An egfr protein degrader with silicon-containing group as hydrophobic tag, preparation method, pharmaceutical composition and application thereof

Abstract

The application belongs to the field of chemical drugs, and discloses an EGFR protein degrading agent with a silicon-containing group as a hydrophobic tag, a preparation method, a pharmaceutical composition and application thereof. The structure of the EGFR protein degrading agent with the silicon-containing group as the hydrophobic tag is shown in formula I, the linker is a saturated aliphatic chain, an unsaturated aliphatic chain, a connecting structure composed of an aromatic ring and a saturated aliphatic chain, or a connecting structure composed of an aromatic ring and an unsaturated aliphatic chain; and R is a specific silicon-containing group as the hydrophobic tag. The application obtains the EGFR protein degrading agent with the silicon-containing group as the hydrophobic tag, the preparation process is simple and easy to implement, the obtained EGFR protein degrading agent has high liver microsomal metabolic stability, has considerable oral bioavailability, shows high treatment efficiency in in-vivo experiments, has certain inhibition effect on proliferation of various tumor cells, and is suitable for development of a cancer drug such as lung cancer.

Description

Technical Field

[0001] The present invention belongs to the field of chemical medicines, and specifically relates to an EGFR protein degrader using a silicon-containing group as a hydrophobic tag, a preparation method thereof, a pharmaceutical composition and applications thereof. Background Art

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase. As a receptor for members of the EGF family, it triggers the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. Increased EGFR activity caused by overexpression, mutation, or amplification of the EGFR gene leads to many human malignancies, including colorectal cancer, lung cancer, esophageal cancer, glioblastoma, anal cancer, and head and neck epithelial cancer. EGFR has been extensively studied in the biomedical community, and several EGFR tyrosine kinase inhibitors have been approved for marketing, such as gefitinib and afatinib. However, clinical data indicate that current drug advances still cannot meet current medical needs, and some patients may develop drug resistance. The development of EGFR degraders may be a solution.

[0003] Hydrophobic tags (Hyt) are bifunctional molecules composed of a target protein ligand, a linker, and a hydrophobic group. By attaching a large, hydrophobic group to a small molecule capable of binding to the target, these bifunctional molecules, upon binding to the target, are mistakenly identified by the cellular protein repair machinery as a misfolded portion of the target protein. This is then folded by chaperones and subsequently degraded by the proteasome. The hydrophobic groups in Hyt molecules tend to have a low molecular weight, potentially resulting in higher solubility and druggability. Currently, the development of hydrophobic tag-based degraders is still in the exploratory stage. For one thing, the reported number of hydrophobic tag fragments is relatively small, leaving considerable room for optimization in degradation activity and physicochemical properties. Furthermore, the precise degradation mechanism remains unclear. Therefore, identifying more hydrophobic fragments with high activity and excellent physicochemical properties, as well as clarifying their corresponding degradation mechanisms, is crucial for the clinical application of hydrophobic tag-based degraders.

[0004] The hydrophobic fragments used in the hydrophobic tag degraders that have been reported so far include adamantane, menthol, norbornene, Boc arginine, carborane, fluorenyl, etc. However, these conventional hydrophobic tag degraders have relatively low degradation effects, poor metabolic stability in liver microsomes, poor solubility and difficulty in oral administration, making them difficult to use for further clinical treatment and development. The development of new hydrophobic tag degraders with better liver microsome stability and oral administration is needed to meet clinical needs. Summary of the Invention

[0005] The purpose of the present invention is to address the deficiencies of the prior art and provide an EGFR protein degrader with high metabolic stability in liver microsomes and oral administration, which uses a silicon-containing group as a hydrophobic tag, as well as a preparation method, pharmaceutical composition, and application thereof. Based on this, the first aspect of the present invention provides an EGFR protein degrader with a silicon-containing group as a hydrophobic tag, the structure of which is shown in Formula I:

[0006]

[0007] Wherein, linker is a saturated fatty chain, an unsaturated fatty chain, a linking structure consisting of an aromatic ring and a saturated fatty chain, or a linking structure consisting of an aromatic ring and an unsaturated fatty chain; R is trimethylsilyl, triethylsilyl, tri-n-propylsilyl, triisopropylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, cyclohexyldimethylsilyl, vinyldimethylsilyl, trimethoxysilyl, triethoxysilyl, phenylvinylmethylsilyl or triphenylsilyl.

[0008] The present invention provides an EGFR protein degrader with a silicon-containing group as a hydrophobic tag. In a bifunctional molecule, the silicon-containing group serves as the hydrophobic tag, and the gefitinib core serves as the target protein ligand, resulting in a protein degrader capable of effectively degrading EGFR. The EGFR protein degrader prepared by the present invention can effectively induce EGFR degradation in human lung cancer cell lines (HCC-827 and PC-9 cell lines) in a dose-dependent and time-dependent manner, exhibits considerable liver microsomal stability and bioavailability, and demonstrates excellent in vivo anticancer effects.

[0009] Among them, the linker is a saturated fatty chain, an unsaturated fatty chain, a linking structure composed of an aromatic ring and a saturated fatty chain, or a linking structure composed of an aromatic ring and an unsaturated fatty chain. By selecting ideal linkers of different types and lengths, the purpose of maintaining the binding of the two proteins without interfering with their spatial binding is achieved. Based on this, in some more preferred implementations, the structure of the EGFR protein degrader with a silicon-containing group as a hydrophobic tag is shown in Formula II, Formula III, Formula IV, Formula V or Formula VI:

[0010]

[0011] wherein m and n are independently selected from integers of 1-3, o is 1 or 2, x is 5 or 6, and y is 2 or 3;

[0012] R1 is R2 is

[0013] In a more preferred embodiment, the structure is any one of compounds 1-20:

[0014]

[0015]

[0016] Wherein, in the structure of formula II, n is 1, R1 is When n is 2, R1 is When n is 3, R1 is When n is 1, R1 is When n is 2, R1 is When n is 3, R1 is When n is 2, R1 is When n is 2, R1 is When n is 2, R1 is When , it is compound 9.

[0017] In the structure of formula III, m is 1, R2 is When m is 2, R2 is When m is 3, R2 is When m is 2, R2 is When m is 3, R2 is When , it is compound 14.

[0018] In the structure of Formula IV, when o is 1, it is Compound 15; when o is 2, it is Compound 16. In the structure of Formula V, when x is 5, it is Compound 17; when x is 6, it is Compound 18. In the structure of Formula VI, when y is 2, it is Compound 19; when y is 3, it is Compound 20.

[0019] More preferably, when the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is as shown in compound 7, it can effectively induce the degradation of EGFR in human lung cancer cell lines (HCC-827, PC-9 cell lines) in a dose-dependent and time-dependent manner, has considerable liver microsomal stability and bioavailability, and exhibits excellent in vivo anti-lung cancer effects.

[0020] A second aspect of the present invention provides a method for preparing the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag. When the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is any one of compounds 1-5, its preparation method is shown in Scheme 1; when the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is any one of compounds 6-14, its preparation method is shown in Scheme 2; when the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is any one of compounds 15-16, its preparation method is shown in Scheme 3; when the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is any one of compounds 17-18, its preparation method is shown in Scheme 4; when the structure of the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag is any one of compounds 19-20, its preparation method is shown in Scheme 5.

[0021] Route 1: Using silicon-containing chlorosilanes (B1-B5) and alkynols of different lengths (A1-A3) under the action of imidazole to obtain intermediates C1-C9, the gefitinib core E and tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate (compound D) are substituted under the action of potassium carbonate and N,N-dimethylformamide to obtain intermediate F, which is then de-Bocated under the action of trifluoroacetic acid to obtain intermediate G. Compound G undergoes a substitution reaction with 2-azidoethyl-4-methylbenzenesulfonate under the action of cesium carbonate to obtain intermediate H, which then undergoes a click reaction with C1-C5 to obtain the final product 1-5.

[0022]

[0023] Route 2: Compound E reacts with 2-azidoethyl-4-methylbenzenesulfonate in the presence of potassium carbonate to produce intermediate I, which then undergoes a click reaction with C1-C9 to obtain the final product 6-14.

[0024]

[0025] Route 3: Tert-butyldiphenylchlorosilane (Compound B1) and bromohydrins of different lengths (Compounds K1-K4) undergo substitution reaction under the action of imidazole to obtain intermediates K1-K4. K1 and K2 undergo substitution reaction with Compound G under the action of cesium carbonate to obtain the final products 15-16.

[0026]

[0027] Route 4: K3, K4 and compound E undergo substitution reaction in the presence of potassium carbonate to obtain the final product 17-18.

[0028]

[0029] Route 5: Bromopolyethylene glycols of different lengths (L1, L2) react with compound E in the presence of potassium carbonate to produce intermediates M1 and M2, which are then reacted with tert-butyldiphenylsilyl chloride in the presence of imidazole to obtain the final products 19-20.

[0030]

[0031] Among them, a) represents the addition of imidazole and dichloromethane; b) represents the addition of potassium carbonate and N,N-dimethylformamide, and the temperature is 60°C; c) represents the addition of trifluoroacetic acid and dichloromethane, and the temperature is 0°C; d) represents the addition of cesium carbonate, potassium iodide, and acetonitrile, and reflux; e) represents the addition of copper sulfate, sodium L-ascorbate, and tert-butanol / water.

[0032] The preparation method of the present invention has a simple route, uses cheap and easily available raw materials, and has a high overall reaction yield.

[0033] The EGFR protein degrader described herein, which utilizes a silicon-containing group as a hydrophobic tag, or a pharmaceutically acceptable salt thereof, can be used to prepare a medicament for treating cancers associated with EGFR abnormalities. These cancers include lung cancer, gastric cancer, breast cancer, colorectal cancer, and pancreatic cancer. More preferably, the cancer is lung cancer.

[0034] The third aspect of the present invention provides a pharmaceutical composition, comprising the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag or a pharmaceutically acceptable salt thereof (or, the above-mentioned EGFR protein degrader with a silicon-containing group as a hydrophobic tag or a pharmaceutically acceptable salt thereof as the main active ingredient). In some preferred implementations, the above-mentioned pharmaceutical composition may also include at least one of an excipient, a solvent and a pharmaceutical carrier. Among them, the excipient is at least one of gum arabic, syrup, lanolin and starch; it has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easy to deform, crack, mildew, or be eaten by insects at room temperature, is harmless to the human body, has no physiological effects, does not produce chemical or physical reactions with the main drug, and does not affect the content determination of the main drug. The solvent can be water, glycerol or ethanol.

[0035] The beneficial effects of the present invention are as follows: the present invention obtains an EGFR protein degrader with a silicon-containing group as a hydrophobic tag, the preparation process is simple and easy, the obtained EGFR protein degrader has high liver microsome metabolic stability, has considerable oral bioavailability, shows a high therapeutic effect in in vivo experiments, has a certain inhibitory effect on the proliferation of various tumor cells, and is suitable for the development of drugs for the treatment of cancers such as lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1The graph shows the effect of compound 7 on the degradation of EGFR in two human lung cancer cell lines, PC-9 and HCC-827, in a concentration-dependent manner; (A) is a Western Blot image, (B) is a DC 50 picture;

[0037] Figure 2 The figure shows the time-dependent degradation effect of compound 7 on EGFR in two human lung cancer cell lines, PC-9 and HCC-827;

[0038] Figure 3 Shown is the effect of compound 7 on maintaining EGFR degradation for a long time in an in vivo xenograft model. DETAILED DESCRIPTION

[0039] The following will be combined with the embodiments and drawings to clearly and completely describe the concept and technical effects of the present invention so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention can be combined with each other without conflict.

[0040] Example 1

[0041] An EGFR protein degrader (denoted as compound 1-5) with a silicon-containing group as a hydrophobic tag, whose structures are shown below:

[0042]

[0043] The structures of the intermediate compounds A1-A3, B1-B2, C1-C5, D, E, F, G, 2-azidoethyl-4-methylbenzenesulfonate, and H are shown below:

[0044]

[0045]

[0046] The specific preparation method is:

[0047] 1) Preparation of compounds C1-C5:

[0048] In an ice bath, compound A1 (140 mg, 2.00 mmol) was dissolved in dichloromethane (12 mL), and compound B1 (912 mg, 2.40 mmol) and imidazole (408 mg, 6.00 mmol) were added respectively. The ice bath was removed after 30 minutes, and the mixture was stirred at room temperature overnight. The solid was filtered out, and the remaining organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel flash column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain compound C1.

[0049] Compound C1 was tested, and the test results were as follows: 1 H NMR(400MHz, CDCl3)δ7.69(dt,J=6.5,1.6Hz,4H),7.52–7.33(m,6H),3.80(t, J=7.1Hz,2H),2.46(td,J=7.1,2.7Hz,2H),1.95(t,J=2.7Hz,1H),1.07(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,133.7,129.9,127.8,81.6,69.5,62.5,26.9,22.7,19.3.

[0050] According to the same method for preparing compound C1, compound A1 was replaced with compound A2 (168 mg, 2.00 mmol) to obtain compound C2.

[0051] Compound C2 was tested, and the test results were as follows: 1 H NMR (400MHz, CDCl3) δ7.82–7.60(m,4H),7.40(qd,J=8.4,7.6,3.6Hz,6H),3.76(t,J=6.0H z,2H),2.36(td,J=7.2,2.7Hz,2H),1.92(t,J=2.7Hz,1H),1.90–1.67(m,2H),1.07(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,134.0,129.7,127.8,84.4,68.4,62.4,31.6,27.0,19.4,15.1.

[0052] According to the same method for preparing compound C1, compound A1 was replaced with compound A3 (196 mg, 2.00 mmol) to obtain compound C3.

[0053] Compound C3 was tested, and the test results were as follows: 1 H NMR (400MHz, CDCl3) δ7.73 (dq, J=6.3, 2.0Hz, 4H), 7.58–7.36 (m, 6H), 3.74 (t, J=5.8Hz, 2H), 2.23(td,J=6.7,2.7Hz,2H),1.97(t,J=2.7Hz,1H),1.82–1.60(m,4H),1.11(s,9H). 13C NMR (100MHz, CDCl3) δ135.7,134.1,129.7,127.8,84.6,68.5,63.4,31.7,27.0,25.1,19.4,18.3.

[0054] According to the same method for preparing compound C1, compound A1 was replaced by compound A2 (168 mg, 2.00 mmol), and compound B1 was replaced by compound B2 (530 mg, 3.00 mmol) to obtain compound C4.

[0055] Compound C4 was tested, and the test results were as follows: 1 H NMR(400MHz, CDCl3) δ3.66(t,J=6.1Hz,2H),2.26(td,J=7.1,2.7Hz,2H),1.92(t,J =2.7Hz,1H),1.82–1.57(m,7H),1.32–1.04(m,5H),0.78–0.54(m,1H),0.04(s,6H). 13 C NMR (100MHz, CDCl3) δ84.3,68.4,61.2,31.6,28.0,27.1,27.0,26.7,15.0,-4.0.

[0056] Compound C5 was obtained by the same method as that for preparing compound C1, except that compound A1 was replaced by compound A3 (196 mg, 2.00 mmol) and compound B1 was replaced by compound B2 (530 mg, 3.00 mmol).

[0057] Compound C5 was tested, and the test results were as follows: 1 H NMR (400MHz, CDCl3) δ3.60(d,J=3.5Hz,1H),2.21(s,2H),1.94(s,1H),1.64(d,J=45.6Hz,10H),1.13(s,4H),0.86(s,2H),0.15--0.12(m,6H). 13 C NMR (100MHz, CDCl3) δ73.5,68.4,62.4,31.9,29.5,28.1,27.1,27.0,25.1,18.4,-4.0.

[0058] 2) Preparation of Compound F: Compound D (1.69 g, 5.50 mmol) and Compound E (1.60 g, 5.00 mmol) were dissolved in N,N-dimethylformamide (15 mL), potassium carbonate (1.73 g, 12.5 mmol) was added, and the reaction was carried out at 60°C overnight. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×40 mL). The organic phases were then combined and the reaction solution was washed with saturated NaCl solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain Compound F.

[0059] Compound F was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.65 (d, J=2.2Hz, 1H), 7.85 (dd, J=6.6, 2.6Hz, 1H), 7.5 8(s,1H),7.53(ddd,J=8.9,4.1,2.7Hz,1H),7.23(s,1H),7.17(s,1H),7.14(t ,J=8.8Hz,1H),4.15(t,J=6.6Hz,2H),3.97(s,3H),3.43(t,J=5.0Hz,4H),2.5 5(t,J=7.0Hz,2H),2.40(t,J=5.1Hz,4H),2.08(p,J=6.8Hz,2H),1.45(s,9H). 13 C NMR (100MHz, CDCl3) δ156.4,156.1,155.3,155.0,153.5,149.2,147.6,135.6,124.3,121.9(d,J F-C =6.6Hz),121.1(d,J F-C =18.6Hz),116.7(d,J F-C =21.9Hz),109.1,108.0,100.9,80.0,67.6,56.3,55.0,53.1,43.3,28.6,26.5. 9 F NMR (376MHz, CDCl3) δ-121.0.

[0060] 3) Preparation of Compound G: Compound F (1.60 g, 2.93 mmol) was dissolved in dichloromethane (9 mL) at 0°C, and trifluoroacetic acid (4.5 mL) was added. The mixture was stirred at 0°C for 0.5 h, and the solvent was then evaporated to obtain crude Compound G, which was used directly in the next step without purification.

[0061] 4) Preparation of Compound H:

[0062] Compound G (1.51 g, 2.93 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of 2-azidoethyl-4-methylbenzenesulfonate (919 mg, 3.81 mmol), cesium carbonate (2.39 g, 7.33 mmol) and potassium iodide (243 mg, 1.47 mmol). The reaction was refluxed overnight, then cooled to room temperature and concentrated, diluted with water (50 mL), and extracted with ethyl acetate (3×40 mL). The organic phases were then combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound H.

[0063] Compound H was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.59(s,2H),7.90(dd,J=6.6,2.7Hz,1H),7.59(dt,J=9.0,3.5Hz,1H),7.41(s,1H),7.13(s,1H),7.06(t,J= 8.8Hz,1H),4.02(t,J=6.8Hz,2H),3.87(s,3H),3.30(t,J=5.9Hz,2H),2.52(dq,J=15.0,7.2,6.8Hz,12H),2.01(q,J=6.9Hz,2H). 13 C NMR (100MHz, CDCl3) δ156.6,155.9,155.2,153.4,148.8,147.3,135.8,124.2,121.9(d,J F-C =6.6Hz),120.8(d,J F-C =18.5Hz),116.5(d,J F-C =21.8Hz),109.2,107.5,101.8,67.6,57.0,56.2,54.8,53.1,52.6,48.2,25.9. 19 F NMR (376MHz, CDCl3) δ-121.4.

[0064] 5) Preparation of compound 1-5:

[0065] H (100 mg, 0.194 mmol) and compound C1 (71.9 mg, 0.233 mmol) were dissolved in a mixed solvent of t-BuOH / H2O (5 mL, 1:1), and CuSO4·5H2O (18.6 mg, 0.116 mmol) and sodium L-ascorbate (38.4 mg, 0.194 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, CuSO4·5H2O was filtered out, and the filtrate was concentrated in vacuo and separated by silica gel flash column chromatography (dichloromethane:methanol=25:1) to obtain compound 1 (white solid, 141 mg, 88%).

[0066] Compound 1 was tested, and the test results were as follows: IR (KBr) ν max 3300,3082,2850,2200,1645,830,763,696cm -1 . 1 H NMR (400MHz, CDCl3) δ8.53(s,2H),7.89(dd,J=6.6,2.7Hz,1H),7.59(ddd,J=8.9,4.1,2.7Hz,1H),7.51( dd,J=7.9,1.5Hz,4H),7.34(s,1H),7.32–7.26(m,4H),7.24(d,J=1.7Hz,1H),7.18(s,1H),7.11(s,1H), 6.99(t,J=8.8Hz,1H),4.29(t,J=6.2Hz,2H),4.04(t,J=6.7Hz,2H),3.84(d,J=4.5Hz,5H),3.41(s,2H), 2.89(t,J=6.4Hz,2H),2.68(t,J=6.3Hz,2H),2.52(d,J=14.6Hz,8H),1.99(t,J=6.9Hz,2H),0.94(s,9H). 13 C NMR (100MHz, CDCl3) δ156.7,155.8,155.1,153.6,153.4,148.5,147.5,145.5,135.5,133.8,129.8,127.8,124.3,122.3,122.1(d,J F-C =6.5Hz),120.7(d,J F-C =18.6Hz),116.4(d,J F-C =22.4Hz),109.4,107.6,103.0,67.4,63.2,57.1,56.2,54.8,52.8,51.5,47.4,29.4,27.0,25.3,19.4. 19F NMR(376MHz,CDCl3)δ-123.0.HRMS(ESI):m / z calc d forC 44 H 53 ClFN8O3Si + [M+H] + :823.3677; found 823.3673.

[0067] Compound 2 was obtained by replacing Compound C1 with Compound C2 (75.1 mg, 0.233 mmol) according to the same method as for preparing Compound 1.

[0068] Compound 2 was tested and the test results were as follows: IR (KBr) ν max 3300,3066,2850,2185,1640,833,763,720,696cm -1 . 1 H NMR(400MHz, CDCl3)δ8.63(s,1H),8.32(s,1H),8.00(d,J=6.9Hz,1H),7.70–7.61(m,5H) ,7.56(s,1H),7.44–7.32(m,6H),7.23(d,J=8.9Hz,2H),7.12(t,J=8.7Hz,1H),4.38(t,J= 6.2Hz,2H),4.22(s,2H),3.97(s,3H),3.71(t,J=6.1Hz,2H),2.82(q,J=6.7,5.8Hz,4H), 2.70(d,J=31.5Hz,8H),2.19(dt,J=17.5,6.9Hz,4H),1.93(p,J=6.6Hz,2H),1.05(s,9H). 13 C NMR (100MHz, CDCl3) δ156.8,156.0,155.2,153.7,153.5,148.5,148.1,148.0,135.7,134.1,129.8,127.8,124.3,122.1(d,J F-C =6.4Hz),121.2(d,J F-C =4.6Hz),121.0,120.8,116.6(d,J F-C =22.5Hz),107.8,103.1,67.5,63.1,57.1,56.3,53.0,51.5,47.5,32.2,29.8,27.0,22.2,19.4,14.3. 19F NMR(376MHz,CDCl3)δ-121.5.HRMS(ESI):m / z calcd for C 45 H 55 ClFN8O3Si + [M+H] + :837.3834; found 837.3831.

[0069] Compound 3 was obtained by replacing Compound C1 with Compound C3 (78.4 mg, 0.233 mmol) according to the same method as that for preparing Compound 1.

[0070] Compound 3 was tested, and the test results were as follows: IR (KBr) ν max 3300,3072,2850,2191,1640,846,763,720cm -1 . 1 H NMR(400MHz, CDCl3)δ8.63(s,1H),8.10(s,1H),7.90(dd,J=6.6,2.6Hz,1H),7.73–7.58(m,5H),7 .45–7.34(m,7H),7.32(s,1H),7.23(s,1H),7.12(t,J=8.8Hz,1H),4.39(t,J=6.3Hz,2H),4.16(t ,J=6.8Hz,2H),3.96(s,3H),3.68(t,J=6.3Hz,2H),2.80(t,J=6.3Hz,2H),2.69(t,J=7.6Hz,2H), 2.59–2.55(m,10H),2.08(p,J=7.2Hz,2H),1.74(p,J=7.4Hz,2H),1.67–1.54(m,2H),1.03(s,9H). 13 C NMR (100MHz, CDCl3) δ156.6,156.0,155.3,153.61,153.55,148.9,148.4,147.6,135.74,135.68,134.1,129.7,127.8,124.3,122.0(d,J F-C =7.5Hz),121.18,116.6(d,J F-C =22.6Hz),109.2,107.9,101.8,67.9,63.7,57.4,56.3,54.8,53.2,52.4,47.6,32.2,29.8,27.0,25.9,19.4,14.3. 19F NMR(376MHz,CDCl3)δ-121.2.HRMS(ESI):m / z calcd for C 46 H 57 ClFN8O3Si + [M+H] + :851.3990;found 851.3985.

[0071] Compound 4 was obtained by replacing Compound C1 with Compound C4 (52.3 mg, 0.233 mmol) according to the same method as that for preparing Compound 1.

[0072] Compound 4 was tested and the test results were as follows: IR (KBr) ν max 3300,3058,2850,2161,1640,858,833,720cm -1 . 1 H NMR (400MHz, CDCl3) δ8.61 (s, 1H), 8.09 (s, 1H), 7.92 (dd, J = 6.5, 2.7Hz, 1H), 7.60 (dt, J = 9.0, 3. 4Hz,1H),7.36–7.29(m,2H),7.24(s,1H),7.14(t,J=8.8Hz,1H),4.44(t,J=6.3Hz,2H),4.22(t, J=6.3Hz,2H),3.96(s,3H),3.48–3.39(m,1H),3.18–2.99(m,1H),2.41–2.21(m,4H),2.02(s,8H ),1.73–1.63(m,4H),1.42–1.29(m,6H),1.22–1.08(m,6H),0.96(d,J=6.8Hz,1H),0.08(s,6H). 13 C NMR (100MHz, CDCl3) δ161.4,156.5,155.7,153.7,153.3,148.8,147.2,135.4,128.4,124.3,122.0(d,J F-C =6.7Hz),121.4,116.7(d,J F-C =22.7Hz),108.9,107.6,102.3,66.2,61.0,56.4,46.0,29.8,28.5,27.9,27.0,26.8,22.8,16.5,14.2,11.6,8.7,1.1,-2.1. 19 F NMR(376MHz,CDCl3)δ-124.1.HRMS(ESI):m / z calcd for C37 H 53 ClFN8O3Si + [M+H] + :739.3677; found 739.3674.

[0073] Compound 5 was obtained by replacing compound C1 with compound C5 (55.6 mg, 0.233 mmol) according to the same method as for preparing compound 1.

[0074] Compound 5 was tested and the test results were as follows: IR (KBr) ν max 3300,3066,2850,2183,1640,858,833,720cm -1 . 1 H NMR(400MHz, CDCl3)δ8.64(s,1H),8.09–7.88(m,2H),7.70–7.61(m,1H),7.46(s,1H),7.38( s,1H),7.24(s,1H),7.14(t,J=8.8Hz,1H),4.43(t,J=6.1Hz,2H),4.26(t,J=6.7Hz,2H),4.00 (d,J=2.9Hz,3H),3.66(t,J=6.4Hz,2H),2.87(t,J=6.2Hz,2H),2.83–2.70(m,6H),2.64(s,8H ),2.59–2.34(m,4H),2.20–2.13(m,2H),1.67–1.59(m,5H),1.42–1.27(m,4H),-0.00(s,6H). 13 C NMR (100MHz, CDCl3) δ161.3,156.2,155.4,154.2,153.4,151.3,148.8,135.0,126.1,124.1,121.6(d,J F-C =6.7Hz),121.0,116.6(d,J F-C =21.2Hz),108.8,107.9,102.0,66.1,60.8,56.2,50.9,31.9,29.7,29.7,29.3,28.4,27.2,26.4,24.3,22.7,22.7,14.1,1.0,-0.1. 19 F NMR(376MHz,CDCl3)δ-123.0.HRMS(ESI):m / zcalcd for C 38 H 55 ClFN8O3Si + [M+H]+ :753.3834; found 753.3833.

[0075] Example 2

[0076] An EGFR protein degrader (denoted as compound 6-14) with a silicon-containing group as a hydrophobic tag, the structures of which are shown below:

[0077]

[0078] The structures of the intermediate compounds A1-A3, B2-B5, C1-C9, E, 2-azidoethyl-4-methylbenzenesulfonate, and I are shown below:

[0079]

[0080]

[0081] The specific preparation method is as follows (the preparation method of compounds C1-C5 and compound E is the same as that of Example 1):

[0082] 1) Preparation of compounds C6-C9:

[0083] According to the same method as that for preparing Compound C1 in Example 1, Compound B1 was replaced with Compound B2 (530 mg, 3.00 mmol) to obtain Compound C6.

[0084] Compound C6 was tested, and the test results were as follows: 1 H NMR(400MHz, CDCl3) δ3.71(t,J=7.2Hz,2H),2.40(td,J=7.2,2.6Hz,2H),1.9 7(t,J=2.7Hz,1H),1.75–1.62(m,4H),1.58(s,2H),1.25(s,5H),0.06(s,6H). 13 C NMR (100MHz, CDCl3) δ69.5, 61.5, 29.9, 28.0, 27.1, 26.9, 26.7, 22.9, -4.0.

[0085] Compound C7 was obtained by the same method as that for preparing Compound C1 in Example 1 except that Compound A1 was replaced by Compound A3 (196 mg, 2.00 mmol) and Compound B1 was replaced by Compound B3 (452 ​​mg, 3.00 mmol).

[0086] Compound C7 was tested, and the test results were as follows: 1H NMR (400MHz, CDCl3) δ3.69(t,J=6.0Hz,2H),2.27(td,J=7.1,2.7Hz,2H),1.92(t,J=2.7Hz,1H),1.81–1.63(m,2H),0.89(s,9H),0.05(s,6H). 13 C NMR (100MHz, CDCl3) δ84.4, 68.4, 61.6, 31.7, 26.1, 18.5, 15.0, -5.2.

[0087] Compound C8 was obtained by the same method as that for preparing Compound C1 in Example 1 except that Compound A1 was replaced by Compound A3 (196 mg, 2.00 mmol) and Compound B1 was replaced by Compound B4 (578 mg, 3.00 mmol).

[0088] Compound C8 was tested, and the test results were as follows: 1 H NMR (400MHz, CDCl3) δ3.77(t,J=6.0Hz,2H),2.30(td,J=7.1,2.7Hz,2H),1.92(t,J=2.6Hz,1H),1.82–1.56(m,2H),1.05(d,J=4.8Hz,21H). 13 C NMR (100MHz, CDCl3) δ84.4, 68.2, 61.7, 31.8, 17.7, 14.9, 12.3.

[0089] Compound C9 was obtained by the same method as that for preparing Compound C1 in Example 1 except that Compound A1 was replaced by Compound A3 (196 mg, 2.00 mmol) and Compound B1 was replaced by Compound B5 (452 ​​mg, 3.00 mmol).

[0090] Compound C9 was tested, and the test results were as follows: 1 H NMR(400MHz, CDCl3) δ3.69(t,J=6.1Hz,2H),2.28(td,J=7.1,2.7Hz,2H),1.93(t ,J=2.7Hz,1H),1.80–1.67(m,2H),0.96(t,J=7.9Hz,9H),0.60(q,J=7.9Hz,6H). 13 C NMR (100MHz, CDCl3) δ84.2, 68.3, 61.1, 31.5, 14.9, 6.8, 4.4.

[0091] 2) Preparation of Compound I: Compound E (959 mg, 3.00 mmol) and compound 2-azidoethyl-4-methylbenzenesulfonate (796 mg, 3.30 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.04 g, 7.50 mmol) was added, and the reaction was carried out at 60°C overnight. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phases were then combined and the reaction solution was washed with saturated NaCl solution (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain Compound I.

[0092] Compound I was tested, and the test results were as follows: 1 H NMR (400MHz, DMSO-d6) δ9.54 (s, 1H), 8.52 (s, 1H), 8.13 (dd, J = 6.9, 2.6Hz, 1H), 7.85 (s, 1H), 7.84–7. 75(m,1H),7.45(t,J=9.1Hz,1H),7.23(s,1H),4.33(t,J=5.0Hz,2H),3.95(s,3H),3.84–3.80(m,2H). 13 C NM R(100MHz,DMSO-d6)δ156.6,154.9,153.6,153.3,148.1,147.6,137.2,123.9,122.7(d,J F-C =7.3Hz),119.3(d,J F-C =18.5Hz),117.0(d,J F-C =21.7Hz),109.1,107.9,103.6,68.3,56.4,49.9.

[0093] 3) Preparation of compound 6-14:

[0094] Compound 6 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol).

[0095] Compound 6 was tested and the test results were as follows: IR (KBr) ν max 3300,3079,2850,2190,1645,821,763,696cm -1 . 1H NMR (400MHz, CDCl3) δ8.62 (s, 1H), 8.54 (s, 1H), 7.89 (dd, J = 6.6, 2.6Hz, 1H) ,7.64(s,1H),7.60–7.55(m,1H),7.55(s,4H),7.38–7.27(m,6H),7.22(s,1H ),7.19(s,1H),7.07–7.02(m,1H),4.68(t,J=4.8Hz,2H),4.34(t,J=4.9Hz, 2H),3.85(s,3H),3.79(t,J=6.5Hz,2H),2.86(t,J=6.5Hz,2H),0.95(s,9H). 13 C NMR (100MHz, CDCl3) δ156.8,156.0,155.5,154.9,153.9,148.4,147.9,146.1,135.5,133.5,129.9,127.8,124.4,124.1,122.1(d,J F-C =6.5Hz),120.8(d,J F-C =18.4Hz),116.5(d,J F-C =21.8Hz),109.1,107.8,102.8,68.2,62.9,56.2,49.9,29.2,26.8,19.2. 19 F NMR(376MHz,CDCl3)δ-121.5.HRMS(ESI):m / z calcd for C 37 H 39 ClFN6O3Si + [M+H] + :697.2520; found 697.2525.

[0096] Compound 7 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound I (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C2 (75.1 mg, 0.233 mmol).

[0097] Compound 7 was tested and the test results were as follows: IR (KBr) ν max 3300,3069,2850,2188,1640,833,763,696cm -1 . 1H NMR (400MHz, CDCl3) δ8.62 (s, 1H), 8.35 (s, 1H), 7.93 (dd, J = 6.8, 2.6Hz, 1H), 7.69 –7.56(m,5H),7.43(s,1H),7.35(dt,J=13.6,6.7Hz,6H),7.20(s,1H),7.14(s,1H) ,7.07(t,J=8.8Hz,1H),4.69(t,J=4.9Hz,2H),4.41(t,J=4.9Hz,2H),3.93(s,3H) ,3.58(t,J=6.0Hz,2H),2.72(t,J=7.7Hz,2H),1.79(p,J=6.6Hz,2H),1.00(s,9H). 13 C NMR (100MHz, CDCl3) δ156.7,156.0,154.8,154.0,153.5,148.8,147.9,147.8,135.6,133.9,129.8,127.8,124.2,123.2,122.0(d,J F-C =6.5Hz),120.9(d,J F-C =19.1Hz),116.5(d,J F-C =21.9Hz),109.1,108.1,102.6,68.3,62.8,56.3,50.0,32.1,26.9,22.0,19.3. 19 F NMR(376MHz,CDCl3)δ-121.3.HRMS(ESI):m / z calcd for C 38 H 41 ClFN6O3Si + [M+H] + :711.2677;found 711.2681.

[0098] Compound 8 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound I (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C3 (78.4 mg, 0.233 mmol).

[0099] Compound 8 was tested, and the test results were as follows: IR (KBr) ν max 3300,3090,2850,2188,1640,833,763,720,696cm -1 . 1H NMR(400MHz, CDCl3) δ8.60(d,J=3.7Hz,1H),7.79(dd,J=6.6,2.7Hz,1H),7.65–7.55(m ,4H),7.54–7.46(m,2H),7.41–7.30(m,6H),7.17(d,J=2.6Hz,2H),7.06(t,J=8.8Hz,2H ),4.66(t,J=5.0Hz,1H),4.28(t,J=5.0Hz,1H),4.15(t,J=5.1Hz,2H),3.88(s,3H),3.8 6(s,2H),3.61(t,J=5.6Hz,2H),2.60(t,J=7.6Hz,2H),1.70–1.48(m,2H),1.00(s,9H). 13 C NMR(100MHz,CDCl3)δ156.7(d,J F-C =13.7Hz),156.03(d,J F-C =10.7Hz),155.5,154.4(d,J F-C =102.7Hz),153.6,149.0,148.4,147.8,135.6,134.0,129.7,127.7,124.4(d,J F-C =4.2Hz),123.0,122.0(d,J F-C =6.2Hz),121.0(d,J F-C =18.7Hz),116.6(d,J F-C =22.5Hz),109.0(d,J F-C =14.8Hz),107.7,102.7,68.3,63.5,56.2,50.1,32.0,26.9,25.6,25.3,19.3. 19 F NMR(376MHz,CDCl3)δ-123.8.HRMS(ESI):m / z calcdfor C 39 H 43 ClFN6O3Si + [M+H] + :725.2833; found 725.2835.

[0100] Compound 9 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C6 (49.0 mg, 0.233 mmol).

[0101] Compound 9 was tested and the test results were as follows: IR (KBr) ν max 3300,3091,2850,2188,1640,833,720cm -1 . 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.43(s,1H),7.94(dd,J=6.6,2.6Hz,1H),7.64(d,J=1 0.5Hz,2H),7.21(s,1H),7.17(s,1H),7.10(t,J=8.8Hz,1H),4.74(t,J=5.0Hz,2H),4.41( t,J=4.9Hz,2H),3.96(s,3H),3.67(t,J=6.5Hz,2H),2.80(t,J=6.5Hz,2H),1.59(dd,J=3 2.3,10.7Hz,5H),1.16–1.07(m,3H),1.04–0.88(m,2H),0.65–0.45(m,1H),-0.11(s,6H). 13 C NMR (100MHz, CDCl3) δ156.7,156.0,154.9,154.0,153.5,147.9,146.3,135.8(d,J F-C =3.6Hz),124.2(d,J F-C =7.9Hz),122.0(d,J F-C =6.9Hz),121.0,120.8,116.5(d,J F-C =22.0Hz),109.2,108.1,102.8,68.4,61.7,56.3,50.1,29.4,27.9,26.9,26.8,26.5,-4.2. 19 F NMR(376MHz,CDCl3)δ-121.2.HRMS(ESI):m / z calcd forC 29 H 37 ClFN6O3Si + [M+H] + :599.2364; found 599.2366.

[0102] Compound 10 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C4 (52.3 mg, 0.233 mmol).

[0103] Compound 10 was tested and the test results were as follows: IR (KBr) ν max 3300,3090,2850,2160,1640,833,720cm -1 . 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 8.61 (s, 1H), 7.87 (dd, J = 6.6, 2.7Hz, 1H), 7.68– 7.52(m,2H),7.30(s,1H),7.18(s,1H),7.07(t,J=8.8Hz,1H),4.71(t,J=4.9Hz,2H ),4.35(t,J=4.9Hz,2H),3.94(s,3H),3.48(t,J=6.1Hz,2H),2.65(t,J=7.8Hz,2H) ,1.86–1.52(m,7H),1.19–0.93(m,5H),0.61(tt,J=12.2,3.0Hz,1H),-0.05(s,6H). 13 C NMR (100MHz, CDCl3) δ156.8,155.9,154.8,153.9,153.5,148.8,147.8(d,J F-C =3.1Hz),135.8(d,J F-C =3.3Hz),124.4,123.2,122.1(d,J F-C =6.6Hz),120.8(d,J F-C =18.5Hz),116.4(d,J F-C =22.6Hz),109.2,108.0,102.8,68.0,61.7,56.2,50.0,32.2,27.9,27.0,26.9,26.6,22.0,-4.1. 19 F NMR(376MHz,CDCl3)δ-121.2.HRMS(ESI):m / z calcd forC 30 H 39 ClFN6O3Si + [M+H] + :613.2520;found 613.2523.

[0104] Compound 11 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C5 (55.6 mg, 0.233 mmol).

[0105] Compound 11 was tested, and the test results were as follows: IR (KBr) ν max 3300,3088,2850,2180,1640,833,720cm -1 . 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),8.02(d,J=5.8Hz,2H),7.69(s,1H),7.54(s,1 H),7.14(t,J=8.7Hz,1H),6.99(s,1H),4.77(s,2H),4.53(s,2H),3.99(s,3H),3. 46(t,J=6.3Hz,2H),2.62(t,J=7.2Hz,2H),1.72–1.53(m,8H),1.48–1.37(m,2H) ,1.16(d,J=7.5Hz,2H),1.13–1.01(m,2H),0.63(t,J=12.4Hz,1H),-0.02(s,6H). 13 C NMR (100MHz, CDCl3) δ158.4,156.7,154.9,153.9,153.5,149.4,148.0,140.3,135.8,124.1,121.8(d,J F-C =7.4Hz),119.9,116.6(d,J F-C =22.2Hz),105.7,102.6,101.8,68.6,62.4,56.4,50.2,32.2,29.8,28.0,26.9,26.7,25.7,25.4,-4.1. 19 F NMR(376MHz,CDCl3)δ-121.4.HRMS(ESI):m / z calcd for C 31 H 41 ClFN6O3Si + [M+H] + :627.2677; found 627.2678.

[0106] Compound 12 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C7 (49.5 mg, 0.233 mmol).

[0107] Compound 12 was tested and the test results were as follows: IR (KBr) ν max 3300,3090,2850,2160,1640,855,833,681cm -1. 1 H NMR (400MHz, CDCl3) δ8.56(s,2H),8.03–7.79(m,1H),7.60(s,2H),7.28(s,1H),7.17(s,1H),7.06(t,J=8.7Hz,1H),4.74(t,J=4.7 Hz,2H),4.45(s,2H),3.92(s,3H),3.53(t,J=6.1Hz,2H),2.68(t,J=7.8Hz,2H),1.75(t,J=7.4Hz,2H),0.83(s,9H),-0.03(s,6H). 13 C NMR (100MHz, CDCl3) δ156.8,156.0,155.0,153.6,149.4,147.9,146.7,135.6,124.4,123.3,122.2(d,J F-C =6.7Hz),120.8(d,J F-C =18.7Hz),116.4(d,J F-C =21.8Hz),109.0,107.3,102.8,68.2,62.1,56.3,50.0,32.3,29.8,26.0,22.0,18.4. 19 FNMR(376MHz,CDCl3)δ-121.8.HRMS(ESI):m / z calcd for C 28 H 37 ClFN6O3Si + [M+H] + :587.2364; found 587.2366.

[0108] Compound 13 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C8 (59.3 mg, 0.233 mmol).

[0109] Compound 13 was tested, and the test results were as follows: IR (KBr) ν max 3300,3089,2850,2198,1640,836,720,687cm -1 . 1H NMR (400MHz, CDCl3) δ8.61 (s, 1H), 8.46 (s, 1H), 7.94 (dd, J = 6.7, 2.6Hz, 1H), 7. 64(dt,J=7.5,3.3Hz,1H),7.59(s,1H),7.20(d,J=11.4Hz,2H),7.10(t,J=8.8H z,1H),4.74(t,J=4.9Hz,2H),4.43(t,J=4.9Hz,2H),3.96(s,3H),3.57(t,J=6. 1Hz, 2H), 2.70 (t, J = 7.8Hz, 2H), 1.75 (p, J = 6.5Hz, 2H), 0.97 (d, J = 4.2Hz, 21H). 13 C NMR (100MHz, CDCl3) δ156.7,156.0,154.8,153.9,153.5,149.0,147.9,135.8(d,J F-C =3.8Hz),124.3,123.3,122.0(d,J F-C =6.7Hz),120.9(d,J F-C =18.5Hz),116.5(d,J F-C =21.8Hz),109.2,108.0,102.7,68.3,62.3,56.3,50.1,32.4,22.0,18.1,12.0. 19 F NMR(376MHz,CDCl3)δ-122.6.HRMS(ESI):m / z calcd for C 31 H 43 ClFN6O3Si + [M+H] + :629.2833;found629.2834.

[0110] Compound 14 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound 1 (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound C9 (49.4 mg, 0.233 mmol).

[0111] Compound 14 was tested and the test results were as follows: IR (KBr) ν max 3300,3093,2850,2160,1644,833,720cm -1 . 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.38(s,1H),7.93(dd,J=6.6,2.7Hz,1H),7.69–7.57(m,2H),7.21(s,1H),7.17–7.04(m,2H),4.74(t,J=4.8Hz, 2H),4.41(t,J=4.9Hz,2H),3.98(s,3H),3.49(t,J=6.1Hz,2H),2.74–2.6 0(m,2H),1.79–1.66(m,2H),0.87(t,J=8.0Hz,9H),0.50(q,J=7.9Hz,6H). 13 C NMR (100MHz, CDCl3) δ156.6,155.8,154.7,153.9,153.4,148.9,147.8,135.7(d,J F-C =3.3Hz),124.1,123.2,121.9(d,J F-C =6.7Hz),120.7,116.4(d,J F-C =22.0Hz),109.0,108.0,102.4,68.2,61.6,56.2,50.0,32.2,21.9,6.7,4.3. 19 F NMR(376MHz,CDCl3)δ-123.2.HRMS(ESI):m / z calcd forC 28 H 37 ClFN6O3Si + [M+H] + :587.2364; found 587.2366.

[0112] Example 3

[0113] An EGFR protein degrader (denoted as compound 15-16) with a silicon-containing group as a hydrophobic tag, whose structures are shown below:

[0114]

[0115] The structures of the intermediate compound B1, compound J1-J2, compound K1-K2, and compound G used are shown below:

[0116]

[0117]

[0118] The specific preparation method is as follows (the preparation method of compound G is the same as that of Example 1):

[0119] 1) Preparation of Compounds K1-K2:

[0120] According to the same method as that for preparing compound C1 in Example 1, compound A1 was replaced with compound J1 (250 mg, 3.00 mmol) to obtain compound K1.

[0121] Compound K1 was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.72(ddd,J=15.2,7.7,1.7Hz,4H),7.51–7.34(m,6H),3.94(t,J=6.4Hz,2H),3.52–3.33(m,2H),1.09(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,134.9,130.0,127.9,64.1,33.3,26.9,19.4.

[0122] According to the same method as that for preparing compound C1 in Example 1, compound A1 was replaced with compound J2 (278 mg, 3.00 mmol) to obtain compound K2.

[0123] Compound K2 was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.67(dt,J=6.6,1.7Hz,4H),7.49–7.35(m,6H),3.79(t,J=5.7Hz,2H),3.59(t,J=6.6Hz,2H),2.14–1.98(m,2H),1.06(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,133.7,129.8,127.9,61.5,35.6,30.7,27.0,19.4.

[0124] 2) Preparation of Compounds 15-16:

[0125] Compound 15 was obtained by the same method as that for preparing compound H in Example 1, except that the weight of compound G was adjusted to 80.0 mg, 0.179 mmol, and compound 2-azidoethyl-4-methylbenzenesulfonate was replaced by compound K1 (84.6 mg, 0.233 mmol).

[0126] Compound 15 was tested, and the test results were as follows: IR (KBr) ν max 3300,3100,2850,2206,1642,833,751,693cm -1 .1 H NMR (400MHz, CDCl3) δ8.64(s,1H),7.94(dd,J=6.5,2.7Hz,2H),7.66(dd,J=7.6,1. 7Hz,4H),7.62–7.58(m,1H),7.44–7.33(m,6H),7.29(d,J=3.9Hz,1H),7.21(s,1H) ,7.12(t,J=8.8Hz,1H),4.14–4.07(m,2H),3.95(d,J=2.5Hz,3H),3.78(t,J=6.2Hz ,2H),2.69–2.54(m,8H),2.52(d,J=5.9Hz,4H),2.08(d,J=9.6Hz,2H),1.03(s,9H). 13 C NMR (100MHz, CDCl3) δ156.5,156.0,155.2,153.5,148.9,147.5,135.9,135.7,133.7,129.8,128.0,127.8,124.2,121.9(d,J F-C =6.9Hz),116.6(d,J F-C =21.9Hz),109.2,107.7,101.4,67.6,62.2,60.2,56.3,55.0,53.3,53.2,26.9,26.0,19.2. 19 F NMR(376MHz,CDCl3)δ-123.8.HRMS(ESI):m / z calcd for C 40 H 48 ClFN5O3Si + [M+H] + :728.3194; found 728.3196.

[0127] Compound 16 was obtained by the same method as that for preparing compound H in Example 1, except that the weight of compound G was adjusted to 80.0 mg, 0.179 mmol, and compound 2-azidoethyl-4-methylbenzenesulfonate was replaced by compound K2 (87.8 mg, 0.233 mmol).

[0128] Compound 16 was tested and the test results were as follows: IR (KBr) ν max 3300,3092,2850,2194,1645,838,762,720,691cm -1 . 1H NMR (400MHz, CDCl3) δ8.86 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J = 6.7, 2.6Hz, 1H), 7.81 (s, 1H), 7 .75(dt,J=9.0,3.5Hz,1H),7.67–7.60(m,4H),7.46–7.34(m,6H),7.22(s,1H),7.09(t,J=8 .9Hz,1H),4.28(t,J=6.8Hz,2H),3.95(s,3H),3.69(t,J=6.1Hz,2H),2.97–2.83(m,4H),2. 73(s,4H),2.56(t,J=7.4Hz,4H),2.22(p,J=7.0Hz,2H),1.74(p,J=6.5Hz,2H),1.03(s,9H). 13 C NMR (100MHz, CDCl3) δ161.2,156.9,156.0,155.0,153.8,153.4,148.2,135.7,133.8,129.8,127.8,124.4,122.2(d,J F-C =6.4Hz),116.4(d,J F-C =21.8Hz),109.5,107.9,106.2,104.2,67.5,61.7,56.3,54.6,52.4,50.9,29.8,27.0,24.6,22.8,19.3. 19 F NMR(376MHz,CDCl3)δ-121.0.HRMS(ESI):m / zcalcd forC 41 H 50 ClFN5O3Si + [M+H] + :742.3350; found 742.3353.

[0129] Example 4

[0130] An EGFR protein degrader (denoted as compound 17-18) with a silicon-containing group as a hydrophobic tag, whose structures are shown below:

[0131]

[0132] The structures of the intermediate compound B1, compound J3-J4, compound K3-K4, and compound E used are shown below:

[0133]

[0134] The specific preparation method is as follows (the preparation method of compound E is the same as that of Example 1):

[0135] 1) Preparation of Compounds K3-K4:

[0136] According to the same method as that for preparing compound C1 in Example 1, compound A1 was replaced with compound J3 (250 mg, 3.00 mmol) to obtain compound K3.

[0137] Compound K3 was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.87–7.57(m,4H),7.56–7.33(m,6H),3.67(t,J=6.4Hz,2H),3.41(t,J=6.9Hz,2H),1 .85(p,J=7.0Hz,2H),1.57(dt,J=12.0,6.6Hz,2H),1.48–1.34(m,4H),1.31(d,J=7.0Hz,2H),1.07(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,134.3,129.7,127.7,64.0,34.1,32.9,32.5,28.6,28.3,27.0,25.7,19.4.

[0138] According to the same method as that for preparing compound C1 in Example 1, compound K4 was obtained by replacing compound A1 with compound J4 (250 mg, 3.00 mmol).

[0139] Compound K4 was tested, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.74–7.66(m,4H),7.40(qd,J=8.4,7.6,3.5Hz,6H),3.67(t,J=6.5Hz,2H),3 .41(t,J=6.9Hz,2H),1.86(p,J=7.0Hz,2H),1.56(q,J=6.7Hz,2H),1.43–1.28(m,8H),1.07(s,9H). 13 C NMR (100MHz, CDCl3) δ135.7,134.3,129.6,127.7,64.1,34.1,32.9,32.6,29.3,28.9,28.2,27.0,25.8,19.4.

[0140] 2) Preparation of Compounds 17-18:

[0141] The same method as that for preparing compound F in Example 1 was used to adjust the equivalent of compound E to (57.2 mg, 0.179 mmol), and compound D was replaced with compound K3 (85.4 mg, 0.197 mmol) to obtain compound 17.

[0142] Compound 17 was tested and the test results were as follows: IR (KBr) ν max 3300,3077,2850,2181,1649,770,720,686cm -1 . 1 H NMR (400MHz, CDCl3) δ8.65 (s, 1H), 7.82 (dd, J = 6.6, 2.7Hz, 1H), 7.72–7.62 ( m,5H),7.55–7.45(m,1H),7.38(qd,J=8.4,7.6,3.6Hz,6H),7.21(s,1H),7.1 7–7.04(m,2H),4.00(t,J=6.7Hz,2H),3.93(s,3H),3.66(t,J=6.4Hz,2H),1 .84(p,J=6.9Hz,2H),1.56(p,J=6.6Hz,2H),1.48–1.28(m,6H),1.05(s,9H). 13 C NMR (100MHz, CDCl3) δ156.3,156.1,155.5,153.7,153.4,149.5,147.4,135.7,134.2,129.7,127.7,124.4,121.9(d,J F-C =6.6Hz),121.1(d,J F-C =18.8Hz),116.7(d,J F-C =22.7Hz),109.0,107.8,100.5,69.5,64.0,56.3,32.6,29.2,29.1,27.0,26.1,25.8,19.3. 19 F NMR(376MHz,CD Cl3)δ-121.14.HRMS(ESI):m / z calcd for C 38 H 44 ClFN3O3Si + [M+H] + :672.2819; found 672.2815.

[0143] According to the same method as that for preparing compound F in Example 1, the equivalent weight of compound E was adjusted to (57.2 mg, 0.179 mmol), and compound D was replaced with compound K4 (88.1 mg, 0.197 mmol) to obtain compound 18.

[0144] Compound 18 was tested, and the test results were as follows: IR (KBr) ν max 3300,3086,2850,2188,1640,770,720,681cm -1 . 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 7.96 (s, 1H), 7.82 (dd, J = 6.5, 2.7Hz, 1H), 7. 67(dd,J=7.4,1.9Hz,4H),7.55–7.45(m,1H),7.45–7.34(m,6H),7.20(s,2H),7 .08(t,J=8.7Hz,1H),3.95(t,J=6.8Hz,2H),3.90(s,3H),3.66(t,J=6.5Hz,2H) ,1.82(t,J=7.3Hz,2H),1.55(p,J=6.7Hz,2H),1.45–1.20(m,8H),1.05(s,9H). 13 C NMR (100MHz, CDCl3) δ156.4,156.1,155.4,153.6,153.3,149.4,147.3,135.7,134.2,129.6,127.7,124.4,122.0(d,J F-C =6.6Hz),121.1(d,J F-C =18.6Hz),116.6(d,J F-C =21.9Hz),109.1,107.6,100.7,69.5,64.0,56.2,32.6,29.4,29.3,29.1,27.0,26.0,25.8,19.3. 19 FNMR(376MHz,CDCl3)δ-120.4.HRMS(ESI):m / z calcd for C 39 H 46 ClFN3O3Si + [M+H] + :686.2976; found 686.2974.

[0145] Example 5

[0146] An EGFR protein degrader (denoted as compound 19-20) with a silicon-containing group as a hydrophobic tag, whose structures are shown below:

[0147]

[0148] The structures of the intermediate compound E, compound L1-L2, compound M1-M2, and compound B1 used are shown below:

[0149]

[0150] The specific preparation method is as follows (the preparation method of compound E is the same as that of Example 1):

[0151] 1) Preparation of Compounds M1-M2:

[0152] The same method as that for preparing compound F in Example 1 was used to adjust the weight of compound E to (120 mg, 0.375 mmol), and compound D was replaced with compound L1 (69.8 mg, 0.413 mmol) to obtain compound M1.

[0153] Compound M1 was tested, and the test results are as follows: 1 H NMR(400MHz, Methanol-d4)δ8.35(d,J=6.7Hz,1H),7.95(dd,J=6.7,2.6Hz,1H),7.71–7.53(m,1H),7.46(s,1 H),7.16(t,J=9.0Hz,1H),6.96(s,1H),4.31–4.08(m,2H),3.95–3.90(m,2H),3.89(s,3H),3.77–3.61(m,4H). 13 C NMR (100MHz, Methanol-d4) δ158.1,156.6,154.6,153.8,150.2,147.6,137.5,125.6,123.6,121.2(d,J F-C =18.5Hz),117.3(d,J F-C =22.5Hz),110.2,107.2,103.4,73.9,70.5,70.0,62.2,56.5. 19 F NMR (376MHz, Methanol-d4) δ-123.0.

[0154] The same method as that for preparing compound F in Example 1 was used to adjust the equivalent of compound E to (120 mg, 0.375 mmol), and compound D was replaced with compound L2 (88.0 mg, 0.413 mmol) to obtain compound M2.

[0155] Compound M2 was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),8.42(s,1H),7.91(dd,J=6.7,2.7Hz,1H),7.62(dt,J=8.7,3.3Hz,1H),7.46(s, 1H),7.20–7.08(m,2H),4.31(t,J=4.9Hz,2H),3.94–3.88(m,J=4.8Hz,5H),3.80–3.69(m,6H),3.66–3.57(m,2H). 13 C NMR (100MHz, CDCl3) δ156.8,156.2,155.4,153.7,148.5,147.8,136.2,124.4,122.1(d,J F-C =7.3Hz),121.9(d,J F-C =18.4Hz),116.5(d,J F-C =21.9Hz),109.2,107.8,104.0,72.5,71.1,70.3,69.9,69.3,61.9,56.2. 19 F NMR (376MHz, CDCl3) δ-121.3.

[0156] 2) Preparation of compounds 19-20:

[0157] Compound 19 was obtained by the same method as that for preparing compound C1 in Example 1, except that compound A1 was replaced with compound M1 (75.0 mg, 0.184 mmol) and the equivalent weight of compound B1 was adjusted to (75.8 mg, 0.276 mmol).

[0158] Compound 19 was tested and the test results were as follows: IR (KBr) ν max 3300,3099,2850,2183,1640,751,693cm -1 . 1H NMR (400MHz, CDCl3) δ8.58(s,1H),8.14(s,1H),7.81(dd,J=6.6,2.6Hz,1H),7.71–7.60(m,4H),7.48(dt,J=9.0,3.3Hz,1H),7.34(dt,J=18.8,7. 2Hz,7H),7.11–6.98(m,2H),4.22(t,J=4.5Hz,2H),3.88(t,J=4.7Hz,2H) ,3.82(t,J=5.1Hz,2H),3.79(s,3H),3.65(t,J=5.0Hz,2H),1.02(s,9H). 13 C NMR (100MHz, CDCl3) δ156.5,155.9,155.2,153.5,153.4,148.7,147.2,135.6,133.4,129.8,127.8,124.4,122.0(d,J F-C =6.6Hz),120.8(d,J F-C =18.5Hz),116.4(d,J F-C =21.8Hz),109.0,107.3,102.3,72.9,69.8,68.9,63.5,56.0,26.9,19.2. 19 F NMR(376MHz,CDCl3)δ-121.0.HRMS(ESI):m / zcalcd forC 35 H 38 ClFN3O4Si + [M+H] + :646.2299; found 646.2297.

[0159] According to the same method as that for preparing compound C1 in Example 1, compound A1 was replaced with compound M2 (83.1 mg, 0.184 mmol), and the equivalent weight of compound B1 was adjusted to (75.8 mg, 0.276 mmol) to obtain compound 20.

[0160] Compound 20 was tested and the test results were as follows: IR (KBr) ν max 3300,3092,2850,2176,1640,758,720,686cm -1 . 1H NMR (400MHz, CDCl3) δ8.57(s,1H),8.23(s,1H),7.87(dd,J=6.6,2.6Hz,1H),7.63–7.57(m,4H),7.55(dt,J=4.2,2.4Hz,1H),7.41(s,1H),7.3 9–7.27(m,6H),7.12–7.01(m,2H),4.29–4.15(m,2H),3.91–3.85(m,2H ),3.80(s,3H),3.76–3.66(m,6H),3.54(t,J=5.1Hz,2H),0.98(s,9H). 13 C NMR (100MHz, CDCl3) δ156.7,155.9,155.1,153.5,153.5,148.5,147.4,135.6,133.4,129.8,127.8,124.6,122.2(d,J F-C =7.1Hz),120.8(d,J F-C =18.5Hz),116.4(d,J F-C =21.9Hz),109.1,107.4,103.0,72.5,70.8,70.7,69.9,69.0,63.5,56.1,26.9,19.2. 19 F NMR(376MHz,CDCl3)δ-121.4.HRMS(ESI):m / z calcdfor C 37 H 42 ClFN3O5Si + [M+H] + :690.2561;found 690.2564.

[0161] Comparative Example 1

[0162] Compounds 21-23 were used as comparative examples of non-silicon-containing hydrophobic tags. Their structures are shown below:

[0163]

[0164] Its synthetic route is as follows:

[0165]

[0166] Among them, a) represents the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate, N,N-diisopropylethylamine, and N,N-dimethylformamide; b) represents the addition of copper sulfate, sodium L-ascorbate, and tert-butanol / water.

[0167] The structures of the intermediate compounds O1-O2, compound N, compound P1-P2, compound R, compound S, and compound I used are shown below:

[0168]

[0169] The specific preparation method is as follows (the preparation method of Compound 1 is the same as that of Example 2):

[0170] 1) Preparation of Compounds P1-P2 and Compound S:

[0171] At 0°C, compound O1 (194 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N-diisopropylethylamine (330 μL, 2.00 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (570 mg, 1.50 mmol). After stirring at the same temperature for ten minutes, compound N (100 mg, 1.20 mmol) was added, and the mixture was reacted at room temperature overnight. After completion of the reaction, ethyl acetate (40 mL) was added, and the organic phase was washed with 1N hydrochloric acid (20 mL), saturated sodium carbonate solution (20 mL), and saturated brine (20 mL), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain compound P1.

[0172] Compound P1 was tested, and the test results were as follows: 1 H NMR (400MHz, CDCl3) δ5.61(s,1H),3.35(q,J=6.6Hz,2H),2.24(td,J=7.0,2.7Hz,2H),1.97(dt,J=8.6,3 .1Hz,4H),1.90(s,2H),1.80(s,1H),1.78–1.69(m,3H),1.67(s,2H),1.63(s,2H),1.60(d,J=2.8Hz,6H). 13 C NMR (100MHz, CDCl3) δ171.2,83.6,69.3,52.0,42.8,38.7,36.9,32.8,28.8,28.3,16.3.

[0173] According to the same method for preparing compound P1, compound O1 was replaced with compound O2 (214 mg, 1.00 mmol) to obtain compound P2.

[0174] Compound P2 was tested, and the test results were as follows: 1H NMR (400MHz, CDCl3) δ6.71(s,1H),4.01(d,J=15.1Hz,1H),3.80(d,J=15.1Hz,1H),3.37(q,J=6.7Hz,2H),3.10(td,J=10 .6,4.1Hz,1H),2.21(td,J=7.0,2.7Hz,2H),2.08(qt,J=7.0,3.5Hz,1H),2.00(dtd,J=12.0,3.7,1.7Hz,1H),1.94(t,J= 2.7Hz,1H),1.72(p,J=7.0Hz,2H),1.61(ddq,J=13.0,9.6,3.0Hz,2H),1.33(dddq,J=11.7,8.3,6.1,3.1Hz,1H),1.23(d dt,J=13.3,6.3,3.1Hz,1H),0.93(dd,J=12.7,3.3Hz,1H),0.90–0.86(m,6H),0.85–0.77(m,2H),0.74(d,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ170.6,83.2,80.5,69.2,67.9,48.1,40.2,37.8,34.4,31.5,28.2,26.1,23.3,22.2,20.9,16.2,16.0.

[0175] Compound S was obtained by the same method as that for preparing compound P1, except that compound N was replaced by compound Q (134 mg, 1.20 mmol) and compound O1 was replaced by compound R (123 mg, 1.00 mmol).

[0176] Compound S was tested, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ6.13 (dd, J=5.8, 3.0Hz, 1H), 5.91 (dd, J=5.9, 2.9Hz, 1H), 5.81(s,1H),2.98(ddd,J=13.0,7.0,5.7Hz,1H),2.88(ddd,J=13.6,8.7,5.7Hz, 1H),2.81–2.72(m,2H),2.23(dtd,J=16.4,14.7,13.7,8.1Hz,6H),1.95(t,J=2. 6Hz,1H),1.87–1.73(m,3H),1.40(dt,J=8.1,2.2Hz,1H),1.20(d,J=8.5Hz,1H). 13C NMR (100MHz, CDCl3) δ172.2,137.8,132.1,83.6,69.2,49.5,44.3,43.6,42.4,38.9,35.2,30.1,24.3,17.9.

[0177] 2) Preparation of compounds 21-23:

[0178] Compound 21 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound I (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound P1 (60.4 mg, 0.233 mmol).

[0179] Compound 21 was tested, and the test results were as follows: IR (KBr) ν max 3300,3081,2850,2180,1650,813,720,678cm -1 . 1 H NMR (400MHz, CDCl3) δ8.93 (s, 1H), 8.58 (s, 1H), 7.87 (dd, J = 6.6, 2.6Hz, 1H), 7.76–7.56 ( m,2H),7.50(s,1H),7.17(s,1H),7.05(t,J=8.8Hz,1H),5.90(t,J=5.9Hz,1H),4.70(t,J= 5.0Hz,2H),4.39(t,J=5.1Hz,2H),3.92(s,3H),3.16(q,J=6.6Hz,2H),2.65(t,J=7.1Hz, 2H),1.90–1.79(m,5H),1.76(t,J=7.0Hz,2H),1.62(d,J=12.6Hz,3H),1.55–1.45(m,9H). 13 C NMR (100MHz, CDCl3) δ171.7,156.9,155.8,155.2,153.9,153.4,147.9,147.5(d,J F-C =8.7Hz),136.0,124.3,123.1,122.1(d,J F-C =6.7Hz),120.7(d,J F-C =18.6Hz),116.4(d,J F-C =21.8Hz),109.3,107.9,104.8,68.4,56.2,51.8,49.8,42.7,38.5,36.7,32.8,28.9,28.6,22.8. 19F NMR(376MHz,CDCl3)δ-121.4.HRMS(ESI):m / z calcd for C 34 H 40 ClFN7O3 + [M+H] + :648.2860; found 648.2862.

[0180] Compound 22 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound I (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound P2 (65.1 mg, 0.233 mmol).

[0181] Compound 22 was tested and the test results were as follows: IR (KBr) ν max 3300,3088,2850,2183,1648,810,720,676cm -1 . 1 H NMR (400MHz, CDCl3) δ8.58(d,J=22.9Hz,2H),7.89(dd,J=6.7,2.4Hz,1H),7.70(s,1H),7.64(q,J=4.8,4.1Hz,1H),7.43(s,1H),7.24(s,1H), 7.13(t,J=8.7Hz,1H),6.68(t,J=6.2Hz,1H),4.75(t,J=4.9Hz,2H),4.50(t,J=4.9Hz,2H),3.99(s,3H),3.89(d,J=15.2Hz,1H),3.68(d,J=15. 1Hz,1H),3.26(q,J=6.7Hz,2H),3.05(td,J=10.6,4.1Hz,1H),2.72(t,J=6.9Hz,2H),2.04(pd,J=7.2,3.0Hz,2H),1.86(t,J=6.9Hz,3H),1.63( ddt,J=13.6,9.5,3.1Hz,2H),1.20(t,J=3.1Hz,1H),1.00–0.91(m,1H),0.89(dd,J=6.8,4.2Hz,6H),0.83–0.77(m,2H),0.73(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.2,157.0,156.2,155.6,154.8,154.2,153.3,148.4,147.5,135.9,124.7,123.3,122.4(d,J F-C=6.6Hz),120.9(d,J F-C =17.5Hz),116.5(d,J F-C =21.9Hz),108.4,106.4,80.7,69.3,67.7,56.3,49.9,48.0,40.2,37.5,34.4,31.5,28.9,26.3,23.4,22.5,22.3,21.0,16.3. 19 F NMR(376MHz,CDCl3)δ-121.1.HRMS(ESI):m / z calcd for C 34 H 44 Cl FN7O4 + [M+H] + :668.3122; found 668.3123.

[0182] Compound 23 was obtained by the same method as that for preparing compound 1 in Example 1 except that compound H was replaced by compound I (75.4 mg, 0.194 mmol) and compound C1 was replaced by compound S (50.6 mg, 0.233 mmol).

[0183] Compound 23 was tested, and the test results were as follows: IR (KBr) ν max 3300,3089,2850,2180,1642,812,688cm -1 . 1 H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.50(s,1H),8.11(dd,J=6.8,2.6Hz,1H),7.96(s,1H),7.86(s,1H) ,7.78(ddt,J=7.0,4.3,2.6Hz,2H),7.43(t,J=9.1Hz,1H),7.20(s,1H),6.21–5.83(m,2H),4.86(t,J=5. 4Hz,2H),4.56(t,J=5.4Hz,2H),3.92(s,3H),2.81(dt,J=12.7,6.2Hz,1H),2.74(d,J=12.7Hz,2H),2.68 –2.59(m,3H),2.13(q,J=7.0Hz,3H),1.90–1.68(m,3H),1.29(dd,J=8.1,2.1Hz,1H),1.23–1.14(m,2H). 13C NMR (100MHz, DMSO-d6) δ171.9,156.6,154.9,153.4,152.4,147.9,147.7,147.1,137.3,137.2(d,J F-C =3.2Hz),136.9(d,J F-C =11.9Hz),133.0,123.9,123.2,122.7(d,J F-C =6.7Hz),119.3(d,J F-C =18.5Hz),117.0(d,J F-C =21.7Hz),108.0,103.9,67.9,56.4,49.4,49.1,44.1,43.1,42.4,38.9,35.4,30.2,25.8,25.1. 19 F NMR(376MHz,DMSO-d6)δ-122.8.HRMS(ESI):m / z calcd for C 31 H 34 ClFN7O3 + [M+H] + :606.2390;found 606.2392.

[0184] Compound performance test

[0185] 1) The EGFR protein degraders containing silicon-containing hydrophobic groups (EGFR protein degraders 1-20 prepared in Examples 1-5) and non-silicon-containing hydrophobic group EGFR protein degraders (EGFR protein degraders 21-23 prepared in Comparative Example 1) were evaluated for their ability to degrade EGFR in the human lung cancer cell line HCC-827 using Western blotting. The compound concentrations used were 0.1 μM and 1 μM. The degradation efficiency results are shown in Table 1. The IC values ​​of each compound against HCC-827 cells were also evaluated. 50 An evaluation was conducted and the results are shown in Table 1.

[0186] Table 1 EGFR degradation efficiency of compounds in human lung cancer cell line HCC-827 and IC of HCC-827 50

[0187]

[0188] As shown in Table 1, each compound has a certain ability to degrade EGFR. Compounds 2-5, 13, 15-20 showed comparable EGFR degradation efficiency and IC values ​​to those of the control compounds 21-23. 50Compounds 1, 6-12, and 14 showed much better EGFR degradation efficiency and IC efficiencies against HCC-827 cells than those of the control compounds 21-23. 50 .

[0189] Among them, compound 7 had the best effect. Compound 7 was selected for further degradation effect evaluation. Two human lung cancer cell lines, PC-9 and HCC-827, were selected and eight concentration gradients of 0, 0.15, 0.3, 0.6, 1.25, 2.5, 5, and 10 μM were set to determine whether these preferred compounds could degrade EGFR in a concentration-dependent manner. The results are shown in Figure 1 The results showed that compound 7 could degrade EGFR in two human lung cancer cell lines, PC-9 and HCC-827, in a concentration-dependent manner, and the degradation of DC 50 1.42 μM and 0.75 μM respectively.

[0190] Two human lung cancer cell lines, PC-9 and HCC-827, were selected and six time gradients of 0, 3, 6, 9, 12, and 24 hours were set to determine whether these preferred compounds could degrade EGFR in a time-dependent manner. Figure 2 The results showed that compound 7 could degrade EGFR in two human lung cancer cell lines, PC-9 and HCC-827, in a time-dependent manner.

[0191] 2) The metabolic stability of compound 7 in liver microsomes was evaluated using non-silicon-containing hydrophobic tag compounds 21-23 as a comparison and Diclofenac as a positive control.

[0192] The metabolic stability of liver microsomes was assessed as follows: liver microsomes were removed from a -80°C freezer and pre-incubated in a 37°C water bath on a constant-temperature oscillator for 3 minutes, allowing them to thaw. A certain amount of NADPH was then weighed and dissolved in magnesium chloride solution to a 2 mM solution. A mixed incubation system solution (excluding NADPH) was prepared according to the experimental incubation system composition (3 mM MgCl2-PB solution, 1 μM test compound, 0.5 mg / mL liver microsomes) and aliquoted into 40 μL tubes. 240 μL of internal standard working precipitant was added to the 0min sample, and then 40 μL of NADPH solution was added (40 μL of magnesium chloride solution was added to the negative control group), and 40 μL of NADPH solution was added to other samples to start the reaction (40 μL of magnesium chloride solution was added to the negative control group), and 240 μL of internal standard precipitant was added after incubation in a 37°C water bath for 5min, 15min, 30min, and 60min. The positive control group was vortexed and centrifuged to obtain 150 μL of the supernatant, vortexed after adding 150 μL of water, and analyzed by LC-MS / MS injection. Through analysis and calculation, it was found that compound 7 showed a medium clearance efficiency in two species, such as humans and mice, which was significantly improved compared to the high clearance efficiency of the comparison compounds 21-23. The results are shown in Table 2.

[0193] Table 2 Metabolic stability of liver microsomes

[0194]

[0195] The oral bioavailability of compound 7 was evaluated.

[0196] The specific method for evaluating oral bioavailability is as follows: after the rats were fasted overnight, three were gavaged with the drug (10 mg / kg) and three were administered with the drug via tail vein (1 mg / kg). Then, blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h, respectively, and placed in a pre-heparinized sodium tube. The blood and sodium heparin were thoroughly mixed by flicking the tube several times, and then centrifuged (4°C, 3000 rpm, 10 min) to obtain plasma. 50 μL of plasma sample was taken, 50 μL of diluent (50% methanol / water) and 250 μL of methanol precipitant were added, and the mixture was vortexed and centrifuged (4°C, 12000 rpm, 10 min). The supernatant was passed through a membrane, sealed, and sent for LC-MS / MS detection.

[0197] The parameters were analyzed by WinNonlin software (see Table 3). The results showed that compound 7 had a good oral bioavailability of 8.67%.

[0198] Table 3 Kinetic parameters

[0199]

[0200] As can be seen from Tables 2 and 3, the present invention has made optimizations in terms of hydrophobic tag type and linker type, and the selected compound 7 can exert higher metabolic stability and in vivo bioavailability.

[0201] 3) In vivo pharmacodynamics PD experiments were evaluated in a xenograft model. Mice received a single oral dose of compound 7 (10 mg / kg). At the designated time points after oral administration (0 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, and 72 hours), the mice were euthanized and tumor tissues were harvested for Western blotting analysis. The results are shown in Figure 3 The results showed that compound 7 significantly reduced EGFR expression within 6 hours, and the effect lasted for up to 48 hours. These findings suggest that degrader 7 can maintain EGFR degradation for a long time in vivo.

[0202] 4) To evaluate the in vivo efficacy of compound 7, a xenograft model was established using HCC-827 cells.

[0203] The specific method was to inject HCC-827 into nu / nu immunodeficient mice. When the average tumor diameter reached 3 mm, the mice were randomly divided into a control group (5 mice), a group 1 orally administered with compound 7 (10 mpk, 5 mice, daily), a group 2 orally administered with compound 7 (10 mpk, 5 mice, every two days), and a group 3 orally administered with compound 7 (10 mpk, 5 mice, every three days). After 18 days, there was no significant fluctuation in the body weight of the mice in the treated and control groups, and the mice showed no significant abnormalities, indicating the good safety of compound 7. The tumor weight and volume of the mice in the treated groups were significantly lower than those in the control group. The tumor inhibition rate ((1-tumor weight in the treated group / tumor weight in the control group) * 100%) is shown in Table 4. The results demonstrate that compound 7 has a strong in vivo therapeutic effect.

[0204] Table 4 TGI of HCC-827 cell xenograft model

[0205]

[0206] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. As long as the technical effects of the present invention are achieved by the same means, they shall fall within the scope of protection of the present invention. Within the scope of protection of the present invention, various modifications and variations of the technical solutions and / or implementation methods may be made.

Claims

1. An EGFR protein degradation agent using a silicon-containing group as a hydrophobic tag, characterized in that: Its structure is any one of compounds 6-14: Compound 6, Compound 7 Compound 8 Compound 9, Compound 10 Compound 11, Compound 12, Compound 13, Compound 14.

2. The EGFR protein degradation agent with a silicon-containing group as a hydrophobic tag according to claim 1, characterized in that Its structure is shown in Compound 7.

3. Use of the EGFR protein degrader having a silicon-containing group as a hydrophobic tag or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating a cancer associated with EGFR abnormality, wherein the cancer associated with the EGFR is lung cancer.

4. A pharmaceutical composition, characterized in that The invention relates to an EGFR protein degrader comprising a silicon-containing group as a hydrophobic tag according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, characterized in that Pharmaceutically acceptable excipients are also included.

6. The pharmaceutical composition according to claim 5, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

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