A 4-azaindoline compound and its synthesis method and application

Abstract

The present invention relates to the technical field of organic chemistry and medicinal chemistry, and specifically to a 4-azaindoline compound and a synthesis method and application thereof. The specific technical scheme is: under alkaline conditions, a substituted 1-aminopyridine salt is suspended in a solvent, and under visible light conditions and inert gas protection, it is stirred with an α, β-unsaturated compound to form a substituted 4-azaindoline compound. The present invention solves the problem that the synthesis of such compounds is highly dependent on intramolecular synthesis, and on the basis of this method, the application of 4-azaindoline skeleton compounds in anti-tumor is discovered.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemistry and medicinal chemistry, and in particular to a 4-azaindoline compound and a synthesis method and application thereof. Background Art

[0002] 4-Azaindoline compounds are widely present in biologically active molecules and are an important class of nitrogen-containing heterocyclic structures. In recent years, molecules based on this skeleton have attracted increasing attention due to their excellent biological activity. Typical representatives include: Turiso reported that compound 1 exhibited significant selective inhibitory activity against leukocyte PI3Kβ / δ subunits, and related animal model experiments showed that it had a good therapeutic effect on rheumatoid arthritis and had high further development value (J.Med.Chem.2012,55,7667-7685); Smith reported that molecules with compound 2 as the skeleton can selectively inhibit the activity of histone lysine demethylase KMD2A / 7A and have the function of regulating gene expression. In addition, the authors of the article also revealed the activity differences between different enantiomers of such compounds by analyzing the structure-activity relationship (Angew.Chem.Int.Ed.2017,56,15555-15559); Badland reported that molecules with the skeleton of compound 3 can regulate the immune system by inhibiting the activity of phosphodiesterase PDE4, and have potential value in treating inflammatory infectious diseases (Tetrahedron Lett.2011,52,5292-5296); In addition, a recent patent revealed that compound 4 has a strong inhibitory effect on the key subunit α-2 / δ of voltage-dependent calcium channels (Ki<100nM), has the function of regulating intracellular calcium ion concentration, and shows potential value in treating epilepsy-related diseases (PCT Patent, WO2019020792).

[0003]

[0004] However, due to the interference of the electronic effect of the pyridine ring in such structures, traditional methods for constructing indoline such as Fischer indoline synthesis and Friedel-Crafts reaction are not suitable for constructing azaindoline (Adv. Heterocycl. Chem. 1990, 27, 263-268), resulting in relatively few reports on the synthesis methods of azaindoline skeletons. Among them, the construction research of 4-azaindoline is particularly scarce. In the early days, only a single example appeared in the reports, including the photocatalytic ring expansion-hydrolysis rearrangement of pyrido-oxazole ring to obtain 4-azaindole product (Eur. J. Org. Chem., 2002, 4211-4216); free radical addition-cyclization tandem reaction to obtain products (Org. Lett. 2003, 26, 4943-4945); nucleophilic substitution reaction under the action of strong base to construct intramolecular CN bond formation product (Org. Lett. 2008, 6, 1071-1074); acid-catalyzed intramolecular cyclization of pyridine amino compounds to construct 4-azapyridine (Synlett. 2011, 5, 684-688); Pd-catalyzed C(sp 3 )-H activation to achieve intramolecular cyclization strategy (Org.Lett.2008,9,1759-1762). It was not until 2015 that Johnston reported the use of high-valent iodine reagents to activate olefins to construct intramolecular CN bonds to synthesize 4-azaindole, and the tolerance of nucleophiles with simple aromatic and alkyl substituents was investigated for the first time (Org.Lett.2015,17,3806-3809). Recently, Chen Jiuxi reported the use of rare earth element yttrium to activate double bonds to achieve intramolecular nucleophilic addition cyclization, and obtained a series of 4-azaindole compounds with a yield of 30%-92% (Adv.Synth.Catal.2020,362,851-857). Although the above method successfully constructed 4-azaindole products, there are generally problems such as low yield, difficulty in synthesizing raw materials, poor substrate extensibility and racemic products, which seriously limit the development and utilization of 4-azaindole structures.

[0005]

[0006] On the other hand, malignant tumors, also known as cancer, are caused by mutations in normal cells that lead to unlimited cell proliferation, metastasis and invasion of other organs, resulting in damage to body functions and possibly death. According to statistics from the World Health Organization, nearly 10 million deaths in 2020 were caused by cancer, accounting for one-sixth of the total number of deaths that year. Therefore, cancer is the leading cause of death in the world. The most common cancers are breast cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, skin cancer and gastric cancer. Chemotherapy is one of the most important ways to treat malignant tumors. It refers to the use of chemical drugs to kill cancer cells to achieve the purpose of treating cancer. Modern anti-tumor drugs began in the mid-20th century, using nitrogen mustard (HN2) to treat malignant lymphoma and achieved short-term efficacy; subsequently, methotrexate was also used to treat acute lymphocytic leukemia, thus opening the prelude to modern chemotherapy. In the 1960s, pharmaceutical chemists successively discovered drugs with significant anti-cancer activity such as vinblastine and cisplatin, which greatly prolonged the survival time and quality of life of cancer patients. In recent years, the development of chemotherapy drugs represented by targeted drugs has made it possible for cancer patients to survive long-term and high-quality. However, with the use of chemotherapy drugs, cancer cells inevitably develop drug resistance, which leads to the failure of existing drugs and worsening of the patient's condition. Therefore, the only effective way to continue to use chemotherapy to treat cancer is to continuously develop new anti-cancer drugs, especially drugs targeting drug-resistant cancer cells. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention provides a 4-azaindole compound and a synthesis method and application thereof, which solves the problem that the synthesis of such compounds is highly dependent on intramolecular synthesis, and based on this method, discovers the application of 4-azaindole skeleton compounds in anti-tumor.

[0008] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0009] The present invention discloses a compound represented by formula (I) or its stereoisomer, tautomer, racemate or pharmaceutically acceptable salt.

[0010]

[0011] Wherein, R1 is one or more of a hydrogen atom, a halogen, an alkyl group, an alkoxy group and an aryl group;

[0012] R2 is one of a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, and a sulfonyl group;

[0013] R3 and R4 are each one of a hydrogen atom, an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, and a sulfonamide group.

[0014] Preferably, when R1 is one or more of an alkyl group, an alkoxy group and an aryl group, R1 may be replaced by one or more independently selected R a Substituent substitution;

[0015] The R a is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a thiol group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group;

[0016] When R2 is one of alkyl, acyl, alkoxycarbonyl, and sulfonyl, R2 may be one or more independently selected R b Substituent substitution;

[0017] The R b is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a thiol group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group;

[0018] When R3 is an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, or a sulfonamide group, R3 may be one or more independently selected R c Substituent substitution;

[0019] The R c is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a thiol group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group;

[0020] When R4 is an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, or a sulfonamide group, R4 may be one or more independently selected R d Substituent substitution;

[0021] The R d It is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group.

[0022] The final structural formula (I) is shown below:

[0023]

[0024] Preferably, when R a When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, amay be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0025] and / or, when R b When R is one of alkyl, alkoxy and aryl, b may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0026] and / or, when R c When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, c may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0027] and / or, when R d When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, d It may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups.

[0028] Correspondingly, the synthesis method of the compound represented by the above formula (I) or its stereoisomer, tautomer, racemate or pharmaceutically acceptable salt is as follows: under alkaline conditions, the substituted 1-aminopyridine salt is suspended in a solvent, and under visible light conditions and the protection of an inert gas (argon or nitrogen), it is stirred with an α, β-unsaturated compound to form a substituted 4-azaindole compound.

[0029] Preferably, the solvent is a mixture of one or more of benzene, toluene, 1,4-dioxane, acetonitrile, dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, DMF, DMSO, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, ethyl acetate, chloroform, acetone, ether, and methyl tert-butyl ether;

[0030] The base is one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium phosphate, cesium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, DBU, DBN, LDA, LiHDMS, NaHDMS, methyl lithium, n-butyl lithium, isobutyl lithium, and tert-butyl lithium;

[0031] The α,β-unsaturated compound is one of α,β-unsaturated ester compounds, α,β-unsaturated aldehyde compounds, α,β-unsaturated ketone compounds, α,β-unsaturated nitro compounds, α,β-unsaturated cyano compounds, α,β-unsaturated sulfone compounds, α,β-unsaturated sulfoxide compounds, α,β-unsaturated amides, and α,β-unsaturated sulfonamide compounds;

[0032] The visible light is one of natural light, incandescent lamp, LED lamp, OLED lamp, fishing lamp, and lighting flashlight;

[0033] The substituted 1-aminopyridine salt is shown in formula (II):

[0034]

[0035] Wherein, the R5-position is an electron-donating group, which is one of an alkoxy group, an aryloxy group, an alkylamino group, an arylamino group, an alkylthiol group and an arylthiol group;

[0036] R6 is one or more of hydrogen, halogen, alkyl, alkoxy, aryl, and amino;

[0037] Negative ion X is:

[0038] One of them.

[0039] Preferably, the reaction concentration of the solvent is 0.001 to 100 mol / L, the amount of the base is 0.1 to 10 equivalents, and the reaction temperature is -80 to 200° C. The molar ratio of the substituted 1-aminopyridinium salt to the α,β-unsaturated compound is 20:1 to 1:20.

[0040] Correspondingly, a pharmaceutical composition comprises the compound represented by the above formula (I) or its stereoisomer, tautomer, racemate or its pharmaceutically acceptable salt or solvate, or the compound synthesized by the above synthesis method or its stereoisomer, tautomer, racemate or its pharmaceutically acceptable salt or solvate.

[0041] Preferably, it also includes one or more pharmaceutically acceptable carriers or excipients.

[0042] Correspondingly, the use of the compound represented by the above formula (I) or its stereoisomer, tautomer, racemate or its pharmaceutically acceptable salt or solvate, or the compound synthesized by the above synthesis method or its stereoisomer, tautomer, racemate or its pharmaceutically acceptable salt or solvate, or the above pharmaceutical composition in the preparation of drugs for treating tumor diseases.

[0043] Preferably, the tumor disease is one or more of lung cancer, gastric cancer, colon cancer, cervical cancer, leukemia, kidney cancer, esophageal cancer, bladder cancer, gallbladder cancer, breast cancer, liver cancer, brain cancer, prostate cancer, thyroid cancer, pancreatic cancer, osteosarcoma, melanoma, and rhabdomyosarcoma.

[0044] The present invention has the following beneficial effects:

[0045] 1. The present invention adopts a one-step synthesis strategy, using easily available α,β-unsaturated compounds and substituted 1-aminopyridine salts as raw materials, and synthesizes a series of 4-azaindoline compounds efficiently and selectively in the presence of alkali and visible light, thereby greatly simplifying the synthesis route of such compounds and improving the synthesis efficiency. It has the advantages of mild synthesis conditions, readily available raw materials, simple operation, high yield, high selectivity, good functional group tolerance, etc.

[0046] 2. The present invention uses simple and readily available raw materials to efficiently and selectively synthesize a series of 4-azaindole compounds, and uses human lung cancer, gastric cancer, colon cancer, cervical cancer, leukemia, kidney cancer, esophageal cancer, bladder cancer, gallbladder cancer, breast cancer, liver cancer, brain cancer, prostate cancer, thyroid cancer, pancreatic cancer, osteosarcoma, melanoma, rhabdomyosarcoma and other cells to evaluate the biological activity of the obtained compounds. The results show that the 4-azaindole compounds obtained by the present invention have good anti-tumor activity. DETAILED DESCRIPTION

[0047] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0048] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0049] (1) The present invention discloses a method for synthesizing a compound represented by the following formula (I) or its stereoisomers, tautomers, racemates or pharmaceutically acceptable salts. The synthesis process is as follows: under alkaline conditions, a substituted 1-aminopyridine salt is suspended in a solvent, and under visible light conditions and under the protection of an inert gas (argon or nitrogen), the mixture is stirred with an α,β-unsaturated compound to form a substituted 4-azaindole compound.

[0050] The solvent is a mixture of one or more of benzene, toluene, 1,4-dioxane, acetonitrile, dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, DMF, DMSO, methanol, ethanol, isopropanol, tert-butanol, trifluoroethanol, ethyl acetate, chloroform, acetone, ether, and methyl tert-butyl ether;

[0051] The base is one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium phosphate, cesium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, DBU, DBN, LDA, LiHDMS, NaHDMS, methyl lithium, n-butyl lithium, isobutyl lithium, and tert-butyl lithium;

[0052] The α,β-unsaturated compound is one of α,β-unsaturated ester compounds, α,β-unsaturated aldehyde compounds, α,β-unsaturated ketone compounds, α,β-unsaturated nitro compounds, α,β-unsaturated cyano compounds, α,β-unsaturated sulfone compounds, α,β-unsaturated sulfoxide compounds, α,β-unsaturated amides, and α,β-unsaturated sulfonamide compounds;

[0053] The visible light is one of natural light, incandescent lamp, LED lamp, OLED lamp, fishing lamp, and lighting flashlight.

[0054] The substituted 1-aminopyridine salt is shown in formula (II):

[0055]

[0056] Wherein, the R5-position is an electron-donating group, which is one of an alkoxy group, an aryloxy group, an alkylamino group, an arylamino group, an alkylthiol group and an arylthiol group;

[0057] R6 is one or more of hydrogen, halogen, alkyl, alkoxy, aryl, and amino;

[0058] Negative ion X is:

[0059] One of them.

[0060] Furthermore, the reaction concentration of the solvent is 0.001 to 100 mol / L, the amount of the base is 0.1 to 10 equivalents, and the reaction temperature is -80 to 200° C. The molar ratio of the substituted 1-aminopyridinium salt to the α,β-unsaturated compound is 20:1 to 1:20, preferably 1:1.2.

[0061] (2) a compound represented by formula (I) or a stereoisomer, tautomer, racemate or a pharmaceutically acceptable salt thereof,

[0062]

[0063] Wherein, R1 is one or more of a hydrogen atom, a halogen, an alkyl group, an alkoxy group and an aryl group;

[0064] R2 is one of a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, and a sulfonyl group;

[0065] R3 and R4 are each one of a hydrogen atom, an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, and a sulfonamide group.

[0066] Further, when R1 is one or more of an alkyl group, an alkoxy group and an aryl group, R1 may be replaced by one or more independently selected R a Substituent substituted; said R a is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a thiol group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group;

[0067] When R2 is one of alkyl, acyl, alkoxycarbonyl, and sulfonyl, R2 may be one or more independently selected R b Substituent substituted; said R b is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a thiol group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group;

[0068] When R3 is an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, or a sulfonamide group, R3 may be one or more independently selected R c Substituent substituted; said R c It is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group.

[0069] When R4 is an alkyl group, a cyano group, an ester group, an aldehyde group, a ketone group, a nitro group, a sulfone group, a sulfoxide group, or a sulfonamide group, R4 may be one or more independently selected R d Substituent substituted; said R d It is one of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, and an ester group.

[0070] The final structural formula (I) is shown below:

[0071]

[0072] Furthermore, when R a When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, a may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0073] and / or, when R b When R is one of alkyl, alkoxy and aryl, b may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0074] and / or, when R c When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, c may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups;

[0075] and / or, when R d When R is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a nitro group, a cyano group, a hydroxyl group, a mercapto group, an alkoxy group, an alkylthio group, an amino group, a sulfone group, a sulfoxide group, a sulfonyl group, an aldehyde group, a keto group, or an ester group, d It may be substituted by one or more hydrogen atoms, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, thiol, alkoxy, alkylthio, amino, sulfone, sulfoxide, sulfonyl, aldehyde, keto, or ester groups.

[0076] (3) The present invention also discloses a pharmaceutical composition, comprising the compound represented by the above formula (I) or its stereoisomer, tautomer, racemate, or its pharmaceutically acceptable salt or solvate, or the compound synthesized by the above synthesis method or its stereoisomer, tautomer, racemate, or its pharmaceutically acceptable salt or solvate.

[0077] Furthermore, it also includes one or more pharmaceutically acceptable carriers or excipients.

[0078] (4) The present invention also discloses the use of the compound represented by the above formula (I) or its stereoisomers, tautomers, racemates or their pharmaceutically acceptable salts or solvates, or the compound synthesized by the above synthesis method or its stereoisomers, tautomers, racemates or their pharmaceutically acceptable salts or solvates, or the above pharmaceutical composition in the preparation of drugs for treating tumor diseases.

[0079] Among them, the tumor disease is one or more of lung cancer, gastric cancer, colon cancer, cervical cancer, leukemia, kidney cancer, esophageal cancer, bladder cancer, gallbladder cancer, breast cancer, liver cancer, brain cancer, prostate cancer, thyroid cancer, pancreatic cancer, osteosarcoma, melanoma, and rhabdomyosarcoma.

[0080] In order to further illustrate the synthesis of 4-azaindoline compounds in the present invention, the present invention selectively synthesized the following substances, and described the synthesis process of each compound in conjunction with specific examples.

[0081]

[0082] 1. The present invention provides a method for synthesizing 4-azaindole compounds, which comprises the following steps: suspending an aminopyridine salt (0.1 mmol) and an α,β-unsaturated compound (0.12 mmol) in toluene (2 mL) under ice bath and argon protection conditions, dropping DBU (23 μL, 0.15 mmol) under light conditions, stirring for 10 min under ice bath conditions, heating to room temperature, and TLC showing that the reaction is complete after 4 to 12 hours, pouring the reaction solution into a saturated sodium bicarbonate solution, extracting with ethyl acetate three times, washing with a saturated NaCl solution, drying with anhydrous Na2SO4, filtering and evaporating to dryness, and purifying the obtained solid by column chromatography.

[0083] The general reaction formula is as follows:

[0084]

[0085] Taking compound 1 as an example, in order to further illustrate the diversity of the types and amounts of reaction solvents and bases in the above synthesis method, compound 1 was synthesized using different types and amounts of solvents and bases, as shown in Table 1 below.

[0086] Table 1 Yields of compound 1 under different synthesis conditions

[0087]

[0088] According to the above-mentioned synthesis method 1, using corresponding raw materials or substituents, the synthesized compounds and spectral data (NMR hydrogen spectrum and carbon spectrum data) are shown in Table 2 below.

[0089] Table 2 Compounds synthesized by Synthesis Method 1

[0090]

[0091]

[0092] 2. The present invention provides a method for synthesizing 4-azaindole compounds, which specifically comprises the following steps: under ice bath and argon protection conditions, an aminopyridine salt (0.1 mmol) and an α,β-unsaturated compound (0.12 mmol) are suspended in toluene (2 mL); under light conditions, DBU (23 μL, 0.15 mmol) is added dropwise; after the addition is completed, stirring is continued under ice bath conditions for 10 min, and the temperature is raised to room temperature; TLC shows that the reaction is complete after 4 to 12 hours; the reaction solution is poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate for 3 times, washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered and evaporated to dryness; the obtained solid is purified by column chromatography and then dissolved in dichloromethane; p-toluenesulfonyl chloride (0.11 mmol) and 4-dimethylaminopyridine (0.11 mmol) are added; the mixture is stirred at room temperature for 12 hours and then dried by rotation; and the obtained crude product is a pure product purified by column chromatography.

[0093] The general reaction formula is as follows:

[0094]

[0095] According to the above-mentioned synthesis method 2, using corresponding raw materials or substituents, the synthesized compounds and spectral data (NMR hydrogen spectrum and carbon spectrum data) are shown in Table 3 below.

[0096] Table 3 Compounds synthesized by Synthesis Method 2

[0097]

[0098]

[0099]

[0100] 3. The present invention provides a method for synthesizing 4-azaindole compounds, and the specific process is as follows: under ice bath and argon protection conditions, aminopyridine salt (0.1mmol) and α,β-unsaturated compound (0.12mmol) are suspended in toluene (2mL), and DBU (23μL, 0.15mmol) is added dropwise under light conditions. After the addition is completed, stirring is continued for 10min under ice bath conditions, and then the temperature is raised to room temperature. TLC shows that the reaction is complete after 4 to 12 hours. The reaction solution is poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate 3 times, washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered and evaporated, and the obtained solid is purified by column chromatography.

[0101] The general reaction formula is as follows:

[0102]

[0103] According to the above-mentioned synthesis method 3, using corresponding raw materials or substituents, the synthesized compounds and spectral data (NMR hydrogen spectrum and carbon spectrum data) are shown in Table 4 below.

[0104] Table 4 Compounds synthesized by Synthesis Method 3

[0105]

[0106]

[0107] 4. The present invention provides a method for synthesizing 4-azaindole compounds, and the specific process is as follows: under ice bath and argon protection conditions, aminopyridine salt (0.1 mmol) and α, β-unsaturated compound (0.12 mmol) are suspended in toluene (2 mL), and DBU (23 μL, 0.15 mmol) is added dropwise under light conditions. After the addition is completed, stirring is continued for 10 minutes under ice bath conditions, and the temperature is raised to room temperature. TLC shows that the reaction is complete after 4 to 12 hours. The reaction solution is poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate 3 times, washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered and evaporated, and the obtained solid is purified by column chromatography.

[0108] The general reaction formula is as follows:

[0109]

[0110] According to the above-mentioned synthesis method 4, using corresponding raw materials or substituents, the synthesized compounds and spectral data (NMR hydrogen spectrum and carbon spectrum data) are shown in Table 5 below.

[0111] Table 5 Compounds synthesized by Synthesis Method 4

[0112]

[0113]

[0114] Example Cytotoxicity Assay

[0115] Cytotoxicity (CCK-8 method) detection principle: The detection principle is that the CCK-8 reagent contains WST-8, which is reduced to a highly water-soluble yellow formazan product (Formazan) by dehydrogenase in the cell mitochondria under the action of the electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate (1-Methoxy PMS). The amount of formazan generated is proportional to the number of living cells.

[0116] Experimental method: (1) Cell inoculation: Cells were prepared into a single cell suspension using culture medium containing 10% fetal bovine serum, and 90 μL of 5×10 cells were inoculated into each well of a 96-well plate. 4 / mL of adherent cells and 9×10 4 / mL of suspension cells were pre-cultured at 5% CO2 and 37°C for 24h.

[0117] (2) Add the sample solution to be tested: add 10 μL of sample solution (concentration of 20 μM, due to space reasons, this example only reflects the first 14 compounds) to each well, set one concentration for each sample in the initial screening of activity, set 3 replicates; place in an incubator and culture for 48 hours. The experiment sets up a blank group (Blank), a control group (Control) and a drug group (Drug).

[0118] (3) Color development: Aspirate the old culture medium and drug solution from adherent cells (add 10 μL CCK-8 solution directly to suspended cells), add 100 μL CCK-8 solution diluted ten times to each well, and continue culturing at 37°C, 5% CO2 for 1 to 4 h (keep away from light and observe in real time).

[0119] (4) Detection: Measure the absorbance at 450 nm using an enzyme-labeled instrument and record the raw data results.

[0120] (5) The original data were standardized using Excel software, and the cell proliferation inhibition rate was calculated by the OD value of each well in the initial screening (formula = (OD Control -OD Drug ) / (OD Control -OD Blank )×100%), and the inhibition rate was calculated. IC 50 The data were calculated using GraphPadPrism 8 (version 8.0.2, GraphPad Software Inc), and the experimental results were expressed as ± SD.

[0121] (6) Positive control: Doxorubicin hydrochloride (Dox).

[0122] The results are shown in Table 6 below.

[0123] Table 6 Cytotoxicity test results

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[0128] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. Any one of the compounds shown below or a pharmaceutically acceptable salt thereof, 2. A pharmaceutical composition, characterized in that: The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that: One or more pharmaceutically acceptable carriers or excipients are also included.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 3 in the preparation of a drug for treating a tumor disease; the tumor disease is one or more of lung cancer, gastric cancer, colon cancer, cervical cancer, leukemia, kidney cancer, esophageal cancer, bladder cancer, gallbladder cancer, breast cancer, liver cancer, brain cancer, prostate cancer, thyroid cancer, pancreatic cancer, osteosarcoma, melanoma, and rhabdomyosarcoma.

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