C-met targeted proteolysis chimera for treating gastric cancer, preparation method, pharmaceutical composition and application thereof

Abstract

The application discloses a C-Met targeted proteolysis chimera for treating gastric cancer and a preparation method, a pharmaceutical composition and application thereof, and belongs to the technical field of chemical medicines. The C-Met inhibitor preparation is complex, the C-Met degradation efficiency is low, the in-vivo and in-vitro anti-tumor activity is insufficient, the oral bioavailability is poor, and the plasma stability is poor, and the like, and the problems of the prepared medicine are solved. The preparation process is simple and easy to implement, the prepared proteolysis targeted chimera or pharmaceutically acceptable salt thereof has the effect of high-efficiency targeted degradation of C-Met, a C-Met degradation agent is obtained, and the in-vivo and in-vitro anti-tumor activity is high. All the prepared compounds show the inhibition ability on human gastric cancer cells SNU-620 and Hs746T, and show the degradation effect on C-Met protein in SNU-620 cells. The liver microsomal stability of the prepared compound is relatively good, and a certain oral bioavailability is shown. In addition, the compound has good plasma stability, has good medicine potential, and is suitable for the development of medicines for treating gastric cancer and other cancers.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug technology, specifically relating to an oral C-Met targeting protein hydrolysis chimera, its preparation method, pharmaceutical composition, and application for the treatment of gastric cancer. Background Technology

[0002] C-Met (hepatocyte growth factor receptor, HGFR), a key member of the receptor tyrosine kinase family, plays a central regulatory role in the development and progression of gastric cancer. Clinical studies have shown that approximately 30-50% of patients with advanced gastric cancer have C-Met amplification or mutations, and this abnormality is closely related to tumor heterogeneity, angiogenesis, and immune escape. Although third-generation MET inhibitors (such as Capmatinib) have shown an objective response rate (ORR) of 20-30% in treatment-naïve patients, the median progression-free survival (mPFS) remains unsatisfactory. This limited efficacy is likely due to complex drug resistance mechanisms, including: 1. kinase domain mutations, such as D1228N / Y1234C, leading to resistance to existing targeted drugs; 2. The effects of HGF bypass activation, or the maintenance of continuous MAPK pathway activation through non-receptor-dependent pathways, promoting the formation of the tumor microenvironment; 3. The effects of clonal evolution, where MET-amplified cell subsets preferentially proliferate under drug pressure, resulting in high expression of drug resistance-related genes. This multifactorial heterogeneity in drug resistance makes it difficult to achieve sustained clinical benefits with a single targeting strategy. PROTAC (Proteolysis-Targeting Chimeras) technology offers an innovative solution to overcome the resistance challenges of traditional C-Met inhibitors. In stark contrast to the traditional occupying antagonistic model, this technology designs bifunctional chimeras, one end binding to the target protein (C-Met) and the other recruiting E3 ubiquitin ligases (such as CRBN), catalyzing ubiquitination and proteasome degradation of the target protein. This "catalytic clearance" mechanism not only achieves dose-dependent degradation of the target protein but also promises to extend the therapeutic window. Therefore, developing novel therapeutic strategies that can simultaneously regulate MET kinase activity and resistance pathways has become a key breakthrough in improving the prognosis of MET-mutant gastric cancer. This invention, through the construction of a proteolysis chimera technology platform, has developed an orally administered C-Met PROTAC molecule, providing an innovative solution for efficiently blocking C-Met to treat gastric cancer. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art and provide a C-Met-type targeted protein hydrolysis chimera, its preparation method, pharmaceutical composition, and application. Specifically, the following technical solution is adopted:

[0004] In a first aspect, the present invention provides a C-Met-type targeting protein hydrolytic chimera comprising an N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-cyclopropane-1,1-dicarboxamide) group, having the following structural formula:

[0005] .

[0006] Preferably, the C-Met-type targeting protein hydrolysis chimera has the general structural formula shown in Formula I:

[0007] Formula I;

[0008] (1) In equation I, when the Linker is When n=1, the corresponding E3 structure is

[0009] , , , ,or .

[0010] (2) When Linker is When n=3, the corresponding E3 structure is

[0011] , , , , , Any one of them; where X is F or H;

[0012] (3) When Linker is When n=4 or 5, the corresponding E3 structure is: ;

[0013] (4) When Linker is The corresponding E3 structure is .

[0014] This invention also provides a method for preparing a C-Met-type target protein hydrolytic chimera, the preparation route of which is shown in Route 1, Route 2, Route 3, Route 4, Route 5, Route 6, Route 7, Route 8 or Route 9:

[0015] Route 1:

[0016]

[0017] Among them, compounds 8a-d are respectively , , , Compounds 9a-d are respectively , , , ;

[0018] Compounds 10a-d are respectively , , , ;

[0019] Compounds A1-A4 are respectively , , , The compounds 8a, 9a, 10a, and A1 correspond to each other in the route; the compounds 8b, 9b, 10b, and A2 correspond to each other; the compounds 8c, 9c, 10c, and A3 correspond to each other; and the compounds 8d, 9d, 10d, and A4 correspond to each other.

[0020] Route 2:

[0021]

[0022] in for , , , Compounds 14-16 are respectively , , , ;

[0023] Compounds A5-A8 are respectively , , , ; in the route Corresponding to compounds 13 and A5, in the route Corresponding to compounds 14 and A6 Corresponding to compounds 15 and A7, Corresponding to compounds 16 and A8;

[0024] Route 3:

[0025] ;

[0026] Route 4:

[0027] ;

[0028] Route 5:

[0029] ;

[0030] Route Six:

[0031] ;

[0032] Route 7:

[0033] ;

[0034] Route 8:

[0035] ;

[0036] Route Nine:

[0037] .

[0038] A third aspect of the present invention also provides the use of the above-mentioned C-Met-targeting protein hydrolytic chimera or a pharmaceutically acceptable salt thereof in the preparation of C-Met inhibitors.

[0039] In a fourth aspect, the present invention also provides the use of the above-mentioned C-Met class targeting protein hydrolytic chimera or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic and / or preventive cancer medicament.

[0040] As a further option, the cancer is stomach cancer.

[0041] In a fifth aspect, the present invention provides a pharmaceutical composition comprising the above-described C-Met-type target protein hydrolytic chimera or a pharmaceutically acceptable salt thereof.

[0042] As a further option, the above-mentioned pharmaceutical composition also includes excipients, solvents, and pharmaceutical carriers.

[0043] As a further option, the excipients mentioned above include at least one of gum arabic, syrup, lanolin, and starch.

[0044] The beneficial effects of this invention are as follows: the preparation process of this invention is simple and easy to carry out, and the prepared protein hydrolysis targeted chimera or its pharmaceutically acceptable salt has a highly efficient targeted degradation effect on C-Met, thus obtaining a C-Met degrading agent with high in vitro and in vivo antitumor activity; in addition, the compound has good plasma stability and good drug development potential, making it suitable for the development of drugs for treating cancers such as gastric cancer. Detailed Implementation

[0045] The following will provide a clear and complete description of the concept, specific structure, and technical effects of the present invention in conjunction with embodiments, so as to fully understand the purpose, solution, and effects of the present invention. It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other.

[0046] Example 1

[0047] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A1) is shown below:

[0048]

[0049] (1) Preparation of compound 7 O-(3-fluoro-4-((7-hydroxy-6-methoxyquinoline-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0050] A solution of compound 6 (450 mg, 0.76 mmol) in MeOH (8 ml) was added, along with degassed Pd / C (16.2 mg, 0.15 mmol), and the mixture was packed with H2 (in a balloon). The reaction mixture was stirred overnight at 25 °C under H2 atmosphere. The mixture was filtered through a diatomaceous earth bed and evaporated to give a crude product. After concentration, 345.7 mg (90%) of the title compound was obtained.

[0051] The detection results for compound 7 are as follows: 1 H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 10.20 (s,1H), 10.02 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 7.91 (dd, J = 13.2, 2.4 Hz,1H), 7.67 - 7.62 (m, 2H), 7.52 (q, J = 3.8 Hz, 2H), 7.40 (t, J = 9.0 Hz, 1H), 7.31 (s, 1H), 7.15 (t, J = 8.9 Hz, 2H), 6.36 (d, J = 5.2 Hz, 1H), 3.96 (s,3H), 1.48 (d, J = 2.9 Hz, 4H). 19 F NMR (376 MHz, DMSO) δ -118.9, -128.8.

[0052] (2) Preparation of compound 9a 2-((4-(2-fluoro-4-(1-(4-fluorophenyl)carbamoyl)cyclopropane-1-carbamoyl)phenoxy)-6-methoxyquinoline-7-yl)oxy)methyl acetate:

[0053] A 4 mL solution of compound 7 (300 mg, 0.59 mmol), methyl 2-bromoacetate (118.0 mg, 0.77 mmol), and potassium carbonate (163.0 mg, 1.18 mmol) in N,N-dimethylformamide was stirred at 60–70°C for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and washed twice with 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane:methanol = 30:1 to give 211.5 mg (65%) of solid.

[0054] The detection results for compound 9a are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.57 (s,1H), 8.47 (d, J = 7.6 Hz, 1H), 7.83 - 7.70 (m, 1H), 7.60 (s, 1H), 7.52 - 7.39(m, 2H), 7.28 (s, 2H), 7.24 - 7.15 (m, 1H), 7.09 - 6.99 (m, 2H), 6.41 (d, J =5.4 Hz, 1H), 4.87 (s, 2H), 4.04 (s, 3H), 3.83 (s, 3H), 1.76 (d, J = 7.3 Hz,2H), 1.63 (d, J = 4.4 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ -116.55, -126.48.

[0055] (3) Preparation of compound A1(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)-2-oxoethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0056] Compound 9a (345.7 mg, 0.60 mmol) was dissolved in 3 mL of lithium hydroxide, 3 mL of water, and 3 mL of tetrahydrofuran. The mixture was reacted at room temperature for 5 h and then concentrated to give compound 10a. Compound 10a (100 mg, 0.18 mmol), compound 11 (72.9 mg, 0.21 mmol), EDCI (41 mg, 0.21 mol), HOBt (29 mg, 0.2 mmol), and N,N-diisopropylethylamine (68.5 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (1 mL) with stirring at room temperature. The mixture was diluted with 10 mL of ethyl acetate and washed twice with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane:methanol = 40:1 to give 79.9 mg (50%).

[0057] The detection results for compound A1 are as follows: 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 10.38 (s,1H), 10.00 (s, 1H), 8.46 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 13.3 Hz, 1H), 7.72(d, J = 8.4 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.53 (d, J = 14.8 Hz, 2H), 7.46 -7.38 (m, 3H), 7.28 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 8.9 Hz, 2H), 6.54 - 6.25(m, 1H), 5.14(s, 1H), 3.97 (s, 3H), 3.78 - 3.38 (m, 10H), 2.96 - 2.69 (m,3H), 2.64 (d, J = 22.1 Hz, 4H), 2.02 (s, 1H).

[0058] Example 2

[0059] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A2) is shown below:

[0060]

[0061] (1) Preparation of compound 9b methyl butyrate 4-((4-(2-fluoro-4-(1-(4-fluorophenyl)carbamoyl)cyclopropane-1-carbamoyl)phenoxy)-6-methoxyquinoline-7-yl)oxy)butyrate:

[0062] A solution of compound 7 (300 mg, 0.59 mmol), compound 8b (139.6 mg, 0.77 mmol), and potassium carbonate (166 mg, 1.2 mmol) in 5 mL of N,N-dimethylformamide was stirred at 60–70°C for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and washed twice with 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane:methanol = 30:1 to give 225.1 mg (63%).

[0063] The detection results for compound 9b are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.50 -8.43 (m, 2H), 7.76 (dd, J = 12.0, 2.4 Hz, 1H), 7.55 (s, 1H), 7.50 - 7.40 (m,2H), 7.38 (s, 1H), 7.30 - 7.14 (m, 2H), 7.10 - 6.99 (m, 2H), 6.38 (dd, J =5.3, 1.1 Hz, 1H), 4.21 (t, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.70 (s, 3H), 2.59(t, J = 7.3 Hz, 2H), 2.26 (p, J = 6.7 Hz, 2H), 1.86 - 1.76 (m, 4H), 1.66 -1.59 (m, 2H).

[0064] (2) Preparation of compound A2 N-(4-(7-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0065] Compound 9b (242.3 mg, 0.4 mmol) was dissolved in 2 mL of lithium hydroxide, 2 mL of water, and 2 mL of tetrahydrofuran. The mixture was reacted at room temperature for 5 h and then concentrated to give compound 10b. A solution of compound 10b (100 mg, 0.17 mmol), compound 11 (68.4 mg, 0.21 mmol), HATU (84 mg, 0.21 mmol), and N,N-diisopropylethylamine (120 mg, 0.93 mmol) in N,N-dimethylformamide (1 mL) was taken. The mixture was diluted with 10 mL of ethyl acetate and washed twice with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with dichloromethane:methanol = 40:1 to give 85.6 mg (55%).

[0066] The detection results for compound A2 are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 8.5 (s,1H), 8.5 - 8.4 (m, 2H), 7.8 - 7.7 (m, 2H), 7.6 (s, 1H), 7.5 - 7.4 (m, 3H),7.3 (s, 2H), 7.2 - 7.1 (m, 2H), 7.1 - 7.0 (m, 3H), 6.4 - 6.4 (m, 1H), 5.0 -4.9 (m, 1H), 4.3 (t, J = 5.9 Hz, 2H), 4.0 (s, 3H), 3.8 (t, J = 5.4 Hz, 2H),3.7 - 3.6 (m, 2H), 3.4 (dt, J = 27.4, 5.4 Hz, 4H), 2.8 (s, 3H), 2.6 (t, J =7.1 Hz, 2H), 2.3 (q, J = 7.9 Hz, 2H), 2.1 (dq, J = 10.0, 3.1 Hz, 1H), 1.8 -1.7 (m, 3H), 1.6 (q, J = 4.7 Hz, 2H). 13C NMR (100 MHz, DMSO) δ 173.3, 170.8,170.5, 168.8, 168.4, 168.0, 167.5, 160.0, 159.8, 157.6, 155.3, 155.0, 152.5,152.3, 150.0, 149.3, 146.8, 138.5, 138.4, 136.2, 136.1, 135.7, 134.3, 125.4,124.3, 123.0, 122.9, 118.9, 118.2, 117.4, 115.6, 115.4, 115.0, 109.6, 109.3, 109.1, 108.4, 102.4, 99.5, 68.2, 56.3, 55.4, 49.3, 47.2, 47.0, 44.5, 40.9, 32.4, 31.5, 29.1, 24.7, 22.7, 15.8.

[0067] Example 3

[0068] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A3) is shown below:

[0069]

[0070] (1) Preparation of methyl valerate of compound 9c 5-((4-(2-fluoro-4-(1-(4-fluorophenyl)carbamoyl)cyclopropane-1-carbamoyl)phenoxy)-6-methoxyquinoline-7-yl)oxy)valerate:

[0071] Compound 7 (300 mg, 0.59 mmol), compound 8c (149.5 mg, 0.77 mmol), and potassium carbonate (163.1 mg, 1.2 mmol) were added to a solution of N,N-dimethylformamide (5 mL) and stirred at 60–70°C for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and washed twice with 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane:methanol = 30:1 to give 242.3 mg (66%).

[0072] Detection results of compound 9c: 1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 10.03 (s,1H), 8.47 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 13.3 Hz, 1H), 7.64 (dd, J = 9.2,5.1 Hz, 2H), 7.52 (d, J = 3.8 Hz, 2H), 7.47 - 7.39 (m, 2H), 7.16 (t, J = 8.9Hz, 2H), 6.41 (d, J = 6.4 Hz, 1H), 4.16 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H),3.60 (s, 3H), 2.43 (t, J = 7.3 Hz, 2H), 1.86 - 1.78 (m, 2H), 1.74 (q, J = 7.5Hz, 2H), 1.47 (d, J = 3.1 Hz, 4H). 19 F NMR (376 MHz, DMSO) δ -118.96, -128.72.

[0073] (2) Preparation of compound A3 N-(4-(7-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)-5-oxopentyl)ox)-6-methoxyquinoline-4-yl)ox)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0074] Compound 9c (245 mg, 0.39 mmol) was dissolved in 2 mL of lithium hydroxide, 2 mL of water, and 2 mL of tetrahydrofuran. The mixture was reacted at room temperature for 5 h and then concentrated to give compound 10c. A solution of compound 10c (100 mg, 0.17 mmol), compound 11 (68.4 mg, 0.21 mmol), HATU (68 mg, 0.21 mol), and N,N-diisopropylethylamine (106.4 mg, 0.83 mmol) in N,N-dimethylformamide (1 mL) was taken. The mixture was diluted with 10 mL of ethyl acetate and washed twice with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with dichloromethane:methanol = 50:1 to give 80.6 mg (51%).

[0075] Detection results for compound A3: 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.54 - 8.31 (m, 3H), 7.82 - 7.66 (m, 2H), 7.56 (s, 1H), 7.49 - 7.41 (m, 3H), 7.25 (d, J =7.7 Hz, 3H), 7.18 (t, J = 8.7 Hz, 1H), 7.05 (t, J = 7.6 Hz, 3H), 6.40 (d, J =5.5 Hz, 1H), 4.94 (dd, J = 12.5, 5.3 Hz, 1H), 4.25 (t, J = 6.2 Hz, 2H), 4.02(s, 3H), 3.85 - 3.59 (m, 4H), 3.40 (d, J = 6.1 Hz, 4H), 3.01 - 2.65 (m, 3H), 2.56 - 2.41 (m, 2H), 2.13 (t, J = 6.7 Hz, 1H), 2.05 - 1.98 (m, 2H), 1.92 (s,2H), 1.78 (s, 2H), 1.62 (s, 2H).

[0076] Example 4

[0077] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A4) is shown below:

[0078]

[0079]

[0080] (1) Preparation of methyl hexanoate of compound 9d6-((4-(2-fluoro-4-(1-(4-fluorophenyl)carbamoyl)cyclopropane-1-carbamoyl)phenoxy)-6-methoxyquinoline-7-yl)oxy)hexanoate:

[0081] Compound 7 (300 mg, 0.59 mmol), compound 8d (161.0 mg, 0.77 mmol), and K₂CO₃ (163.1 mg, 1.2 mmol) were stirred in a solution of N,N-dimethylformamide (5 mL) at 60–70 °C for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and washed twice with 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using dichloromethane:methanol = 40:1 to give 239.3 mg (64%).

[0082] Compound 9d detection results:1 H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.62 (s,1H), 8.49 - 8.44 (m, 1H), 7.82 - 7.71 (m, 1H), 7.55 (s, 1H), 7.49 - 7.39 (m,2H), 7.35 (s, 1H), 7.30 - 7.24 (m, 1H), 7.23 - 7.16 (m, 1H), 7.11 - 6.98 (m,2H), 6.38 (d, J = 5.3 Hz, 1H), 4.15 (t, J = 6.7 Hz, 2H), 4.02 (d, J = 2.8 Hz, 3H), 3.67 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 1.94 (t, J = 7.6 Hz, 2H), 1.81 -1.66 (m, 4H), 1.63 (d, J = 4.4 Hz, 2H), 1.58 - 1.50 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ -116.51, -126.55.

[0083] (2) Preparation of compound A4 N-(4-((7-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)-6-oxohexyl)ox)-6-methoxyquinoline-4-yl)ox)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0084] Compound 9d (239.3 mg, 0.38 mmol) was dissolved in 2 mL of lithium hydroxide, 2 mL of water, and 2 mL of tetrahydrofuran. The mixture was reacted at room temperature for 5 h and then concentrated to obtain compound 10d. Compound 10d (50 mg, 0.08 mmol), compound 11 (32.8 mg, 0.1 mmol), T3P (68 mg, 0.16 mmol), and N,N-diisopropylethylamine (51.6 mg, 0.4 mmol) were stirred in a solution of N,N-dimethylformamide (0.5 mL). The mixture was diluted with 10 mL of ethyl acetate and washed twice with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give 40.0 mg (53%).

[0085] Detection results for compound A4: 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.51 - 8.40 (m, 2H), 8.36 (s, 1H), 7.76 - 7.67 (m, 2H), 7.56 (s, 1H), 7.48 - 7.40 (m,3H), 7.29 - 7.22 (m, 4H), 7.16 (t, J = 8.6 Hz, 1H), 7.09 - 6.98 (m, 3H), 6.38 (d, J = 5.3 Hz, 1H), 4.94 (dd, J = 12.5, 5.4 Hz, 1H), 4.22 (t, J = 6.6 Hz,2H), 4.03 (s, 3H), 3.83 - 3.71 (m, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.39 (q, J= 5.3 Hz, 4H), 2.97 - 2.65 (m, 4H), 2.40 (t, J = 7.6 Hz, 2H), 2.12 (dd, J =13.6, 5.6 Hz, 1H), 1.98 (p, J = 6.6 Hz, 2H), 1.77 (q, J = 4.9 Hz, 5H), 1.62(t, J = 3.9 Hz, 5H).

[0086] Example 5

[0087] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A5) is shown below:

[0088]

[0089] (1) Preparation of compound A5 N-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)-2-oxoethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0090] Compound 12 (500 mg, 1.8 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylic acid (491 mg, 2.17 mmol) was dissolved in 5 mL of N-methylpyrrolidone, and 0.5 mL of N,N-dimethylformamide was slowly added at 90 °C. oThe reaction was carried out at C for 6 hours. After the reaction was complete, purified water was added to precipitate the product, which was then filtered to obtain intermediate 13 for later use. Compound 13 (873 mg, 1.8 mmol) was dissolved in 5 mL of 4N-dioxane hydrochloride solution and stirred at room temperature for 1 hour, then evaporated to dryness. Compound 10a (1014 mg, 1.8 mmol) and T3P (566 mg, 1.8 mmol) were then added to a solution of N,N-dimethylformamide (20 mL) and stirred at room temperature. The mixture was diluted with 50 mL of ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give 1052 mg (63%).

[0091] Detection results of compound A5: 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.38 (s,1H), 10.00 (s, 1H), 8.46 (d, J = 4.2 Hz, 1H), 7.90 (d, J = 13.2 Hz, 1H), 7.64(s, 2H), 7.59 - 7.50 (m, 4H), 7.41 (t, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.16(d, J = 7.3 Hz, 4H), 7.04 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.42 (d, J = 5.1Hz, 1H), 5.05 (s, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.63 (s, 2H), 3.50 (d, J =25.7 Hz, 2H), 2.86 (d, J = 18.6 Hz, 2H), 2.00 (s, 2H), 1.68 (s, 2H), 1.56 (s,2H), 1.47 (s,4H). 19 F NMR (376 MHz, DMSO) δ -118.97, -128.75.

[0092] Example 6

[0093] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A6) is shown below:

[0094]

[0095] (1) Preparation of compound A6 N-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-2-oxoethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0096] Compound 12 (500 mg, 1.8 mmol), hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (460 mg, 2.17 mmol) was dissolved in 5 mL of N-methylpyrrolidone, and 0.5 mL of N,N-dimethylformamide was slowly added at 90 °C. o The reaction was carried out at C for 6 hours. After the reaction was complete, purified water was added to precipitate the product, which was then filtered to obtain intermediate 14 for later use. Compound 14 (843 mg, 1.8 mmol) was dissolved in 5 mL of 4N-dioxane hydrochloride solution and stirred at room temperature for 1 hour, then evaporated to dryness. Compound 10a (1014 mg, 1.8 mmol) and T3P (566 mg, 1.8 mmol) were then added to a solution of N,N-dimethylformamide (20 mL) and stirred at room temperature. The mixture was diluted with 50 mL of ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give 1056 mg (76%).

[0097] Detection results for compound A6: 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.38 (s,1H), 10.00 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 13.2 Hz, 1H), 7.69- 7.62 (m, 3H), 7.52 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 8.8 Hz, 1H), 7.35 (s,1H), 7.15 (t, J = 8.3 Hz, 2H), 6.95 (s, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.41(d, J = 5.1 Hz, 1H), 5.75 (s, 1H), 5.09 - 5.03 (m, 1H), 4.98 (s, 2H), 3.95(s, 3H), 3.88 (t, J = 8.8 Hz, 1H), 3.68 (d, J = 9.6 Hz, 3H), 3.58 (s, 1H), 3.40 (t, J = 12.8 Hz, 3H), 3.24 - 3.15 (m, 2H), 3.08 (s, 1H), 2.88 (t, J =15.0 Hz, 1H), 2.03 - 1.97 (m, 1H), 1.47 (s, 4H). 19 F NMR (376 MHz, DMSO) δ -118.97, -128.77.

[0098] Example 7

[0099] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A7) is shown below:

[0100]

[0101] (1) Preparation of compound A7 N-(4-((7-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-oxoethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0102] Compound 12 (500 mg, 1.8 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid (430 mg, 2.17 mmol) was dissolved in 5 mL of N-methylpyrrolidone, and 0.5 mL of N,N-dimethylformamide was slowly added at 90 °C. o The reaction was carried out at C for 6 hours. After the reaction was complete, purified water was added to precipitate the product, which was then filtered to obtain intermediate 15 for later use. Compound 15 (873 mg, 1.8 mmol) was dissolved in 5 mL of 4N-dioxane hydrochloride solution and stirred at room temperature for 1 hour, then evaporated to dryness. Compound 10a (1014 mg, 1.8 mmol) and T3P (566 mg, 1.8 mmol) were then added to a solution of N,N-dimethylformamide (20 mL) and stirred at room temperature. The mixture was diluted with 50 mL of ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give 1200 mg (74%).

[0103] Detection results for compound A7: 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 10.00 (s,1H), 8.48 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 12.6 Hz, 1H), 7.64 (dd, J = 9.0,4.7 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.52 (s, 2H), 7.42 (t, J = 8.9 Hz,1H), 7.35 (s, 1H), 7.19 - 7.10 (m, 4H), 6.97 (d, J = 8.4 Hz, 1H), 6.43 (d, J= 5.2 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.84 (s, 2H), 4.19 (d, J =10.7 Hz, 2H), 4.03 (s, 2H), 3.93 (s, 3H), 3.86 - 3.76 (m, 2H), 3.57 (d, J =5.8 Hz, 2H), 2.93 - 2.81 (m, 1H), 2.00 (d, J = 11.4 Hz, 1H), 1.48 (d, J = 2.9Hz, 4H), 1.23 (s, 1H). 19 F NMR (376 MHz, DMSO) δ -118.92, -128.72.

[0104] Example 8

[0105] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A8) is shown below:

[0106]

[0107] (1) Preparation of compound A8 N-(4-((7-(2-(2-(2-(2-(2-(2-(2-6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonhepta-yl)-2-oxoethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0108] Compound 12 (500 mg, 1.8 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylic acid (491 mg, 2.17 mmol) was dissolved in 5 mL of N-methylpyrrolidone, and 0.5 mL of N,N-dimethylformamide was slowly added at 90 °C. o The reaction was carried out at C for 6 hours. After the reaction was complete, purified water was added to precipitate the product, which was then filtered to obtain intermediate 16 for later use. Compound 16 (873 mg, 1.8 mmol) was dissolved in 5 mL of 4N-dioxane hydrochloride solution and stirred at room temperature for 1 hour, then evaporated to dryness. Compound 10a (1014 mg, 1.8 mmol) and T3P (566 mg, 1.8 mmol) were then added to a solution of N,N-dimethylformamide (20 mL) and stirred at room temperature. The mixture was diluted with 50 mL of ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give 1052 mg (63%).

[0109] Detection results for compound A8: 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.38 (s,1H), 10.00 (s, 1H), 8.46 (d, J = 4.2 Hz, 1H), 7.90 (d, J = 13.2 Hz, 1H), 7.64(s, 2H), 7.59 - 7.50 (m, 4H), 7.41 (t, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.16(d, J = 7.3 Hz, 4H), 7.04 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.42 (d, J = 5.1Hz, 1H), 5.05 (s, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.63 (s, 2H), 3.50 (d, J =25.7 Hz, 2H), 2.86 (d, J = 18.6 Hz, 2H), 2.00 (s, 2H), 1.68 (s, 2H), 1.56 (s,2H), 1.47 (s,4H).

[0110] Example 9

[0111] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound A9) is shown below:

[0112]

[0113]

[0114] (1) Preparation of compound 17 (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)tert-butyl acetate:

[0115] Compound 11 (100 mg, 0.3 mmol), tert-butyl bromoacetate (69 mg, 0.36 mmol), and N,N-diisopropylethylamine (78 mg, 0.6 mmol) were stirred at room temperature for 1 h in a solution of N,N-dimethylformamide (2 mL). The mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 50:1) to give 78.1 mg (57%). Compound 17 was stirred at room temperature for 5 h in a solution of trifluoroacetic acid:dichloromethane = 1:1 to give compound 18.

[0116] The detection results for compound 17 are as follows: 1H NMR (400 MHz, CDCl3) δ 8.9 (s, 1H), 7.7 (dd, J =8.9, 2.7 Hz, 1H), 7.0 (d, J = 8.4 Hz, 1H), 4.9 (dd, J = 11.6, 5.1 Hz, 1H), 3.6 - 3.4 (m, 4H), 3.2 (d, J = 2.9 Hz, 2H), 2.9 - 2.6 (m, 7H), 2.1 - 2.1 (m,1H), 1.5 (d, J = 2.7 Hz, 9H).

[0117] (2) Preparation of compound 19 (2-((4-(2-fluoro-4-(1-(((4-fluorophenyl)carbamoyl)cyclopropane-1-carbamoyl)phenoxy)-6-methoxyquinoline-7-yl)oxy)ethyl)tert-butyl carbamate:

[0118] Compound 7 (1000 mg, 2.0 mmol), N-Boc ethyl bromide (535.2 mg, 2.4 mmol), and cesium carbonate (1300 mg, 4.0 mmol) were stirred at room temperature for 3 h in a solution of N,N-dimethylformamide (10 mL). The mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 50:1) to give 843.3 mg (65%).

[0119] The detection results for compound 19 are as follows: 1 H NMR (600 MHz, CDCl3) δ 10.3 (s, 1H), 9.0 (s,1H), 8.5 (d, J = 5.3 Hz, 1H), 7.8 (dd, J = 12.1, 2.5 Hz, 1H), 7.6 (s, 1H),7.5 (dd, J = 8.9, 4.8 Hz, 2H), 7.4 (s, 1H), 7.3 - 7.3 (m, 1H), 7.2 (t, J =8.6 Hz, 1H), 7.0 (t, J = 8.4 Hz, 2H), 6.4 (d, J = 5.3 Hz, 1H), 4.5 (t, J =8.0 Hz, 1H), 4.2 (t, J = 5.1 Hz, 2H), 4.0 (s, 3H), 3.6 (d, J = 8.0 Hz, 2H), 1.8 (q, J = 4.7 Hz, 2H), 1.7 - 1.6 (m, 2H), 1.5 (s, 9H).

[0120] (3) Preparation of compound A9 N-(4-((7-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)acetamido)ethoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0121] Compound 19 (778 mg, 1.2 mmol) was dissolved in 2 mL of 4M 1,4-dioxane hydrochloric acid, and concentrated by rotary evaporation after the reaction was complete. 1-Propylphosphine anhydride (115 mg, 0.36 mmol), compound 18 (480 mg, 1.2 mmol), N,N-diisopropylethylamine (46.4 mg, 0.36 mmol), and N,N-dimethylformamide (1 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the mixture was washed with water, extracted with EA, and concentrated. Column chromatography (dichloromethane:methanol = 50:1) yielded 105.6 mg (63%).

[0122] The detection results for compound A9 are as follows: 1 H NMR (400MHz, CDCl3) ) δ 10.05 (s, 1H), 8.84 (s,1H), 8.72 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.69 (d, J = 14.8,5.6 Hz, 3H), 7.56 (s, 1H), 7.52 - 7.45 (m, 3H), 7.26 (s, 2H), 7.15 (d, J =13.5 Hz, 1H), 7.03 (t, J = 8.4 Hz, 2H), 6.96 (d, J = 9.6 Hz, 2H), 6.41(d, J =5.1 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.30 (d, J = 5.3 Hz, 2H), 3.94 (s, 3H), 3.89 - 3.80 (m, 2H), 3.45 (s, 2H), 3.29 (d, J = 21.8 Hz, 4H), 3.09 (s, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 2.81 - 2.67 (m, 2H), 2.63 (t, J = 4.9 Hz, 4H), 2.14 - 2.05 (m, 2H), 1.76 (s, 2H), 1.64 (s, 2H), 1.50 (d, J = 21.9 Hz, 1H).

[0123] Example 10

[0124] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B1) is shown below:

[0125]

[0126] (1) Preparation of compound B1 N-(4-((7-(4-(4-(((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0127] Compound 21 (100 mg, 0.35 mmol) was dissolved in 4M hydrochloric acid and 1 mL of 1,4-dioxane. After reacting for 1 h, the system was concentrated by rotary evaporation. Compound 10b (241 mg, 0.42 mmol), 1-propylphosphonic anhydride (222.6 mg, 0.70 mmol), N,N-diisopropylethylamine (90.3 mg, 0.70 mmol), and N,N-dimethylformamide (2 mL) were added to the system and stirred at room temperature. The mixture was diluted with ethyl acetate and washed with brine. Column chromatography (dichloromethane:methanol = 50:1) yielded 178.2 mg (59%).

[0128] The detection results for compound B1 are as follows: 1 H NMR(400 MHz, CDCl3) δ10.19 (s, 1H), 9.05 (s, 1H),8.89 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 12.1 Hz, 1H), 7.56 (s,1H), 7.46 (dd, J = 14.4, 7.5 Hz, 3H), 7.29 (s, 1H), 7.17 (t, J = 8.7 Hz, 1H), 7.09 - 6.91 (m, 4H), 6.79 (d, J = 7.3 Hz, 2H), 6.37 (d, J = 6.2 Hz, 1H), 4.73(t, J = 7.2 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.01 (s, 3H), 3.69 (d, J =48.7 Hz, 4H), 3.08 - 2.84 (m, 5H), 2.63 (t, J = 7.9 Hz, 3H), 2.27 (d, J = 7.1Hz, 5H), 1.70 (d, J = 47.8 Hz, 4H).

[0129] Example 11

[0130] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B2) is shown below:

[0131]

[0132] (1) Preparation of compound B2 N-(4-((7-(4-(4-(((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0133] Compound 23a (100 mg, 0.35 mmol) was dissolved in 1 mL of 4M hydrochloric acid and 1,4-dioxane. After reacting for 1 h, the system was concentrated by rotary evaporation. Compound 10b (229.3 mg, 0.42 mmol), 1-propylphosphonic anhydride (318 mg, 0.70 mmol), and N,N-diisopropylethylamine (90.3 mg, 0.70 mmol) in N,N-dimethylformamide (2 mL) solution were added to the system and stirred at room temperature. The mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 50:1) to give 181.0 mg (60%).

[0134] The detection results for compound B2 are as follows: 1H NMR (600 MHz, DMSO) δ 10.78 (s, 1H), 10.39 (s,1H), 10.01 (s, 1H), 8.48 (t, J = 4.9 Hz, 1H), 7.90 (d, J = 13.1 Hz, 1H), 7.64(dd, J = 8.5, 4.9 Hz, 3H), 7.52 (d, J = 13.5 Hz, 3H), 7.42 (q, J = 7.0 Hz, 3H), 7.15 (t, J = 8.7 Hz, 3H), 6.92 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.1 Hz,2H), 6.44 (d, J = 5.2 Hz, 1H), 5.75 (s, 1H), 5.68 - 5.64 (m, 1H), 4.55 (d, J= 12.8 Hz, 1H), 4.27 - 4.15 (m, 4H), 4.00 (d, J = 13.4 Hz, 1H), 3.95 (s, 4H), 3.08 (t, J = 12.9 Hz, 1H), 2.98 (s, 1H), 2.83 (s, 1H), 2.72 (ddt, J = 19.7,13.0, 6.5 Hz, 1H), 2.57 (dp, J = 13.3, 8.4 Hz, 5H), 2.06 (dq, J = 12.2, 6.3Hz, 4H), 1.85 (qd, J = 12.2, 4.6 Hz, 1H), 1.71 (d, J = 12.9 Hz, 2H), 1.48 (d,J = 5.9 Hz, 7H).

[0135] Example 12

[0136] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B3) is shown below:

[0137]

[0138] (1) Preparation of compound B3 N-(4-((7-(4-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0139] Compound 23b (100 mg, 0.35 mmol) was dissolved in 1 mL of 4 M hydrochloric acid and 1 mL of 1,4-dioxane. After reacting for 1 h, the system was concentrated by rotary evaporation. Compound 10b (229.3 mg, 0.42 mmol), 1-propylphosphonic anhydride (318 mg, 0.70 mmol), and N,N-diisopropylethylamine (90.3 mg, 0.70 mmol) in 2 mL of N,N-dimethylformamide solution were added to the system and stirred at room temperature. The reaction mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 40:1) to give 190.9 mg (62%).

[0140] The detection results for compound B3 are as follows: 1 H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 10.39 (s,1H), 10.00 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 13.2 Hz, 1H), 7.64(dd, J = 8.5, 5.0 Hz, 2H), 7.52 (d, J = 9.8 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.15 (t, J = 8.6 Hz, 2H), 6.80 (t, J = 9.3 Hz, 1H), 6.53 (d, J = 14.8Hz, 1H), 6.42 (t, J = 7.3 Hz, 2H), 5.86 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 1.5Hz, 2H), 4.26 (p, J = 5.9 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 3.60 (s, 4H), 2.82 (d, J = 16.0 Hz, 4H), 2.71 (dd, J = 12.4, 5.2 Hz, 1H), 2.61 - 2.53 (m, 3H), 2.08 (q, J = 6.5 Hz, 3H), 1.85 (tt, J = 13.9, 7.0 Hz,1H), 1.48 (s, 4H), 1.23 (s, 1H), 0.81 - 0.73 (m, 1H). 19 F NMR (376 MHz, CDCl3)δ -116.44, -121.89, -126.56.

[0141] Example 13

[0142] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B4) is shown below:

[0143]

[0144] (1) Preparation of compound B4 N-(4-((7-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0145] Compound 25 (100 mg, 0.28 mmol) was dissolved in 1 mL of 4M hydrochloric acid and 1,4-dioxane. After reacting for 1 h, the system was concentrated by rotary evaporation. Compound 10b (194.7 mg, 0.33 mmol), 1-propylphosphonic anhydride (178.1 mg, 0.56 mmol), and N,N-diisopropylethylamine (72.2 mg, 0.56 mmol) in 1.5 mL of N,N-dimethylformamide were added to the system and stirred at room temperature for 2 h. The reaction mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 50:1) to give 146.3 mg (56%).

[0146] The detection results for compound B4 are as follows: 1 H NMR (600 MHz, CDCl3) δ 10.15 (s, 1H), 9.18 (s,1H), 8.74 (s, 1H), 8.46 (d, J = 5.4 Hz, 1H), 7.72 (t, J = 13.0 Hz, 1H), 7.60- 7.43 (m, 4H), 7.30 (s, 2H), 7.17 (d, J = 17.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.38 (s, 1H), 4.92 (d, J = 18.0 Hz, 1H), 4.27 (s, 2H), 4.02 (s, 3H),3.73 (d, J = 79.4 Hz, 4H), 3.15 (d, J = 35.1 Hz, 4H), 2.96 - 2.58 (m, 5H), 2.30 (s, 2H), 2.11 (s, 1H), 1.76 (s, 2H), 1.63 (s, 2H), 1.45 (d, J = 54.5 Hz, 1H).

[0147] Example 14

[0148] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B5) is shown below:

[0149]

[0150] (1) Preparation of compound B5 N-(4-((7-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0151] The solution of compound 29 (500 mg, 0.90 mmol) and palladium on carbon (23.2 mg, 0.43 mmol) in tetrahydrofuran (9 mL) was degassed, and hydrogen gas (in a balloon) was injected. The reaction mixture was allowed to react at room temperature for 12 h. The mixture was filtered through diatomaceous earth and concentrated, then dissolved in 1 mL of 1,4-dioxane in 4M hydrochloric acid. After the reaction was complete, the system was concentrated by rotary evaporation. Compound 10b (234.8 mg, 0.43 mmol), 1-propylphosphonic anhydride (235.32 mg, 0.74 mmol), and N,N-diisopropylethylamine (95.5 mg, 0.74 mmol) were stirred in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture was extracted and column chromatography (dichloromethane:methanol = 40:1) to give 172.3 mg (55%).

[0152] The detection results for compound B5 are as follows: 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.39 (s,1H), 10.00 (s, 1H), 8.48 (t, J = 7.1 Hz, 2H), 7.91 (d, J = 15.5 Hz, 1H), 7.78(d, J = 8.6 Hz, 2H), 7.72 - 7.62 (m, 2H), 7.53 (d, J = 10.1 Hz, 2H), 7.50 -7.38 (m, 2H), 7.16 (t, J = 8.9 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.42 (d, J= 5.2 Hz, 1H), 4.84 - 4.68 (m, 1H), 4.22 (t, J = 6.5 Hz, 2H), 3.97 (s, 3H), 3.64 (s, 4H), 3.31 - 3.18 (m, 2H), 2.66 - 2.54 (m, 3H), 2.11 (qd, J = 13.3,5.7 Hz, 3H), 2.04 - 1.90 (m, 1H), 1.49 (d, J = 6.3 Hz, 4H).

[0153] Example 15

[0154] The synthetic route for the C-Met-targeting protein hydrolysis chimera (compound B6) is shown below:

[0155]

[0156] (1) Preparation of compound B6 N-(4-((7-(4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0157] Compound 32 (300 mg, 0.95 mmol), compound 10b (622.0 mg, 1.14 mmol), 1-propylphosphoric anhydride (604.2 mg, 1.90 mmol), N,N-diisopropylethylamine (245.1 mg, 1.90 mmol), and N,N-dimethylformamide (5 ml) were added to a reaction flask and stirred at room temperature. The reaction mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 60:1) to give 481.9 mg (57%).

[0158] The detection results for compound B6 are as follows: 1 H NMR (600 MHz, DMSO) δ 10.83 (s, 1H), 10.39 (s,1H), 10.00 (s, 1H), 8.48 (dd, J = 18.4, 6.8 Hz, 2H), 7.90 (d, J = 13.0 Hz,1H), 7.77 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 8.9, 5.0 Hz, 2H), 7.52 (d, J =13.1 Hz, 2H), 7.40 (d, J = 11.2 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 6.98 (d, J= 8.5 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.74 (ddd, J = 13.2, 8.1, 5.3 Hz,1H), 4.21 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.63 (t, J = 5.1 Hz, 4H), 3.29(dt, J = 26.0, 5.5 Hz, 4H), 2.78 (ddd, J = 18.1, 13.3, 5.5 Hz, 1H), 2.61 -2.53 (m, 2H), 2.09 (tt, J = 14.3, 5.8 Hz, 3H), 2.01 - 1.92 (m, 1H), 1.48 (d,J = 5.7 Hz, 4H).

[0159] Example 16

[0160] The synthetic route for the C-Met-type target protein hydrolysis chimera (compound B7) is shown below:

[0161]

[0162]

[0163] (1) Preparation of compound 34 3-(prop-2-en-1-yl)piperidine-2,6-dione:

[0164] Compound 33 (300 mg, 2.7 mmol), 3-bromoprop-1-yne (321.2 mg, 2.7 mmol), and sodium hydride (71.3 mg, 3.0 mmol) were stirred in a solution of tetrahydrofuran (25 mL) at -20°C. The reaction mixture was extracted and subjected to column chromatography (dichloromethane:methanol = 50:1) to give 322.2 mg (79%).

[0165] The detection results for compound 34 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 2.80 (ddt,J = 17.4, 13.9, 3.5 Hz, 2H), 2.67 - 2.49 (m, 3H), 2.28 (dtd,J = 13.7, 5.1,3.4 Hz, 1H), 2.07 - 1.87 (m, 2H).

[0166] (2) Preparation of compound 36, 4-azidopiperidine-1-carboxylic acid tert-butyl ester:

[0167] Compound 35 (50 mg, 0.25 mmol) and stick were placed at -20 °C. ， The reagent s (53 mg, 0.25 mmol) and potassium carbonate (42 mg, 0.25 mmol) were dissolved in 2 mL of methanol. The reaction solution was extracted and subjected to column chromatography (dichloromethane:methanol = 20:1) to give 38 mg (68%).

[0168] The detection results for compound 36 are as follows: 1 H NMR (400 MHz, CDCl3) δ 3.79 (d, J = 13.5 Hz, 2H), 3.54 (tt, J = 8.7, 3.9 Hz, 1H), 3.05 (ddd, J = 13.2, 9.4, 3.4 Hz, 2H), 1.95 - 1.73 (m, 2H), 1.52 (ddt, J = 13.7, 9.3, 4.6 Hz, 2H), 1.42 (s, 9H). 1

[0169] (3) Preparation of compound 37 4-(4-((2,6-dioxopiperidin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester:

[0170] Compound 34 (100 mg, 0.7 mmol), compound 36 (135.8 mg, 0.6 mmol), copper sulfate pentahydrate (100 mg, 0.4 mmol), and sodium L-ascorbate (118.8 mg, 0.6 mmol) were added to a mixed solution of tert-butanol / tetrahydrofuran / water (2 mL: 2 mL: 2 mL) and reacted at room temperature for 5 h. The reaction solution was extracted and subjected to column chromatography (dichloromethane:methanol = 40:1) to give 203.3 mg (77%).

[0171] The detection results for compound 37 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.41 (s,1H), 4.55 (tt, J = 11.6, 4.0 Hz, 1H), 4.24 (s, 2H), 3.30 (dd, J = 14.9, 4.7Hz, 1H), 3.02 (dd, J = 14.9, 7.2 Hz, 1H), 2.97 - 2.79 (m, 3H), 2.70 (dt, J =17.7, 4.0 Hz, 1H), 2.53 (ddd, J = 17.9, 12.7, 5.3 Hz, 1H), 2.25 - 2.09 (m,3H), 1.89 (dtd, J = 23.7, 12.3, 7.9 Hz, 3H), 1.45 (s, 9H).

[0172] (4) Preparation of compound B7 N-(4-((7-(4-(4-(((2,6-dioxopiperidin-3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxobutoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

[0173] Compound 37 (300 mg, 1.08 mmol) was dissolved in 2 mL of 4M hydrochloric acid containing 1,4-dioxane. After the reaction was complete, the solution was concentrated by rotary evaporation. Compound 10b (709.8 mg, 1.30 mmol), 1-propylphosphonic anhydride (686.9 mg, 2.16 mmol), and N,N-diisopropylethylamine (278.6 mg, 2.16 mmol) were added to the system in 5 mL of N,N-dimethylformamide and stirred. The reaction solution was extracted and column chromatography was performed using dichloromethane:methanol = 50:1 to give 523.8 mg (57%).

[0174] The detection results for compound B7 are as follows:1 H NMR (600 MHz, DMSO) δ 10.69 (s, 1H), 10.51 (s,1H), 10.06 (s, 1H), 8.66 (d, J = 6.0 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.65 (q, J= 4.4 Hz, 3H), 7.62 - 7.56 (m, 2H), 7.49 (t, J = 9.0 Hz, 1H), 7.15 (t, J =8.7 Hz, 2H), 6.69 (d, J = 6.0 Hz, 1H), 4.74 (ddt, J = 11.5, 8.2, 4.1 Hz, 1H),4.50 (d, J = 13.0 Hz, 1H), 4.24 (t, J = 6.4 Hz, 2H), 4.01 (s, 3H), 3.28 -3.15 (m, 2H), 2.83 - 2.70 (m, 3H), 2.60 (t, J = 7.3 Hz, 2H), 2.09 (dq, J =18.4, 8.5 Hz, 4H), 1.97 - 1.77 (m, 2H), 1.65 (qd, J = 12.2, 4.9 Hz, 1H), 1.53- 1.46 (m, 4H).

[0175] Activity evaluation

[0176] The compounds (A1-A9, B1-B7) prepared in Examples 1-15 were subjected to performance testing, and the specific process is as follows:

[0177] (1) To detect the in vitro proliferation inhibitory activity of the above PROTACs compounds against cancer cells, human gastric cancer cells SNU-620 and Hs746T were selected in this invention. The antiproliferative activity of the synthesized compounds was tested by CCK-8 assay. The experimental results are shown in Table 1. As can be seen from Table 1, all compounds showed inhibitory ability. Specifically, compounds A2, A3, A8, A9, B1, B2, B3, B4, B5, B6, and B7 showed strong cytotoxicity against SNU-620, while compounds A2, A3, A4, and B1-B7 showed strong cytotoxicity against Hs746T.

[0178] Table 1. CCK8 assay of PROTAC molecules in SNU-620 and Hs746T cells (unit: nM)

[0179] (2) The degradation effect of the above PROTAC molecules on C-Met protein in SNU-620 cells was evaluated by Western Blot experiment. The expression of C-Met protein in cells was detected by Western Blot experiment and quantified by ImageJ software. The results are shown in Table 2. All compounds showed the ability to degrade c-Met. Specifically, compounds A3, A4, A9 and B1-B7 showed stronger degradation ability and more reasonable linker structure.

[0180] Table 2. Compound structure and degradation ability evaluation (%)

[0181] (3) Determination of the stability of the compound in plasma and buffer solutions

[0182] Furthermore, we conducted in vivo liver microsomal stability tests in humans and mice to examine the stability of the candidate compounds. The results are shown in Table 3. It can be seen that most of them have certain liver microsomal stability, among which compounds A2 and compounds B1-B7 have relatively good liver microsomal stability.

[0183] Table 3. Liver microsomal stability test of PROTAC molecules

[0184] Half-life: +++: > 120 min; ++: 60-120 min; +: < 60 min.

[0185] (4) Pharmacokinetic assay of the compound

[0186] To understand the bioavailability of the active compounds, we conducted pharmacokinetic experiments. The results are shown in Table 4. Most compounds showed a certain degree of oral bioavailability.

[0187] Table 4 Pharmacokinetic Tests of PROTAC Molecules

[0188] (5) Compound animal tumor inhibition experiment

[0189] To evaluate the antitumor activity of the active molecule B1 in vivo, we conducted animal experiments in two xenograft tumor models in mice (SNU-620 and Hs746T). Mice were divided into four groups of five mice each: a control group and a treatment group (30 mg / kg) administered orally once daily for 14 days. Daily mouse weight was recorded. As shown in Table 5, most compounds exhibited antitumor activity, indicating that the C-met degrader demonstrated good tumor-suppressing effects in all four animal models.

[0190] Table 5 Animal Experiments

[0191] (6) Evaluation of the degradation ability of the compound on the C-met mutant

[0192] We constructed a D1128N mutant cell line in SNU620 cells and evaluated its degradation ability using Western blot. The results are shown in Table 6, indicating that all the candidate molecules we screened exhibited a certain degree of degradation ability against the mutant.

[0193] Table 6. Cytotoxicity of PROTAC molecules against mutant cells

[0194] Degradation rate (%): +++: >80; ++: 50-80; +: <50.

[0195] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. Any embodiment that achieves the technical effects of the present invention using the same means should fall within the protection scope of the present invention. Within the protection scope of the present invention, various modifications and variations can be made to the technical solutions and / or implementation methods.

Claims

1. A C-Met-type targeted protein hydrolysis chimera for the treatment of gastric cancer, characterized in that, The general structural formula is shown in Formula I: Equation I; (1) In equation I, when the Linker is When n=1, the corresponding E3 structure is , , , ,or ; (2) When Linker is When n=3, the corresponding E3 structure is , , , , , Any one of them; where X is F or H; (3) When Linker is When n=4 or 5, the corresponding E3 structure is: ; (4) When Linker is The corresponding E3 structure is .

2. A method for preparing the C-Met-type target protein hydrolytic chimera for treating gastric cancer as described in claim 1, characterized in that, The preparation routes are shown as Route 1, Route 2, Route 3, Route 4, Route 5, Route 6, Route 7, Route 8, or Route 9: Route 1: Among them, compounds 8a-d are respectively , , , ; Compounds 9a-d are respectively , , , ; Compounds 10a-d are respectively , , , ; Compounds A1-A4 are respectively , , , The compounds 8a, 9a, 10a, and A1 correspond to each other in the route; the compounds 8b, 9b, 10b, and A2 correspond to each other; the compounds 8c, 9c, 10c, and A3 correspond to each other; and the compounds 8d, 9d, 10d, and A4 correspond to each other. Route 2: in for , , , Compounds 14-16 are respectively , , , ; Compounds A5-A8 are respectively , , , ; in the route Corresponding to compounds 13 and A5, in the route Corresponding to compounds 14 and A6 Corresponding to compounds 15 and A7, Corresponding to compounds 16 and A8; Route 3: ； Route 4: ； Route 5: ； Route Six: ； Route 7: ； Route 8: ； Route Nine: 。 3. The use of the C-Met-targeting protein hydrolytic chimera of claim 1 for treating gastric cancer or a pharmaceutically acceptable salt thereof in the preparation of a C-Met inhibitor.

4. The use of the C-Met class targeting protein hydrolytic chimera of claim 1 for treating gastric cancer or a pharmaceutically acceptable salt thereof in the preparation of a cancer medicament for treating and / or preventing gastric cancer.

5. A pharmaceutical composition, characterized in that, Includes the C-Met class targeting protein hydrolysis chimera as described in claim 1, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition also includes excipients, solvents, and pharmaceutical carriers.

7. The pharmaceutical composition according to claim 6, characterized in that, The excipients include at least one of gum arabic, syrup, lanolin, and starch.

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