CN114195843B - Loose lupin alkane derivative and application thereof in preparation of multi-target inhibitor - Google Patents

Loose lupin alkane derivative and application thereof in preparation of multi-target inhibitor Download PDF

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CN114195843B
CN114195843B CN202111381929.XA CN202111381929A CN114195843B CN 114195843 B CN114195843 B CN 114195843B CN 202111381929 A CN202111381929 A CN 202111381929A CN 114195843 B CN114195843 B CN 114195843B
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赵岩
王豪豪
杜锐
李平亚
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Jilin Agricultural University
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Abstract

The invention relates to a lupin alkane derivative and application thereof in preparing multi-target inhibitor, belonging to the field of medicines. The lupin alkane derivatives are compounds for preventing and treating related diseases mediated by Cyclin D1, PLK1, FASN and GPX 4. The invention has the advantages that: a series of Cyclin D1, PLK1, FASN and GPX4 receptor antagonists are obtained by using a semisynthetic mode, and can be used for preventing, treating or relieving the split-ring lupin alkane derivatives of the Cyclin D1, PLK1, FASN and GPX4 mediated related diseases, pharmacological experiments prove that the Cyclin D1, PLK1, FASN and GPX4 antagonists act, and the compounds can be further developed into medicaments for preventing, treating or relieving the Cyclin D1, PLK1, FASN and GPX4 mediated related diseases such as tumors, cancers, obesity, diabetes mellitus, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases through further experiments.

Description

Loose lupin alkane 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-split ring lupin alkane derivative, an optical isomer or a pharmaceutically acceptable salt thereof, and application thereof in preparing medicines for preventing and treating related diseases mediated by Cyclin D1, PLK1, FASN and GPX 4.
Background
G1/S-specific Cyclin-D1 (Cyclin D1), a Cyclin closely related to cell proliferation. Cyclin D1 phosphorylates retinoblastoma protein Rb by binding to Cyclin dependent kinase 4/6 (CDK 4/6), releasing transcription factor E2F, and thus initiates the synthesis of deoxyribonucleic acid DNA, accelerating the transition of the cell cycle from G1 phase to S phase, and having the property of tumor gene, and over-expression of Cyclin D1 can cause uncontrolled cell proliferation and malignant growth, eventually forming tumors (Lakshminarayana S et al, J Carcinog,2018,17 (1): 7; zhang Yan et al, 2011,9 (3): 443-444.). Polo-like kinase 1 (PLK 1) is a member of the serine/threonine kinase family and can regulate processes such as cell mitosis, cytokinesis, DNA damage response, development and the like through interaction of kinase activity and various substrates, and is closely related to diseases such as cancers, acute leukemia, myelodysplastic syndromes and the like. FASN, also known as fatty acid synthase, has multiple functions and is a key enzyme for synthesizing fatty acids. FASN is not expressed or 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 fat deposition in animals. The abnormal fatty acid metabolism is closely related to the occurrence and development of a plurality of diseases, and is mainly represented in the aspects of obesity, diabetes, cancer and the like. GPX4 is a selenoprotein which can reduce lipid peroxide into corresponding lipidol, inhibit lipid peroxidation, and is closely related to aspects of tumors, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases (Gu Zhongwei, et al, J.Zhonghua tumor prevention and control, 2019,26 (3): 155-161.). It has also been found that Cyclin D1, PLK1, FASN and GPX4 are overexpressed in a variety of tumors and are associated with tumor progression and poor prognosis (Polonio-Alcal E et al, cancers (Basel), 2020,12 (5): 308-15; zaytsiva YY et al, carcinogensis, 2014,35 (6): 1341-51; liu H et al, biochemistry,2018,57 (14): 2059-2060.), while inhibiting them can reduce the tumor-forming capacity in tumor cells, which makes Cyclin D1, PLK1, FASN and GPX4 promising targets for anti-tumor therapy.
Lupane type triterpene and its saponin 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, tumor, virus, oxidation, bacteria, improving immunity (AMIRI S, etc., biotechnol Adv,2020,38:107409;Bian X, etc., RSC Adv,7 (66): 41640-41650; CHANIAD P, etc., adv Pharmacol Sci,2019:11;BELLAMPALLI S S, etc., paint, 2019,160 (1): 117-135; cheng Xiaohua, etc., chinese herbal medicine, 2007,38 (5): 792-795), etc. In recent years, more and more complex and novel lupin-alkane triterpenes have been found. The discovery and activity research of novel triterpene compounds with substitution, ring cleavage, carbon reduction, rearrangement and the like at different positions on a framework and complex triterpene saponins with a plurality of sugar linkages have become research hot spots for natural product research.
Disclosure of Invention
The invention provides a lupin alkane derivative and application thereof in preparing multi-target inhibitors, in particular to application of the compounds and the compositions in preparing medicines for preventing and treating related diseases mediated by Cyclin D1, PLK1, FASN and GPX 4.
The technical scheme adopted by the invention is as follows:
a secoisolaricireside is shown in the general formula I:
wherein R is a Selected from: -OH, -NH 2 、-SH、-F、-Cl。
The split ring lupin alkane derivative shown in the general formula II is obtained by taking the split ring lupin alkane derivative and Ra as glycosyl compounds as raw materials through a series of chemical reactions:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
the split ring lupin alkane derivative and Ra of the invention are taken as raw materials, and the split ring lupin alkane derivative shown in the general formula III is obtained through a series of chemical reactions:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
the split ring lupin alkane derivative and Ra of the invention are taken as raw materials, and the split ring lupin alkane derivative shown in the general formula IV is obtained through a series of chemical reactions:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
R c selected from: C1-C9 alkyl.
In the technical scheme of the invention, the optical isomer of the compound shown in the general formulas I-IV or pharmaceutically acceptable salt or solvate thereof.
The invention also provides a pharmaceutical composition which contains the split ring lupin alkane derivative, optical isomer thereof or pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable carrier and excipient.
The carrier comprises protein, folic acid, antibody, nano material and the like which are commonly used in the pharmaceutical field. The term "excipient" refers to an adjunct to the main drug in pharmaceutical formulations, also known as an auxiliary material, such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice and the like in the traditional Chinese medicine pill; a base portion in a semisolid formulation ointment, cream; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid formulations may be referred to as excipients.
The medicine of the invention 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 methods in the pharmaceutical field.
The invention also provides application of the derivative and the optical isomer thereof or the pharmaceutically acceptable salt or solvate thereof and the composition in preparing medicines for preventing and treating related diseases mediated by Cyclin D1, PLK1, FASN and GPX 4;
related diseases mediated by Cyclin D1, PLK1, FASN and GPX4 include tumors, cancers, obesity, diabetes, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases.
The derivatives of the present invention, and optical isomers thereof, or pharmaceutically acceptable salts or solvates thereof, may be administered alone, in combination with a plurality of medicaments.
The secoisolaricireside related by the invention is a special 3, 4-secoisolaricireside 3, 11-cyclized lupin alkane type triterpene derivative in the current lupin alkane type triterpene compounds. Based on the structure, chemical means are used for structural modification and reconstruction, so that a class of split-ring lupin alkane derivatives capable of preventing and treating related diseases mediated by Cyclin D1, PLK1, FASN and GPX4 is formed.
The invention has the advantages that: a series of Cyclin D1, PLK1, FASN and GPX4 antagonists are obtained by using a semi-synthetic mode, and can be used for preventing, treating or relieving the ring-splitting lupin alkane derivatives of the Cyclin D1, PLK1, FASN and GPX4 mediated related diseases. Pharmacological experiments prove that the Cyclin D1, PLK1, FASN and GPX4 antagonists have the same actions, and the compounds can be developed into medicines applied to preventing, treating or relieving related diseases mediated by the Cyclin D1, PLK1, FASN and GPX4 through further experiments.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
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 conjunction with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art. Wherein preferred embodiments include, but are not limited to, embodiments of the present invention.
Synthesis of the derivatives:
the solvent and its synthetic medicine used in the present invention may be obtained commercially. Abbreviations used herein have the following respective definitions: lawesson,2, 4-bis (p-methoxyphenyl) -1, 3-dithio-2, 4-diphosphatetidine-2, 4-disulfide; DAST, diethylaminosulfur trifluoride; SOCl 2 Sulfoxide 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, t-butyl hydroperoxide; MOPS:3- (N-morpholino) propanesulfonic acid; EGTA: ethylene glycol bis (2-aminoethylether) tetraacetic acid; EDTA: ethylenediamine tetraacetic acid; DTT: dithiothreitol; BSA: bovine serum albumin; MBP: myelin basic protein; DMSO: dimethyl sulfoxide; t., room temperature; O/N, overnight; reflux, reflux; stir, stirring.
Example 1: preparation of Compound I-1 (Chiisanogenin) of formula I
Chiisanoside (1910.2 mg,2.0 mmol) 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, the solid powder was separated by silica gel column chromatography, and dried to give a white solid (Chiisanogenin, C-1) 363.51mg in 75% yield. C (C) 30 H 44 O 5 .MS：[M] + 484.31969. 1 H 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 of the general formulae I-2, I-3, I-4 and I-5
Compound I-1 (484.68 mg,1.0 mmol) was dissolved in DMF (10 mL) and SOCl was added 2 (118.96 mg,1.0 mmol) was refluxed for 2 hours and concentrated. Then 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 separated by silica gel column chromatography and dried to give 305.79mg of a white powder (C-2) in a yield of 63.22%. C (C) 30 H 45 NO 4 .MS：[M] + 483.32584. 1 H 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 (484.68 mg,1.0 mmol) was dissolved in anhydrous THF (10 mL), lawesson's reagent was added and stirred at room temperature for 4 hours. Recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, and drying to obtain299.64mg to pale yellow powder (C-3) was obtained in a yield of 59.84%. C (C) 30 H 44 O 4 S.MS：[M] + 500.29626. 1 H 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 (484.68 mg,1.0 mmol) was dissolved in DMF (10 mL) and SOCl was added 2 (118.96 mg,1.0 mmol) was refluxed for 2 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography and dried to obtain 350.88mg of yellow powder (C-4) with a yield of 69.74%. C (C) 30 H 43 ClO 4 .MS：[M] + 502.27726. 1 H 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 (484.68 mg,1.0 mmol) was dissolved in DCM (10 mL), 600. Mu.L DAST solution was added, and the reaction was continued for 6 hours at-78℃and then gradually warmed to room temperature. The solvent was recovered under reduced pressure to give a solid powder, which was separated by silica gel column chromatography and dried to give 302.27mg of a white powder (C-5) in a yield of 62.13%. C (C) 30 H 43 FO 4 .MS：[M] + 486.30548. 1 H 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
Compound I-1 (484.68 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 3-dibromopropane (605.67. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 506.02mg of white powder (II-1-1) with a yield of 81.85%. C (C) 33 H 49 BrO 5 .MS：[M] + 604.27659. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-1-1 (605.65 mg,1.0 mmol) was dissolved in CAN (10 mL), imidazole (136.15 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was carried out under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 483.61mg of white powder (II-1-1-1) with a yield of 55.21%. C (C) 36 H 52 N 2 O 5 .MS：[M] + 592.38328. 1 H 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 (484.68 mg,1.0 mmol) in PA (10 mL), adding 1, 4-dibromobutane (647.73 μL,3.0 mmol), adding appropriate amount of anhydrous potassium carbonate, reflux reacting for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatographyAfter drying, 496.67mg of a white powder (II-1-2) was obtained in a yield of 80.15%. C (C) 34 H 51 BrO 5 .MS：[M] + 618.28558. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-1-2 (605.65 mg,1.0 mmol) was dissolved in CAN (10 mL), 1,2, 4-triazole (138.14 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the mixture was refluxed for 12 hours, the solvent was recovered under reduced pressure to obtain solid powder, and silica gel column chromatography was carried out to obtain 517.94mg of white powder (II-1-2-1) after drying, the yield was 71.84%. C (C) 40 H 60 N 6 O 6 .MS：[M] + 720.45587. 1 H 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
Compound I-1 (484.68 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 5-dibromopentane (689.82. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 506.02mg of white powder (II-1-3) with a yield of 79.85%. C (C) 35 H 53 BrO 5 .MS：[M] + 632.31659. 1 H NMR (300 MHz, chloride-d) delta 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). Compounds II-1 to 3(689.82 mg,1.0 mmol) was dissolved in CAN (10 mL), tryptamine (320.43 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure, a solid powder was obtained, and silica gel column chromatography was separated, and after drying, a pale yellow powder (II-1-3-1) was obtained, 464.96mg, the yield was 65.21%. C (C) 45 H 64 N 2 O 5 .MS：[M] + 712.47328. 1 H 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
Compound I-1 (484.68 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 10-dibromopentane (900.21. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 456.58mg of white powder (II-1-5) with a yield of 64.87%. C (C) 40 H 63 BrO 5 .MS：[M] + 702.38522. 1 H NMR (300 MHz, chloride-d) delta 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 (647.74 mg,1.0 mmol) was dissolved in CAN (10 mL), 5-hydroxytryptamine (352.44 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 443.13mg of pale yellow powder (II-1-5-1) with a yield of 55.45%. C (C) 50 H 74 N 2 O 6 .MS：[M] + 798.54576. 1 H 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
Compound I-2 (483.69 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 3-dibromopropane (605.67. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and silica gel column chromatography was carried out to obtain 383.36mg of white powder (II-2-1) after drying, the yield was 63.40%. C (C) 33 H 50 BrNO 4 .MS：[M] + 603.28582. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-2-1 (604.67 mg,1.0 mmol) was dissolved in CAN (10 mL), 2-ethylimidazole (226.14 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was carried out under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 320.17mg of white powder (II-2-1-1) with a yield of 51.66%. C (C) 38 H 57 N 3 O 4 .MS：[M] + 619.42336. 1 H 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
Compound I-2 (483.69 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 5-dibromopentane (689.82. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and silica gel column chromatography was carried out to obtain 381.02mg of white powder (II-2-3) after drying, the yield was 60.22%. C (C) 35 H 54 BrNO 4 .MS：[M] + 631.31889. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-2-3 (632.72 mg,1.0 mmol) was dissolved in CAN (10 mL), 4-methylimidazole (164.2 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 326.34mg of pale yellow powder (II-2-3-1) with a yield of 51.48%. C (C) 39 H 59 N 3 O 4 .MS：[M] + 633.44288. 1 H 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
Compound I-3 (500.74 mg,1.0 mmol) was dissolved in PA (10 mL) and 1, 4-di-addedBromobutane (647.73. Mu.L, 3.0 mmol) was added with an appropriate amount of anhydrous potassium carbonate, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 392.89mg of a white powder (II-3-1) with a yield of 61.80%. C (C) 34 H 51 BrO 5 .MS：[M] + 634.26775. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-3-1 (635.74 mg,1.0 mmol) was dissolved in CAN (10 mL), 7-benzyloxychromine (504.64 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 473.47mg of white powder (II-3-1-1) with a yield of 58.66%. C (C) 50 H 66 N 2 O 5 S.MS：[M] + 806.46787. 1 H 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 (500.74 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 6-dibromopentane (731.97. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 419.39mg of white powder (II-3-4) with a yield of 63.18%. C (C) 36 H 55 BrO 4 S.MS：[M] + 662.29645. 1 H NMR(300MHz,Chloroform-d)δ8.44(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). Compound II-3-4 (663.80 mg,1.0 mmol) was dissolved in CAN (10 mL), 2-methylimidazole (164.20 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 371.99mg of pale yellow powder (II-3-4-1) with a yield of 55.94%. C (C) 40 H 60 N 2 O 4 S.MS：[M] + 664.42748. 1 H 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
Compound I-4 (486.67 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 5-dibromopentane (689.82. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was refluxed for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 370.87mg of white powder (II-4-1) with a yield of 58.34%. C (C) 35 H 53 BrO 5 .MS：[M] + 634.29774. 1 H NMR (300 MHz, chloride-d) delta 5.25 (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 compound II-4-1 (635.70 mg,1.0 mmol) in CAN (10 mL), adding 5-methoxy tryptamine (380.5 mg,2.0 mmol), adding appropriate amount of anhydrous potassium carbonate, reflux reacting for 12h, recovering solvent under reduced pressure to obtain solid powderFinally, silica gel column chromatography separation and drying are carried out to obtain 414.24mg of light yellow powder (II-4-1-1) with the yield of 55.60 percent. C (C) 46 H 65 FN 2 O 5 .MS：[M] + 744.48726. 1 H 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
Compound I-5 (503.12 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 10-dibromopentane (900.21. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 435.18mg of white powder (II-5-1) with a yield of 60.25%. C (C) 40 H 62 BrClO 4 .MS：[M] + 720.34632. 1 H NMR (300 MHz, chloride-d) delta 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). Compound II-5-1 (722.29 mg,1.0 mmol) was dissolved in CAN (10 mL), 5-fluorochrome amine hydrochloride (429.34 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 469.95mg of pale yellow powder (II-5-1-1) with a yield of 57.34%. C (C) 50 H 72 ClFN 2 O 4 .MS：[M] + 819.57674. 1 H 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 Compound III-1 of formula III
Compound I-1 (484.68 mg,1.0 mmol) 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 pale yellow solid (III-1) in 63.54% yield. C (C) 30 H 46 O 6 .MS：[M] + 502.32367. 1 H 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 of the general formulae III-2, III-3, III-4 and III-5
Compound III-1 (502.69 mg,1.0 mmol) was dissolved in DMF (10 mL) and SOCl was added 2 (118.96 mg,1.0 mmol) was refluxed for 2 hours and concentrated. Then 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 separated by silica gel column chromatography and dried to give 302.08mg of pale yellow solid (III-2) in a yield of 60.33%. C (C) 30 H 48 N 2 O 4 .MS：[M] + 500.35588. 1 H 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 (502.69 mg,1.0 mmol) was dissolved in anhydrous THF (10 mL), 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 separated by silica gel column chromatography and dried to give 361.10mg of a white solid (III-3) in a yield of 67.52%. C (C) 30 H 46 O 4 S 2 .MS：[M] + 534.27437. 1 H 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 (502.69 mg,1.0 mmol) was dissolved in DMF (10 mL) and SOCl was added 2 (118.96 mg,1.0 mmol) was refluxed for 2 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography and dried to obtain 351.70mg of yellow powder (III-4) in a yield of 65.18%. C (C) 30 H 44 Cl 2 O 4 .MS：[M] + 538.25774. 1 H 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 (502.69 mg,1.0 mmol) was dissolved in DCM (10 mL), 600. Mu.L 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 separated by silica gel column chromatography, and dried to give 303.85mg of a white powder (III-5) in a yield of 59.97%. C (C) 30 H 44 F 2 O 4 .MS：[M] + 506.31589. 1 H 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 general formulae III-1-1 and III-1-1-1
Compound III-1 (502.69 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 3-dibromopropane (605. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 522.97mg of white powder (III-1-1) with a yield of 70.23%. C (C) 36 H 56 Br 2 O 6 .MS：[M] + 744.23996. 1 H NMR (300 MHz, chloroform-d) delta 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). Compound III-1-1 (744.65 mg,1.0 mmol) was dissolved in CAN (10 mL), imidazole (136.15 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 429.09mg of white powder (III-1-1-1) with a yield of 59.68%. C (C) 42 H 62 N 4 O 6 .MS：[M] + 718.46428. 1 H 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 general formulae III-1-2 and III-1-2-1
Compound III-1 (502.69 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 5-dibromopentane (689.82. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, and the reaction was refluxed for 1Recovering the solvent under reduced pressure for 2h to obtain solid powder, separating by silica gel column chromatography, and drying to obtain 534.82mg of white powder (III-1-2) with a yield of 66.79%. C (C) 40 H 64 Br 2 O 6 .MS：[M] + 800.29554. 1 H NMR (300 MHz, chloride-d) delta 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). Compound III-1-2 (744.65 mg,1.0 mmol) was dissolved in CAN (10 mL), tryptamine (320.43 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography, and dried to obtain 513.64mg of white powder (III-1-2-1) with a yield of 53.58%. C (C) 60 H 86 N 4 O 6 .MS：[M] + 958.64477。 1 H 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 general formulae III-2-1 and III-2-1-1
Compound III-2 (500.27 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 4-dibromobutane (647.73. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 481.24mg of white powder (III-2-1) with a yield of 62.44%. C (C) 38 H 62 Br 2 N 2 O 4 .MS：[M] + 770.30668. 1 H NMR(300MHz,Chloroform-d)δ6.98(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). Compound III-2-1 (744.65 mg,1.0 mmol) was dissolved in CAN (10 mL), 2-ethylimidazole (226.14 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 413.88mg of white powder (III-2-1-1) with a yield of 51.66%. C (C) 48 H 76 N 6 O 4 .MS：[M] + 800.58622. 1 H 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 general formulae III-2-2 and III-2-2-1
Compound III-2 (500.27 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 3-dibromopropane (605. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 450.29mg of white powder (III-2-2) with a yield of 60.63%. C (C) 36 H 58 Br 2 N 2 O 4 .MS：[M] + 742.26478. 1 H NMR (300 MHz, chloroform-d) delta 6.97 (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 (742.68 mg,1.0 mmol) in CAN (10 mL), adding 7-benzyloxy tryptamine (504.64 mg,2.0 mmol), adding appropriate amount of anhydrous potassium carbonate, reflux reacting for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, drying to obtain white powder (III-2-2-1) 538 51mg, yield 49.61%. C (C) 68 H 88 N 6 O 6 .MS：[M] + 1084.67728. 1 H 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 general formulae III-3-1 and III-3-1-1
Compound III-3 (534.81 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 6-dibromopentane (731.91. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 543.94mg of white powder (III-3-1) with a yield of 63.18%. C (C) 42 H 68 Br 2 O 4 S 2 .MS：[M] + 860.28755. 1 H NMR (300 MHz, chloroform-d) delta 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). Compound III-3-1 (860.93 mg,1.0 mmol) was dissolved in CAN (10 mL), 5-methoxytryptamine (380.5 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 540.67mg of white powder (III-3-1-1) with a yield of 50.08%. C (C) 64 H 94 N 4 O 6 S 2 .MS：[M] + 1078.65887. 1 H 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 general formulae III-3-2 and III-3-2-1
Compound III-3 (534.81 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 4-dibromobutane (647.73. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 519.03mg of white powder (III-3-2) with a yield of 64.49%. C (C) 38 H 60 Br 2 O 4 S 2 .MS：[M] + 804.22377. 1 H NMR (300 MHz, chloride-d) delta 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). Compound III-3-2 (804.82 mg,1.0 mmol) was dissolved in CAN (10 mL), 2-methylimidazole (164.20 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 465.36mg of white powder (III-3-2-1) with a yield of 57.65%. C (C) 46 H 70 N 4 O 4 S 2 .MS：[M] + 806.47326. 1 H 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 general formulae III-4-1 and III-4-1-1
Compound III-4 (539.58 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 10-dibromodecane (900.21. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography, and dried to obtain 491.20mg of white powder (III-4-1) with a yield of 50.23%. C (C) 50 H 82 Br 2 Cl 2 O 4 .MS：[M] + 976.38489. 1 H NMR (300 MHz, chloride-d) delta 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). Compound III-4-1 (977.91 mg,1.0 mmol) was dissolved in CAN (10 mL), 5-hydroxytryptamine (352.44 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 622.36mg of white powder (III-4-1-1) with a yield of 54.76%. C (C) 70 H 104 Cl 2 N 4 O 4 .MS：[M] + 1134.73388. 1 H 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 general formulae III-4-2 and III-4-2-1
Dissolving compound III-4 (539.58 mg,1.0 mmol) in PA (10 mL), adding 1, 6-dibromopentane (731.91 μL,3.0 mmol), adding appropriate amount of anhydrous potassium carbonate, reflux reacting for 12h, recovering solvent under reduced pressure to obtain solid powder, separating by silica gel column chromatography, drying to obtain white powder (III-4-2) 526.17mg, yield 60.78%. C (C) 42 H 66 Br 2 Cl 2 O 4 .MS：[M] + 864.26655. 1 H NMR (300 MHz, chloroform-d) delta 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). Compound III-4-2 (865.69 mg,1.0 mmol) was dissolved in CAN (10 mL), 4-methylimidazole (164.2 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, and the solid powder was separated by silica gel column chromatography and dried to obtain 456.09mg of white powder (III-4-2-1) with a yield of 52.54%. C (C) 50 H 76 Cl 2 N 4 O 4 .MS：[M] + 866.52421. 1 H 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 general formulae III-5-1 and III-5-1-1
Compound III-5 (506.67 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 10-dibromodecane (900.21. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, a solid powder was obtained, and silica gel column chromatography was separated, and 497.36mg of white powder (III-5-1) was obtained after drying, with a yield of 52.63%. C (C) 50 H 82 Br 2 F 2 O 4 .MS：[M] + 944.44665. 1 H NMR (300 MHz, chloride-d) delta 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). Will be converted intoCompound III-5-1 (860.93 mg,1.0 mmol) was dissolved in CAN (10 mL), 1,2, 4-triazole (138.14 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure to obtain a solid powder, the solid powder was separated by silica gel column chromatography, and dried to obtain 519.44mg of white powder (III-5-1-1) with a yield of 56.38%. C (C) 54 H 86 F 2 N 6 O 4 .MS：[M] + 920.66437. 1 H 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 general formulae III-5-2 and III-5-2-1
Compound III-5 (506.67 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 5-dibromopentane (689.82. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure to obtain a solid powder, which was separated by silica gel column chromatography, and dried to obtain 440.35mg of white powder (III-5-2) with a yield of 54.72%. C (C) 40 H 62 Br 2 F 2 O 4 .MS：[M] + 804.29388. 1 H NMR (300 MHz, chloride-d) delta 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 (804.74 mg,1.0 mmol) was dissolved in CAN (10 mL), 5-fluorochrome amine hydrochloride (429.34 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure to obtain a solid powder, and silica gel column chromatography was carried out to obtain 450.50mg of white powder (III-5-2-1) after drying, the yield was 45.08%. C (C) 60 H 82 F 4 N 4 O 4 .MS：[M] + 998.62467. 1 H 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 (502.69 mg,1.0 mmol) was dissolved in 80% MeOH and 6% HCl aqueous solution, followed by heat refluxing for 2 hours, and after the reaction was completed, the solvent was recovered under reduced pressure, and dried to obtain 277.22mg of pale yellow powder (IV-1) in a yield of 53.65%. C (C) 31 H 48 O 6 .MS：[M] + 516.34754. 1 H NMR (300 MHz, chloroform-d) delta 4.80 (1H), 4.75 1H), 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 (516.72 mg,1.0 mmol) was dissolved in PA (10 mL), 1, 3-dibromopropane (605. Mu.L, 3.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 418.20mg of white powder (IV-1-1) with a yield of 65.58%. C (C) 34 H 53 BrO 6 .MS：[M] + 636.29784. 1 H NMR (300 MHz, chloroform-d) delta 4.80 (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). Compound IV-1-1 (637.70 mg,1.0 mmol) was dissolved in CAN (10 mL), tryptamine (320.43 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 468.70mg of yellow powder (C-12-f) with a yield of 65.37%. C (C) 44 H 64 N 2 O 6 .MS：[M] + 716.47364. 1 H 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 (516.72 mg,1.0 mmol) was dissolved in DMF (10 mL) and SOCl was added 2 (118.96 mg,1.0 mmol) was refluxed for 2 hours and concentrated. Then 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 separated by silica gel column chromatography and dried to give 339.97mg of pale yellow solid (IV-1 a) in a yield of 65.92%. C (C) 31 H 49 NO 5 .MS：[M] + 515.35674. 1 H NMR (300 MHz, chloride-d) delta 6.52 (s, 2H), 4.80 (1H), 4.75 1H), 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). To compound IV-1a (515.74 mg,1.0 mmol) PA (10 mL) was added 1, 3-dibromopropane (605. Mu.L, 3.0 mmol), an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed under reflux for 12 hours, the solvent was recovered under reduced pressure, and a solid powder was obtained, which was separated by silica gel column chromatography and dried to obtain 388.49mg of white powder (IV-1 a-1) in a yield of 58.44%. C (C) 36 H 58 BrNO 5 .MS：[M] + 663.34755. 1 H NMR (300 MHz, chloroform-d) delta 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). By reacting compound I V-1a-1 (664.77 mg,1.0 mmol) was dissolved in CAN (10 mL), tryptamine (320.43 mg,2.0 mmol) was added, an appropriate amount of anhydrous potassium carbonate was added, the reaction was performed for 12 hours under reflux, the solvent was recovered under reduced pressure, a solid powder was obtained, and silica gel column chromatography was separated, and after drying, 389.60mg of pale yellow powder (IV-1 a-1-1) was obtained in a yield of 52.36%. C (C) 46 H 69 N 3 O 5 .MS：[M] + 774.06667. 1 H 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 shown in examples 25 and 26, giving 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.
Biological activity test:
example 27: enzyme Activity assay of derivatives
Experimental materials: protein-human CDK6/CyclinD1 protein kinase complex, CDK6, PLK1, FASN, GPX4 protein kinase (available from Sigma, abcam and Abnova corporation, respectively); substrate- [ gamma 32P ] ATP (from Perkinelme); cellulose paper (purchased from whattnan); other reagents are all analytically pure products.
The testing method comprises the following steps: the CDK6/CyclinD1 protein kinase complex, CDK6, PLK1, FASN, GPX4 inhibition activity was tested using [ gamma-32P ] ATP method, and 6. Mu.L of buffer (25 mM MOPS (pH=7.2), 2.5mM EGTA,2.5mM EDTA,0.5mM DTT,0.25mg/mL BSA,20mM beta-phosphoglycerate), 3. Mu.L of MBP solution (5.0. Mu.g/. Mu.L), 0.3. Mu.L of PLK1, FASN and GPX4 protein kinase (0.1. Mu.g/. Mu.L), 10.25. Mu.L of water were added to the reaction solution. Then 19. Mu.L of the reaction solution was taken at room temperature and rapidly added to a l.5mL EP tube.
The test substance was dissolved in DMSO to prepare a stock solution at 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 ratio of 100. Mu. Ci/. Mu.M.
Will contain 150. Mu.M ATP,30mM MgCl 2 15mM MOPS, ATP solution at pH=7.2 was added to the reaction solution at a final concentration of 100mM, reacted at 30℃for 20 minutes, quenched by the addition of 20. Mu.L of 0.5M phosphoric acid, spotted on a 20mm filter plate coated with cellulose test paper, washed three times with 0.075M phosphoric acid solution at room temperature and dried. The dried filter plates were placed in a Tri-Caxb 2800-TR liquid scintillation counter for reading. Positive control 1M DMSO was substituted for the test stock.
The inhibitory activity of the derivatives was tested by [ gamma-32P ] ATP method and the results are shown in tables 1 to 5.
TABLE 1 half inhibition concentration of derivatives on CDK6/CyclinD1 protein kinase Complex
Compounds of formula (I) IC 50 (nM) value Grade Compounds of formula (I) IC 50 (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 that: a is less than or equal to 25nM; b is more than 25nM and less than or equal to 200nM; c > 200nM
The above data illustrate: 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 a-1-3 and IV-1 b-1-1 have better inhibitory activity on CDK6/CyclinD1 protein kinase complex.
TABLE 2 half inhibition concentration of CDK6 protein kinase by derivatives
Compounds of formula (I) IC 50 (nM) value Grade Compounds of formula (I) IC 50 (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
Note that: a is less than or equal to 25nM; b is more than 25nM and less than or equal to 200nM; c > 200nM
The above data illustrate: the compounds have no better inhibiting activity on CDK6, and also indirectly indicate that the inhibiting effect of the 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 on CDK6/cyclin D1 protein kinase complex is derived from the direct effect on cyclin D1.
TABLE 3 half inhibition concentration of derivatives on PLK1 protein kinase
Compounds of formula (I) IC 50 (nM) value Grade Compounds of formula (I) IC 50 (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
Note that: a is less than or equal to 25nM; b is more than 25nM and less than or equal to 200nM; c > 200nM
The above data illustrate: 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-4-1-1, III-5-2-1, IV-1-1-1, IV-1a-1-3 and IV-1 c-1-1 have good inhibitory activity on PLK1 protein kinase.
TABLE 4 half inhibition concentration of derivatives on FASN protein kinase
Compounds of formula (I) IC 50 (nM) value Grade Compounds of formula (I) IC 50 (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
Note that: a is less than or equal to 25nM; b is more than 25nM and less than or equal to 200nM; c > 200nM
The above data illustrate: 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, IV-1 a-1-2 and IV-1a-1-3 have good inhibition activity on FASN protein kinase.
TABLE 5 half inhibition concentration of derivatives on GPX4 protein kinase
Compounds of formula (I) IC 50 (nM) value Grade Compounds of formula (I) IC 50 (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
Note that: a is less than or equal to 25nM; b is more than 25nM and less than or equal to 200nM; c > 200nM
The above data illustrate: 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-1 a-1-3 and IV-1 b-1-1 have good inhibitory activity on GPX4 protein kinase.
Conclusion: the lupin alkane 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 and IV-1 a-1-3 have remarkable inhibition effects on Cyclin D1, PLK1, FASN and GPX 4.
Example 28: pharmacokinetic testing
Animal experiment: 24 SD rats were selected for this study, and the male and female halves (7-8 weeks old, body weight 200-220 g). The cells were randomly divided into 6 groups of 4 cells. The same dose (20 mg/kg) of drug was administered intravenously or intragastrically to evaluate the pharmacokinetic properties of the test drug in its body.
Rats were fed using standard conditions and given maintenance diet at 12h day/12 h night. The test drug was formulated with 0.5% sodium carboxymethylcellulose or dimethyl sulfoxide. The same dose of the lupin derivative was injected intravenously and intragastrically, respectively. Blood is taken from tail veins at 0, 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration, the obtained blood sample is centrifuged at 5000rpm for 15 minutes at 4 ℃, and then blood plasma and red blood cells are separated, and heparin is added for freezing at-20 ℃.
The concentration of each compound in plasma was measured using LC-MS/MS. Pharmacokinetic parameters were calculated based on the blood concentration of each animal at different time points.
Conclusion: the plasma pharmacokinetics results show that each lupin derivative has better pharmacokinetics.
Preparation of the dosage form:
example 29: tablet preparation
Reagent: starch (pharmaceutical grade, tianjin, east-day fine chemical reagent plant); citric acid (Shanghai microphone Biochemical technologies Co., ltd.); magnesium stearate (Shanghai microphone Biochemical technologies Co., ltd.).
The preparation method comprises the following steps:
(1) preparation of 10% starch slurry: 0.25g of citric acid is dissolved in 25mL of pure water, 2.5g of starch is added for uniform dispersion, and the mixture is heated to gelatinize the starch, thus obtaining 10% starch slurry.
(2) Granulating: mixing the obtained lupin derivative powder with starch, adding 10% starch slurry, grinding, making soft mass, sieving with 16 mesh sieve, granulating, and drying at 50-60deg.C for 1 hr. After the 16 mesh sieve is sized, a proper amount of lubricant magnesium stearate is added, and the mixture is pressed into tablets by a shallow punch with the diameter of 10 mm.
Results: the obtained tablet has the advantages of off-white color, uniform thickness and moderate hardness. Tablet weight and disintegration time meet the requirements.
Conclusion: the tablet of the obtained lupin derivative meets the requirements and can be used as a tablet.
Example 30: preparation of suspension injection
Reagent: polylactic acid (PLA, shanghai screening quasi-biotechnology limited); polylactic-co-glycolic acid (PLGA, shanghai-derived biotechnology limited); poloxamer 188 (sienna n pharmaceutical excipients limited); dichloromethane, methanol, acetonitrile, etc. (Tianjin Tiantai chemical Co., ltd.).
The preparation method comprises the following steps:
(1) preparation of polymer microparticles: weighing a proper amount of the split ring lupin alkane derivative and a carrier (PLA/PLGA), placing the split ring lupin alkane derivative and the carrier into a 50mL round bottom flask, adding 5mL of dichloromethane for dissolution, distilling at 28 ℃ under reduced pressure to remove most of the organic solvent, drying at 40 ℃ in vacuum for 24 hours until the solvent is completely removed, crushing, and sieving with a screen with the pore diameter of 150 mu m to obtain the polymer particles of the split ring lupin alkane derivative.
(2) Preparing a suspension injection of the lupin derivative of the split ring: 2.5g of the above product was dispersed in 250mL of an aqueous solution containing 10g/L poloxamer 188 stabilizer with continuous stirring to complete the dispersion. Grinding the medicinal dispersion liquid to desired particle diameter, and taking out to obtain polymer microparticle suspension of lupin derivative, 3 000r.min -1 Centrifuge for 1min and disperse with 10mL of aqueous stabilizer to concentrate the formulation to about 25g/L.
Results: the obtained suspension injection has uniform particle size, and the water content and the surface particle size of the preparation meet the regulations. The in vitro slow release effect is better, and the stability is better.
Conclusion: the suspension injection prepared from the obtained lupin derivative meets the requirements, and can be used as a suspension injection.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims (8)

1. A split ring lupin alkane derivative, which is characterized by being shown in a general formula I:
wherein R is a Selected from: -NH 2 、-SH、-F、-Cl。
2. A lupin alkane derivative, which is characterized by being shown in a general formula II:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
3. a split ring lupin alkane derivative, which is characterized by being shown in a general formula III:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
4. a lupin alkane derivative, which is characterized by being shown in a general formula IV:
wherein X is selected from: - (CH) 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 10 -；
R a Selected from: -OH, -NH 2 、-SH、-F、-Cl；
R b Selected from:
R c selected from: C1-C9 alkaneA base.
5. A pharmaceutically acceptable salt of a lupin alkane derivative according to any one of claims 1 to 4.
6. A pharmaceutical composition comprising a split ring lupin alkane derivative according to any one of claims 1-4 or a pharmaceutically acceptable salt of the split ring lupin alkane derivative according to claim 5, a pharmaceutically acceptable excipient and a carrier.
7. Use of a split-ring lupin alkane derivative according to any one of claims 1-4, a pharmaceutically acceptable salt of a split-ring lupin alkane derivative according to claim 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the prevention or treatment of a related disease mediated by Cyclin D1, PLK1, FASN and GPX 4.
8. The use according to claim 7, wherein: the related diseases mediated by Cyclin D1, PLK1, FASN and GPX4 include tumor, obesity, diabetes, nervous system diseases, cardiovascular diseases, acute kidney injury and autoimmune diseases.
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