Preparation method and application of a new type of CDK8 hydrophobic tag degrader

Abstract

The application discloses a CDK8 hydrophobic tag degrading agent and a preparation method and application thereof. The CDK8 hydrophobic tag degrading agent is a 7,8-dibromo-9-methyl-2-(piperazine-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-iJ]quinoline derivative, and has excellent CDK8 degrading activity and antitumor activity.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of CDK8 hydrophobic tag degrading agents, their preparation methods, and applications. Background Technology

[0002] In 2008, Hahn and his collaborators at the Dana-Farber Cancer Institute in the United States first proposed that CDK8 acts as an oncogene for colorectal cancer by regulating β-catenin. Subsequent studies have shown that CDK8 is overexpressed in melanoma, breast cancer, acute myeloid leukemia, pancreatic cancer, prostate cancer, and other cancers. Research has shown that CDK8 kinase activity weakens the defense of natural killer cells against malignant cells and inhibits tumor surveillance of precancerous cells. This evidence suggests the oncogenic role of CDK8 in these cancers and that inhibiting CDK8 protein activity can suppress tumor growth. Therefore, the discovery of effective and selective small-molecule CDK8 inhibitors for cancer treatment could serve as a novel cancer therapy strategy. However, small-molecule inhibitors suffer from problems such as drug resistance and selectivity, limiting their further development. In recent years, degradation agents, due to their different mechanisms of action, have been successfully used in drug development.

[0003] This invention is based on hydrophobic tag degradation technology. Using the clinical drug SEL-120 34A as the target warhead, different linkers and hydrophobic tags are designed. Based on the structural pharmaceutical chemistry optimization, the development of "CDK8 hydrophobic tag degrading agent" with adamantane as the core hydrophobic fragment is discovered and determined, with the aim of discovering a CDK8 degrading agent with high activity and high selectivity. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a novel CDK8 hydrophobic tag degrading agent and its preparation method.

[0005] To address the shortcomings of existing CDK8 degrading agents, this invention provides a novel class of 7,8-dibromo-9-methyl-2-(piperazin-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-i] J Quinoline derivatives possess excellent CDK8 degradation activity and antitumor activity.

[0006] The first object of the present invention is to provide a compound as shown in general formula (I): ; Wherein, R is selected from substituted or unsubstituted C. 6-20 Aryl C 0-6 Alkyl; C 6-20 Aryl vinyl; Phthalimide-C 1-6 alkyl; C 3-12 cycloalkyl C0-6 Alkyl group; -(CH2) 0-6 -C(O)-(CH2) 0-8 -R', where R' is diphenylmethylamino, C 3-12 cycloalkyl, C 3-12 Cycloalkylamino, C 3-12 cycloalkyl C 1-6 Alkylamino, C 3-12 cycloalkyl C 1-6 Alkyl C(O)NH-;-(CH2) 0-6 -NHC(O)-(CH2) 0-8 -C 3-12 Cycloalkyl groups, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 - C(O)NH-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 -NHC(O)-C 1-6 Alkyl-C 3-12 Cycloalkyl groups, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 0-6 -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -NHC(O)-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-C 3-12 Cycloalkyl.

[0007] In any part of this invention, the substituents in the substituted or unsubstituted form are selected from C. 1-6 Alkyl, halogen, -CN, -NO2, -OH, C 1-6 Haloalkyl, C 1-6 Acyl group, C 1-6 Acyloxy group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0008] In any part of this invention, the term "alkyl" refers to a hydrocarbon chain that may be straight-chain or branched and contains a specified number of carbon atoms, such as C1-C2.20 Alkyl groups can have 1 to 20 (inclusive) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0009] In any part of this invention, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic carbocyclic system having the indicated carbon atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracene, tetrahydronaphthyl, fluorenyl, indenyl, biphenyl, and acenaphthene.

[0010] In any part of this invention, the term "heterocyclic" includes the definitions of "heterocyclic alkyl" and "heteroaryl". The term "heterocyclic alkyl" refers to a 3- to 10-membered non-aromatic, saturated or partially saturated monocyclic or polycyclic system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, and C(O). Exemplary heterocyclic alkyl groups include tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanecycloyl, 1,4-dioxanecycloyl, etc. "Heteroaryl" refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulfur, and nitrogen. Examples of heteroaryl compounds include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazolium, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzoisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those rings in which a phenyl, pyridine, pyrimidine, or pyridazine ring is fused to a 5- or 6-membered monocyclic heterocyclic base ring, the 5- or 6-membered monocyclic heterocyclic base ring having one or two nitrogen atoms in the ring, a nitrogen atom in the ring connected to an oxygen or sulfur atom, or an O or S ring atom.

[0011] In any part of this invention, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic saturated carbocyclic system having the indicated carbon atoms. Examples of aryl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.

[0012] In any part of the invention, as described in C 6-20 Aryl, (CH2) 0-8、 C 1-6 The numerical range for alkyl groups refers to integers that encompass the indicated endpoint values, such as (CH2). 0-8 It contains 0, 1, 2, 3, 4, 5, 6, 7, and 8 methylene groups; for example, C... 1-6Alkyl groups include C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0013] In this invention, preferably, R is selected from substituted or unsubstituted phenyl C. 0-6 Alkyl; styryl; phthalimide-C 1-6 alkyl; adamantyl C 0-6 Alkyl group; -(CH2) 0-6 -C(O)-(CH2) 0-8 -R', where R' is diphenylmethylamino, adamantyl, adamantylamino, or adamantyl C. 1-6 Alkylamino, adamantyl C 1-6 Alkyl C(O)NH-;-(CH2) 0-6 -NHC(O)-(CH2) 0-8 -Adamantyl group, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 - C(O)NH-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 -NH C(O)-C 1-6 Alkyl-adamantyl, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH- (CH2) 0-6 -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -NHC(O)-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-adamantyl.

[0014] Most preferably, the 7,8-dibromo-9-methyl-2-(piperazin-1-yl)-5,6-dihydro-4H-imidazo[4,5,1-i] J Quinoline derivatives are selected from the following compounds 1-37: ; .

[0015] In this invention, the method for preparing the compound includes the following steps: (1) Compound SEL-12034A undergoes a condensation reaction with an acyl chloride derivative to obtain the product shown in Formula I. Compounds 1-2; The reaction equation is as follows: ; (2) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to obtain compound 3-11 as shown in Formula I; The reaction equation is as follows: ; (3) Compounds a and b undergo a nucleophilic substitution reaction to give intermediate M1; (4) Intermediate M1 undergoes ester hydrolysis to obtain intermediate M2; (5) Intermediate M2 undergoes a condensation reaction to give compound 12 as shown in Formula I; The reaction equation is as follows: ; (6) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to give compounds 13-15 as shown in Formula I; The reaction equation is as follows: ; (7) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to give compounds 16-17 as shown in Formula I; The reaction equation is as follows: ; (8) The alcohol derivative and p-toluenesulfonyl chloride undergo esterification to give intermediates M3-M6; (9) Intermediates M3-M6 undergo a nucleophilic substitution reaction with compound SEL-120 34A to give intermediates M7-M10; (10) Intermediate M7-M10 undergoes a deBoc reaction to yield intermediates M11-M14; (11) Intermediates M11-M14 undergo a condensation reaction with adamantaneacetic acid under condensing agent conditions to obtain compounds 18-21 as shown in Formula I; The reaction equation is as follows: ; (12) The carboxylic acid derivative and adamantane ethylamine undergo a condensation reaction to give intermediates M15-M18; (13) Intermediate M15-M18 undergoes a deBoc reaction to give intermediate M19-M22; (14) Intermediates M19-M22 and M2 undergo a condensation reaction under condensing agent conditions to obtain compounds 22-25 as shown in Formula I; The reaction equation is as follows: ; (15) The amino derivative and adamantaneacetic acid undergo a condensation reaction to give intermediates M23-M25; (16) Intermediate M23-M25 undergoes a deBoc reaction to give intermediates M26-M28; (17) Intermediate M26-M28 undergoes a condensation reaction with intermediate M2 under condensing agent conditions to obtain compound 26-28 as shown in Formula I; The reaction equation is as follows: ; (18) The carboxylic acid derivative and adamantane methylamine undergo a condensation reaction to give intermediates M29-M30; (19) Intermediate M29-M30 undergoes a deBoc reaction to give intermediates M31-M32; (20) Intermediates M31-M32 and intermediate M2 undergo a condensation reaction under condensing agent conditions to obtain compounds 29-30 as shown in Formula I; The reaction equation is as follows: ; (21) Adamantaneacetic acid is first reacted with oxalyl chloride to give intermediate M33; (22) Intermediate M33 undergoes a condensation reaction with an amino derivative to obtain intermediate M34-M40; (23) Intermediate M34-M40 undergoes a deBoc reaction to give intermediate M41-M47; (24) Intermediates M41-M47 react with chloroacetyl chloride to give intermediates M48-M54; (25) Intermediates M48-M54 and SEL-120 34A undergo a condensation reaction under condensing agent conditions to obtain compounds 31-37 as shown in Formula I; The reaction equation is as follows: .

[0016] As another aspect of the present invention, the present invention provides the use of the arylurea compounds in the preparation of CDK8 inhibitors.

[0017] As another aspect of the present invention, the present invention provides the use of the arylurea compounds in the preparation of treatments for colon cancer.

[0018] The beneficial effects of this invention are: (1) The CDK8 hydrophobic tag degrader of the present invention can be used for biological or pharmacological phenomena, CDK8-involved signaling pathway transduction studies, and evaluation of novel CDK8 hydrophobic tag degraders; (2) The CDK8 hydrophobic tag degrader of the present invention was screened for in vitro cell activity, and the results showed that it exhibited strong inhibitory activity against tumor cells, while having low toxicity. (3) The CDK8 hydrophobic tag degrader described in this invention has a novel structure, a simple synthesis process, and high product purity, and has good application prospects. Attached Figure Description

[0019] Figure 1 Effects of compound 32 on CDK8 protein and mRNA levels in HCT116 cells. (A) Representative bands of CDK8 protein expression after treatment with different concentrations of compound 32; (B) Relative expression levels of CDK8 mRNA.

[0020] Figure 2 Effect of compound 32 on the proliferation of HCT116 cells. (A) EdU staining flow cytometry histograms of the control group and the compound 32 treatment group; (B) Macroscopic observation results of plate colony formation assay.

[0021] Figure 3 Effects of compound 32 on cell cycle distribution and apoptosis levels in HCT116 cells. A: Flow cytometry histograms of cell cycle in each group; B: Quantitative analysis of the proportion of each phase of the cell cycle; C: Annexin V. PI double staining flow cytometry plot; D: quantitative statistics of total apoptosis rate.

[0022] Figure 4 Effects of compound 32 on the expression of apoptosis-related proteins in HCT116 cells. A: Representative bands of Cleaved-Caspase-3, Bax, Bcl-2, and Mcl-1 proteins; B–E: Quantitative analysis of the relative expression levels of each protein. ***p<0.001: indicates highly significant difference; NS: indicates no statistical significance.

[0023] Figure 5 Effects of compound 32 on the expression of core proteins in the WNT / β-catenin pathway. (A): Representative bands of WNT-3α, LRP6, DVL2, AXIN1, GSK-3β, and β-catenin proteins; (BG): Quantitative analysis of the relative expression levels of each protein. ***p<0.001: indicates highly significant difference; ns: indicates no statistical significance.

[0024] Figure 6Effect of compound 32 on β-catenin nuclear transcriptional activity. (A) Major protein expression; (BE) Protein grayscale analysis. ***p<0.001: indicates highly significant difference; NS: indicates no statistical significance. Detailed Implementation

[0025] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0026] Example 1 (4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i) J Synthetic steps of quinolino-2-yl)piperazin-1-yl)(phenyl)methyl ketone (1): SEL-120 34A (300 mg, 0.666 mmol) and DIPEA (168.43 mg, 0.231 mmol) were added to a flask, dissolved in 8 mL of dichloromethane, stirred at room temperature for 10 minutes, and benzoyl chloride (140 mg, 0.999 mmol) was slowly added under ice bath. After the addition was completed, the reaction was carried out at room temperature for 3 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:2) After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. Product 1 was then purified by column chromatography using eluent (DCM:MeOH = 100:1), yielding a white solid with a yield of 63.8%. 1 H NMR (400 MHz, DMSO) d 7.48 (dd, J = 6.3, 3.1 Hz, 5H), 4.04 (t, J = 5.7 Hz, 2H), 3.82 (s, 2H), 3.46 (d, J = 40.2 Hz, 6H), 2.85 (t, J = 6.0 Hz,2H), 2.53 (s, 3H), 2.08 (t, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO) d169.75, 156.12, 138.93, 136.12, 132.12, 130.13, 128.96, 127.47, 126.40, 120.88, 117.66, 114.52, 48.97, 43.22, 26.15, 23.16, 18.81.

[0027] Example 2 The synthesis steps for final product 2 are the same as in Example 1: 1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinolin-2-yl)piperazin-1-yl)-2-phenylethane-1-one (2), white solid, yield 68.4% 1 H NMR (400 MHz, DMSO) d 7.36 – 7.30 (m, 2H), 7.24 (dd, J = 12.0, 7.1 Hz, 3H), 4.03 (t, J = 5.7 Hz, 2H), 3.79 (s, 2H), 3.67 (s, 4H), 3.32 – 3.24 (m, 4H), 2.84 (t, J =6.0 Hz, 2H), 2.52 (s, 3H), 2.06 (t, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 163.07, 158.25, 156.03, 155.89, 150.65, 146.58, 136.13, 130.66, 120.26, 115.69, 115.46, 112.27, 112.04, 100.68, 99.62, 60.26, 43.61, 20.20, 14.56.

[0028] Example 3 The final product is 1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i JSynthetic steps of quinolino-2-yl)piperazin-1-yl)-3-phenylpropane-1-one (3): 3-phenylpropionic acid (200 mg, 1.33 mmol), DIPEA (516.38 mg, 4 mmol), HATU (658.3 mg, 1.73 mmol), and 6 mL DMF were stirred at room temperature for 30 minutes. SEL-120 34A (720.12 mg, 1.6 mmol) was added, and the reaction was carried out at room temperature for 6 hours after the addition was complete (the reaction process was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:3). After the reaction was completed, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was washed twice with saturated brine, and then anhydrous sodium sulfate was added to the organic phase to keep it dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography using eluent (DCM:MeOH = 100:1) to give a white solid, with a yield of 56.9%. 1 H NMR (400 MHz, DMSO) d 7.31 – 7.24 (m, 4H), 7.22 – 7.15 (m, 1H), 4.04 (t, J = 5.7 Hz, 2H), 3.68 – 3.58 (m, 4H), 3.34 – 3.27 (m, 4H), 2.84 (t, J = 7.6 Hz, 4H), 2.69 (dd, J = 8.9, 6.6 Hz, 2H), 2.53 (s, 3H), 2.07 (t, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 170.80, 156.19, 141.74, 138.92, 132.10, 128.89, 128.74, 126.38, 120.89, 117.65, 114.48, 49.06, 48.88, 44.84, 43.23, 34.41, 31.18, 26.14, 23.16, 18.82.

[0029] Example 4 The synthesis steps for final product 4 are the same as in Example 3: (E)-1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinolino-2-yl)piperazin-1-yl)-3-phenylprop-2-en-1-one (4), white solid, yield 48.2%1 HNMR (400 MHz, DMSO) d 7.75 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 15.3 Hz, 1H), 7.41(t, J = 7.6 Hz, 3H), 7.33 (d, J = 15.3 Hz, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.92 (s,2H), 3.77 (s, 2H), 3.40 (s, 4H), 2.86 (t, J = 6.0 Hz, 2H), 2.54 (s, 3H), 2.09(t, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO) d 165.21, 156.15, 142.32, 138.98, 135.52, 132.14, 130.12, 129.27, 128.53, 126.37, 120.87, 118.50, 117.65, 114.47, 43.26, 41.68, 26.16, 23.20, 18.83.

[0030] Example 5 The synthesis steps of final product 5 are the same as in Example 3: 1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinolino-2-yl)piperazin-1-yl)-2-(4-isobutylphenyl)propane-1-one (5), white solid, yield 57.6% 1 H NMR (400 MHz, DMSO) d 7.18 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.71 (d, J = 4.2 Hz, 1H), 3.62 (d, J = 6.8 Hz, 2H), 3.52– 3.40 (m, 2H), 3.31 (d, J= 6.5 Hz, 2H), 3.25 – 3.11 (m, 2H), 2.81 (t, J = 6.0Hz, 2H), 2.51 (s, 3H), 2.40 (d, J = 7.2 Hz, 2H), 2.03 (d, J = 5.3 Hz, 2H), 1.79(dt, J = 13.5, 6.7 Hz, 1H), 1.29 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.5 Hz, 6H). 13 CNMR (101 MHz, CDCl3) d 176.91, 160.79, 144.67, 144.56, 143.65, 136.81, 134.51, 132.12, 131.10, 125.54, 122.34, 119.20, 53.59, 49.70, 49.40, 47.88, 46.27, 46.15, 34.82, 30.88, 27.87, 27.37, 27.35, 25.83, 23.49.

[0031] Example 6 The synthesis steps for final product 6 are the same as in Example 3: 1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinolin-2-yl)piperazin-1-yl)-2-((2-isopropyl-5-methylcyclohexyl)oxy)ethane-1-one (6), white solid, yield 45.2% 1 H NMR (400 MHz, CDCl3) d 4.27 (d, J = 12.7 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 4.00 (t, J = 5.8 Hz, 2H), 3.85 – 3.71 (m, 4H), 3.51 – 3.37 (m,4H), 3.20 (d, J = 4.1 Hz, 1H), 2.96 (s, 2H), 2.69 (s, 3H), 2.28 – 2.10 (m, 5H), 1.65 (s, 2H), 0.96 – 0.85 (m, 9H), 0.78 (d,J = 7.0 Hz, 4H). 13 C NMR (101 MHz, CDCl3) d 168.79, 131.29, 127.58, 119.93, 68.45, 49.30, 49.24, 48.27, 45.05, 43.14, 41.26, 40.01, 36.52, 34.39, 31.48, 29.72, 26.12, 25.52, 23.22, 23.13, 22.32, 21.05, 18.83, 16.15.

[0032] Example 7 The synthesis steps of final product 7 are the same as in Example 3: 2-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione (7), white solid, yield 64.4% 1 H NMR (400 MHz, CDCl3) d 7.89 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J =5.5, 3.1 Hz, 2H), 4.56 (s, 2H), 4.00 (t, J = 5.8 Hz, 2H), 3.79 (s, 4H), 3.60(s, 2H), 3.41 (d, J = 5.2 Hz, 2H), 2.96 (t, J = 6.1 Hz, 2H), 2.69 (s, 3H), 2.23 –2.15 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 168.00, 164.38, 155.08, 134.17, 132.20, 131.48, 127.78, 123.58, 119.93, 119.02, 116.01, 53.48, 49.18, 48.85, 44.29, 43.00, 41.71, 39.11, 29.72, 26.13, 23.23, 18.72.

[0033] Example 8 The synthesis steps for final product 8 are the same as in Example 3: 2-(3-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)-3-oxopropyl)isoindoline-1,3-dione (8), white solid, yield 51.3% 1 H NMR (400 MHz, CDCl3) d 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J =5.5, 3.1 Hz, 2H), 4.06 (t, J = 7.6 Hz, 2H), 4.00 (t, J = 5.8 Hz, 2H), 3.79 (t, J =5.1 Hz, 2H), 3.68 (s, 2H), 3.50 (s, 2H), 3.37 (s, 2H), 2.98 – 2.93 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.68 (s, 3H), 2.23 – 2.15 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 168.69, 168.20, 155.13, 134.08, 132.06, 131.40, 127.66, 123.34, 123.26, 119.91, 116.05, 49.25, 49.04, 44.92, 43.06, 41.00, 34.18, 31.68, 29.72, 26.12, 23.22, 18.76.

[0034] Example 9 The synthesis steps of final product 9 are the same as in Example 3: 2-(4-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)-4-oxobutyl)isoindoline-1,3-dione (9), white solid, yield 55.7% 1 H NMR (400 MHz, CDCl3) d 7.86 (dd, J = 5.3, 3.1 Hz, 2H), 7.73 (dd, J=5.4, 3.1 Hz, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.78 (dt, J = 10.1, 5.8 Hz, 4H), 3.64(d, J = 5.0 Hz, 2H), 3.46 (d, J = 5.8 Hz, 2H), 3.34 (d, J = 5.1 Hz, 2H), 2.95 (t, J =6.0 Hz, 2H), 2.67 (s, 3H), 2.44 (t, J = 7.3 Hz, 2H), 2.18 (p, J = 6.0 Hz, 2H), 2.08 (p, J = 7.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 170.43, 168.51, 155.50, 138.65, 134.01, 132.08, 131.60, 127.73, 123.29, 119.83, 118.84, 115.82, 49.35, 49.01, 44.91, 42.98, 41.12, 37.51, 30.35, 26.16, 24.13, 23.25, 18.66. Example 10 The synthesis steps of final product 10 are the same as in Example 3: adamantane-1-yl(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)methyl ketone (10), white solid, yield 53.0% 1 H NMR (400 MHz, CDCl3) d 4.00 (t, J = 5.8 Hz, 2H), 3.90 (t, J = 5.0 Hz, 4H), 3.41 (d, J =5.0 Hz, 4H), 2.95 (t, J = 6.0 Hz, 2H), 2.68 (s, 3H), 2.18 (q, J = 5.9 Hz, 2H),2.10 – 2.05 (m, 3H), 2.03 (d, J= 2.9 Hz, 6H), 1.79 – 1.69 (m, 6H). 13 C NMR (101MHz, CDCl3) d 53.46, 49.59, 44.85, 41.76, 39.10, 36.60, 28.43, 26.11, 23.21.

[0035] Example 11 The synthesis steps of final product 11 are the same as in Example 3: 2-(adamantane-1-yl)-1-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinolin-2-yl)piperazin-1-yl)ethane-1-one (11), white solid, yield 49.1% 1 H NMR (400 MHz, CDCl3) d 4.01 (t, J = 5.8 Hz, 2H), 3.84 (t, J = 5.1 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.52 (s, 2H), 3.38 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H),2.70 (s, 3H), 2.20 (d, J = 10.8 Hz, 4H), 1.99 (s, 3H), 1.68 (q, J = 6.6, 5.4 Hz, 12H). 13 C NMR (101 MHz, CDCl3) d 170.00, 131.33, 127.58, 119.93, 116.17, 49.60, 49.27, 46.45, 46.02, 43.10, 42.92, 40.95, 36.74, 33.73, 28.67, 26.13, 23.22, 18.84.

[0036] Example 12 Intermediate ethyl 2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i JThe synthesis steps of quinoline-2-yl)piperazin-1-yl)acetate (M1) were as follows: 200 mg (0.549 mmol) of 7,8-dibromo-2-chloro-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-IJ]quinoline were weighed and added to a flask. Then, 1-(ethoxycarbonylmethyl)piperazine (113.41 mg, 0.659 mmol) dissolved in 10 mL of DMF was added, and the mixture was stirred with a magnetic stir bar. Subsequently, Et3N (212.77 mg, 1.65 mmol) was added. After the addition was complete, the mixture was placed in a 90°C oil bath for 8 h. The reaction was monitored by TLC (the reaction progress was monitored by thin-layer chromatography, developing solvent: DCM:MeOH = 100:2). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography using eluent (DCM:MeOH=100:1) to obtain a white solid, which was intermediate product M1.

[0037] Intermediate 2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i) J Synthetic steps of quinoline-2-yl)piperazin-1-yl)acetic acid (M2): The intermediate product M1 was added to a flask, followed by 5 ml of dilute sodium hydroxide solution. The mixture was magnetically stirred at 55 °C for 4 h. After the reaction was completed, hydrochloric acid was added to adjust the pH to weakly acidic. A solid precipitated out and was filtered to obtain a white solid, which was the intermediate product M2.

[0038] The final product is N-benzyl-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i]). J Synthetic steps of quinoline-2-yl)piperazin-1-yl)acetamide (12): M2 (250 mg, 0.529 mmol), DIPEA (205.29 mg, 1.59 mmol), HATU (261.71 mg, 0.688 mmol), and 6 mL DMF were stirred at room temperature for 30 minutes. Diphenylmethylamine (116.43 mg, 0.635 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4) After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine, and then anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was concentrated to obtain the crude product. Product 12 was then purified by column chromatography with eluent (DCM:MeOH = 100:2), yielding a white solid in 57.9% yield. 1 H NMR (400 MHz, CDCl3) d 7.89 (d, J = 9.1 Hz, 1H), 7.37 (dd, J = 8.1,6.5 Hz, 4H), 7.33 – 7.29 (m, 2H), 7.29 – 7.24 (m, 4H), 6.33 (d, J = 8.9 Hz, 1H), 3.97 (t, J = 5.8 Hz, 2H), 3.41 (s, 4H), 3.21 (s, 2H), 2.97 (t, J = 6.1 Hz, 2H), 2.76 (s, 4H), 2.70 (s, 3H), 2.22 – 2.13 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 168.85, 155.84, 141.59, 131.57, 128.81, 127.67, 127.57, 127.20, 119.82, 118.85, 115.84, 61.61, 56.19, 53.11, 49.30, 42.93, 26.17, 23.23, 18.74.

[0039] Example 13 The final product is 1-(adamantane-1-yl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinolino-2-yl)piperazin-1-yl)ethane-1-one (13): The intermediate product SEL-120 34A (192.74 mg, 0.428 mmol), DIPEA (150.77 mg, 1.17 mmol), and 6 mL DMF were added to flasks and stirred at room temperature for 10 minutes. Then, compound 1-(adamantane-1-yl)-2-bromoethane-1-one (100 mg, 0.389 mmol) was added. After the addition was complete, the reaction was carried out in an oil bath at 80 °C for 8 hours. (The reaction process was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:2) After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH = 100:1) to obtain a white solid with a yield of 39.7%. 1 H NMR (400 MHz, CDCl3) d 3.95 (t, J = 5.8 Hz, 2H), 3.49 (t, J = 4.9 Hz, 4H), 3.44 (s, 2H), 2.93(t, J = 6.0 Hz, 2H), 2.70 (t, J = 4.9 Hz, 4H), 2.66 (s, 3H), 2.14 (p, J = 6.0 Hz,2H), 2.08 – 2.03 (m, 3H), 1.85 (d, J = 2.9 Hz, 6H), 1.76 (d, J = 12.7 Hz, 4H), 1.69 (d, J = 11.4 Hz, 5H). 13 C NMR (101 MHz, CDCl3) d 211.48, 131.66, 127.37, 119.58, 61.78, 52.62, 48.84, 45.92, 43.27, 38.76, 38.21, 36.49, 27.87, 26.17, 23.34, 21.98, 18.74.

[0040] Example 14 The synthesis steps of final product 14 are the same as in Example 13: N-(adamantane-1-yl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamide (14), white solid, yield 45.1% 1 H NMR (400 MHz, CDCl3) d 6.94 (s, 1H), 3.97 (t, J = 5.8 Hz, 2H), 3.45 (s, 4H), 3.00 (d, J = 5.5 Hz, 2H), 2.95 (t,J = 6.0 Hz, 2H), 2.75 (s, 4H), 2.69 (s, 3H), 2.17 (t, J = 5.9 Hz, 2H), 2.09 (s, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.70 (d, J = 3.1Hz, 6H). 13 C NMR (101 MHz, CDCl3) d 62.18, 52.78, 49.41, 42.99, 41.70, 36.32, 29.72, 29.40, 26.17, 23.23, 18.79.

[0041] Example 15 The synthesis steps of final product 15 are the same as in Example 13: N-(adamantane-1-ylmethyl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamide (15), white solid, yield 36.5% 1 H NMR (400 MHz, CDCl3) d 3.98 (t, J = 5.8 Hz, 2H), 3.48 (t, J = 4.8 Hz, 4H), 3.14 (s, 2H), 2.99 (d, J = 6.4 Hz, 2H), 2.95 (t, J = 6.1 Hz, 2H), 2.84 – 2.73 (m,4H), 2.69 (s, 3H), 2.17 (p, J = 6.1 Hz, 2H), 2.01 – 1.97 (m, 3H), 1.73 (d, J =12.0 Hz, 3H), 1.61 (d, J = 12.1 Hz, 3H), 1.49 (d, J = 2.9 Hz, 6H). 13 C NMR (101MHz, CDCl3) d155.63, 131.44, 127.59, 119.87, 115.99, 61.63, 53.16, 50.46, 49.37, 43.03, 40.40, 36.95, 36.80, 33.65, 29.72, 29.34, 28.15, 26.15, 23.22, 18.82.

[0042] Example 16 The final product is 2-(adamantane-1-yl)-N-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinoline-2-yl)piperazin-1-yl)-2-oxoethyl)acetamide (16): 100 mg (0.398 mmol) of (2-(adamantane-1-yl)acetyl)glycine, 77.14 mg (0.597 mmol) of DIPEA, 196.68 mg (0.517 mmol) of HATU, and 6 mL of DMF were added. The mixture was stirred at room temperature for 30 minutes. SEL-120 34A (197.22 mg, 0.438 mmol) was then added. After the addition was complete, the mixture was reacted at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with a developing solvent of DCM:MeOH = 100:2). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:1) to obtain a white solid with a yield of 43.3%. 1 H NMR (400 MHz, CDCl3) d 6.46 (s, 1H), 4.12 (d, J = 3.9 Hz, 2H), 4.00 (t, J = 5.8 Hz,2H), 3.88 – 3.79 (m, 2H), 3.64 (s, 2H), 3.46 (d, J = 27.1 Hz, 4H), 2.96 (t, J =6.1 Hz, 2H), 2.68 (s, 3H), 2.23 – 2.14 (m, 2H), 2.03 (s, 2H), 1.97 (s, 3H),1.68 (s, 4H), 1.63 (d, J = 3.0 Hz, 8H). 13C NMR (101 MHz, CDCl3) d 171.17, 166.99, 127.77, 119.99, 51.54, 49.14, 49.03, 43.93, 43.03, 42.61, 41.48, 41.21, 38.63, 36.74, 32.83, 29.72, 29.34, 28.63, 26.12, 23.19, 18.80.

[0043] Example 17 The synthesis steps of final product 17 are the same as in Example 16: 2-(adamantane-1-yl)-N-(3-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)-3-oxopropyl)acetamide (17), white solid, yield 44.1% 1 H NMR (400 MHz, CDCl3) d 6.18 (t, J = 6.3 Hz, 1H), 3.92 (t, J =5.8 Hz, 2H), 3.72 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (dd, J = 6.5, 3.8 Hz, 2H), 3.50(q, J = 5.8 Hz, 2H), 3.34 (dd, J = 6.4, 3.6 Hz, 2H), 3.31 – 3.24 (m, 2H), 2.88(t, J = 6.0 Hz, 2H), 2.58 (s, 3H), 2.52 (t, J = 5.6 Hz, 2H), 2.15 – 2.06 (m, 2H), 1.89 (d, J = 3.3 Hz, 3H), 1.84 (s, 2H), 1.64 – 1.49 (m, 13H). 13 C NMR (101 MHz, CDCl3) d171.16, 170.48, 155.31, 138.57, 131.57, 127.80, 119.89, 118.90, 115.92, 55.21, 51.81, 49.26, 49.20, 44.81, 43.24, 42.93, 42.61, 41.05, 36.77, 34.87, 33.01, 32.76, 28.64, 26.15, 23.23, 18.65, 12.42.

[0044] Example 18 The synthesis steps of intermediate 2-((tert-butyloxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (M3) were as follows: tert-butyl(2-hydroxyethyl)carbamate (500 mg, 3.10 mmol) was added to a flask, followed by dissolution with 10 mL of THF solvent. Then, an aqueous solution of NaOH (372 mg, 9.3 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Finally, 4-methylbenzenesulfonyl chloride (887 mg, 4.652 mmol) was added, and the mixture was reacted at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with a developing solvent of DCM:MeOH = 100:2). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:1) to obtain a white solid, which was intermediate M3.

[0045] Intermediate tert-butyl(4-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i) J The synthesis steps of quinoline-2-yl)piperazin-1-yl)butyl)carbamate (M7) were as follows: M3 (500 mg, 1.11 mmol) was weighed and added to a flask. Then, intermediate 2-((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (438.63 mg, 1.33 mmol) was dissolved in 10 mL of acetonitrile, and the mixture was stirred with a magnetic stir bar. Subsequently, K2CO3 (306.71 mg, 2.22 mmol) and KI (18.42 mg, 0.11 mmol) were added. After the addition was complete, the mixture was allowed to react at room temperature for 8 h. The reaction was monitored by TLC (the reaction progress was monitored by thin-layer chromatography, developing solvent: DCM:MeOH = 100:2). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:1) to obtain a white solid, which was intermediate product M7.

[0046] Intermediate 4-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinolino-2-yl)piperazin-1-yl)butane-1-amine hydrochloride (M11): The intermediate product M7 was added to a flask, followed by 5 ml of ethyl acetate hydrochloride solution. The mixture was magnetically stirred for 4 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the white solid intermediate product M11.

[0047] The final product is 2-(adamantane-1-yl)-N-(4-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinoline-2-yl)piperazin-1-yl)butyl)acetamide (18): 2-(adamantane-1-yl)acetic acid (67.03 mg, 0.345 mmol), DIPEA (130.06 mg, 1.01 mmol), HATU (136.65 mg, 0.360 mmol), and 6 mL DMF were added and stirred at room temperature for 30 minutes. M11 (150 mg, 0.289 mmol) was then added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. Product 18 was then purified by column chromatography using eluent (DCM:MeOH = 100:2), yielding a white solid with a yield of 43.5%. 1 H NMR (400 MHz, CDCl3) d 5.80 (s, 1H), 3.90 (t, J = 5.8 Hz, 2H), 3.54 – 3.45 (m, 4H), 3.25 – 3.16 (m, 3H), 3.10 (d, J =7.5 Hz, 1H), 2.87 (s, 4H), 2.68 (s, 2H), 2.58 (s, 3H), 2.08 (d,J = 6.1 Hz, 4H), 1.98 (s, 3H), 1.88 (d, J = 11.6 Hz, 7H), 1.63 (d, J = 11.5 Hz, 7H), 1.38 (d, J = 6.6 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 170.01, 155.57, 138.56, 131.58, 127.70, 119.86, 118.88, 115.89, 49.63, 49.20, 48.27, 47.75, 46.45, 46.04, 45.52, 42.97, 42.93, 42.73, 40.96, 36.86, 36.73, 33.73, 28.71, 28.67, 26.31, 26.16, 24.47, 23.24, 18.70.

[0048] Example 19 The synthesis steps of final product 19 are the same as in Example 18: 2-(adamantane-1-yl)-N-(5-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)pentyl)acetamide (19), white solid, yield 36.7% 1 H NMR (400 MHz, CDCl3) d 5.98 (s, 1H), 3.96 (t, J = 5.8 Hz, 2H), 3.76(t, J = 4.8 Hz, 4H), 3.32 (s, 4H), 3.23 (q, J = 6.1 Hz, 2H), 3.01 (d, J = 8.4 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.62 (s, 3H), 2.15 (p, J = 5.9 Hz, 2H), 2.05 (s,1H), 1.94 (d, J = 5.5 Hz, 4H), 1.82 (s, 2H), 1.72 – 1.60 (m, 6H), 1.56 (s, 6H), 1.46 (dd, J= 18.9, 7.5 Hz, 4H). 13 C NMR (101 MHz, CDCl3) d 170.94, 156.01, 138.93, 131.72, 127.41, 119.61, 118.55, 115.35, 62.60, 58.42, 52.56, 51.94, 48.85, 43.18, 42.65, 39.23, 36.78, 32.73, 32.25, 29.66, 29.57, 29.34, 28.64, 26.17, 24.79, 23.33, 18.70, 16.69.

[0049] Example 20 The synthesis steps of final product 20 are the same as in Example 18: 2-(adamantane-1-yl)-N-(6-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)hexyl)acetamide (20), white solid, yield 46.1% 1 H NMR (400 MHz, DMSO) d 7.78 (t, J = 5.6 Hz, 1H), 4.04 (t, J = 5.7 Hz, 2H), 3.55 (s, 4H), 3.39 (s, 6H), 3.01 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.0 Hz,2H), 2.54 (s, 3H), 2.07 (t, J = 5.8 Hz, 2H), 1.93 – 1.87 (m, 3H), 1.81 (s, 2H), 1.64 (d, J = 12.2 Hz, 4H), 1.57 (s, 4H), 1.54 (d, J = 2.9 Hz, 6H), 1.39 (t, J = 6.7Hz, 2H), 1.33 – 1.25 (m, 4H). 13 C NMR (101 MHz, DMSO) d170.37, 132.12, 126.52, 120.99, 117.73, 114.67, 51.05, 50.50, 43.13, 42.57, 38.59, 36.92, 32.60, 29.40, 28.49, 26.47, 26.13, 23.11, 18.82.

[0050] Example 21 The synthesis steps of final product 21 are the same as in Example 18: 2-(adamantane-1-yl)-N-(2-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)ethoxy)ethyl)acetamide (21), white solid, yield 36.7% 1 H NMR (400 MHz, CDCl3) d 5.94 (s, 1H), 4.21 (d, J = 6.9 Hz, 2H), 4.09 (t, J = 8.2 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.58 (d, J = 5.1 Hz, 2H), 3.48 (d, J = 5.7 Hz, 4H), 2.96 (t, J = 6.1 Hz, 2H), 2.79– 2.71 (m, 4H), 2.68 (s, 3H), 2.17 (t, J = 5.8 Hz, 2H), 2.06 (d, J = 5.8 Hz, 1H), 1.97 (d, J = 10.6 Hz, 4H), 1.72 (d, J = 12.0 Hz, 6H), 1.64 (s, 6H). 13 C NMR (101MHz, DMSO) d 170.47, 139.07, 120.75, 69.59, 50.38, 43.31, 42.54, 38.72, 36.93, 32.61, 28.51, 23.23, 18.79.

[0051] Example 22 The synthesis steps of the intermediate tert-butyl(3-((adamantane-1-ylmethyl)amino)-3-oxopropyl)carbamate (M15) were as follows: 3-tert-butoxycarbonylaminopropionic acid (600 mg, 3.17 mmol), Et3N (802.22 mg, 7.93 mmol), HATU (1.27 g, 3.33 mmol), and 8 mL DMF were added and stirred at room temperature for 30 minutes. Then, adamantane-1-ylmethylamine (524.11 mg, 3.17 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:2) to obtain a white solid M15.

[0052] Synthetic steps of intermediate N-(adamantane-1-ylmethyl)-3-aminopropionamide hydrochloride (M19): Intermediate product M15 was added to a flask, followed by 5 ml of ethyl acetate hydrochloride solution. The mixture was magnetically stirred for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain a white solid intermediate product M19.

[0053] The final product is N-(adamantane-1-ylmethyl)-3-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinoline-2-yl)piperazin-1-yl)acetamyl)propionamide (22): M2 (200 mg, 0.424 mmol), DIPEA (164.23 mg, 1.27 mmol), HATU (169.11 mg, 0.445 mmol), and 6 mL DMF were stirred at room temperature for 30 minutes. M19 (120.14 mg, 0.508 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4) After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine, and then anhydrous sodium sulfate was added to the organic phase for drying. The organic phase was concentrated to obtain the crude product. Product 22 was then purified by column chromatography with eluent (DCM:MeOH = 100:2), yielding a white solid with a yield of 39.9%. 1 H NMR (400 MHz, CDCl3) d7.78 (s, 1H), 5.80 (s, 1H), 3.95 (t, J = 5.8 Hz, 2H), 3.59 (d, J = 6.1 Hz, 2H), 3.44 (t, J = 4.6 Hz, 4H), 3.08(s, 2H), 2.95 (d, J = 6.2 Hz, 4H), 2.68 (d, J = 10.9 Hz, 6H), 2.47 (t, J = 6.1 Hz, 3H), 2.15 (t, J = 5.9 Hz, 2H), 1.97 (s, 3H), 1.71 (d, J = 11.8 Hz, 3H), 1.61 (d, J = 10.0 Hz, 3H), 1.47 (s, 6H). 13 C NMR (101 MHz, CDCl3) d 171.22, 170.16, 161.36, 155.85, 131.62, 127.53, 119.69, 118.71, 61.57, 52.97, 50.97, 49.10, 43.09, 40.20, 40.18, 36.89, 36.86, 35.83, 35.34, 35.24, 34.21, 33.63, 31.94, 30.19, 29.72, 29.68, 29.38, 28.17, 28.15, 26.17, 23.30, 22.72, 18.68, 14.16.

[0054] Example 23 The synthesis steps of final product 23 are the same as in Example 22: N-(adamantane-1-ylmethyl)-6-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)hexamylamide (23), white solid, yield 31.2% 1 H NMR (400 MHz, CDCl3) d 3.98 (t, J = 5.8 Hz, 2H), 3.51 (s, 4H), 3.30 (q, J= 6.7 Hz, 2H), 3.12 (s, 2H), 2.99 – 2.89 (m, 4H), 2.77 (s, 4H), 2.70 (s, 3H), 2.24 – 2.15 (m, 4H), 1.96 (s, 3H), 1.69 (d, J = 7.9 Hz, 6H), 1.57 (dd, J = 18.0, 10.1 Hz, 6H), 1.45 (s, 4H), 1.40 – 1.35 (m, 2H). 13 C NMR (101 MHz, CDCl3) d 172.89, 127.50, 119.94, 61.50, 52.95, 50.89, 49.32, 43.11, 40.22, 38.77, 36.92, 36.71, 33.64, 29.72, 29.43, 28.19, 26.62, 26.14, 25.43, 23.21, 18.87.

[0055] Example 24 The synthesis steps of final product 24 are the same as in Example 22: N-(adamantane-1-ylmethyl)-7-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)heptanamide (24), white solid, yield 42.5% 1 H NMR (400 MHz, CDCl3) d 4.04 (t, J = 5.8 Hz, 2H), 3.73 (s, 4H), 3.30 (q, J = 6.6 Hz, 4H), 2.97 (t, J = 6.1 Hz, 4H), 2.92 (d, J = 6.3 Hz, 4H), 2.76(s, 3H), 2.21 (t, J = 7.5 Hz, 4H), 1.96 (s, 3H), 1.78 – 1.56 (m, 10H), 1.55 (s,2H), 1.46 (d, J = 2.8 Hz, 4H), 1.37 (s, 4H). 13 C NMR (101 MHz, CDCl3) d173.21,127.05, 120.33, 61.03, 52.59, 50.88, 48.94, 43.45, 40.23, 39.02, 36.93,36.75, 33.67, 29.33, 28.82, 28.20, 26.61, 26.01, 25.72, 23.09, 19.27.

[0056] Example 25 The synthesis steps of final product 25 are the same as in Example 22: N-(adamantane-1-ylmethyl)-8-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)octylamide (25), white solid, yield 38.8% 1 H NMR (400 MHz, CDCl3) d 7.71 (s, 1H), 6.22 (s, 1H), 3.99 (t, J =5.8 Hz, 2H), 3.60 (s, 4H), 3.44 (s, 4H), 3.17 (s, 2H), 2.96 (t, J = 6.1 Hz, 2H), 2.82 (s, 4H), 2.71 (s, 3H), 2.18 (d, J = 5.8 Hz, 3H), 1.95 (d, J = 6.5 Hz, 6H), 1.69 (d, J = 12.6 Hz, 3H), 1.66 – 1.57 (m, 9H), 1.31 (dd, J = 33.5, 14.3 Hz, 6H), 0.86 (d, J = 20.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 120.09, 61.22, 52.81, 51.72, 48.97, 42.59, 40.07, 39.56, 36.74, 32.77, 28.64, 26.06, 23.18, 19.09.

[0057] Example 26 The synthesis steps of the intermediate tert-butyl(2-(2-(adamantane-1-yl)acetamito)ethyl)carbamate (M23) were as follows: 2-(adamantane-1-yl)acetic acid (1 g, 5.15 mmol), DIPEA (997.92 mg, 7.72 mmol), HATU (2.54 g, 6.69 mmol), and 8 mL DMF were added and stirred at room temperature for 30 minutes. Then, tert-butyl(2-aminoethyl)carbamate (907.17 mg, 5.66 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:2) to obtain a white solid M23.

[0058] The synthesis steps of intermediate 2-(adamantane-1-yl)-N-(2-aminoethyl)acetamide hydrochloride (M26) were as follows: Intermediate product M23 was added to a flask, followed by 5 ml of ethyl acetate hydrochloride solution. The mixture was magnetically stirred for 4 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain white solid intermediate product M26.

[0059] The final product is 2-(adamantane-1-yl)-N-(2-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthetic steps of quinoline-2-yl)piperazin-1-yl)acetamyl)ethyl)acetamide (26): M2 (150 mg, 0.318 mmol), DIPEA (61.59 mg, 0.477 mmol), HATU (157.03 mg, 0.413 mmol), and 6 mL DMF were stirred at room temperature for 30 minutes. M26 (82.59 mg, 0.349 mmol) was then added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography using eluent (DCM:MeOH = 100:2), yielding a white solid with a yield of 36.6%. 1H NMR (400 MHz, CDCl3) d 7.72 (s, 1H), 6.23 (s, 1H), 3.99 (t, J = 5.8 Hz, 2H), 3.60 (t, J = 4.6 Hz, 4H), 3.44 (t, J = 5.6 Hz, 4H), 3.17 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.82 (s, 4H), 2.71 (s, 3H), 2.18 (t, J =5.9 Hz, 2H), 1.96 (s, 2H), 1.94 (s, 3H), 1.69 (d, J = 12.4 Hz, 4H), 1.64 – 1.58(m, 8H). 13 C NMR (101 MHz, CDCl3) d 171.94, 120.16, 61.14, 52.77, 51.71, 48.91, 43.43, 42.59, 40.01, 39.59, 36.74, 32.77, 28.64, 26.03, 23.15, 19.14.

[0060] Example 27 The synthesis steps of final product 27 are the same as in Example 26: 2-(adamantane-1-yl)-N-(3-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)propyl)acetamide (27), white solid, yield 38.4% 1 H NMR (400 MHz, CDCl3) d 7.57 (s, 1H), 6.18 (t, J = 6.3Hz, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.56 (d, J = 4.9 Hz, 4H), 3.37 (q, J = 6.3 Hz, 2H), 3.26 (q, J = 6.2 Hz, 2H), 3.15 (s, 2H), 2.95 (t, J = 6.1 Hz, 2H), 2.80 (d,J =4.8 Hz, 4H), 2.70 (s, 3H), 2.18 (q, J = 6.0 Hz, 2H), 1.95 (d, J = 5.0 Hz, 5H),1.75 – 1.66 (m, 5H), 1.63 (d, J = 2.8 Hz, 9H). 13 C NMR (101 MHz, CDCl3) d 171.35, 170.45, 155.49, 131.35, 127.47, 119.85, 119.06, 115.97, 61.47, 53.03, 51.90, 49.22, 43.13, 42.65, 36.77, 35.65, 35.61, 32.73, 30.00, 28.64, 26.14, 23.24, 18.82.

[0061] Example 28 The synthesis steps of final product 28 are the same as in Example 26: 2-(adamantane-1-yl)-N-(2-(2-(2-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)ethoxy)ethoxy)ethyl)acetamide (28), white solid, yield 48.5% 1 H NMR (400 MHz, CDCl3) d 7.54 (s, 1H), 6.16 (s, 1H), 4.00 (t, J = 5.8 Hz, 2H), 3.63 (s, 4H), 3.61 – 3.47 (m, 10H), 3.43 (q, J = 5.4 Hz, 2H), 3.16 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.79 (s, 4H), 2.71 (s, 3H), 2.21 – 2.16 (m, 2H), 1.95 – 1.89 (m, 3H), 1.84 (s, 2H), 1.67(d, J = 12.4 Hz, 4H), 1.58 (d, J = 12.1 Hz, 4H), 1.54 (d, J = 2.8 Hz, 4H).13 C NMR (101 MHz, CDCl3) d 171.15, 127.38, 120.05, 70.29, 70.20, 69.97, 69.79, 61.48, 52.91, 51.55, 49.29, 43.18, 42.53, 38.93, 38.71, 36.75, 32.65, 28.63, 26.11, 23.19, 18.95.

[0062] Example 29 The synthesis steps of the intermediate tert-butyl(7-(adamantane-1-ylamino)-7-oxohepyl)carbamate (M29) were as follows: 7-((tert-butyloxycarbonyl)amino)heptanoic acid (1 g, 4.08 mmol), DIPEA (790.28 mg, 6.11 mmol), HATU (2.01 g, 5.30 mmol), and 8 mL DMF were added and stirred at room temperature for 30 minutes. Then, adamane-1-ylmethylamine (741.11 mg, 4.48 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, developing solvent: DCM:MeOH = 100:4) After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography with eluent (DCM:MeOH=100:2) to obtain a white solid M29.

[0063] Synthetic steps of intermediate N-(adamantane-1-yl)-7-aminoheptanamide hydrochloride (M31): Intermediate product M29 was added to a flask, followed by 5 ml of ethyl acetate hydrochloride solution. The mixture was magnetically stirred for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain white solid intermediate product M31.

[0064] The final product is N-(adamantane-1-yl)-7-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i JSynthetic steps of quinoline-2-yl)piperazin-1-yl)acetamyl)heptanamide (29): M2 (150 mg, 0.318 mmol), DIPEA (61.59 mg, 0.477 mmol), HATU (157.03 mg, 0.413 mmol), and 6 mL DMF were stirred at room temperature for 30 minutes. M29 (7.30 mg, 0.349 mmol) was then added. After the addition was complete, the reaction was carried out at room temperature for 6 hours. (The reaction progress was monitored by thin-layer chromatography, with the developing solvent being DCM:MeOH = 100:4). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. The product was then purified by column chromatography using eluent (DCM:MeOH = 100:2), yielding a white solid with a yield of 42.1%. 1 H NMR (400 MHz, CDCl3) d 3.98 (t, J = 5.8 Hz, 2H), 3.49(t, J = 4.8 Hz, 4H), 3.28 (q, J = 6.7 Hz, 2H), 3.12 (s, 2H), 2.95 (t, J = 6.0 Hz,2H), 2.76 (s, 4H), 2.69 (s, 3H), 2.23 – 2.12 (m, 3H), 2.06 (d, J = 10.0 Hz,4H), 1.97 (s, 6H), 1.65 (s, 6H), 1.52 (t, J = 4.6 Hz, 2H), 1.33 (d, J = 3.4 Hz, 3H), 1.26 (d, J = 12.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 172.13, 127.55, 119.90, 61.53, 52.98, 51.80, 49.32, 43.05, 41.68, 38.89, 37.58, 36.36, 29.71, 29.49, 29.43, 28.75, 26.70, 26.15, 25.60, 23.22, 18.82.

[0065] Example 30 The synthesis steps of final product 30 are the same as in Example 29: N-(adamantane-1-yl)-8-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamyl)octylamide (30), white solid, yield 36.8% 1 H NMR (400 MHz, CDCl3) d 3.99 (t, J = 5.8 Hz, 2H), 3.58 – 3.45 (m,4H), 3.29 (q, J = 6.7 Hz, 2H), 3.13 (s, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.77 (s,4H), 2.70 (s, 3H), 2.21 – 2.15 (m, 2H), 2.06 (dd, J = 8.7, 5.4 Hz, 5H), 1.97(d, J = 2.8 Hz, 6H), 1.66 (s, 6H), 1.52 (s, 2H), 1.37 – 1.29 (m, 8H). 13 C NMR (101 MHz, CDCl3) d 172.23, 127.59, 119.86, 61.56, 53.03, 51.76, 49.36, 43.00, 41.69, 38.90, 37.67, 36.36, 29.57, 29.43, 29.02, 28.94, 26.70, 26.17, 25.61, 23.24, 18.78.

[0066] Example 31 The synthesis steps of intermediate 2-((3r,5r,7r)-adamantane-1-yl)acetyl chloride (M33) were as follows: Under nitrogen protection, 2-((3r,5r,7r)-adamantane-1-yl)acetic acid (5.00 g, 24.0 mmol) and 40 mL of DCM were added sequentially to a dry 100 mL flask, and the mixture was magnetically stirred until the solid dissolved. Anhydrous DMF (0.10 mL, 1.3 mmol) was then added, and the reaction mixture was cooled in an ice-water bath. Oxaloyl chloride (3.05 g, 24.0 mmol) was slowly added dropwise under stirring, during which obvious bubbles were observed. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm naturally to room temperature. The reaction was continued with stirring for 4 hours. The reaction progress was monitored by TLC (electrolyte: petroleum ether / ethyl acetate = 3:1, v / v). The sample spots were quenched with anhydrous methanol, and the reaction was considered complete when the starting material spots disappeared. After the reaction was completed, the reaction solution was concentrated under reduced pressure in a water bath to remove the solvent and excess oxalyl chloride. A pale yellow oily substance was obtained, which gradually solidified into a white to off-white solid upon standing, which is the intermediate product M33. This product is sensitive to moisture and can be used directly in the next reaction step.

[0067] The synthesis steps of the intermediate tert-butyl(1-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)azacyclobutane-3-yl)carbamate (M34) were as follows: Under nitrogen protection, tert-butylazacyclobutane-3-ylcarbamate hydrochloride (5.1 g, 24.43 mmol) and anhydrous dichloromethane (40 mL) were added to a dry flask, and a suspension was formed by magnetic stirring. The reaction system was cooled in an ice-water bath, and triethylamine (10.41 g, 102.86 mmol) was slowly added dropwise. During the addition, the suspension gradually became clear, and the system became a homogeneous solution, indicating that the hydrochloride was neutralized and free amine was released. M33 (5.47 g, 25.71 mmol) was dissolved in anhydrous dichloromethane (10 mL) and slowly added dropwise to the above reaction solution through a constant pressure dropping funnel. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally to room temperature. The reaction was then stirred for 3 hours. The reaction progress was monitored by TLC (evolving solvent: petroleum ether / ethyl acetate = 2:1, v / v). After the reaction was complete, the reaction mixture was washed with saturated brine (30 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the crude product was obtained as a pale yellow solid. The crude product was purified by silica gel column chromatography to obtain the target compound as a white solid, M34.

[0068] The synthesis steps of intermediate 2-((3r,5r,7r)-adamantane-1-yl)-1-(3-aminoazacyclobutane-1-yl)ethane-1-one (M41) were as follows: Intermediate M34 was added to a flask, followed by 10 ml of hydrochloric acid-ethyl acetate solution. The mixture was magnetically stirred for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation to obtain a white solid. This solid was then added to a flask, dissolved in water, and adjusted to alkaline pH with dilute sodium hydroxide solution. The solution was extracted with ethyl acetate, and the organic phase was rotary evaporated under reduced pressure to obtain intermediate M41.

[0069] The synthesis steps of intermediate N-(1-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)azacyclobutane-3-yl)-2-chloroacetamide (M48) were as follows: Under nitrogen protection, M41 (5.01 g, 20.17 mmol) and anhydrous dichloromethane (40 mL) were added sequentially to a dry 100 mL flask, and the mixture was magnetically stirred until the solid was completely dissolved. The reaction mixture was cooled in an ice-water bath, and then anhydrous triethylamine (6.12 g, 60.51 mmol) was added and stirred for 5 minutes to ensure homogeneity. 2-Chloroacetyl chloride (2.85 g, 25.21 mL) was dissolved in anhydrous dichloromethane (10 mL) and transferred to a constant-pressure dropping funnel. The solution was slowly added dropwise to the above reaction mixture under stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm naturally to room temperature. The reaction was then stirred for 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was transferred to a separatory funnel and washed with saturated saline (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow crude solid. The crude product was purified by silica gel column chromatography to give a white solid product M48.

[0070] The final product is N-(1-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)azacyclobutane-3-yl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Synthesis steps of quinoline-2-yl)piperazin-1-yl)acetamide (31): Weigh M48 (147.07 mg, 0.453 mmol) into a flask, then add SEL-120 34A (150 mg, 0.362 mmol) dissolved in 10 mL of DMF, and stir with a magnetic stir bar. Then add Et3N (187.25 mg, 1.45 mmol), and after the addition is complete, place in a 90℃ oil bath for 8 h. The reaction is monitored by TLC (the reaction progress is monitored by thin-layer chromatography, developing solvent: DCM:MeOH = 100:2). After the reaction was complete, dichloromethane and water were added and stirred thoroughly. The mixture was allowed to stand and separated, retaining the organic phase. The organic phase was then washed twice with saturated brine. Anhydrous sodium sulfate was then added to the organic phase and kept dry. The organic phase was concentrated to obtain the crude product. Product 31 was then purified by column chromatography with eluent (DCM:MeOH = 100:1), yielding a white solid in 37.4% yield. 1 H NMR (400 MHz, CDCl3) d 7.56 (d, J = 7.5 Hz, 1H), 4.69 (tdd, J =7.7, 5.3, 2.4 Hz, 1H), 4.51 – 4.32 (m, 2H), 3.97 (d, J = 6.0 Hz, 2H), 3.95 –3.77 (m, 2H), 3.55 – 3.32 (m, 4H), 3.12 (s, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.74(t, J = 4.8 Hz, 4H), 2.66 (s, 3H), 2.16 (td, J = 6.6, 6.2, 3.3 Hz, 2H), 2.00 –1.95 (m, 3H), 1.87 (s, 2H), 1.72 – 1.59 (m, 12H). 13 C NMR (101 MHz, CDCl3) d 171.70, 170.03, 119.84, 61.31, 58.47, 54.60, 53.07, 49.32, 45.60, 42.91, 42.61, 38.40, 36.72, 33.52, 28.60, 26.17, 23.24, 18.69.

[0071] Example 32 The synthesis steps of final product 32 are the same as in Example 31: N-(1-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)pyrrolidine-3-yl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamide (32), white solid, yield 44.3% 1 H NMR (400 MHz, CDCl3) d 4.50 (dq, J=25.5, 6.1 Hz, 1H), 3.95 (t, J = 5.7 Hz, 2H), 3.83 – 3.73 (m, 1H), 3.60 (q, J =6.8 Hz, 2H), 3.40 (q, J = 5.1 Hz, 4H), 3.10 (s, 2H), 2.94 (d, J = 6.1 Hz, 2H),2.72 (s, 3H), 2.66 (s, 3H), 2.31 – 2.22 (m, 1H), 2.18 (d, J = 6.2 Hz, 2H), 2.08(d, J = 13.0 Hz, 2H), 2.01 (d, J = 6.0 Hz, 1H), 1.96 (s, 4H), 1.84 (dq, J = 12.9, 6.6 Hz, 1H), 1.67 (t, J = 4.1 Hz, 12H). 13 C NMR (101 MHz, CDCl3) d 170.51, 170.00, 169.65, 155.77, 138.67, 131.59, 127.72, 119.81, 118.80, 61.34, 53.20, 53.01, 50.94, 49.45, 49.33, 48.22, 47.84, 47.47, 45.80, 43.58, 42.90, 42.71, 42.66, 36.77, 33.79, 32.47, 30.20, 28.66, 28.64, 26.17, 23.24, 18.69.

[0072] Example 33 The synthesis steps of final product 33 are the same as in Example 31: N-(1-(2-((1s,3s)-adamantane-1-yl)acetyl)piperidin-4-yl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazolium[4,5,1-i] J Quinoline-2-yl)piperazin-1-yl)acetamide (33), white solid, yield 46.4% 1 H NMR (400 MHz, CDCl3) d 7.10 (d, J = 8.2 Hz, 1H), 4.57 (dd,J = 11.7, 6.6 Hz, 1H), 4.05 – 3.89 (m, 4H), 3.41 (t, J = 4.8 Hz, 4H), 3.10 (s, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.73 (d, J = 4.9 Hz, 4H), 2.67 (s, 3H), 2.17 (d, J = 4.1 Hz, 4H), 2.04 – 1.90 (m, 6H), 1.72 – 1.62 (m, 12H), 1.35 (dt, J = 11.2, 5.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 169.76, 169.11, 155.88, 138.67, 131.59, 127.70, 119.82, 118.79, 115.80, 61.47, 53.00, 49.37, 46.10, 45.73, 42.89, 42.83, 40.36, 36.77, 33.65, 32.80, 32.03, 28.68, 26.17, 23.23, 18.70.

[0073] Example 34 The synthesis steps of final product 34 are the same as in Example 31: N-(2-N-(2-(4-(2-((3r,5r,7r)-adamantane-1-yl)acetyl)piperazin-1-yl)ethyl)-2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazo[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetamide (34), white solid, yield 38.1% 1 H NMR (400 MHz, CDCl3) d 7.50 (s, 1H), 3.96 (t, J = 5.7 Hz, 2H), 3.67 (t, J = 4.9 Hz, 2H), 3.56 (t, J = 5.0Hz, 2H), 3.43 (q, J = 5.8, 4.8 Hz, 6H), 3.12 (s, 2H), 2.94 (t, J= 6.1 Hz, 2H), 2.74 (t, J = 4.8 Hz, 4H), 2.66 (s, 3H), 2.57 (t, J = 5.9 Hz, 2H), 2.50 (dd, J =12.0, 5.8 Hz, 4H), 2.15 (d, J = 8.4 Hz, 4H), 1.95 (s, 3H), 1.72 – 1.56 (m,12H). 13 C NMR (101 MHz, CDCl3) d 169.84, 169.78, 155.81, 138.64, 131.60, 127.60, 119.81, 118.80, 115.76, 61.55, 56.83, 53.22, 53.01, 52.84, 49.40, 46.80, 45.97, 42.99, 42.86, 41.27, 36.73, 35.43, 33.66, 28.65, 26.16, 23.25, 18.72.

[0074] Example 35 The synthesis steps of final product 35 are the same as in Example 31: 2-((3r,5r,7r)-adamantane-1-yl)-N-(1-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazolium[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetyl)pyrrolidine-3-yl)acetamide (35), white solid, yield 42.4% 1 H NMR (400 MHz, CDCl3) d 5.65 (dd, J = 14.2, 6.9 Hz, 1H), 4.49 (q, J = 5.9 Hz, 1H), 3.95 (t, J = 5.8 Hz, 2H), 3.86 – 3.73 (m,1H), 3.62 (dd, J = 16.8, 7.9 Hz, 2H), 3.43 (d, J = 4.6 Hz, 4H), 3.33 – 3.09 (m,2H), 2.93 (t, J= 6.1 Hz, 2H), 2.82 – 2.72 (m, 3H), 2.66 (s, 3H), 2.30 – 2.17(m, 2H), 2.14 (t, J = 6.0 Hz, 2H), 1.97 (d, J = 4.5 Hz, 4H), 1.92 (d, J = 5.1 Hz, 2H), 1.85 (p, J = 6.4 Hz, 1H), 1.76 – 1.61 (m, 6H), 1.60 (d, J = 2.9 Hz, 6H). 13 CNMR (101 MHz, CDCl3) d 171.22, 170.99, 168.32, 156.04, 131.67, 127.44, 119.70, 61.40, 61.10, 52.74, 52.20, 51.56, 51.46, 51.12, 49.81, 49.01, 47.82, 44.53, 43.94, 43.08, 42.64, 36.71, 32.87, 32.84, 32.43, 29.93, 28.59, 28.57, 26.17, 23.28, 18.70.

[0075] Example 36 The synthesis steps of final product 36 are the same as in Example 31: 2-((3r,5r,7r)-adamantane-1-yl)-N-(1-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazolium[4,5,1-i J Quinoline-2-yl)piperazin-1-yl)acetyl)piperidin-4-yl)acetamide (36), white solid, yield 48.8% 1 H NMR (400 MHz, CDCl3) d 5.33 (d, J = 8.2 Hz, 1H), 4.55 (d, J = 13.6 Hz, 1H), 4.16 – 4.02 (m, 2H), 3.96 (q, J = 5.7 Hz, 2H), 3.45 – 3.36 (m, 4H), 3.13 (dd, J = 24.8, 13.5 Hz, 2H), 2.94 (q, J= 5.9 Hz, 2H), 2.71 (dt, J = 10.2, 5.1 Hz, 4H), 2.67 (s, 3H), 2.15 (q, J = 7.5, 6.9 Hz, 2H), 1.99 (d, J = 14.2 Hz, 6H), 1.91 (s, 3H), 1.76 – 1.63 (m, 6H), 1.61 (d, J = 3.0Hz, 6H), 1.38 (tt, J = 11.8, 6.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 170.37, 167.62, 156.08, 138.71, 131.63, 127.50, 119.77, 118.72, 115.66, 61.53, 52.57, 51.82, 49.21, 46.47, 44.86, 43.01, 42.67, 41.07, 36.74, 33.19, 32.80, 32.36, 28.60, 26.18, 23.26, 18.74.

[0076] Example 37 The synthesis steps of final product 37 are the same as in Example 31: 2-((3r,5r,7r)-adamantane-1-yl)-1-(4-(2-(4-(7,8-dibromo-9-methyl-5,6-dihydro-4H-imidazolium[4,5,1-i J Quinolin-2-yl)piperazin-1-yl)acetyl)piperazin-1-yl)ethane-1-one (37), white solid, yield 46.1% 1 H NMR (400 MHz, CDCl3) d 3.96 (t, J = 5.8Hz, 2H), 3.70 – 3.51 (m, 8H), 3.41 (d, J = 5.0 Hz, 4H), 3.30 (s, 2H), 2.93 (t, J = 6.1 Hz, 2H), 2.71 (d, J = 5.2 Hz, 4H), 2.66 (s, 3H), 2.16 (d, J = 12.8 Hz, 4H), 1.98 (s, 3H), 1.73 – 1.62 (m, 12H).13 C NMR (101 MHz, CDCl3) d 170.06, 169.90, 168.09, 167.79, 155.97, 131.64, 127.57, 61.28, 52.57, 49.20, 49.13, 46.71, 46.10, 46.00, 45.70, 42.85, 42.02, 41.76, 41.32, 36.72, 33.74, 28.64, 26.17, 23.27, 18.70.

[0077] Example 38 In vitro cell activity studies of compounds To further evaluate the in vitro activity of the compounds, this study selected three cell lines from three different tumors and the Heprag normal cell line to evaluate their in vitro antitumor proliferative activity and cytotoxicity. As shown in Tables 1-2, several compounds exhibited good antitumor activity. Compared to the positive control drug sorafenib, compounds 32, 34, and 37 showed significantly enhanced antitumor activity and lower toxicity. Compared to the positive control drug SEL-120 34A, compounds 32-35 showed lower toxicity and stronger anti-colorectal cancer activity.

[0078] Table 1: In vitro cell activity of compounds 1-12 ; ; ; Table 2: In vitro cell activity of compound 13-37 ;

[0079] ; ; ; Example 39 Compound 32 targets CDK8 and specifically degrades the CDK8 protein. CDK8, as a serine / threonine kinase that regulates gene transcription, plays a role in WNT / β... Catenin plays a key oncogenic role in colorectal cancer with overactivated signaling pathways and is an important potential target for novel antitumor drug development. To clarify the target and molecular effects of compound 32, this study used Western blot to detect the effect of compound 32 on CDK8 protein levels in HCT116 cells, and simultaneously detected CDK8 gene transcription levels to distinguish between protein degradation and transcriptional repression effects. The results showed that after treatment with compound 32, CDK8 protein expression in HCT116 cells decreased significantly in a dose-dependent manner. Meanwhile, RT... qPCR results confirmed that compound 32 had no significant effect on CDK8 mRNA levels, suggesting that compound 32 does not regulate CDK8 by inhibiting gene transcription, but rather directly targets the CDK8 protein and induces its degradation. These results clarify that compound 32 has a highly targeted and selective degradation effect on CDK8, laying a clear target foundation for subsequent mechanistic studies.

[0080] Example 40 Compound 32 significantly inhibited the proliferation of HCT116 cells by degrading CDK8. Abnormal proliferation of tumor cells is a core biological characteristic of malignant progression in colorectal cancer. To investigate the effect of compound 32 on the proliferative capacity of tumor cells, flow cytometry was used to quantitatively analyze the effects of compound 32 on DNA synthesis and proliferative activity of HCT116 cells; simultaneously, a plate colony formation assay was used to verify the effect of compound 32 on the long-term colony formation ability of cells. EdU incorporation assay results showed that the inhibitory effect of compound 32 on cell proliferation was strictly dose-dependent, highly consistent with the degree of CDK8 protein degradation. The plate colony formation assay showed that the number and size of HCT116 cell clones were significantly reduced after treatment with compound 32, and high concentration groups could hardly form complete clones, indicating that compound 32 can inhibit the independent survival and clonal expansion ability of tumor cells in a long-term and stable manner. The above results confirm that compound 32 effectively blocks the DNA replication and proliferation process of HCT116 cells by targeting and degrading CDK8 protein, exerting a significant in vitro anti-proliferative effect.

[0081] Example 41 Compound 32 induces cell cycle arrest and promotes apoptosis in HCT116 cells. Cell cycle dysregulation is a crucial molecular basis for the sustained proliferation of tumor cells, and CDK8 can maintain tumor cell cycle progression by regulating the transcription of downstream cell cycle-related genes. To further elucidate the intrinsic mechanism by which compound 32 inhibits proliferation, this study used flow cytometry to detect the effect of compound 32 on the cell cycle distribution of HCT116 cells and simultaneously analyzed the level of apoptosis. Cell cycle analysis results showed that the cell cycle distribution in the control group conformed to the characteristics of rapidly proliferating tumor cells; after treatment with compound 32, the cell cycle distribution underwent significant and dose-dependent remodeling: the proportion of cells in the G0 / G1 phase significantly increased, while the proportions of cells in the S and G2 / M phases significantly decreased, indicating that compound 32 can effectively arrest the HCT116 cell cycle in the G0 / G1 phase, blocking the transition to the S phase, thereby inhibiting DNA replication and cell division. This result is completely consistent with the proliferation inhibition phenotype shown in the EdU experiment, revealing the anti-proliferation mechanism of compound 32 from the perspective of cell cycle regulation. Meanwhile, Annexin V... PI double staining flow cytometry results showed that compound 32 significantly induced apoptosis in HCT116 cells, and the apoptosis rate increased significantly with increasing drug concentration. Compared with the control group, the proportion of early and late apoptotic cells in the compound 32 treatment group was significantly increased, showing a typical dose-response relationship of apoptosis, suggesting that compound 32 can effectively initiate the tumor cell apoptosis program while inhibiting proliferation.

[0082] Example 42 Compound 32 activates tumor cell apoptosis through the mitochondrial pathway. To further elucidate the molecular mechanism by which compound 32 induces apoptosis, this study investigated proteins in the core apoptosis pathway. Western blot results showed that treatment with compound 32 significantly upregulated the level of cleaved-caspase-3 protein in a dose-dependent manner. As a core marker of the apoptosis execution phase, its cleavage activation directly indicates that the caspase cascade reaction was effectively activated, and cells entered the programmed cell death process. Simultaneously, the expression of the pro-apoptotic protein Bax was significantly increased, while the expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 was significantly decreased, and the Bax / Bcl-2 ratio significantly increased, suggesting that the mitochondrial apoptosis pathway was significantly activated. The downregulation of Mcl-1, a highly stable anti-apoptotic protein closely related to apoptosis resistance in tumor cells, further confirms that compound 32 can effectively break apoptosis tolerance in tumor cells. In summary, these results indicate that compound 32 initiates and activates the endogenous mitochondrial-dependent apoptosis pathway by upregulating pro-apoptotic proteins, downregulating anti-apoptotic proteins, and activating caspase-3 cleavage, ultimately inducing apoptosis in HCT116 cells.

[0083] Example 43 Compound 32 significantly inhibits WNT / β Activation of the catenin signaling pathway The WNT / β-catenin pathway is frequently and aberrantly activated in colorectal cancer, serving as a core pathway driving tumor proliferation, apoptosis inhibition, and malignant progression. CDK8 is a key transcriptional kinase regulating this pathway. To elucidate the upstream molecular mechanism of the antitumor effect of compound 32, this study systematically examined the expression changes of core proteins in the WNT / β-catenin pathway. The results showed that treatment with compound 32 significantly reduced the expression of upstream regulatory molecules WNT-3α, LRP6, and DVL2, indicating that the WNT ligand-dependent pathway initiation activation process was effectively blocked. Simultaneously, the expression of AXIN1, the core scaffold protein of the β-catenin degradation complex, was significantly upregulated, and GSK-3β levels increased synchronously, indicating that the assembly and function of the β-catenin degradation complex were significantly enhanced, thereby accelerating the phosphorylation and ubiquitination degradation of β-catenin. As a core effector molecule of the pathway, the β-catenin protein level decreased significantly with increasing compound 32 concentration, confirming that the aberrant activation of the WNT / β-catenin pathway was significantly inhibited.

[0084] Example 44 Compound 32 exerts its antitumor effect by degrading CDK8, regulating the WNT pathway, and activating apoptosis. Analysis of the above experimental results shows that compound 32 specifically induces CDK8 protein degradation without affecting its gene transcription level, thus effectively inhibiting the abnormally activated WNT pathway. Based on the inhibition of the WNT pathway, its effect on the nuclear transcriptional function of β-catenin was further analyzed. Under normal circumstances, β-catenin accumulates in the cytoplasm and translocates to the nucleus, binding to TCF / LEF transcription factors and initiating the expression of downstream oncogenes. Experimental results showed that after treatment with compound 32, the expression of TCF1 and LEF proteins significantly decreased. Simultaneously, the expression of typical target genes c-Myc and Cyclin D1 was also significantly reduced. c-Myc, as a classic oncogene transcription factor, participates in cell proliferation, metabolic regulation, and anti-apoptosis processes; its reduced expression directly weakens the proliferative capacity of tumor cells. Cyclin D1 is a key regulatory protein for the G1 / S phase transition of the cell cycle; its decrease indicates that cell cycle progression is inhibited. The reduced activity of the TCF / LEF complex indicates that the nuclear transcriptional function of β-catenin is inhibited. This result is consistent with the aforementioned decrease in β-catenin protein levels, further demonstrating that compound 32 inhibits the WNT signaling pathway at multiple levels. Compound 32 significantly inhibited tumor cell proliferation by reducing the expression of TCF1 / LEF and its target genes c-Myc and Cyclin D1, thereby suppressing β-catenin-mediated transcriptional activity. In summary, compound 32 inhibits WNT / β-catenin-mediated tumor cell proliferation by targeting and degrading CDK8 protein. It targets the catenin pathway, exerts a highly efficient and specific anti-tumor effect, and is a CDK8-targeted anti-colorectal cancer candidate compound with potential development value.

Claims

1. A compound as shown in general formula (I): (I)； in, in, R is selected from substituted or unsubstituted C. 6-20 Aryl C 0-6 Alkyl; C 6-20 Aryl vinyl; Phthalimide-C 1-6 alkyl; C 3-12 cycloalkyl C 0-6 Alkyl group; -(CH2) 0-6 -C(O)-(CH2) 0-8 -R', where R' is diphenylmethylamino, C 3-12 cycloalkyl, C 3-12 Cycloalkylamino, C 3-12 cycloalkyl C 1-6 Alkylamino, C 3-12 cycloalkyl C 1-6 Alkyl C(O)NH-;-(CH2) 0-6 -NHC(O)-(CH2) 0-8 -C 3-12 Cycloalkyl groups, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 - C(O)NH-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 -NHC(O)-C 1-6 Alkyl-C 3-12 Cycloalkyl groups, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 0-6 -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -NHC(O)-C 0-6 Alkyl-C 3-12 Cycloalkyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-C 3-12 cycloalkyl; Furthermore, the substituents in the substituted or unsubstituted form are selected from C. 1-6 Alkyl, halogen, -CN, -NO2, -OH, C 1-6 Haloalkyl, C 1-6 Acyl group, C 1-6 Acyloxy group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

2. The compound according to claim 1, characterized in that, R is selected from substituted or unsubstituted phenyl C. 0-6 Alkyl; styryl; phthalimide-C 1-6 alkyl; adamantyl C 0-6 Alkyl group; -(CH2) 0-6 -C(O)-(CH2) 0-8 -R', where R' is diphenylmethylamino, adamantyl, adamantylamino, or adamantyl C. 1-6 Alkylamino, adamantyl C 1-6 Alkyl C(O)NH-;-(CH2) 0-6 -NHC(O)-(CH2) 0-8 -Adamantyl group, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 - C(O)NH-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O)NH-(CH2) 1-8 -NH C(O)-C 1-6 Alkyl-adamantyl, wherein non-adjacent CH2 groups are optionally replaced by O; -(CH2) 0-6 - C(O)NH- (CH2) 0-6 -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -NHC(O)-C 0-6 Alkyl-adamantyl; -(CH2) 0-6 - C(O) -C 3-6 Heterocyclic group -C(O)-C 0-6 Alkyl-adamantyl; Furthermore, the substituents in the substituted or unsubstituted form are selected from methyl, isobutyl, chlorine, fluorine, bromine, isopropyl, and trifluoromethyl.

3. The compound according to claim 1, characterized in that, Selected from compounds having the following structural formulas: ； 。 4. The method for preparing the compound according to claim 3, characterized in that, The steps include the following: (1) Compound SEL-12034A undergoes a condensation reaction with an acyl chloride derivative to give compounds 1-2 as shown in Formula I; the reaction equation is as follows: ； (2) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to give compound 3-11 as shown in Formula I; the reaction equation is as follows: ； (3) Compounds a and b undergo a nucleophilic substitution reaction to give intermediate M1; (4) Intermediate M1 undergoes ester hydrolysis to obtain intermediate M2; (5) Intermediate M2 undergoes a condensation reaction to give compound 12 as shown in Formula I; the reaction equation is as follows: ； (6) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to give compounds 13-15 as shown in Formula I; the reaction equation is as follows: ； (7) Compound SEL-120 34A undergoes a condensation reaction with a carboxylic acid derivative under condensing agent conditions to give compounds 16-17 as shown in Formula I; the reaction equation is as follows: ； (8) The alcohol derivative and p-toluenesulfonyl chloride undergo esterification to give intermediates M3-M6. (9) Intermediates M3-M6 undergo a nucleophilic substitution reaction with compound SEL-120 34A to give intermediates M7-M10; (10) Intermediate M7-M10 undergoes a deBoc reaction to yield intermediates M11-M14; (11) Intermediates M11-M14 undergo a condensation reaction with adamantaneacetic acid under condensing agent conditions to obtain compounds 18-21 as shown in Formula I; The reaction equation is as follows: ； (12) The carboxylic acid derivative and adamantane ethylamine undergo a condensation reaction to give intermediates M15-M18; (13) Intermediate M15-M18 undergoes a deBoc reaction to give intermediate M19-M22; (14) Intermediates M19-M22 and M2 undergo a condensation reaction under condensing agent conditions to give compounds 22-25 as shown in Formula I; the reaction equation is as follows: ； (15) The amino derivative and adamantaneacetic acid undergo a condensation reaction to give intermediates M23-M25; (16) Intermediate M23-M25 undergoes a deBoc reaction to give intermediates M26-M28; (17) Intermediates M26-M28 and M2 undergo a condensation reaction under condensing agent conditions to give compounds 26-28 as shown in Formula I; the reaction equation is as follows: ； (18) The carboxylic acid derivative and adamantane methylamine undergo a condensation reaction to give intermediates M29-M30; (19) Intermediate M29-M30 undergoes a deBoc reaction to give intermediates M31-M32; (20) Intermediates M31-M32 and M2 undergo a condensation reaction under condensing agent conditions to give compounds 29-30 as shown in Formula I; the reaction equations are as follows: ； (21) Adamantaneacetic acid is first reacted with oxalyl chloride to give intermediate M33; (22) Intermediate M33 undergoes a condensation reaction with an amino derivative to give intermediates M34-M40; (23) Intermediate M34-M40 undergoes a deBoc reaction to give intermediate M41-M47; (24) Intermediates M41-M47 react with chloroacetyl chloride to give intermediates M48-M54; (25) Intermediates M48-M54 and SEL-120 34A undergo a condensation reaction under condensing agent conditions to give compounds 31-37 as shown in Formula I; the reaction equation is as follows: 。 5. The use of the compound according to any one of claims 1-3 in the preparation of CDK8 inhibitors.

6. The use of the compound according to any one of claims 1-3 in the treatment of colon cancer.

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