4H), 3.46-3.40 (m,5H),2.52(1H),2.40(1H),2.34(1H), 2.12-1.78 (m,8H),1.75(s,3H), 1.76-1.38 (m,39H),1.73(s,3H),1.14(s,3H),1.08(s,3H),1.00(s, 3H). Dissolving the compound III-4-2 (865.69mg,1.0mmol) in CAN (10mL), adding 4-methylimidazole (164.2mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-4-2-1) 456.09mg with the yield of 52.54%. C₅₀H₇₆Cl₂N₄O₄.MS：[M]⁺866.52421.¹H NMR(300MHz,Chloroform-d)δ7.44(2H),6.80(2H),4.83(1H),4.79–4.74(m,2H),4.73(1H),4.22(1H),4.05(1H),3.92(1H),3.84(s,3H),3.75–3.41(m,9H),3.04(4H),2.95–2.81(m,4H),2.51(1H),2.42(1H),2.30(1H),2.15–1.77(m,8H),1.75(s,3H),1.78–1.72(m,3H),1.75–1.38(m,39H),1.73(s,3H),1.15(s,3H),1.07(s,3H),0.98(s,3H)。

Example 23: preparation of Compounds of the formulae III-5-1 and III-5-1-1

Dissolving the compound III-5(506.67mg, 1.0mmol) in PA (10mL), adding 1, 10-dibromodecane (900.21 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-5-1)497.36mg with the yield of 52.63%. C₅₀H₈₂Br₂F₂O₄.MS：[M]⁺944.44665.¹H NMR (300MHz, Chloroform-d) Δ 4.83(1H), 4.76-4.72 (m,2H),4.70(1H),4.20(1H),4.07(1H),3.90(1H), 3.74-3.54 (m,4H), 3.47-3.39 (m,5H),2.54(1H),2.43(1H),2.35(1H), 2.12-1.78 (m,8H),1.77(s,3H), 1.75-1.38 (m,50H),1.13(s,3H),1.06(s,3H),1.00(s, 3H). Dissolving a compound III-5-1 (860.93mg,1.0mmol) in CAN (10mL), adding 1,2, 4-triazole (138.14mg, 2.0mmol), adding a proper amount of anhydrous potassium carbonate, carrying out reflux reaction for 12h, recovering the solvent under reduced pressure to obtain solid powder, carrying out silica gel column chromatography separation, and drying to obtain white powder (III-5-1-1) (519.44 mg) with the yield of 56.38%. C₅₄H₈₆F₂N₆O₄.MS：[M]⁺920.66437.¹H NMR(300MHz,Chloroform-d)δ8.20(2H),7.72(2H),4.83(1H),4.79–4.72(m,2H),4.70(1H),4.18(1H),4.06(1H),3.92(1H),3.75–3.56(m,4H),3.48–3.41(m,5H),2.52(1H),2.43(1H),2.30(1H),2.14–1.80(m,8H),1.76(s,3H),1.79–1.40(m,50H)1.12(s,3H),1.05(s,3H),0.99(s,3H)。

Example 24: preparation of Compounds of the formulae III-5-2 and III-5-2-1

Dissolving the compound III-5(506.67mg, 1.0mmol) in PA (10mL), adding 1, 5-dibromopentane (689.82 muL, 3.0mmol), adding a proper amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-5-2)440.35mg with the yield of 54.72%. C₄₀H₆₂Br₂F₂O₄.MS：[M]⁺804.29388.¹H NMR (300MHz, Chloroform-d) Δ 4.83(1H), 4.80-4.74 (m,2H),4.73(1H),4.18(1H),4.05(1H),3.90(1H), 3.75-3.54 (m,4H), 3.48-3.41 (m,5H),2.52(1H),2.43(1H),2.31(1H), 2.12-1.78 (m,8H),1.76(s,3H), 1.76-1.38 (m,35H),1.12(s,3H),1.04(s,3H),0.97(s, 3H). Compound III-5-2(804.74mg,1.0mmol) was dissolved in CAN (10mL) and 5-fluorotryptamine hydrochloride (429.34mg, 2.0mmol) was addedmmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain white powder (III-5-2-1)450.50mg with yield of 45.08%. C₆₀H₈₂F₄N₄O₄.MS：[M]⁺998.62467.¹H NMR(300MHz,Chloroform-d)δ7.45(2H),7.30(2H),7.08(2H),6.95(s,2H),4.83(1H),4.79–4.73(m,2H),4.69(1H),4.16(1H),4.06(1H),3.91(1H),3.75–3.41(m,9H),3.05(4H),2.94–2.81(m,4H),2.50(1H),2.43(1H),2.30(1H),2.13–1.91(m,7H),1.88–1.79(m,1H),1.76(s,3H),1.79–1.75(m,3H),1.73(s,3H),1.75–1.35(m,39H),1.12(s,3H),1.05(s,3H),0.98(s,3H)。

Example 25: preparation of Compounds of the general formulae IV-1, IV-1-1 and IV-1-1-1

III-1(502.69mg, 1.0mmol) was dissolved in 80% MeOH in 6% HCl, heated under reflux for 2h, taken out after the reaction was complete, the solvent was recovered under reduced pressure, and dried to give 277.22mg of (IV-1) as a pale yellow powder with a yield of 53.65%. C₃₁H₄₈O₆.MS：[M]⁺516.34754.¹H NMR (300MHz, Chloroform-d) Δ 4.80(1H), 4.751H, 4.25-4.12 (m,2H),3.66(s,3H),3.44(1H), 2.69-2.57 (m,2H),2.20(1H),2.09(1H),2.04(1H),1.97(1H),1.86(1H), 1.82-1.46 (m,16H),1.23(s,3H),1.16(s,3H),1.08(s,3H),1.01(s,3H),0.96(s, 3H). Compound IV-1(516.72mg, 1.0mmol) was dissolved in PA (10mL), 1, 3-dibromopropane (605. mu.L, 3.0mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, reflux reaction was carried out for 12h, the solvent was recovered under reduced pressure to give a solid powder, which was separated by silica gel column chromatography and dried to give 418.20mg of (IV-1-1) as a white powder with a yield of 65.58%. C₃₄H₅₃BrO₆.MS：[M]⁺636.29784.¹H NMR(300MHz,Chloroform-d)δ4.80(1H),4.75(1H),4.25–4.12(m,2H),3.67(1H),3.66(s,3H),3.59(1H),3.48–3.40(m,3H),2.69–2.57(m,2H),2.20(1H),2.09(1H),2.04(1H),2.03–1.98(m,2H),1.97(1H),1.86(1H),1.82–1.46(m,16H),1.23(s,3H),1.16(s,3H),1.08(s,3H),1.01(s,3H),0.96(s, 3H). Dissolving compound IV-1-1(637.70mg,1.0mmol) in CAN (10mL), adding tryptamine (320.43mg, 2.0mmol), adding an appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering the solvent under reduced pressure to obtain a solid powder, separating by silica gel column chromatography, and drying to obtain yellow powder (C-12-f)468.70mg with the yield of 65.37%. C₄₄H₆₄N₂O₆.MS：[M]⁺716.47364.¹H NMR(300MHz,Chloroform-d)δ7.65–7.60(m,2H),7.44(2H),7.28(2H),7.09(2H),6.94(s,2H),4.80(1H),4.75 1H),4.25–4.12(m,2H),4.03(2H),3.67(1H),3.66(s,3H),3.59(1H),3.44(1H),3.04(2H),2.94–2.81(m,2H),2.69–2.57(m,2H),2.20(1H),2.09(1H),2.04(1H),2.03–1.98(m,2H),1.97(1H),1.86(1H),1.82–1.46(m,18H),1.23(s,3H),1.16(s,3H),1.08(s,3H),1.01(s,3H),0.96(s,3H)。

Example 26: preparation of Compounds of the general formulae IV-1a, IV-1a-1 and IV-1a-1-1

Compound IV-1(516.72mg, 1.0mmol) was dissolved in DMF (10mL) and SOCl was added₂(118.96mg, 1.0mmol), refluxed for 2 hours, and concentrated. Subsequently, ammonia gas was introduced and the reaction was carried out at room temperature for 2 hours. The solvent was recovered under reduced pressure to give a solid powder, which was subjected to silica gel column chromatography and dried to give 339.97mg of a pale yellow solid (IV-1a) in a yield of 65.92%. C₃₁H₄₉NO₅.MS：[M]⁺515.35674.¹H NMR (300MHz, Chloroform-d) Δ 6.52(s,2H),4.80(1H), 4.751H, 4.25-4.12 (m,2H),3.66(s,3H),3.44(1H), 2.69-2.57 (m,2H),2.20(1H),2.09(1H),2.04(1H),1.97(1H),1.86(1H), 1.82-1.46 (m,16H),1.23(s,3H),1.16(s,3H),1.08(s,3H),1.01(s,3H),0.96(s, 3H). 1, 3-dibromopropane (605 mu L, 3.0mmol) is added into compound IV-1a (515.74mg, 1.0mmol) PA (10mL), an appropriate amount of anhydrous potassium carbonate is added, reflux reaction is carried out for 12h, the solvent is recovered under reduced pressure to obtain solid powder, silica gel column chromatography separation is carried out, and drying is carried out to obtain 388.49mg of white powder (IV-1a-1) with the yield of 58.44%. C₃₆H₅₈BrNO₅.MS：[M]⁺663.34755.¹H NMR (300MHz, Chloroform-d) Δ 6.54(s,2H),4.82(1H),4.75(1H), 4.24-4.13 (m,2H),3.67(1H),3.66(s,3H),3.59(1H), 3.48-3.39 (m,3H), 2.69-2.57 (m,2H),2.20(1H),2.10(1H),2.05(1H), 2.03-1.98 (m,2H),1.97(1H),1.86(1H), 1.83-1.46 (m,16H),1.24(s,3H),1.17(s,3H),1.08(s,3H),1.02(s,3H),0.97(s, 3H). Dissolving compound IV-1a-1(664.77mg,1.0mmol) in CAN (10mL), adding tryptamine (320.43mg, 2.0mmol), adding appropriate amount of anhydrous potassium carbonate, refluxing for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain light yellow powder (IV-1a-1-1)389.60mg with yield of 52.36%. C₄₆H₆₉N₃O₅.MS：[M]⁺774.06667.¹H NMR(300MHz,Chloroform-d)δ7.68–7.62(m,2H),7.45(2H),7.28(2H),7.08(2H),6.93(s,2H),6.52(s,2H),4.81(1H),4.75(1H),4.25–4.14(m,2H),4.05(2H),3.67(1H),3.65(s,3H),3.59(1H),3.45(1H),3.04(2H),2.95–2.81(m,2H),2.69–2.57(m,2H),2.22(1H),2.10(1H),2.04(1H),2.02–1.97(m,2H),1.96(1H),1.86(1H),1.82–1.46(m,18H),1.23(s,3H),1.15(s,3H),1.07(s,3H),1.01(s,3H),0.95(s,3H)。

The remaining active compound synthesis procedures are as described in examples 25 and 26 to give the compounds of the following table.

The compound has corresponding changes in data such as yield, mass-to-charge ratio, nuclear magnetic data and the like.

And (3) biological activity test:

example 27: enzymatic activity assay of derivatives

Experimental materials: protein-human CDK6/cyclin d1 protein kinase complex, CDK6, PLK1, FASN, GPX4 protein kinase (purchased from Sigma, Abcam, and Abnova, respectively); substrate- [ γ 32P ] ATP (purchased from PerkinElme); cellulose test paper (from Whatrnan); other reagents are analytical pure grade products.

The test method comprises the following steps: CDK6/CyclinD1 protein kinase complex, CDK6, PLK1, FASN, GPX4 inhibitory activity assay Using [ γ -32P ] ATP method, 6. mu.L of buffer (25mM MOPS (pH 7.2),2.5mM EGTA,2.5mM EDTA,0.5mM DTT,0.25mg/mL BSA,20 mM. beta. -phosphoglycerol), 3. mu.L of MBP solution (5.0. mu.g/. mu.L), 0.3. mu.L PLK1, FASN and GPX4 protein kinase (0.1. mu.g/. mu.L), 10.25. mu.L water were added to the reaction. Then, 19. mu.L of the reaction mixture was taken at room temperature and rapidly introduced into a l.5mL EP tube.

The test substance was dissolved in DMSO to prepare a stock solution with an initial concentration of 1mM, and then 1. mu.L of the test substance solution was added to each EP tube, mixed well with a pipette, and incubated on ice for 10 minutes.

Each sample contained 0.5mCi [ gamma-32P ] ATP with a radioactivity of 100. mu. Ci/. mu.M.

Will contain 150. mu.M ATP, 30mM MgCl₂15mM MOPS, pH 7.2 ATP solution was added to the reaction solution at a final concentration of 100mM, reacted at 30 ℃ for 20 minutes, 20. mu.L of 0.5M phosphoric acid was added to stop the reaction, the reaction solution was spotted on a 20mM filter plate spread with cellulose test paper, and the filter plate was washed three times with 0.075M phosphoric acid solution at room temperature and dried. The dried filter plate was read in a Tri-Caxb 2800-TR liquid scintillation counter. Positive controls replaced the test stock with 1M DMSO.

The [ gamma-32P ] ATP method is used for carrying out inhibitory activity experiments on the derivatives, and the results are shown in tables 1-5.

TABLE 1 median inhibitory concentration of derivatives against the CDK6/CyclinD1 protein kinase complex

Compound (I)	IC₅₀(nM) value	Grade	Compound (I)	IC₅₀(nM) value	Grade
						Ⅰ-1	358.10	C	Ⅲ-1-2	299.59	C
Ⅰ-2	337.01	C	Ⅲ-1-2-1	10.33	A
						Ⅰ-3	368.55	C	Ⅲ-2-1	245.29	C
Ⅰ-4	381.68	C	Ⅲ-2-1-1	67.40	B
						Ⅰ-5	396.94	C	Ⅲ-2-2	233.18	C
Ⅱ-1-1	229.76	C	Ⅲ-2-2-1	19.22	A
						Ⅱ-1-1-1	157.18	B	Ⅲ-3-1	199.69	B
Ⅱ-1-2	209.83	C	Ⅲ-3-1-1	9.20	A
						Ⅱ-1-2-1	191.13	B	Ⅲ-3-2	258.51	C
Ⅱ-1-3	148.49	B	Ⅲ-3-2-1	97.31	B
						Ⅱ-1-3-1	0.52	A	Ⅲ-4-1	294.32	C
Ⅱ-1-5	174.97	B	Ⅲ-4-1-1	38.26	B
						Ⅱ-1-5-1	3.94	A	Ⅲ-4-2	377.59	C
Ⅱ-2-1	169.10	B	Ⅲ-4-2-1	112.28	B
						Ⅱ-2-1-1	102.36	B	Ⅲ-5-1	304.46	C
Ⅱ-2-3	152.69	B	Ⅲ-5-1-1	165.06	B
						Ⅱ-2-3-1	101.49	B	Ⅲ-5-2	274.30	C
Ⅱ-3-1	108.15	B	Ⅲ-5-2-1	14.07	A
						Ⅱ-3-1-1	18.73	A	Ⅳ-1	330.17	C
Ⅱ-3-4	116.90	B	Ⅳ-1-1	366.38	C
						Ⅱ-3-4-1	86.43	B	Ⅳ-1-1-1	32.99	B
Ⅱ-4-1	164.23	B	Ⅳ-1a	342.62	C
						Ⅱ-4-1-1	22.85	A	Ⅳ-1a-1	303.93	C
Ⅱ-5-1	173.41	B	Ⅳ-1a-1-1	10.55	A
						Ⅱ-5-1-1	13.66	A	Ⅳ-1-1-2	131.00	B
Ⅲ-1	354.50	C	Ⅳ-1-2-1	77.64	B
						Ⅲ-2	292.47	C	Ⅳ-1a-1-2	31.48	B
Ⅲ-3	262.65	C	Ⅳ-1a-1-3	20.39	A
						Ⅲ-4	389.66	C	Ⅳ-1b-1-1	18.14	A
Ⅲ-5	378.71	C	Ⅳ-1b-1-2	62.04	B
						Ⅲ-1-1	206.87	C	Ⅳ-1c-1-1	38.82	B
Ⅲ-1-1-1	147.11	B	Ⅳ-1d-1-1	26.02	B

Note: a is less than or equal to 25 nM; b is more than 25nM and less than or equal to 200 nM; c > 200nM

The above data illustrate that: II-1-3-1, II-1-5-1, II-3-1-1, II-5-1-1, III-1-2-1, III-2-2-1, III-3-1-1, III-5-2-1, IV-1a-1-3 and IV-1b-1-1 have better inhibitory activity to CDK6/CyclinD1 protein kinase complex.

TABLE 2 Semitained concentrations of derivatives against CDK6 protein kinase

Compound (I)	IC₅₀(nM) value	Grade	Compound (I)	IC₅₀(nM) value	Grade
						Ⅰ-1	448.39	C	Ⅲ-1-2	387.14	C
Ⅰ-2	396.51	C	Ⅲ-1-2-1	343.36	C
						Ⅰ-3	402.45	C	Ⅲ-2-1	403.65	C
Ⅰ-4	397.33	C	Ⅲ-2-1-1	371.31	C
						Ⅰ-5	433.23	C	Ⅲ-2-2	494.59	C
Ⅱ-1-1	388.30	C	Ⅲ-2-2-1	270.60	C
						Ⅱ-1-1-1	353.68	C	Ⅲ-3-1	310.09	C
Ⅱ-1-2	433.11	C	Ⅲ-3-1-1	287.33	C
						Ⅱ-1-2-1	375.46	C	Ⅲ-3-2	396.43	C
Ⅱ-1-3	364.53	C	Ⅲ-3-2-1	317.62	C
						Ⅱ-1-3-1	299.28	C	Ⅲ-4-1	469.53	C
Ⅱ-1-5	453.69	C	Ⅲ-4-1-1	370.18	C
						Ⅱ-1-5-1	364.37	C	Ⅲ-4-2	419.37	C
Ⅱ-2-1	407.43	C	Ⅲ-4-2-1	409.28	C
						Ⅱ-2-1-1	351.31	C	Ⅲ-5-1	332.49	C
Ⅱ-2-3	274.43	C	Ⅲ-5-1-1	271.29	C
						Ⅱ-2-3-1	230.41	C	Ⅲ-5-2	412.44	C
Ⅱ-3-1	422.23	C	Ⅲ-5-2-1	350.64	C
						Ⅱ-3-1-1	364.17	C	Ⅳ-1	420.67	C
Ⅱ-3-4	473.27	C	Ⅳ-1-1	427.13	C
						Ⅱ-3-4-1	395.49	C	Ⅳ-1-1-1	281.39	C
Ⅱ-4-1	383.24	C	Ⅳ-1a	467.37	C
						Ⅱ-4-1-1	323.10	C	Ⅳ-1a-1	323.52	C
Ⅱ-5-1	395.01	C	Ⅳ-1a-1-1	287.57	C
						Ⅱ-5-1-1	373.00	C	Ⅳ-1-1-2	281.00	C
Ⅲ-1	479.65	C	Ⅳ-1-2-1	335.42	C
						Ⅲ-2	427.20	C	Ⅳ-1a-1-2	335.20	C
Ⅲ-3	404.40	C	Ⅳ-1a-1-3	317.45	C
						Ⅲ-4	420.15	C	Ⅳ-1b-1-1	290.69	C
Ⅲ-5	448.56	C	Ⅳ-1b-1-2	294.27	C
						Ⅲ-1-1	447.70	C	Ⅳ-1c-1-1	321.43	C
Ⅲ-1-1-1	385.48	C	Ⅳ-1d-1-1	274.21	C

The above data illustrate that: none of the above compounds has a good inhibitory activity against CDK6, which also indirectly indicates that the inhibitory effect of compounds II-1-3-1, II-1-5-1, II-3-1-1, II-5-1-1, III-1-2-1, III-2-2-1, III-3-1-1, III-5-2-1, IV-1a-1-3 and IV-1b-1-1 on the CDK6/CyclinD1 protein kinase complex derives from its direct effect on CyclinD 1.

TABLE 3 median inhibitory concentration of derivatives against PLK1 protein kinase

Compound (I)	IC₅₀(nM) value	Grade	Compound (I)	IC₅₀(nM) value	Grade
						Ⅰ-1	255.97	C	Ⅲ-1-2	215.44	C
Ⅰ-2	284.60	C	Ⅲ-1-2-1	18.34	A
						Ⅰ-3	271.32	C	Ⅲ-2-1	184.93	B
Ⅰ-4	336.02	C	Ⅲ-2-1-1	46.02	B
						Ⅰ-5	328.30	C	Ⅲ-2-2	205.96	C
Ⅱ-1-1	206.37	C	Ⅲ-2-2-1	14.16	A
						Ⅱ-1-1-1	117.09	B	Ⅲ-3-1	148.73	B
Ⅱ-1-2	232.77	C	Ⅲ-3-1-1	15.54	A
						Ⅱ-1-2-1	200.88	C	Ⅲ-3-2	226.82	C
Ⅱ-1-3	152.71	B	Ⅲ-3-2-1	103.88	B
						Ⅱ-1-3-1	1.63	A	Ⅲ-4-1	218.60	C
Ⅱ-1-5	183.99	B	Ⅲ-4-1-1	22.96	A
						Ⅱ-1-5-1	9.86	A	Ⅲ-4-2	299.26	C
Ⅱ-2-1	139.94	B	Ⅲ-4-2-1	106.72	B
						Ⅱ-2-1-1	94.31	B	Ⅲ-5-1	268.51	C
Ⅱ-2-3	112.91	B	Ⅲ-5-1-1	115.82	B
						Ⅱ-2-3-1	94.86	B	Ⅲ-5-2	235.28	C
Ⅱ-3-1	88.67	B	Ⅲ-5-2-1	24.01	A
						Ⅱ-3-1-1	20.85	A	Ⅳ-1	304.83	C
Ⅱ-3-4	137.90	B	Ⅳ-1-1	336.28	C
						Ⅱ-3-4-1	95.59	B	Ⅳ-1-1-1	19.58	A
Ⅱ-4-1	129.44	B	Ⅳ-1a	337.52	C
						Ⅱ-4-1-1	32.13	B	Ⅳ-1a-1	285.30	C
Ⅱ-5-1	102.92	B	Ⅳ-1a-1-1	7.17	A
						Ⅱ-5-1-1	8.25	A	Ⅳ-1-1-2	64.61	B
Ⅲ-1	267.44	C	Ⅳ-1-2-1	83.54	B
						Ⅲ-2	222.61	C	Ⅳ-1a-1-2	46.15	B
Ⅲ-3	261.85	C	Ⅳ-1a-1-3	24.69	A
						Ⅲ-4	279.58	C	Ⅳ-1b-1-1	11.05	A
Ⅲ-5	294.20	C	Ⅳ-1b-1-2	108.64	B
						Ⅲ-1-1	193.09	B	Ⅳ-1c-1-1	15.02	A
Ⅲ-1-1-1	117.43	B	Ⅳ-1d-1-1	37.10	B

The above data illustrate that: II-1-3-1, II-1-5-1, II-3-1-1, II-5-1-1, III-1-2-1, III-3-1-1, III-4-1-1, III-5-2-1, IV-1-1-1, IV-1a-1-3 and IV-1 c-1-1 have better inhibitory activity to PLK1 protein kinase.

TABLE 4 half inhibitory concentration of derivatives on FASN protein kinase

Compound (I)	IC₅₀(nM) value	Grade	Compound (I)	IC₅₀(nM) value	Grade
						Ⅰ-1	327.98	C	Ⅲ-1-2	221.22	C
Ⅰ-2	333.17	C	Ⅲ-1-2-1	11.19	A
						Ⅰ-3	372.39	C	Ⅲ-2-1	180.56	C
Ⅰ-4	398.68	C	Ⅲ-2-1-1	89.99	B
						Ⅰ-5	335.41	C	Ⅲ-2-2	213.91	C
Ⅱ-1-1	232.56	C	Ⅲ-2-2-1	9.28	A
						Ⅱ-1-1-1	127.46	B	Ⅲ-3-1	146.01	B
Ⅱ-1-2	226.33	C	Ⅲ-3-1-1	15.54	A
						Ⅱ-1-2-1	128.53	B	Ⅲ-3-2	242.66	C
Ⅱ-1-3	142.76	B	Ⅲ-3-2-1	75.43	B
						Ⅱ-1-3-1	5.34	A	Ⅲ-4-1	266.26	C
Ⅱ-1-5	187.58	B	Ⅲ-4-1-1	52.07	B
						Ⅱ-1-5-1	1.55	A	Ⅲ-4-2	299.97	C
Ⅱ-2-1	226.59	C	Ⅲ-4-2-1	201.26	B
						Ⅱ-2-1-1	120.85	B	Ⅲ-5-1	296.20	C
Ⅱ-2-3	151.36	B	Ⅲ-5-1-1	184.57	B
						Ⅱ-2-3-1	97.38	B	Ⅲ-5-2	271.89	C
Ⅱ-3-1	123.91	B	Ⅲ-5-2-1	20.83	A
						Ⅱ-3-1-1	21.96	A	Ⅳ-1	233.15	C
Ⅱ-3-4	127.05	B	Ⅳ-1-1	231.74	C
						Ⅱ-3-4-1	76.70	B	Ⅳ-1-1-1	17.93	A
Ⅱ-4-1	173.14	B	Ⅳ-1a	307.01	C
						Ⅱ-4-1-1	18.87	A	Ⅳ-1a-1	222.23	C
Ⅱ-5-1	211.61	C	Ⅳ-1a-1-1	26.16	B
						Ⅱ-5-1-1	27.66	B	Ⅳ-1-1-2	169.02	B
Ⅲ-1	336.26	C	Ⅳ-1-2-1	141.83	B
						Ⅲ-2	331.89	C	Ⅳ-1a-1-2	14.86	A
Ⅲ-3	324.74	C	Ⅳ-1a-1-3	17.02	A
						Ⅲ-4	345.88	C	Ⅳ-1b-1-1	28.80	B
Ⅲ-5	373.74	C	Ⅳ-1b-1-2	33.43	B
						Ⅲ-1-1	256.87	C	Ⅳ-1c-1-1	30.72	B
Ⅲ-1-1-1	158.13	B	Ⅳ-1d-1-1	25.99	A

The above data illustrate that: II-1-3-1, II-1-5-1, II-3-1-1, II-5-1-1, III-1-2-1, III-3-1-1, III-5-2-1, IV-1 a-1-2 and IV-1a-1-3 all have better inhibitory activity to FASN protein kinase.

TABLE 5 median inhibitory concentration of derivatives against GPX4 protein kinase

Compound (I)	IC₅₀(nM) value	Grade	Compound (I)	IC₅₀(nM) value	Grade
						Ⅰ-1	442.59	C	Ⅲ-1-2	268.90	C
Ⅰ-2	434.07	C	Ⅲ-1-2-1	21.57	A
						Ⅰ-3	453.36	C	Ⅲ-2-1	280.29	C
Ⅰ-4	468.52	C	Ⅲ-2-1-1	181.87	B
						Ⅰ-5	488.21	C	Ⅲ-2-2	285.99	C
Ⅱ-1-1	296.71	C	Ⅲ-2-2-1	19.52	A
						Ⅱ-1-1-1	175.84	B	Ⅲ-3-1	315.70	C
Ⅱ-1-2	252.55	C	Ⅲ-3-1-1	17.44	A
						Ⅱ-1-2-1	188.10	B	Ⅲ-3-2	338.65	C
Ⅱ-1-3	239.95	C	Ⅲ-3-2-1	25.62	B
						Ⅱ-1-3-1	1.11	A	Ⅲ-4-1	245.32	C
Ⅱ-1-5	229.10	C	Ⅲ-4-1-1	20.73	A
						Ⅱ-1-5-1	3.81	A	Ⅲ-4-2	394.09	C
Ⅱ-2-1	326.86	C	Ⅲ-4-2-1	133.27	B
						Ⅱ-2-1-1	195.54	B	Ⅲ-5-1	337.39	C
Ⅱ-2-3	311.30	C	Ⅲ-5-1-1	205.02	B
						Ⅱ-2-3-1	136.24	B	Ⅲ-5-2	322.43	C
Ⅱ-3-1	383.18	C	Ⅲ-5-2-1	21.88	A
						Ⅱ-3-1-1	15.63	A	Ⅳ-1	203.59	C
Ⅱ-3-4	338.85	C	Ⅳ-1-1	191.59	B
						Ⅱ-3-4-1	144.32	B	Ⅳ-1-1-1	19.08	A
Ⅱ-4-1	357.59	C	Ⅳ-1a	229.40	C
						Ⅱ-4-1-1	11.36	A	Ⅳ-1a-1	202.75	C
Ⅱ-5-1	210.93	C	Ⅳ-1a-1-1	14.42	A
						Ⅱ-5-1-1	14.76	A	Ⅳ-1-1-2	251.99	C
Ⅲ-1	361.87	C	Ⅳ-1-2-1	164.91	B
						Ⅲ-2	430.12	C	Ⅳ-1a-1-2	83.54	B
Ⅲ-3	392.90	C	Ⅳ-1a-1-3	11.48	A
						Ⅲ-4	430.65	C	Ⅳ-1b-1-1	4.71	A
Ⅲ-5	440.61	C	Ⅳ-1b-1-2	119.12	B
						Ⅲ-1-1	217.19	C	Ⅳ-1c-1-1	28.78	B
Ⅲ-1-1-1	166.53	B	Ⅳ-1d-1-1	31.28	B

The above data illustrate that: II-1-3-1, II-1-5-1, II-3-1-1, II-4-1-1, II-5-1-1, III-1-2-1, III-2-2-1, III-3-1-1, III-4-1-1, III-5-2-1, IV-1-1-1, IV-1a-1-3 and IV-1b-1-1 all have better inhibitory activity to GPX4 protein kinase.

And (4) conclusion: the split-ring lupane derivatives II-1-3-1, II-1-5-1, II-3-1-1, II-5-1-1, III-1-2-1, III-2-2-1, III-3-1-1, III-5-2-1, IV-1-1-1 and IV-1a-1-3 have obvious inhibition effects on Cyclin D1, PLK1, FASN and GPX 4.

Example 28: pharmacokinetic testing

Animal experiments: 24 SD rats, male and female halves (7-8 weeks old, 200-220g body weight) were selected for this study. The groups were randomized into 6 groups of 4 individuals. The same dose (20mg/kg) of drug was injected intravenously or gavaged to evaluate the pharmacokinetic properties of the test drug in vivo.

Rats were fed standard conditions and were given maintenance feed at 12h day/12 h night. The test drug is formulated with 0.5% sodium carboxymethylcellulose or dimethyl sulfoxide. The same dose of lupane derivatives was injected intravenously and gavaged into rats, respectively. Collecting blood from tail vein at 0, 0.083, 0.25, 0.5, 1,2, 3,4, 6, 8, 12, and 24 hr after administration, centrifuging at 5000rpm for 15min at 4 deg.C, separating blood plasma and red blood cells, and adding heparin and freezing at-20 deg.C.

The concentration of each compound in plasma was measured by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

And (4) conclusion: the plasma pharmacokinetics results show that each secolupane derivative of the invention has better pharmacokinetic properties.

Preparation of a dosage form:

example 29: tablet preparation

Reagent: starch (pharmaceutical grade, jin dong tian zheng fine chemical reagent factory, Tianjin city); citric acid (Shanghai Michelin Biochemical technologies, Inc.); magnesium stearate (Shanghai Michelin Biotechnology, Inc.).

The preparation method comprises the following steps:

preparation of 10% starch slurry: dissolving 0.25g of citric acid in 25mL of pure water, adding 2.5g of starch, uniformly dispersing, and heating to gelatinize to obtain 10% starch slurry.

Granulating: mixing appropriate amount of the obtained lupane derivative powder with starch, adding appropriate amount of 10% starch slurry, mixing, grinding, making soft material, sieving with 16 mesh sieve, granulating, and drying at 50-60 deg.C for 1 hr. After finishing granules with a 16-mesh sieve, adding a proper amount of lubricant magnesium stearate, and pressing into tablets by using a shallow punch with the diameter of 10 mm.

As a result: the obtained tablet is beige in color, uniform in thickness and moderate in hardness. The tablet weight and the disintegration time meet the requirements.

And (4) conclusion: the obtained lupane derivative can be made into tablet, and can be used as tablet.

Example 30: preparation of suspension injection

Reagent: polylactic acid (PLA, shanghai julian biotechnology limited); poly (lactic-co-glycolic acid) (PLGA, shanghai-derived leaf biotechnology limited); poloxamer 188 (sitaxentan pharmaceutical excipients, ltd); dichloromethane, methanol, acetonitrile, etc. (Tianjin Tiantai chemical Co., Ltd.).

The preparation method comprises the following steps:

preparation of polymer microparticles: weighing appropriate amount of lupane derivatives and carrier (PLA/PLGA), placing in 50mL round bottom flask, adding 5mL dichloromethane for dissolving, distilling under reduced pressure at 28 deg.C to remove most organic solvent, vacuum drying at 40 deg.C for 24 hr until all solvent is removed, pulverizing, and sieving with 150 μm mesh to obtain polymer microparticles of lupane derivatives.

Preparing a secolupane derivative suspension injection: dispersing 2.5g of the above product in 250mL of poloxamer 188 stabilizer containing 10g/L under continuous stirringThe fixing agent is completely dispersed in the water solution. Grinding the drug dispersion to desired particle diameter, taking out to obtain lupane derivative polymer microparticle suspension, 3000 r min^-1Centrifuge for 1min and disperse with 10mL aqueous stabilizer solution to concentrate the formulation to about 25 g/L.

As a result: the obtained suspension injection has uniform particle size, and the water content and the surface particle size of the preparation meet the specification. The in vitro slow release effect is better, and the stability is better.

And (4) conclusion: the obtained suspension injection prepared from the lupane derivatives meets the requirements and can be used as a suspension injection.

The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims

1. A secolupane derivative represented by the general formula i:

wherein R is_aSelected from: -OH, -NH₂、-SH、-F、-Cl。

2. Starting from the secolupane derivative of claim 1 and a glycosyl compound Ra, a secolupane derivative of general formula II is obtained by a series of chemical reactions:

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

3. starting from the secolupane derivative of claim 1 and a glycosyl compound Ra, the secolupane derivative of formula III is obtained by a series of chemical reactions:

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

4. the method for producing a seco-lupane derivative of the present invention comprises using the seco-lupane derivative of claim 1 and a glycosyl compound Ra as starting materials, wherein the seco-lupane derivative of the following general formula IV is obtained by a series of chemical reactions:

R_aSelected from: -OH, -NH₂、-SH、-F、-Cl；

R_bSelected from:

R_cselected from: C1-C9 alkyl.

5. An optical isomer of the compound of claims 1-4 or a pharmaceutically acceptable salt or solvate thereof.

6. A pharmaceutical composition comprising a compound of claims 1-5 and pharmaceutically acceptable excipients and carriers.

7. Use of the compounds and compositions of claims 1-6 for the preparation of medicaments for the prevention or treatment of Cyclin D1, PLK1, FASN and GPX4 mediated diseases related thereto.

8. The use of claim 7, wherein: the related diseases mediated by Cyclin D1, PLK1, FASN and GPX4 comprise tumors, cancers, obesity, diabetes, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases.