Gamma-carboline ketone derivatives, methods of synthesis and use thereof

Abstract

The application provides a gamma-carboline ketone derivative and a synthesis method and application thereof. The synthesis method of the gamma-carboline ketone derivative provided by the application comprises the following steps: step 1: reacting a compound (1), a compound (2), a compound (3) and a compound (4) in an organic solvent to obtain a compound (5); step 2: dissolving the compound (5) with a solvent, then adding an acid, and reacting under microwave conditions to obtain a gamma-carboline ketone derivative (6); and a reaction formula is as follows. The synthesis method of the gamma-carboline ketone derivative provided by the application has the advantages of simple and efficient operation process, low cost, high yield, no need of metal catalysis, wide substrate application range and the like. The gamma-carboline ketone derivative prepared by the application has antitumor activity and can be used for preparing antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a γ-carboline ketone derivative, its synthesis method, and its applications. Background Technology

[0002] Carboline ketone skeletons are widely found in the molecular structures of natural products and drugs. Compounds containing γ-carboline ketone skeletons have attracted widespread attention due to their good biological activities, such as 5-HT3 receptor antagonists and topoisomerase I inhibitors.

[0003]

[0004] Traditional methods for synthesizing γ-carboxylinone compounds often employ intramolecular cyclization reactions. For example, Clark's group reported a method using N,2-dimethylindole-3-carboxamide reacted with n-butyllithium and DMF, followed by dehydroxylation with hydrochloric acid to obtain γ-carboxylinone derivatives. Fresneda's group used ylide reagent and aldehydes as starting materials in an eight-step reaction to obtain 3-(2-azidophenyl)-substituted quinolinones, which were then heated to 150°C in o-xylene to obtain γ-carboxylinone derivatives. Chen's group developed a method using 4-hydroxyquinolinone as a starting material, reacting it with hydrazine to obtain 4-hydrazinoquinolinone, then reacting it with cyclohexanone to prepare a hydrazone, and finally synthesizing γ-carboxylinone compounds under Pd / C conditions. In addition, Beccalli's group reported a method for synthesizing γ-carboxylinone compounds based on an intramolecular Heck reaction. These methods all require long synthetic steps and have high reaction costs.

[0005] In recent years, transition metal-catalyzed C-H bond activation reactions have gradually become an important route for the synthesis and modification of complex molecules, and therefore have wide applications in biomedicine, materials science, pharmacy, and other industries. Based on this method, Li's research group developed a palladium-catalyzed intramolecular double-C (sp) bond activation reaction of indole-2-carboxamide. 2 Methods for preparing γ-carboxylinone have been developed using 1,2-acyl migration reactions and activation with α-H groups. The Yao & Lin group reported a palladium-catalyzed method for synthesizing γ-carboxylinone compounds from indole-3-carboxamide via a two-stage C-H bond activation reaction with iodobenzene. Furthermore, the Jiao group reported a palladium-catalyzed method for preparing γ-carboxylinone from indole-3-carboxamide via a [4+2] cycloaddition reaction with alkyne. Subsequently, the Zhang group developed a copper-catalyzed method for preparing γ-carboxylinone compounds via a [4+2] cyclization reaction of indole-3-carboxamide with benzyne. All these methods require the noble metal palladium or a large amount of copper as a catalyst, highlighting the growing interest in developing inexpensive metal-catalyzed methods for synthesizing γ-carboxylinone.

[0006] Recently, Liu & Zeng's research group developed a method for preparing γ-carbazone by indole-3-carboxamide and alkynes via a [4+2] cycloaddition reaction catalyzed by inexpensive cobalt and assisted by bidentate ligands. They also found that salicylaldehyde can promote the reaction when used as a ligand.

[0007] In summary, the synthesis of compounds containing the γ-carbolineone skeleton has attracted widespread attention from chemists, and numerous methods for synthesizing these compounds have been disclosed in the existing technology. However, existing methods suffer from problems such as lengthy synthesis steps, high synthesis costs, or the need for the use of precious metals or metal catalysis. Using metal catalysis to prepare drug-active compounds can easily lead to metal contamination and purification difficulties, posing potential risks to the drugs. Therefore, it is necessary to develop novel, efficient, and metal-catalyzed methods for synthesizing γ-carbolineone compounds, and to provide more novel γ-carbolineone compounds to facilitate the development of more drug molecules containing the γ-carbolineone skeleton. Summary of the Invention

[0008] Therefore, the purpose of this invention is to provide a novel and efficient method for synthesizing γ-carboline ketone derivatives.

[0009] To achieve the above-mentioned objectives, the present invention includes the following technical solutions.

[0010] A method for synthesizing γ-carbolinone derivatives includes the following steps:

[0011] Step 1: React compounds (1), (2), (3) and (4) in an organic solvent to obtain compound (5);

[0012] Step 2: Dissolve the compound (5) in a solvent, add acid, and react under microwave conditions to obtain a γ-carboline ketone derivative;

[0013] The reaction formula is as follows:

[0014]

[0015] Wherein, R1 is selected from: R5-substituted or unsubstituted C1-C8 alkyl, R5-substituted or unsubstituted C3-C8 cycloalkyl, R6-substituted or unsubstituted C6-C 10 Aryl;

[0016] R2 is selected from: hydrogen, halogen, C1-C6 alkoxy group;

[0017] R3 is selected from: C6-C with or without R6 substitution. 10 Aryl;

[0018] R4 is selected from: R5 substituted or unsubstituted C1-C8 alkyl groups;

[0019] Each R5 is independently selected from: hydrogen, halogen, R6-substituted or unsubstituted C6-C. 10 Aryl;

[0020] Each R6 is independently selected from: hydrogen, halogen, and C1-C3 alkoxy groups.

[0021] In some embodiments, R1 is selected from: R5-substituted or unsubstituted C1-C4 alkyl groups, R5-substituted or unsubstituted C5-C6 cycloalkyl groups, and R6-substituted or unsubstituted C6-C4 cycloalkyl groups. 10 Aryl.

[0022] In some of these embodiments, R1 is selected from: C1-C4 alkyl, R5-substituted C1-C2 alkyl, C5-C6 cycloalkyl, R6-substituted or unsubstituted phenyl.

[0023] In some of these embodiments, R1 is selected from: C1-C4 alkyl, phenyl-substituted C1-C2 alkyl, methoxy-substituted benzyl, C5-C6 cycloalkyl, phenyl, and halogen-substituted phenyl.

[0024] In some of these embodiments, R1 is selected from: isobutyl, phenethyl, benzyl, 4-methoxybenzyl, cyclohexyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-dichlorophenyl.

[0025] In some of these embodiments, R2 is selected from hydrogen, halogen, and C1-C3 alkoxy groups.

[0026] In some of these embodiments, R2 is selected from hydrogen, bromine, chlorine, and methoxy.

[0027] In some of these embodiments, R3 is a phenyl group.

[0028] In some of these embodiments, R4 is selected from: R5-substituted or unsubstituted C1-C4 alkyl groups.

[0029] In some of these embodiments, R4 is selected from: C1-C4 alkyl, phenyl-substituted C1-C2 alkyl.

[0030] In some of these embodiments, R4 is selected from tert-butyl and benzyl.

[0031] In some embodiments, the γ-carbolineone derivative is selected from the following compounds:

[0032]

[0033] In some embodiments, the molar ratio of compound (1), compound (2), compound (3) and compound (4) is 1:0.8-1.2:0.8-1.2:0.8-1.2.

[0034] In some embodiments, the organic solvent in step 1 is selected from at least one of methanol, ethanol, trifluoroethanol, isopropanol, acetonitrile, DMF, and dichloromethane.

[0035] In some embodiments, the temperature of the reaction in step 1 is 20°C-30°C, and the reaction time is 6 hours-18 hours.

[0036] In some embodiments, the reaction time in step 1 is 8 to 16 hours.

[0037] In some embodiments, the reaction time in step 1 is 10-14 hours.

[0038] In some embodiments, the reaction time in step 1 is 11 to 13 hours.

[0039] In some embodiments, the solvent in step 2 is selected from at least one of dichloroethane (DCE), dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, toluene, and methanol.

[0040] In some embodiments, the solvent in step 2 is at least one of dichloroethane, dichloromethane, tetrahydrofuran, and acetonitrile.

[0041] In some embodiments, the solvent in step 2 is tetrahydrofuran or acetonitrile.

[0042] In some embodiments, the acid in step 2 is selected from at least one of trifluoroacetic acid (TFA), p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0043] In some embodiments, the acid in step 2 is p-toluenesulfonic acid.

[0044] In some embodiments, the reaction in step 2 is carried out in a microwave reactor at a temperature of 60°C-110°C.

[0045] In some embodiments, the reaction in step 2 is carried out in a microwave reactor at a temperature of 70°C-110°C.

[0046] In some embodiments, the reaction described in step 2 is carried out in a microwave reactor at a temperature of 80°C-105°C.

[0047] In some embodiments, the reaction described in step 2 is carried out in a microwave reactor at a temperature of 95°C-105°C.

[0048] In some embodiments, the reaction time in step 2 is 5 min to 30 min.

[0049] In some embodiments, the reaction time in step 2 is 8 min to 15 min.

[0050] The present invention provides applications of the γ-carbolinone derivative, including the following technical solutions.

[0051] The use of the above-mentioned γ-carboline ketone derivatives or their pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of tumors.

[0052] In some embodiments, the tumor is: lung cancer, prostate cancer, or colon cancer.

[0053] The present invention also provides a pharmaceutical composition for the prevention and / or treatment of tumors, comprising the following technical solutions.

[0054] A pharmaceutical composition for the prevention and / or treatment of tumors, prepared from an active ingredient and pharmaceutically acceptable excipients, said active ingredient including the above-described γ-carbolineone derivatives or their pharmaceutically acceptable salts.

[0055] This invention uses indole-3-carboxaldehyde, amines, benzoylcarboxylic acid, and isonitriles as raw materials to prepare a series of γ-carboxylinone derivatives via a Ugi reaction and a one-pot microwave cyclization reaction under acidic conditions. The synthetic method for γ-carboxylinone derivatives provided by this invention has advantages such as simple and efficient operation, low cost, high yield, no need for metal catalysis, and wide substrate applicability.

[0056] In addition, the γ-carboline ketone derivatives prepared in this invention have anti-tumor activity. The test results of their in vitro tumor cell inhibitory activity show that these compounds have inhibitory effects on tumor cells such as lung cancer, prostate cancer, and colon cancer, and can be used to prepare anti-tumor drugs. Detailed Implementation

[0057] Unless otherwise specified, the experimental methods described in the following embodiments of the present invention are generally performed under conventional conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the embodiments are commercially available products.

[0058] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0059] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0060] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0061] In one embodiment of the present invention, a method for synthesizing γ-carbolineone derivatives is provided, comprising the following steps:

[0062] Step 1: React compounds (1), (2), (3) and (4) in an organic solvent to obtain compound (5);

[0063] Step 2: Dissolve the compound (5) in a solvent, add acid, and react under microwave conditions to obtain a γ-carboline ketone derivative;

[0064] The reaction formula is as follows:

[0065]

[0066] Wherein, R1 is selected from: R5-substituted or unsubstituted C1-C8 alkyl, R5-substituted or unsubstituted C3-C8 cycloalkyl, R6-substituted or unsubstituted C6-C 10 Aryl;

[0067] R2 is selected from: hydrogen, halogen, C1-C6 alkoxy group;

[0068] R3 is selected from: C6-C with or without R6 substitution. 10 Aryl;

[0069] R4 is selected from: R5 substituted or unsubstituted C1-C8 alkyl groups;

[0070] Each R5 is independently selected from: hydrogen, halogen, R6-substituted or unsubstituted C6-C. 10 Aryl;

[0071] Each R6 is independently selected from: hydrogen, halogen, and C1-C3 alkoxy groups.

[0072] In the compounds of this invention, when any variable appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. A line drawn from a substituent into the ring system indicates that the bond referred to can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It will be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms, as long as structural stability is achieved.

[0073] As used in this invention, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. Specifically, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0074] The term “substituted” as used in this article refers to the replacement of a hydrogen group in a specific structure with a group of a specified substituent.

[0075] As will be understood by those skilled in the art, the term “halo” or “halogen” as used herein refers to chlorine, fluorine, bromine, and iodine.

[0076] In another embodiment of the present invention, a compound having the structure shown in formula (6) and its pharmaceutically acceptable salts are provided for treating tumor diseases in humans or other mammals; wherein the tumor may be a lung cancer, prostate cancer, colon cancer, or other tumors.

[0077] In another embodiment of the invention, the invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and a pharmaceutically acceptable carrier or excipient.

[0078] The “active ingredient” referred to in this invention refers to the compound of formula (6) or its pharmaceutically acceptable salt.

[0079] The "active ingredient" and pharmaceutical composition described in this invention can be used to prepare drugs for the prevention and / or treatment of tumors.

[0080] "Safe and effective dose" means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0081] "Pharmaceutically acceptable carriers or excipients" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0082] "Compatibility" here refers to the ability of the components in the composition to interact with and blend with the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

[0083] Pharmaceutically acceptable examples of carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers. Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0084] In another preferred embodiment, the compound of formula (6) of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula (6) of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through chemical bonds. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0085] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0086] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0087] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components:

[0088] (a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

[0089] (b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0090] (c) Moisturizers, such as glycerin;

[0091] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

[0092] (e) Slow solvents, such as paraffin;

[0093] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0094] (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0095] (h) Adsorbents, such as kaolin; and

[0096] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0097] The solid dosage form can also be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient from this composition can be delayed in a portion of the digestive tract. Examples of suitable encapsulating components are polymers and waxes.

[0098] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0099] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0100] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0101] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0103] All reagents used in the following examples are commercially available.

[0104] In the following examples, room temperature refers to an indoor temperature of 25±5℃.

[0105] The microwave reactor used in the following examples is the BiotageInitiator+ microwave synthesizer from Biotage Trading (Shanghai) Co., Ltd.

[0106] The specific synthetic routes of the γ-carboline ketone derivatives in the following examples are as follows:

[0107]

[0108] Wherein, R1 is selected from: R5-substituted or unsubstituted C1-C8 alkyl, R5-substituted or unsubstituted C3-C8 cycloalkyl, R6-substituted or unsubstituted C6-C 10 Aryl;

[0109] R2 is selected from: hydrogen, halogen, C1-C6 alkoxy group;

[0110] R3 is selected from: C6-C with or without R6 substitution. 10 Aryl;

[0111] R4 is selected from: R5 substituted or unsubstituted C1-C8 alkyl groups;

[0112] Each R5 is independently selected from: hydrogen, halogen, R6-substituted or unsubstituted C6-C. 10 Aryl;

[0113] Each R6 is independently selected from: hydrogen, halogen, and C1-C3 alkoxy groups.

[0114] Example 1: Synthesis of N-tert-butyl-3-oxo-2,4-diphenyl-3,5-2H-pyrido[4,3-b]indole-1-carboxamide

[0115]

[0116] Step (1): In a 5 mL reaction tube, p-indole-3-carboxaldehyde (1.0 mmol) and aniline (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and tert-butylisocyanate (1.0 mmol) were added to the solution in sequence. The reaction solution was stirred at room temperature for 12 hours. Then, thin-layer chromatography was used for detection. After the reaction was completed, the solvent was removed by vacuum rotary evaporation. The residue was separated by silica gel column chromatography to obtain compound 5 with a yield of 78%.

[0117] Step (2): Compound 5 was dissolved in 5.0 mL of solvent, and then acid (1.0 mmol) was added. The reaction was carried out in a microwave reactor. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), and then washed once each with 20 mL of saturated sodium bicarbonate solution and saturated brine solution. The organic phase was dried with anhydrous sodium sulfate and then separated by silica gel column chromatography to obtain the target compound N-tert-butyl-3-oxo-2,4-2phenyl-3,5-2H-pyrido[4,3-b]indole-1-carboxamide.

[0118] 1 H NMR (400MHz, DMSO) δ10.84(s,1H),8.56(s,1H),7.69-7.56(m,3H),7.46(m,5H),7.39-7.17(m,5H),7.12-7.04(m,1H),1.04(s,9H). 13 C NMR (101MHz, DMSO) δ160.85,160.24,148.08,143.36,139.09,138.96,134.89,130.53,130.08, 128.73,127.26,121.64,120.83,120.57,111.65,106.66,104.38,51.49,28.18.HRMS(ESI)m / z calcd forC 28 H 26 N3O2 + (M+H) + 436.2020, found 436.2016.

[0119] The solvent, acid, reaction temperature, time, and yield in step (2) are shown in Table 1.

[0120] Table 1

[0121]

[0122]

[0123] Example 2: Synthesis of N-tert-butyl-2-(4-chlorophenyl)-3-oxo-4-phenyl-3,5-2H-pyrido[4,3-b]indole-1-carboxamide

[0124]

[0125] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and p-chloroaniline (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and tert-butylisocyanate (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated saline solution, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-tert-butyl-2-(4-chlorophenyl)-3-oxo-4-phenyl-3,5-2H-pyrido[4,3-b]indole-1-carboxamide in 57% yield.

[0126] 1 H NMR(400MHz,DMSO)δ10.84(s,1H),8.60(s,1H),7.65-7.54(m,5H),7.49(t, J=7.6Hz,3H),7.40-7.26(m,4H),7.10(dt,J=8.0,4.1Hz,1H),1.09(s,9H). 13 C NMR (101MHz, DMSO) δ160.73,160.09,148.15,143.38,138.61,137.93,134.70,133.48,131.91,130 .50,128.75,127.35,121.49,120.91,120.57,111.68,106.86,104.39,51.58,28.14.HRMS(ESI)m / z calcd for C 28 H 25 ClN3O2 + (M+H) + 470.1630, found 470.1618.

[0127] Example 3 Synthesis of 2-(4-bromophenyl)-N-tert-butyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0128]

[0129] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and p-bromoaniline (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and tert-butylisocyanate (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated saline solution, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound 2-(4-bromophenyl)-N-tert-butyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide in 64% yield.

[0130] 1 H NMR (400MHz, DMSO) δ10.85(s,1H),8.60(s,1H),7.71(d,J=8.0Hz,2H),7.61(t,J=8.2Hz, 3H),7.49(t,J=7.6Hz,2H),7.34(dt,J=12.9,8.3Hz,5H),7.13-7.06(m,1H),1.09(s,9H). 13 C NMR (101MHz, DMSO) δ160.72,160.04,148.16,143.38,138.38,134.70,132.25,131.83,130.50,128.75,127 .39,123.93,121.95,121.49,120.91,120.58,112.89,111.68,106.88,104.40,51.58,28.14.HRMS(ESI)m / z calcd for C 28 H 25 BrN3O2 + (M+H) + 514.1125, found 514.1132.

[0131] Example 4: Synthesis of N-tert-butyl-8-methoxy-3-oxo-2,4-diphenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0132]

[0133] In a 5 mL reaction tube, 1.0 mmol of 5-methoxyindole-3-carboxaldehyde and 1.0 mmol of aniline were dissolved in 2.0 mL of methanol. Then, 1.0 mmol of benzoylformic acid and 1.0 mmol of tert-butylisocyanate were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and the reaction was detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under vacuum. The solution was then dissolved in 5.0 mL of acetonitrile, and p-toluenesulfonic acid (1.0 mmol) was added. The reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with 15 mL of ethyl acetate, washed once with 20 mL of saturated sodium bicarbonate aqueous solution, and twice with saturated saline solution. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-tert-butyl-8-methoxy-3-oxo-2,4-diphenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide, with a yield of 78%.

[0134] 1 H NMR (400MHz, DMSO) δ10.63(s,1H),8.56(s,1H),7.59(d,J=7.2Hz,2H),7.55-7.39(m,6H),7.39-7.26(m, 2H),7.22(d,J=8.5Hz,1H),7.16(d,J=5.6Hz,1H),6.94(dd,J=8.6,1.3Hz,1H),3.72(s,3H),1.05(s,9H). 13 C NMR (101MHz, DMSO) δ160.80,160.08,154.39,148.51,139.08,137.64,134.99,130.46,128.69 ,127.15,122.31,114.65,112.15,106.75,104.88,103.95,55.92,51.49,28.14.HRMS(ESI)m / z calcd for C 29 H 28 N3O3 + (M+H) + 466.2125, found 466.2112.

[0135] Example 5: Synthesis of N-tert-butyl-8-methoxy-3-oxo-2-phenylethyl-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0136]

[0137] In a 5 mL reaction tube, 1.0 mmol of 5-methoxyindole-3-carboxaldehyde and 1.0 mmol of phenethylamine were dissolved in 2.0 mL of methanol. Then, 1.0 mmol of benzoylformic acid and 1.0 mmol of tert-butylisocyanate were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, followed by detection using thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under vacuum. The solution was then dissolved in 5.0 mL of acetonitrile, and 1.0 mmol of p-toluenesulfonic acid was added. The reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with 15 mL of ethyl acetate, washed once with 20 mL of saturated sodium bicarbonate aqueous solution, and twice with saturated brine. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-tert-butyl-8-methoxy-3-oxo-2-phenylethyl-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide in 73% yield.

[0138] 1 H NMR (400MHz, DMSO) δ10.57(s,1H),9.11(s,1H),7.62-7.56(m,2H),7.50(t,J=7.2Hz,2H),7.36(t,J=7.9Hz,3H),7.30-7.24(m,3H),7.21(dd,J =5.3,3.2Hz,2H),6.97-6.92(m,1H),4.32(dt,J=12.5,7.6Hz,1H),4.0 7(dt,J=12.3,7.3Hz,1H),3.77(s,3H),3.10-3.00(m,2H),1.51(s,9H). 13 C NMR (101MHz, DMSO) δ161.95,159.32,154.38,147.95,139.09,138.84,137.42,135.14,130.51,129.12,128.88,128.68,1 27.15,127.00,122.22,114.49,112.11,106.69,104.85,104.05,56.11,52.28,48.10,35.71,28.66.HRMS(ESI)m / zcalcd for C 31 H 32 N3O3+ (M+H) + 494.2438, found 494.2436.

[0139] Example 6 Synthesis of 8-bromo-N-tert-butyl-2-(4-chlorophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0140]

[0141] In a 5 mL reaction tube, 1.0 mmol of 6-bromoindole-3-carboxaldehyde and 1.0 mmol of p-chloroaniline were dissolved in 2.0 mL of methanol. Then, 1.0 mmol of benzoylformic acid and 1.0 mmol of tert-butylisocyanate were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, followed by detection using thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under vacuum. The solution was then dissolved in 5.0 mL of acetonitrile, and 1.0 mmol of p-toluenesulfonic acid was added. The reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with 15 mL of ethyl acetate, washed once with 20 mL of saturated sodium bicarbonate aqueous solution, and twice with 20 mL of saturated saline solution each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound 8-bromo-N-tert-butyl-2-(4-chlorophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide in 46% yield.

[0142] 1 H NMR (400MHz, DMSO) δ11.00 (s, 1H), 8.70 (s, 1H), 7.72 (d, J = 1.6Hz, 1H), 7.59 (m ,4H),7.48(m,4H),7.37(t,J=7.4Hz,2H),7.26(d,J=8.5Hz,1H),1.11(s,9H). 13 C NMR (101MHz, DMSO) δ160.39,160.12,148.16,142.39,139.25,137.65,134.36,133.65,131.76,130.44, 129.76,128.82,127.51,123.67,122.89,113.54,112.59,105.76,104.74,51.71,28.06.HRMS(ESI)m / z calcd for C 28 H 24 BrClN3O2 + (M+H) +548.0735, found 548.0740.

[0143] Example 7 Synthesis of N-benzyl-2-(4-bromophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0144]

[0145] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and p-bromoaniline (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and benzylisocyanate (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated saline solution, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-benzyl-2-(4-bromophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide in 58% yield.

[0146] 1 H NMR (400MHz, DMSO) δ10.88(s,1H),9.57(t,J=5.9Hz,1H),7.68-7.54(m,4H),7.48(t,J=7.6Hz ,2H),7.38(t,J=7.4Hz,2H),7.32-7.23(m,7H),7.03-6.98(m,1H),6.88(s,2H),4.39(s,2H). 13 C NMR (101MHz, DMSO) δ161.60,160.07,148.04,143.48,138.12,137.83,134.55,132.15,131.97,130.52,128.75,1 28.61,127.91,127.56,127.46,,122.23,121.19,120.94,120.80,111.66,107.40,104.60,42.91.HRMS(ESI)m / z calcd forC 31 H 23 BrN3O2 + (M+H) + 548.0968, found 548.0962.

[0147] Example 8: Synthesis of N-benzyl-3-oxo-2-phenylethyl-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0148]

[0149] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and phenethylamine (1.0 mmol) were dissolved in 2.0 mL of methanol. Benzoylcarboxylic acid (1.0 mmol) and benzylisocyanate (1.0 mmol) were then added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, followed by detection by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under vacuum. The solution was then dissolved in 5.0 mL of acetonitrile, and p-toluenesulfonic acid (1.0 mmol) was added. The reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), washed once with saturated sodium bicarbonate aqueous solution, and twice with saturated brine (20 mL each time). The organic phase was dried over anhydrous sodium sulfate and separated using a silica gel column to obtain the target compound N-benzyl-3-oxo-2-phenylethyl-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide, in 52% yield.

[0150] 1 H NMR (400MHz, DMSO) δ10.51(s,1H),9.17(s,1H),7.42-7.25(m,10H),7.20(t,J=7.3Hz,1H),7.10(t,J=7.7Hz,2H),7.00(d,J=2.6Hz,1H),6 .97-6.90(m,1H),6.67(d,J=7.6Hz,2H),6.55(t,J=3.8Hz,2H),4.74(d,J=15.0Hz,1H),4.17(m,2H),3.52-3.41(m,1H),3.17-2.98(m,2H). 13 C NMR (101MHz, DMSO) δ173.44,167.65,150.54,139.58,139.01,136.74,129.80,129.31,129.18,129.14,128 .30,128.16,128.00,127.11,126.57,126.34,125.33,117.79,110.42,63.30,42.54,32.70.HRMS(ESI)m / z calcd for C 33 H 28 N3O2 + (M+H)+ 498.2176, found 498.2173.

[0151] Example 9: Synthesis of N-benzyl-2-cyclohexyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0152]

[0153] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and cyclohexylamine (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and benzyl isonitrile (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the mixture was reacted in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated saline solution, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-benzyl-2-cyclohexyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide, with a yield of 63%.

[0154] 1 H NMR (400MHz, DMSO) δ11.20(s,1H),9.19(s,1H),8.08-8.01(m,2H),7.96(d,J=7.8Hz,1H),7.56- 7.48(m,2H),7.44-7.25(m,5H),7.13-7.06(m,2H),7.04-6.97(m,3H),4.26(d,J=15.1Hz,1H),3. 98(d,J=15.1Hz,1H),3.44(t,J=11.5Hz,1H),2.03-1.89(m,1H),1.52(d,J=10.8Hz,3H),1.45-1 .34(m,2H),1.29(d,J=10.2Hz,1H),1.05(dd,J=17.4,7.7Hz,1H),0.87(dt,J=16.1,13.0Hz,2H). 13C NMR (101MHz, DMSO) δ164.69,163.91,148.37,141.38,137.30,134.01,127.72,127.58,126.81,126.63,12 5.72,125.59,125.25,124.16,122.11,119.66,114.22,58.07,46.13,28.53,24.95,24.79.HRMS(ESI)m / z calcdfor C 31 H 30 N3O2 + (M+H) + 476.2333, found 476.2328.

[0155] Example 10 Synthesis of N-benzyl-2-isobutyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0156]

[0157] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and isobutylamine (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and benzylisocyanate (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the mixture was reacted in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated saline solution, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-benzyl-2-isobutyl-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide, with a yield of 61%.

[0158] 1H NMR (400MHz, DMSO) δ10.78(s,1H),9.18(s,1H),7.37(t,J=7.2Hz,2H),7.32(d,J=7.0Hz,1H),7.27 (d,J=5.4Hz,5H),7.02(dd,J=8.0,4.4Hz,3H),6.94(t,J=7.4Hz,1H),6.63-6.49(m,2H),6.19(t,J =7.3Hz,1H),4.70(d,J=14.9Hz,1H),4.17(d,J=15.0Hz,1H),3.43(dd,J=13.3,7.0Hz,1H),3.23(d d,J=13.3,7.5Hz,1H),2.17(dt,J=13.5,6.7Hz,1H),0.94(d,J=6.5Hz,3H),0.86(d,J=6.6Hz,3H). 13 C NMR (101MHz, DMSO) δ162.75,160.80,150.56,140.01,136.56,129.79,129.12,128.50,128.31,128.22,1 27.99,126.71,126.53,125.40,117.81,110.45,49.94,42.42,26.90,21.14,21.00.HRMS(ESI)m / zcalcd for C 29 H 28 N3O2 + (M+H) + 450.2176, found 450.2168.

[0159] Example 11 Synthesis of N-benzyl-2-(4-methoxybenzyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0160]

[0161] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and p-methoxybenzylamine (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and benzyl isonitrile (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the mixture was reacted in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated brine, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, separation was performed using a silica gel column to obtain the target compound N-benzyl-2-(4-methoxybenzyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide in 53% yield.

[0162] 1 H NMR (400MHz, DMSO) δ10.45 (s, 1H), 8.61 (s, 1H), 7.61 (d, J = 6.8Hz, 3H), 7.54-7.43 (m, 4H) ,7.27(m,9H),6.87(d,J=8.6Hz,2H),4.36-4.20(m,2H),3.79(s,3H),3.12-3.00(m,2H). 13 C NMR (101MHz, DMSO) δ159.99,157.00,154.44,152.57,148.01,138.97,137.14,135.46,134.83,134.36,133.29,132.66,132.03,131 .43,130.46,129.25,128.97,128.55,127.72,126.88,123.20,114.07,112.00,110.28,103.99,55.96,51.78,35.75.HRMS(ESI)m / z calcd for C 33 H 28 N3O2 + (M+H) + 514.2125, found 514.2121.

[0163] Example 1: Synthesis of 2N-benzyl-2-(2,4-dichlorophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide

[0164]

[0165] In a 5 mL reaction tube, indole-3-carboxaldehyde (1.0 mmol) and 2,4-dichloroaniline (1.0 mmol) were first dissolved in 2.0 mL of methanol. Then, benzoylformic acid (1.0 mmol) and benzylisocyanate (1.0 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 12 hours, and then detected by thin-layer chromatography. After the reaction was complete, the solvent was removed by vacuum rotary evaporation, and then dissolved in 5.0 mL of acetonitrile. Then, p-toluenesulfonic acid (1.0 mmol) was added, and the reaction was carried out in a microwave reactor at 100 °C for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL), then washed once with saturated sodium bicarbonate aqueous solution and twice with saturated brine, 20 mL each time. After drying the organic phase with anhydrous sodium sulfate, the phase was separated by silica gel column chromatography to obtain the target compound N-benzyl-2-(2,4-dichlorophenyl)-3-oxo-4-phenyl-3,5-dihydropyrido[4,3-b]indole-1-carboxamide, with a yield of 57%.

[0166] 1 H NMR (400MHz, DMSO) δ10.54(s,1H),8.98(s,1H),7.78(d,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),7.48-7.26(m, 6H),7.18-6.93(m,5H),6.84(s,1H),6.59(d,J=7.6Hz,1H),4.64(d,J=15.2Hz,1H),4.14(d,J=15.2Hz,1H). 13 CNMR(101MHz,DMSO)δ173.45,167.46,150.76,139.45,136.60,135.35,131.17,130.09,129.13,128.60,128.4 7,127.92,126.87,126.72,126.58,124.46,117.78,110.50,82.73,75.92,63.63,61.14,42.18.HRMS(ESI)m / z calcd for C 31 H 22 Cl2N3O2 + (M+H) + 538.1084, found 538.1082.

[0167] Example 13 Antitumor Activity Test

[0168] The cells used in the anti-tumor test in this embodiment were lung cancer cells A549, prostate cancer cells DU145, and colon cancer cells HCT116.

[0169] The cells were cultured in DMEM medium containing fetal bovine serum and penicillin-streptomycin solution, and cultured under constant temperature conditions of 37°C in a 5% CO2 incubator. The specific steps are as follows:

[0170] (1) After counting the cells using a hemocytometer, dilute them to 5 × 10⁻⁶ using DMEM low glucose culture medium. 4 cells / mL;

[0171] (2) Add 100 μL of cell suspension to each well of a 96-well plate, mix well by pipetting, and incubate at 37°C for 24 h.

[0172] (3) Dilute the compound to be tested to a concentration of 10 μM, add the drug sequentially according to this concentration, and incubate at 37°C for 48 h.

[0173] (4) Add MTT at a concentration of 5 mg / mL and incubate at 37°C for 4 hours;

[0174] (5) Add DMSO to dissolve the cells, and measure the OD values ​​at 490nm and 630nm using an enzyme-linked immunosorbent assay reader;

[0175] (6) Process the data and calculate the inhibition rate based on the OD value. The results are shown in Table 2.

[0176] Table 2. Antitumor activity results of γ-carbolinone derivatives (inhibition rate %)

[0177]

[0178] The test results show that the γ-carboline ketone derivative of the present invention can effectively inhibit the proliferation of tumor cells and has anti-tumor activity. It can be used to prepare drugs for treating tumors such as lung cancer, prostate cancer and colon cancer.

[0179] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0180] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A γ-carbazone derivative having the structure shown in formula (6) or a pharmaceutically acceptable salt thereof, in, R1 is selected from: C1-C8 alkyl groups with or without R5 substituted or unsubstituted C3-C8 cycloalkyl groups; R2 is selected from: hydrogen, halogen, C1-C6 alkoxy group; R3 is selected from: C6-C with or without R6 substitution. 10 Aryl; R4 is selected from: phenyl-substituted C1-C2 alkyl groups; Each R5 is independently selected from: hydrogen or halogen; Each R6 is independently selected from: hydrogen, halogen, and C1-C3 alkoxy groups.

2. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, R1 is selected from: C1-C4 alkyl groups with or without R5 substituted or unsubstituted C5-C6 cycloalkyl groups.

3. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 2, characterized in that, R1 is selected from: C1-C4 alkyl, C5-C6 cycloalkyl.

4. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 3, characterized in that, R1 is selected from: isobutyl or cyclohexyl.

5. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, R2 is selected from: hydrogen, halogen, C1-C3 alkoxy group.

6. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, R2 is selected from: hydrogen, bromine, chlorine, methoxy.

7. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, R3 is a phenyl group.

8. The γ-carblinone derivative or its pharmaceutically acceptable salt according to any one of claims 1-7, characterized in that, R4 is benzyl.

9. The γ-carbolinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, The γ-carbolineone derivative is selected from the following compounds: 。 10. A method for synthesizing the γ-carbolinone derivative according to any one of claims 1-9, characterized in that, Includes the following steps: Step 1: React compounds (1), (2), (3) and (4) in an organic solvent to obtain compound (5); Step 2: Dissolve the compound (5) in a solvent, add acid, and react under microwave conditions to obtain γ-carboline ketone derivative (6). The reaction formula is as follows: ； Wherein, R1, R2, R3, and R4 are as described in any one of claims 1-9.

11. The method for synthesizing γ-carblinone derivatives according to claim 10, characterized in that, The molar ratio of compounds (1), (2), (3) and (4) is 1:0.8-1.2:0.8-1.2:0.8-1.

2.

12. The method for synthesizing γ-carbolinone derivatives according to claim 10, characterized in that, The organic solvent in step 1 is selected from at least one of methanol, ethanol, trifluoroethanol, isopropanol, acetonitrile, DMF and dichloromethane.

13. The method for synthesizing γ-carbolinone derivatives according to claim 10, characterized in that, The reaction temperature in step 1 is 20℃-30℃, and the reaction time is 6 hours-18 hours.

14. The method for synthesizing γ-carbolinone derivatives according to claim 10, characterized in that, The solvent in step 2 is selected from at least one of dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile, toluene, and methanol.

15. The method for synthesizing γ-carblinone derivatives according to claim 14, characterized in that, The solvent used in step 2 is tetrahydrofuran or acetonitrile.

16. The method for synthesizing γ-carbolinone derivatives according to claim 10, characterized in that, The acid in step 2 is selected from at least one of trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

17. The method for synthesizing γ-carbolinone derivatives according to claim 16, characterized in that, The acid mentioned in step 2 is p-toluenesulfonic acid.

18. The method for synthesizing γ-carblinone derivatives according to claim 10, characterized in that, The reaction described in step 2 is carried out in a microwave reactor at a temperature of 60°C-110°C.

19. The method for synthesizing γ-carbolinone derivatives according to claim 18, characterized in that, The reaction described in step 2 is carried out in a microwave reactor at a temperature of 80°C-105°C.

20. The method for synthesizing γ-carbolinone derivatives according to claim 10, characterized in that, The reaction time in step 2 is 5 min to 30 min.

21. The method for synthesizing γ-carblinone derivatives according to claim 20, characterized in that, The reaction time in step 2 is 8-15 minutes.

22. The use of the γ-carbolinone derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9 in the preparation of a medicament for the prevention and / or treatment of tumors.

23. The application according to claim 22, characterized in that, The tumors mentioned are: lung cancer, prostate cancer, and colon cancer.

24. A pharmaceutical composition for the prevention and / or treatment of tumors, characterized in that, It is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the γ-carbolineone derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9.

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