A heteroindole derivative, its synthesis method and application

Abstract

This invention relates to the pharmaceutical field, specifically to a heteroindole derivative, its synthesis method, and its applications. The heteroindole compound derivative has the structure shown in general formula (I), wherein R1 is selected from any one of N-Boc-trans-1,4-cyclohexanediamine, N-Boc-piperazinyl, trans-1,4-cyclohexanediamine, piperazinyl, and N-methylpiperazinyl; R2 is selected from H or a halogen atom; and X, Y, and Z are all selected from CH or N. This invention demonstrates through experiments that the heteroindole derivative possesses good CDK9 inhibitory activity and selectivity, providing a theoretical basis for the treatment of diseases related to the activity or expression level of the cell cycle-dependent kinase CDK9, and exhibits good pharmaceutical potential.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical science, specifically to a heteroindole derivative, its synthesis method, and its applications. Background Technology

[0002] The human genome encodes 20 cyclin-dependent kinase inhibitors (CDKs), the evolutionary relationships of most of which are well-established. CDKs are divided into two subfamilies: cell cycle-related CDKs (CDKs 1-7 and 14-18) and transcription-related CDKs (CDKs 7-13, 19, and 20). Different CDKs interact with different cyclins to regulate cell cycle phases or perform other functions. CDK9 is particularly important in the development and progression of various tumors, and intervention in CDK9 can affect the biological functions of tumor cells. Mechanistically, inhibiting CDK9 blocks the phosphorylation of RNAPIICTD, induces downregulation of MYC and Mcl-1 protein levels, and promotes tumor cell apoptosis. Currently, due to issues such as toxicity, lack of specificity, or drug resistance in early-developed CDK9 inhibitors, there are no drugs targeting CDK9 available clinically. Therefore, developing novel small-molecule inhibitors targeting CDK9 could provide candidate compounds for the treatment of CDK9-related diseases. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a heteroindole derivative, its synthesis method, and its applications.

[0004] To achieve the above objectives, the specific technical solution of the present invention is as follows.

[0005] This invention provides a heteroindole derivative having a structure as shown in general formula (I):

[0006]

[0007] R1 is selected from any one of N-Boc-trans-1,4-cyclohexanediamine, N-Boc-piperazinyl, trans-1,4-cyclohexanediamine, piperazinyl, and N-methylpiperazinyl;

[0008] R2 is selected from H or a halogen atom;

[0009] X, Y, and Z are all selected from CH or N.

[0010] In some embodiments of the present invention, R1 is preferably trans-1,4-cyclohexanediamine.

[0011] In some embodiments of the present invention, the heteroindole derivative is any one of the following compounds:

[0012]

[0013] The present invention also provides a method for synthesizing the aforementioned heteroindole derivative, comprising the following steps:

[0014] The heteroindole derivative is obtained by Suzuki coupling reaction of the R3-substituted indole or heteroindole shown in formula (1) with the boric acid or borate intermediate shown in formula (2), wherein R1 in formula (I) is selected from any one of N-Boc-trans-1,4-cyclohexanediamine, N-Boc-piperazinyl, trans-1,4-cyclohexanediamine, piperazinyl and N-methylpiperazinyl;

[0015] Alternatively, an indole or heteroindole substituted with R3 as shown in formula (1) can undergo a Suzuki coupling reaction with a boric acid or borate intermediate as shown in formula (2) to obtain a Suzuki coupling reaction product as shown in formula (3). The Suzuki coupling reaction product is then subjected to an acid hydrolysis reaction to remove the protecting group Boc to obtain the heteroindole derivative, wherein R1 in formula (I) is selected from trans-1,4-cyclohexanediamine or piperazine.

[0016]

[0017] In the above-mentioned steps for synthesizing heteroindole derivatives,

[0018] The molar ratio of the R3-substituted indole or heteroindole to the boric acid or borate intermediate is 1:1 to 1.5.

[0019] R2 is selected from H or a halogen atom;

[0020] R3 is selected from any one of Cl, Br, and I;

[0021] R4 is selected from N-Boc-trans-1,4-cyclohexanediamine or N-Boc-piperazinyl;

[0022] In some embodiments of the present invention, the position of R3 substitution in formula (1) is as shown in formula (4) or formula (5):

[0023]

[0024] In some embodiments of the present invention, the R3-substituted heteroindole is selected from any one of 4-azaindole, 5-azaindole, 7-azaindole, and 1,3,7-triazaindole.

[0025] In some embodiments of the present invention, the boric acid or borate intermediate is selected from any one of tert-butyl((1r,4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate, (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid, and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid.

[0026] In some embodiments of the present invention, the Suzuki coupling reaction comprises: weighing an R3-substituted indole or heteroindole and a boric acid or borate intermediate as a raw material, weighing 0.01 to 0.02 equivalents of the raw material [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride as a catalyst, using ethylene glycol dimethyl ether solution as a solvent, dissolving the raw material and the catalyst in the solvent, adjusting the pH to 8 to 9, heating the reaction at 90 to 120°C for 6 hours, monitoring the reaction after completion, purifying the reaction, and obtaining the heteroindole derivative;

[0027] The acidolysis reaction includes: removing the protecting group from the Suzuki coupling reaction product in an organic solvent containing a moderately strong acid to obtain the heteroindole derivative;

[0028] The moderately strong acid is selected from trifluoroacetic acid or hydrogen chloride; the organic solvent is any one of methanol, 1,4-dioxane and dichloromethane; the volume ratio of the moderately strong acid to the organic solvent is 1:2.

[0029] The present invention also provides the use of the aforementioned heteroindole derivatives or structural analogs of heteroindole derivatives in the preparation of CDK9 kinase inhibitors, wherein the structural analogs of the heteroindole derivatives include one or more of their pharmaceutically acceptable salts, cocrystals, solvates, esters, acids, metabolites, hydrates, prodrugs, and intermediates.

[0030] The present invention also provides the use of the aforementioned heteroindole derivatives or structural analogs of heteroindole derivatives in the preparation of medicaments for diseases related to cell cycle-dependent kinase CDK9 activity or expression levels, wherein the structural analogs of the heteroindole derivatives include one or more of their pharmaceutically acceptable salts, cocrystals, solvates, esters, acids, metabolites, hydrates, prodrugs, and intermediates.

[0031] In some embodiments of the present invention, diseases associated with the expression level of cell cycle-dependent kinase CDK9 include one or more of breast cancer, liver cancer, colorectal cancer, lung cancer, cervical cancer, and glioma.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] This invention designs and synthesizes a new class of heteroindole derivatives, which have good CDK9 inhibitory activity and selectivity, providing a theoretical basis for the treatment of diseases related to cell cycle-dependent kinase CDK9 activity or expression levels, and have good pharmaceutical potential. Attached Figure Description

[0034] Figure 1 This is a graph showing the results of the study on the inhibition of CDK9 function by the aza-indole compound C6 in Experimental Example 3 of this invention.

[0035] Figure 2 Figure 4 shows the results of the inhibition experiment of the azaindole compound C6 on the HCT116 cell mouse subcutaneous xenograft tumor model in Experiment Example 4 of this invention; Figure A shows the tumor results after the administration, with the top row representing the control group and the bottom row representing the administration group; Figure B shows the curve of the change in mouse tumor volume during the administration period; Figure C shows the average weight of the tumors in each group after the administration period; Figure D shows the curve of the change in mouse body weight during the administration period; In Figures B to D, Con represents the control group and C6 25 mg / kg represents the administration group. Detailed Implementation

[0036] The present invention will be described in detail below with reference to specific embodiments, but should not be construed as limiting the present invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following embodiments can be obtained commercially unless otherwise specified.

[0037] Example 1

[0038] Synthesis of tert-butyl(4-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (C2) and (1r,4r)-N1-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C6)

[0039] (1) Synthesis of the intermediate tert-butyl ((1r,4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate:

[0040]

[0041] 2-Fluoro-4-iodo-5-chloropyridine (5.14 g, 20 mmol) and N-Boc-1,4-cyclohexanediamine (4.28 g, 20 mmol) were dissolved in 60 mL of N,N-dimethylformamide (DMF). Anhydrous potassium carbonate (K₂CO₃, 8.28 g, 60 mmol) was added, and the reaction system was purged with nitrogen. The temperature was raised to 120 °C and reacted for 4 h. After the reaction was confirmed to be complete by TLC, heating was stopped, and the reaction solution was poured into 200 mL of ice water with stirring. A solid precipitated out. The solid was filtered, and the filter cake was dried to give 8.11 g of tert-butyl((1r,4r)-4-((5-chloro-4-iodopyridin-2-yl)amino)cyclohexyl)carbamate, a white solid, with a yield of 90%.

[0042] The white solid obtained in the previous step (3.61 g, 8 mmol), pinacol terbinate (2.57 g, 10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.1 mmol), and anhydrous potassium acetate (2.35 g, 24 mmol) were added to 25 mL of dry N,N-dimethylformamide. Nitrogen gas was purged, and the mixture was heated to 90 °C for 4 h under nitrogen protection. TLC analysis was performed to confirm the complete reaction of tert-butyl((1r,4r)-4-((5-chloro-4-iodopyridin-2-yl)amino)cyclohexyl)carbamate. The solution was poured into 100 mL of ice water under stirring, extracted with (3 × 25 mL) ethyl acetate, and the organic phases were combined. After back-extraction with saturated sodium chloride, the organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, concentrated, and mixed with silica gel. The mixture was then purified by column chromatography with silica gel as the developing solvent (petroleum ether: ethyl acetate = 4:1) to obtain 2.53 g of tert-butyl ((1r,4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate, yield 70%).

[0043] (2) Synthesis of tert-butyl(4-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (C2) and (1r,4r)-N1-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C6):

[0044]

[0045] Take a thick-walled, pressure-resistant bottle and weigh the following raw materials: 4-chloro-7-azaindole (153 mg, 1 mmol), intermediate tert-butyl((1r,4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (497 mg, 1.1 mmol), potassium carbonate (414 mg, 3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (30 mg, 0.04 mmol). Dissolve them in 5 mL of solvent (ethylene glycol dimethyl ether:water = 4:1). The gas was purged three times, and the reaction was carried out overnight (6 h) at 120 °C. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of ethylene glycol dimethyl ether and dried to obtain the crude product. The crude product was dissolved in a 10:1 dichloromethane:methanol system, and silica gel was added and stirred. The mixture was then separated and purified by column chromatography using petroleum ether:ethyl acetate as the developing solvent to obtain the compound tert-butyl(4-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (C2), a white powder, 225 mg, yield 51%. 1 HNMR(600MHz,DMSO-d6)δ11.85(br s,1H),8.29(d,J=4.95Hz,1H),8.12(s,1H),7.50-7.55(m,1H),7.03(d,J=4.95Hz, 1H),6.76(brt,J=8.53Hz,2H),6.55(s,1H),6.25(dd,J=1.83,3.48Hz,1H),3.61(br s,1H),3.18-3.29(m,1H),1.94-2.03(m,2H),1.80(br d,J=11.19Hz,2H),1.38(s,9H),1.25-1.28(m,2H),1.19-1.24(m,2H).

[0046] The obtained C2 was dissolved in a system with a volume ratio of dichloromethane:trifluoroacetic acid = 2:1 and stirred at room temperature for 2 h. Dichloromethane and trifluoroacetic acid were removed by vacuum distillation. The residual solid was further dispersed in dichloromethane and treated with triethylamine until alkaline (pH = 8) with stirring. The organic phase was concentrated and mixed with silica gel. The mixture was then purified by column chromatography with silica gel. The developing solvent was changed from dichloromethane:methanol:ammonia = 10:1:0 to dichloromethane:methanol:ammonia = 10:1:0.1. The purified solid yielded (1r,4r)-N1-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C6), a white solid. 1H NMR (600MHz, DMSO-d6) δ11.88(br s,1H),8.29(d,J=4.77Hz,1H),8.12(s,1H),7.53(d,J=3.30Hz,1H),7.04(d,J=4.77Hz,1H),6.75(br d,J=7.52Hz,1H),6.55(s,1H),6.25(d,J=3.48Hz,1H),3.62(brs,2H),2.62(br s,1H),1.97(br d,J=9.54Hz,2H),1.81(br d,J=8.44Hz,2H),1.22(brs,2H),1.14-1.19(m,2H).

[0047] Example 2

[0048] Synthesis of 6-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridine (C10)

[0049]

[0050] Take a thick-walled, pressure-resistant bottle and weigh 197 mg (1 mmol) of 6-bromo-3H-imidazo[4,5-b]pyridine, 242 mg (1.1 mmol) of (4-(4-methylpiperazin-1-yl)phenyl)boronic acid, 414 mg (3 mmol) of potassium carbonate, and 30 mg (0.04 mmol) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. Dissolve them in 5 mL of solvent (ethylene glycol dimethyl ether:water = 4:1). Purge the solution with nitrogen three times and heat to 90 °C to react. After overnight (6 h), the reaction was monitored by TLC. The mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of ethylene glycol dimethyl ether and dried to obtain the crude product. The crude product was dissolved in a dichloromethane:methanol 10:1 system, mixed with silica gel, and purified by column chromatography with a dichloromethane:methanol ratio of 20:1 to obtain compound 6-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridine (C10), white powder, 140 mg, yield 48%. NMR (600MHz, DMSO-d6) δ12.94-13.37(m,1H),8.59(br s,1H),8.44(br s,1H),8.22(br s,1H),7.61(brd,J=8.44Hz,2H),7.05(br d,J=8.25Hz,2H),3.20(br s,4H),2.48(br d,J=4.03Hz,4H),2.24(s,3H).

[0051] Example 3

[0052] Synthesis of (1r,4r)-N1-(5-chloro-4-(1H-indol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C12)

[0053]

[0054] Take a thick-walled, pressure-resistant bottle and weigh 4-bromo-1H-indole (195 mg, 1 mmol), the intermediate tert-butyl((1r, 4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (497 mg, 1.1 mmol), potassium carbonate (414 mg, 3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (30 mg, 0.04 mmol) into 5 mL of solvent (ethylene glycol dimethyl ether:water = 4:1). The reaction mixture was purged with nitrogen three times and heated to 90°C overnight (6 h). After the reaction was completed by TLC, the mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of ethylene glycol dimethyl ether and dried to obtain the crude product. The crude product was dissolved in a 10:1 dichloromethane:methanol system, mixed with silica gel, and purified by column chromatography with a dichloromethane:methanol ratio of 20:1 to obtain 205 mg of the intermediate tert-butyl((1r,4r)-4-((5-chloro-4-(1H-indol-4-yl)pyridin-2-yl)amino)cyclohexyl)carbamate, a white solid with a yield of 47%.

[0055] The intermediate tert-butyl((1r,4r)-4-((5-chloro-4-(1H-indol-4-yl)pyridin-2-yl)amino)cyclohexyl)carbamate obtained above was dissolved in a system with a volume ratio of dichloromethane:trifluoroacetic acid = 2:1 and stirred at room temperature for 2 h. After removing the protecting group, the final product (1r,4r)-N1-(5-chloro-4-(1H-indol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C12) was obtained. The purification method and post-treatment are described in Example 1. 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),8.30(d,J=1.28Hz,1H),8.08(s,1H),8.03(d,J=1.83Hz,1H),6.69(m,1H),6 .47-6.60(m,2H),3.49-3.56(m,1H),3.18-3.25(m,1H),1.87-1.94(m,2H),1.76-1.81(m,2H),1.16-1.28(m,4H).

[0056] Example 4

[0057] Synthesis of tert-butyl ((1r,4r)-4-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)amino)cyclohexyl)carbamate (C1)

[0058] The synthesis of C1 is similar to that of C2 in Example 1, except that 4-chloro-7-azaindole is replaced with 5-chloro-7-azaindole. The other raw materials, reaction conditions and post-treatment methods are the same.

[0059] Example 5

[0060] Synthesis of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (C3)

[0061] The synthesis method of C3 is similar to that of C2 in Example 1, except that the starting materials are different. 4-chloro-7-azaindole is replaced with 5-chloro-7-azaindole, and tert-butyl((1r,4r)-4-((5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxin-2-yl)pyridin-2-yl)amino)cyclohexyl)carbamate is replaced with (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid. Other reaction conditions and post-treatment methods are the same.

[0062] Example 6

[0063] Synthesis of 4-(4-(3H-imidazo[4,5-b]pyridin-6-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (C4)

[0064] The synthesis of C4 is similar to that of C3 in Example 5, except that 4-chloro-7-azaindole is replaced with 6-bromo-3H-imidazo[4,5-b]pyridine. Other starting materials, reaction conditions and post-treatment methods are the same.

[0065] Example 7

[0066] Synthesis of (1r,4r)-N1-(5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C5)

[0067] The synthesis method of C5 is similar to that of C6 in Example 1, except that C5 uses C1 as the raw material and C6 uses C2 as the raw material.

[0068] Example 8

[0069] Synthesis of 4-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (C7)

[0070] The synthesis conditions of C7 are similar to those of C6 in Example 1, except that C7 uses C3 as the raw material and C6 uses C2 as the raw material.

[0071] Example 9

[0072] Synthesis of 6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridine (C8)

[0073] The synthesis conditions of C8 are similar to those of C6 in Example 1, except that C8 uses C4 as the raw material and C6 uses C2 as the raw material.

[0074] Example 10

[0075] Synthesis of 4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (C9)

[0076] The synthesis of C9 is similar to that of C3 in Example 5, except that (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid is replaced with (4-(4-methylpiperazin-1-yl)phenyl)boronic acid. Other raw materials, reaction conditions and post-treatment methods are the same.

[0077] Example 11

[0078] Synthesis of (1r,4r)-N1-(5-chloro-4-(1H-indol-5-yl)pyridin-2-yl)cyclohexane-1,4-diamine (C11)

[0079] The synthesis of C11 is similar to that of C12 in Example 3, except that 4-bromo-1H-indole is replaced with 5-bromo-1H-indole. Other raw materials, reaction conditions and post-treatment methods are the same.

[0080] The mass spectrometry and NMR data of compounds C1-C12 are assigned in Table 1.

[0081] Table 1. Structures and high-resolution mass spectrometry and NMR characterizations of the indole or heteroindole compounds of the present invention.

[0082]

[0083]

[0084]

[0085] Experimental Example 1

[0086] Cytotoxicity test results of indole or heteroindole compounds of the present invention

[0087] Antiproliferation experiments were conducted on the series of compounds of the present invention at concentrations of 1 μM and 20 μM on six types of tumor cells: human hepatocellular carcinoma HepG2, human highly metastatic hepatocellular carcinoma MHCC-97H, human hepatocellular carcinoma SMMC-7221, human colon cancer HCT116, human alveolar adenocarcinoma basal epithelial cells A549, and human hepatocellular carcinoma BEL7402. The cell mortality results are shown in Table 2.

[0088] Table 2. Cytotoxicity test results of some indole or heteroindole compounds of the present invention.

[0089]

[0090] As can be seen from Table 2, the C1 to C12 compounds all have certain killing effects on different tumor cells.

[0091] Experimental Example 2

[0092] The inhibitory effect of certain indole or heteroindole compounds of this invention on CDK9 kinase activity

[0093] Based on the results of cell experiments, compounds C5 and C6, which exhibited the best activity at the cellular level, were selected for an inhibition experiment on CDK9 kinase activity at concentrations of 1 μM / 50 nM. The results are shown in Table 3. Table 3 shows that both compounds C5 and C6 inhibited CDK9 kinase activity, with C6 showing a stronger inhibitory effect.

[0094] Table 3. Results of the inhibition of CDK9 kinase activity by compounds C5 and C6.

[0095] compound CDK9 kinase activity (%) @ 1 μM C5 4 C6 1

[0096] Experimental Example 3

[0097] Study on the CDK9 inhibition function of C6 in the aza-indole compounds of this invention

[0098] CDK9 / cyclin T1 forms a complex with the transcription elongation factor P-TEFb. CDK9 inhibitors can block the phosphorylation of serine 2 at the C-terminal domain of RNA polymerase II by CDK9 / cyclin T1. Therefore, this experiment tested the phosphorylation level of serine 2 at the C-terminal domain of RNA polymerase II and the level of parp protein in MDA-MB231 cells treated with compound C6, which exhibited the best kinase activity. The results showed that compound C6 inhibited phosphorylation at serine 2 and induced parp cleavage. (See attached table). Figure 1 .

[0099] Experiment Example 4

[0100] Inhibition experiment of the aza-indole compound C6 of the present invention on a mouse subcutaneous xenograft model of colon cancer cell HCT116.

[0101] Experimental animals: 10 female BALB / c nude mice aged 4-6 weeks, weighing 16-18g.

[0102] Establishment of HCT116 cell mouse tumor model: HCT116 cell suspension (100 μL, approximately 10 μg) was subcutaneously injected into the right anterior axilla of nude mice. 6 (Number of mice). A control group (5% glucose solution) and a treatment group (25 mg / kg) were set up. The mice were administered the medication continuously for 14 days, and the body weight of each group was recorded daily. After the administration was completed, the nude mice were sacrificed, the tumors were removed, photographed, and weighed.

[0103] After establishing a mouse tumor model using standard HCT116 cells, the tumor was allowed to initially grow to 50 mm. 3 Afterwards, administration began, and the pharmacodynamic test results were as follows: Figure 2 As shown, after 14 days of intraperitoneal injection of 25 mg / kg, the tumor volume in mice increased more slowly compared to the control group, and the final tumor weight after removal was also statistically different. Meanwhile, the weight changes in mice after administration were all within the normal range.

[0104] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0105] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A heteroindole derivative, characterized in that, The heteroindole derivative is any one of the following compounds: 。 2. The use of the heteroindole derivative or its structural analogue as described in claim 1 in the preparation of CDK9 kinase inhibitors, characterized in that, The structural analogues of the heteroindole derivatives are pharmaceutically acceptable salts.

3. The use of the heteroindole derivative or its structural analogue as described in claim 1 in the preparation of a medicament for diseases related to cell cycle-dependent kinase CDK9 activity or expression levels, characterized in that... The structural analogues of the heteroindole derivatives are pharmaceutically acceptable salts.

4. The application as described in claim 3, characterized in that, Diseases associated with the expression level of cell cycle-dependent kinase CDK9 include one or more of liver cancer, colorectal cancer, and lung cancer.

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