A protein degrading agent with rosin acid as a hydrophobic group, a preparation method, a pharmaceutical composition and an application thereof

Abstract

The application belongs to the technical field of chemical drugs, and particularly relates to a protein degrading agent with rosin acid as a hydrophobic group, a preparation method, a pharmaceutical composition and application thereof. The protein degrading agent with rosin acid as a hydrophobic group has a structural formula as shown in formula I, and Linker is any chemically feasible connecting structure. The protein degrading agent prepared by the application can effectively induce degradation of AR and AR-V7 in a cancer cell line. Compared with the AR protein degrading agent based on adamantane as a hydrophobic tag reported by the previous person, the protein degrading agent has considerable improvement in solubility, considerable oral bioavailability, and excellent in-vivo anti-prostate cancer effect. The protein degrading agent can be applied to preparation of an AR degrading agent, and is suitable for development of a cancer drug such as a prostate cancer drug. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a protein degrading agent with rosin acid as a hydrophobic group, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] A bifunctional hydrophobic tag (Hyt) molecule consists of a target protein ligand, a linker, and a hydrophobic group. By attaching a large hydrophobic group to a small molecule that can bind to the target, this biheaded molecule, once bound to the target, is mistakenly identified by intracellular protein repair mechanisms as a misfolded portion of the target protein. Subsequently, it is folded by chaperone proteins and degraded by the proteasome. [1] Hydrophobic groups in hydroxyl (Hyt) molecules often have small molecular weights, thus potentially leading to higher solubility and drug-likeness. Currently, the development of hydrophobic tag-based degradative agents is still in the exploratory stage. This is partly due to the limited number of reported hydrophobic tag fragments, leaving significant room for optimization in terms of degradation activity and physicochemical properties. Furthermore, the exact degradation mechanism remains unclear. Therefore, exploring more hydrophobic fragments with high activity and excellent physicochemical properties, and clarifying their corresponding degradation mechanisms, is crucial for the clinical application of hydrophobic tag-based fragments.

[0003] Androgen receptor (AR) is a clinically validated target for treating human prostate cancer. Androgen receptor antagonists are effective in treating metastatic castration-resistant prostate cancer (mCRPC), significantly improving patient survival and demonstrating good tolerability. However, current clinical androgen receptor antagonists (such as enzalutamide) often induce resistance within 18 months of treatment. In most patients who develop resistance to enzalutamide, the androgen receptor signaling pathway is still functioning; therefore, targeting androgen receptor protein degradation may be a very promising therapeutic strategy, potentially more effective than androgen receptor antagonists. A research team previously developed the protein degraders SARD279 and SARD033, which can degrade AR, based on hydrophobic tagging technology.

[0004]

[0005] Figure 1 SARD279, SARD033, RU59063 structure

[0006] These two degradation agents are obtained by using adamantane as a hydrophobic tag and linking AR ligand RU59063 with polyethylene glycol of different lengths. Figure 1 SARD279 can degrade 50% of AR protein (DC) at a concentration of 1 μM in LNCaP cells. 50However, neither conventional PROTAC molecules nor these hydrophobic tag degraders have a significant impact on AR-V7 protein levels. Furthermore, conventional AR degraders have relatively low degradation efficiency, poor stability in liver microsomes and plasma metabolism, and poor solubility, making them difficult to administer orally. This hinders their use in further clinical treatment and development, necessitating the development of novel orally administered AR protein degraders to meet clinical needs. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a protein degrading agent with rosin acid as a hydrophobic group, its preparation method, pharmaceutical composition, and application. Specifically, the following technical solution is adopted:

[0008] A protein degrading agent with rosin acid as a hydrophobic group, the structural formula of which is shown in Formula I:

[0009] Formula I;

[0010] Linker can be any chemically feasible linker structure.

[0011] This invention provides a protein degrader with rosin acid as a hydrophobic group. In this bifunctional molecule, rosin acid serves as the hydrophobic group, and enzalutamide as the target protein ligand. By replacing different linkers, this invention screens for protein degraders that can effectively degrade AR. Furthermore, this rosin acid-based protein degrader significantly improves the oral bioavailability of the drug molecule. Based on this, the AR protein degrader prepared by this invention can effectively induce the degradation of AR and AR-V7 in a dose-dependent manner in a human prostate cancer cell line (22Rv1 cell line), exhibiting considerable bioavailability and excellent in vivo anti-prostate cancer effects.

[0012] Preferably, the linker is a saturated fatty acid chain or an unsaturated fatty acid chain. By selecting ideal linkers of different types and lengths, the goal is to maintain the binding of the two proteins spatially without affecting their binding.

[0013] Preferably, the molecular structure of the protein degrading agent with rosin acid as the hydrophobic group is any one of Formula II, Formula III, or Formula IV:

[0014] Formula II;

[0015] Formula III;

[0016] Formula IV;

[0017] In Equations II and III, m is taken independently from any positive integer from 2 to 10; in Equation IV, o is any positive integer from 1 to 8.

[0018] More preferably, the molecular structure of the protein degrading agent with rosin acid as the hydrophobic group is shown in Formula V:

[0019] Formula V.

[0020] Experimental results showed that the compound shown in Formula V could effectively induce the degradation of AR and AR-V7 in the human prostate cancer cell line 22Rv1 in a dose-dependent manner, with considerable bioavailability and exhibiting the best in vivo anti-prostate cancer effect, with a tumor inhibition rate of 72.6%.

[0021] According to a second aspect of the present invention, a method for preparing the above-mentioned protein degrading agent with rosin acid as a hydrophobic group is also provided, wherein the preparation route is Route 1, Route 2 or Route 3:

[0022] Route 1:

[0023] ;

[0024] Route 2:

[0025] ;

[0026] Route 3:

[0027] .

[0028] The above route is simple, uses inexpensive and readily available raw materials, and has a relatively high overall reaction yield. In route one, rosinic acid formic acid (A) is used to condense with aminoalkyl bromides of different lengths (B1-B7) under HATU to obtain intermediates C1-C7, wherein C4-C7 react with enzalutamine core D in K2CO3, In Route 2, enzalutamine core D is substituted with 4-(2-bromoacetyl)piperazine-1-carboxylic acid tert-butyl ester under K2CO3 and DMF, followed by removal of Boc under TFA to obtain intermediate G. Compound G undergoes substitution reaction with C1-C3 under cesium carbonate and potassium iodide to obtain final products H1-H3. In Route 3, rosinic acid formic acid (A) is amide condensed with alkynylamines of different lengths (I1-I5) under HATU to obtain intermediates J1-J5. Subsequently, enzalutamine core D is substituted with 2-azidoethyl-4-methylbenzenesulfonate (compound K) under K2CO3 and DMF to obtain intermediate L, which then undergoes a Click reaction with J1-J5 to obtain final products M1-M5.

[0029] According to a third aspect of the present invention, the above-mentioned protein degrading agent with rosin acid as a hydrophobic group or its pharmaceutically acceptable salt can also be used in the preparation of AR degrading agents.

[0030] Preferably, the above-mentioned AR degrading agent can be used to prepare drugs for treating and / or preventing related cancers with AR abnormalities and resistance to traditional AR inhibitors. Related cancers include: prostate cancer, breast cancer, ovarian cancer, and endometrial cancer. It is preferably used for the treatment of prostate cancer.

[0031] According to a fourth aspect of the present invention, a pharmaceutical composition is also provided, wherein the aforementioned protein degrading agent with a hydrophobic group of rosin acid or a pharmaceutically acceptable salt thereof is used as the main active ingredient. The pharmaceutical composition comprises one or more pharmaceutically acceptable excipients or carriers. The excipients include at least one selected from gum arabic, syrup, lanolin, and starch. The excipients are stable, have no incompatibility with the active pharmaceutical ingredient, do not produce side effects, do not affect efficacy, are not easily deformed, cracked, moldy, or infested by insects at room temperature, are harmless to the human body, have no physiological effects, do not react chemically or physically with the active pharmaceutical ingredient, and do not affect the content determination of the active pharmaceutical ingredient. Solvents include water, glycerol, or ethanol.

[0032] The beneficial effects of this invention are as follows: This invention provides a protein degrading agent with rosin acid as a hydrophobic group. The preparation process is simple and easy, and various protein degrading agents can be obtained through different pathways. These can be applied to the preparation of AR degrading agents. Compared with the positive control SARD279, the obtained protein degrading agent has higher solubility and oral bioavailability, and can be administered orally in in vivo experiments, overcoming the current limitation of difficult oral administration of protein degrading agents. Furthermore, this protein degrading agent with rosin acid as a hydrophobic group can also be used to form pharmaceutical compositions, exhibiting certain inhibitory effects on the proliferation of various tumor cells, making it suitable for the development of drugs for treating prostate cancer and other cancers. Attached Figure Description

[0033] Figure 1 The diagram shows the concentration-dependent degradation of AR and AR-V7 proteins by compounds H1, M1, M2, M3, and M5 in the 22Rv1 cell line. Detailed Implementation

[0034] The following will provide a clear and complete description of the concept, specific structure, and technical effects of the present invention in conjunction with the embodiments and accompanying drawings, 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.

[0035] Example 1

[0036] A protein degrading agent with rosin acid as a hydrophobic group

[0037] (1) Preparation of compound E4

[0038] The structure of compound E4 is as follows:

[0039] Compound E4; its preparation process is as follows:

[0040] Step 1: Preparation of compound C4

[0041] Compound A (453 mg, 1.50 mmol) was dissolved in N,N-dimethylformamide (5 mL) under ice bath conditions. Then, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (684 mg, 1.80 mmol), diisopropylethylamine (291 mg, 2.25 mmol), and compound B4 (5-bromopentylamine, 371 mg, 1.50 mmol) were added. After 5 minutes, the ice bath was removed, and the mixture was stirred overnight at room temperature. The liquid in the flask was then diluted with ethyl acetate (15 mL), followed by washing with 1 N HCl solution (15 mL), saturated sodium bicarbonate solution (15 mL), and saturated saline solution (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound C4.

[0042] The structures of compounds A, B4, and C4 obtained in the above preparation process are shown below:

[0043] Compound A Compound B4

[0044] Compound C4;

[0045] The detection results for compound C4 are as follows: HRMS (ESI) calculated for C 25 H 41 BrNO + [M+H] + : 450.2366, found. 450.2363.

[0046] Step 2: Preparation of compound E4

[0047] Compound D (203 mg, 0.50 mmol) and compound C4 (226 mg, 0.500 mmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (138 mg, 1.00 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 8 mL). The organic phases were then combined and washed with saturated NaCl solution (30 mL). The organic phases were dried with anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound E4.

[0048] The structure of compound D in the above preparation process is shown below:

[0049] Compound D;

[0050] The results of the detection of compound E4 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.13 – 7.06 (m, 2H), 6.86 – 6.78 (m, 2H), 6.68 (d, J = 0.7 Hz, 1H), 6.20 (t, J =1.0 Hz, 1H), 5.78 (s, 1H), 4.01 (s, 2H), 3.17 – 3.04 (m, 2H), 2.52 (s, 1H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 1.96(s, 1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.78 (s, 2H), 1.71 (d, J = 13.0Hz, 1H), 1.59 – 1.43 (m, 12H), 1.39 – 1.29 (m, 2H), 1.24 (d, J= 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 178.26,172.88, 171.30, 159.04, 146.69, 138.95, 136.87, 135.57, 133.83, 133.64,126.04, 125.66, 125.33, 124.79, 124.42, 122.31, 119.43, 117.54, 106.85,78.29, 66.95, 50.36, 49.09, 48.85, 41.63, 40.58, 37.98, 37.65, 34.10, 33.53,31.29, 30.51, 30.44, 29.56, 25.67, 23.78, 23.57, 22.03, 20.48, 16.96. HRMS(ESI) calculated for C 44 H 54 F3N4O3S + [M+H] + : 775.3863, found. 775.3862.

[0051] (2) Preparation of compound E5

[0052] The structure of compound E5 is as follows:

[0053] Compound E5; its preparation process is as follows:

[0054] The specific preparation method is as follows: Compound E5 is obtained by following the synthesis steps of compound E4. Compared with compound E4, only 5-bromopentylamine is replaced with 6-bromohexylamine to obtain compound C5. Then, compound D and compound C5 are reacted to obtain compound E5.

[0055] In the above reaction, the structure of compound C5 is as follows:

[0056] Compound C5;

[0057] The results of the detection of compound E5 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J= 2.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.13 – 7.06 (m, 2H), 6.86 – 6.78 (m, 2H), 6.68 (d, J = 0.7 Hz, 1H), 6.20 (t, J =1.0 Hz, 1H), 5.78 (s, 1H), 4.01 (s, 2H), 3.17 – 3.04 (m, 2H), 2.52 (s, 1H),2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 1.96(s, 1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.77 (s, 2H), 1.71 (d, J = 13.0Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.56 (s, 3H), 1.54 – 1.43 (m, 5H), 1.36 (s,2H), 1.34 (dd, J = 13.0, 9.2 Hz, 2H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m,9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 178.26, 172.88, 171.30,159.04, 146.69, 138.95, 136.87, 135.57, 133.83, 133.64, 126.04, 125.66,125.33, 124.79, 124.42, 122.31, 119.43, 117.54, 106.85, 78.29, 66.95, 50.36,49.09, 48.85, 41.83, 40.58, 37.98, 37.51, 34.10, 33.53, 31.29, 31.01, 30.56,29.56, 28.33, 27.11, 23.78, 23.57, 22.03, 20.48, 16.96. HRMS (ESI): m / z calcdfor C 45 H 56 F3N4O3S + [M+H] + : 789.4020; found 789.4018.

[0058] (3) Preparation of compound E6

[0059] The structure of compound E6 is as follows:

[0060] Compound E6; Its preparation process is as follows:

[0061] The specific preparation method is as follows: Compound E6 is obtained by following the synthesis steps of compound E4. Compared with compound E4, only 5-bromopentylamine is replaced with 7-bromoheptylamine to obtain compound C6. Then, compound D and compound C6 are reacted to obtain compound E6.

[0062] In the above reaction, the structure of compound C6 is as follows:

[0063] Compound C6;

[0064] The results of the detection of compound E6 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.69 (dd, J= 7.5, 2.1 Hz, 1H),7.13 – 7.06 (m, 2H), 6.86 – 6.78 (m, 2H), 6.68 (d, J = 0.7 Hz, 1H), 6.20 (t, J =1.0 Hz, 1H), 5.78 (s, 1H), 4.01 (s, 2H), 3.13 (d, J = 12.5 Hz, 1H), 3.09 (s,1H), 2.52 (s, 1H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 –2.06 (m, 2H), 1.96 (s, 1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.77 (s,2H), 1.71 (d, J = 13.0 Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.56 (s, 3H), 1.54 –1.47 (m, 3H), 1.43 (s, 2H), 1.39 – 1.27 (m, 6H), 1.24 (d, J = 13.0 Hz, 1H),1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 178.26,172.88, 171.30, 159.04, 146.69, 138.95, 136.87, 135.57, 133.83, 133.64,126.04, 125.66, 125.33, 124.79, 124.42, 122.31, 119.43, 117.54, 106.85,78.29, 66.95, 50.36, 49.09, 48.85, 41.86, 40.58, 37.98, 37.39, 34.10, 33.53,31.29, 31.05, 30.83, 30.53, 29.56, 28.68, 27.05, 23.78, 23.57, 22.03, 20.48,16.96. HRMS (ESI): m / z calcd for C46 H 58 F3N4O3S + [M+H] + : 803.4176; found 803.4179.

[0065] (4) Preparation of compound E7

[0066] The structure of compound E7 is as follows:

[0067] Compound E7; Its preparation process is as follows:

[0068] The specific preparation method is as follows: Compound E7 is obtained by following the synthesis steps of compound E4. Compared with compound E4, only 5-bromopentylamine is replaced with 8-bromooctylamine to obtain compound C7. Then, compound D and compound C7 are reacted to obtain compound E7.

[0069] In the above reaction, the structure of compound C7 is as follows:

[0070] Compound C7;

[0071] The results of the detection of compound E7 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.13 – 7.06 (m, 2H), 6.86 – 6.78 (m, 2H), 6.68 (d, J = 0.7 Hz, 1H), 6.20 (t, J =1.0 Hz, 1H), 5.78 (s, 1H), 4.01 (s, 2H), 3.13 (d, J = 12.5 Hz, 1H), 3.09 (s,1H), 2.52 (s, 1H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 –2.06 (m, 2H), 1.96 (s, 1H), 1.86 (d, J= 13.0 Hz, 1H), 1.82 (s, 1H), 1.77 (s,2H), 1.71 (d, J = 13.0 Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.56 (s, 3H), 1.54 –1.47 (m, 3H), 1.45 (s, 2H), 1.39 – 1.28 (m, 9H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 178.26,172.88, 171.30, 159.04, 146.69, 146.68, 138.95, 136.87, 135.57, 133.83,133.64, 126.04, 125.66, 125.33, 124.79, 124.42, 122.31, 119.43, 117.54,106.85, 78.29, 66.95, 50.36, 49.09, 48.85, 41.86, 40.58, 37.98, 37.89, 34.10,33.53, 31.29, 31.05, 30.83, 30.50, 30.48, 29.56, 28.67, 27.05, 23.78, 23.57,22.03, 20.48, 16.96. HRMS (ESI): m / z calcd for C 47 H 60 F3N4O3S + [M+H] + : 817.4333;found 817.4337.

[0072] (5) Preparation of compound H1

[0073] The structure of compound H1 is as follows:

[0074] Compound H1; Its preparation process is as follows:

[0075] Step 1: Preparation of compound G

[0076] Compound D (405 mg, 1.00 mmol) and compound F (307 mg, 1.00 mmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (277 mg, 2.00 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were then combined and washed with saturated NaCl solution (15 mL). The organic phases were dried with anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain an intermediate, which was then dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was then added, and the mixture was stirred at room temperature for 0.5 hours. The solvent was then evaporated to obtain crude compound G.

[0077] The structures of compounds D, F, and G obtained in the above preparation process are shown below:

[0078] Compound D Compound F,

[0079] Compound G;

[0080] The detection results for compound G are as follows: HRMS (ESI) calculated for C 25 H 25 F3N5O3S + [M+H] + : 532.1625, found. 532.1626.

[0081] Step 2: Preparation of compound C1

[0082] The specific preparation method is as follows: Compound C1 is obtained by following the synthesis steps of compound C4 above, except that 5-bromopentamine is replaced with 2-bromoethylamine.

[0083] Step 3: Preparation of compound H1:

[0084] Compound G (266 mg, 0.500 mmol) and compound C1 (204 mg, 0.500 mmol) were dissolved in dioxane (3 mL) under ice bath conditions. Cesium carbonate (407 mg, 1.25 mmol) and potassium iodide (208 mg, 1.25 mmol) were added, respectively. The mixture was refluxed and stirred overnight. The liquid in the flask was cooled and evaporated. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The solution was then subjected to silica gel rapid column chromatography (dichloromethane:methanol = 20:1) to obtain compound H1.

[0085] The structure of compound C1 in the above preparation process is shown below:

[0086] Compound C1;

[0087] The results of the detection of compound H1 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.21 – 7.14 (m, 2H), 6.94 – 6.86 (m, 3H), 6.20 (t, J = 1.0 Hz, 1H), 5.78 (s,1H), 4.77 (s, 2H), 3.57 (s, 2H), 3.51 (s, 2H), 3.37 – 3.30 (m, 1H), 3.28 –3.21 (m, 1H), 2.56 – 2.47 (m, 8H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21(m, 2H), 2.17 – 2.06 (m, 2H), 1.96 (s, 1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s,1H), 1.71 (d, J = 13.0 Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.50 (d, J= 8.2 Hz,4H), 1.39 – 1.29 (m, 4H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77(s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 177.89, 172.88, 171.30, 170.16,158.32, 146.69, 138.95, 136.87, 135.57, 133.83, 133.64, 126.04, 125.66,125.33, 124.79, 124.52, 122.31, 119.43, 117.70, 106.85, 67.50, 66.95, 57.90,53.59, 50.36, 49.37, 49.09, 48.85, 40.58, 40.06, 37.98, 37.11, 34.10, 33.53,31.29, 29.56, 23.78, 23.53, 22.03, 20.48, 16.96. HRMS (ESI): m / z calcd forC 47 H 58 F3N6O4S + [M+H] + : 859.4187; found 859.4190.

[0088] (6) Preparation of compound H2

[0089] The structure of compound H2 is as follows:

[0090] Compound H2; Its preparation process is as follows:

[0091] The specific preparation method is as follows: Compound H2 is obtained by following the synthesis steps of compound H1. Compared with compound H1, only 2-bromoethylamine is replaced with 3-bromopropylamine to obtain compound C2. Then, compound G and compound C2 are reacted to obtain compound H2.

[0092] In the above reaction, the structure of compound C2 is as follows:

[0093] Compound C2;

[0094] The results of the detection of compound H2 are as follows: 1H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.21 – 7.14 (m, 2H), 6.94 – 6.86 (m, 2H), 6.75 (s, 1H), 6.20 (t, J = 1.0 Hz,1H), 5.78 (s, 1H), 4.77 (s, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 3.18 – 3.06 (m,2H), 2.54 – 2.43 (m, 7H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H),2.17 – 2.06 (m, 2H), 1.96 (s, 1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H),1.75 – 1.66 (m, 6H), 1.59 (d, J = 12.9 Hz, 1H), 1.50 (d, J = 8.2 Hz, 4H), 1.39 –1.29 (m, 2H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 CNMR (100 MHz, Chloroform- d) δ 178.21, 172.88, 171.30, 170.16, 158.32, 146.69,138.95, 136.87, 135.57, 133.83, 133.64, 126.04, 125.66, 125.33, 124.79,124.52, 122.31, 119.43, 117.70, 106.85, 67.50, 66.95, 54.59, 53.72, 50.36,49.37, 49.09, 48.85, 41.43, 40.58, 37.98, 36.60, 34.10, 33.53, 31.29, 29.56,27.94, 23.78, 23.57, 22.03, 20.48, 16.96. HRMS (ESI): m / z calcd forC 48 H 60 F3N6O4S + [M+H] + : 873.4343; found 873.4341.

[0095] (7) Preparation of compound H3

[0096] The structure of compound H3 is as follows:

[0097] Compound H3; its preparation process is as follows:

[0098] The specific preparation method is as follows: Compound H2 is obtained by following the synthesis steps of compound H1. Compared with compound H1, only 2-bromoethylamine is replaced with 4-bromobutylamine to obtain compound C3. Then, compound G and compound C3 are reacted to obtain compound H3.

[0099] In the above reaction, the structure of compound C3 is as follows:

[0100] Compound C3;

[0101] The results of the detection of compound H3 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.69 (dd, J= 7.5, 2.1 Hz, 1H),7.21 – 7.14 (m, 2H), 6.94 – 6.86 (m, 2H), 6.70 (d, J = 0.7 Hz, 1H), 6.20 (t, J =1.0 Hz, 1H), 5.78 (s, 1H), 4.77 (s, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 3.11 (s,1H), 3.10 – 3.03 (m, 1H), 2.54 – 2.42 (m, 8H), 2.46 – 2.37 (m, 4H), 2.30 –2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 1.96 (s, 1H), 1.86 (d, J = 13.0 Hz, 1H),1.82 (s, 1H), 1.71 (d, J = 13.0 Hz, 1H), 1.63 – 1.53 (m, 7H), 1.50 (d, J = 10.1Hz, 2H), 1.39 – 1.29 (m, 2H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H),0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 178.24, 172.88, 171.30, 170.16,158.32, 146.69, 138.95, 136.87, 135.57, 133.83, 133.64, 126.04, 125.66,125.33, 124.79, 124.52, 122.31, 119.43, 117.70, 106.85, 67.50, 66.95, 57.13,53.72, 50.36, 49.37, 49.09, 48.85, 42.03, 40.58, 37.98, 36.92, 34.10, 33.53,31.29, 29.56, 28.90, 26.46, 23.78, 23.57, 22.03, 20.48, 16.96. HRMS (ESI): m / z calcd for C 49 H 62 F3N6O4S +[M+H] + : 887.4500; found 887.4503.

[0102] (8) Preparation of compound M1

[0103] The structure of compound M1 is as follows:

[0104] Compound M1; its preparation process is as follows:

[0105] Step 1: Preparation of compound J1

[0106] Compound A (605 mg, 2.00 mmol) was dissolved in N,N-dimethylformamide (6 mL) under ice bath conditions. N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (912 mg, 2.40 mmol), diisopropylethylamine (388 mg, 3.00 mmol), and compound I1 (propargylamine, 110 mg, 2.00 mmol) were added separately. After 5 minutes, the ice bath was removed, and the mixture was stirred overnight at room temperature. The liquid in the flask was then diluted with ethyl acetate (20 mL), followed by washing with 1 N HCl solution (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated saline solution (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel rapid column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound J1.

[0107] The structures of compounds A, I1, and J1 obtained in the above preparation process are shown below:

[0108] Compound A Compound I1 Compound J1;

[0109] The detection results for compound J1 are as follows: HRMS (ESI) calculated for C 23 H 34 NO + [M+H] + : 340.2635, found. 340.2638.

[0110] Step 2: Preparation of compound L

[0111] Compound D (811 mg, 2.00 mmol) and compound K (483 mg, 2.00 mmol) were dissolved in N,N-dimethylformamide (6 mL), and potassium carbonate (553 mg, 4.00 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were then combined and washed with saturated NaCl solution (30 mL). The organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to obtain compound L.

[0112] The structures of compounds D, K, and L in the above preparation process are shown below:

[0113] Compound D Compound K, Compound L;

[0114] The detection results for compound L are as follows: HRMS (ESI) calculated for C 21 H 18 F3N6O2S + [M+H] + : 475.1159, found. 475.1161.

[0115] Step 3: Preparation of compound M1

[0116] L (237 mg, 0.500 mmol) and compound J1 (168 mg, 0.500 mmol) were dissolved in... t In a 1:1 mixture of BuOH / H2O (67 mL), CuSO4•5H2O (62.5 mg, 0.250 mmol) and sodium L-ascorbate (89.1 mg, 0.450 mmol) were added. The mixture was reacted overnight at room temperature. After the reaction was complete, CuSO4•5H2O was removed by filtration. The filtrate was concentrated under vacuum and then separated by silica gel rapid column chromatography (dichloromethane: methanol = 15:1) to obtain compound M1.

[0117] The results of the detection of compound M1 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J= 7.4 Hz, 1H), 7.70 (s, 1H), 7.73 – 7.66 (m,1H), 7.34 (d, J = 0.7 Hz, 1H), 7.14 – 7.07 (m, 2H), 6.89 – 6.81 (m, 2H), 6.20(t, J = 1.0 Hz, 1H), 5.78 (s, 1H), 4.48 – 4.29 (m, 6H), 2.52 (s, 1H), 2.42 (dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 1.96 (s, 1H),1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.71 (d, J = 13.0 Hz, 1H), 1.59 (d, J =12.9 Hz, 1H), 1.50 (d, J = 8.2 Hz, 4H), 1.39 – 1.29 (m, 5H), 1.24 (d, J = 13.0Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ177.63, 172.88, 171.30, 158.13, 146.69, 141.05, 138.95, 136.87, 135.57,133.83, 133.64, 127.50, 126.04, 125.66, 125.33, 124.79, 124.48, 122.31,119.43, 117.70, 106.85, 71.91, 66.95, 57.14, 50.36, 49.14, 49.09, 41.40,40.58, 37.98, 36.61, 34.10, 33.53, 31.29, 29.56, 23.78, 23.51, 22.03, 20.48,16.96. HRMS (ESI): m / z calcd for C 44 H 51 F3N7O3S + [M+H]+ : 814.3721; found 814.3723.

[0118] (9) Preparation of compound M2

[0119] The structure of compound M2 is as follows:

[0120] Compound M2; its preparation process is as follows:

[0121] The specific preparation method is as follows: Compound M2 is obtained by following the synthesis steps of compound M1. Compared with compound M1, only the propargylamine is replaced with but-3-yn-1-amine to obtain compound J2. Then, compound L and compound J2 are reacted to obtain compound M2.

[0122] In the above reaction, the structure of compound J2 is as follows:

[0123] Compound J2;

[0124] The results of the detection of compound M2 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.04 – 7.93 (m, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 4.77 (s, 1H), 4.62 (t, J = 5.1 Hz, 1H), 4.46 – 4.35 (m, 3H), 3.75 (s, 2H), 3.63 (s, 2H), 2.87(dd, J = 44.9, 6.4 Hz, 2H), 2.45 (s, 2H), 1.89 (d, J = 20.9 Hz, 2H), 1.58 (s,6H), 1.56 (d, J = 6.1 Hz, 6H), 1.47 (d, J = 11.3 Hz, 2H), 1.27 (s, 1H), 1.25 (s,3H), 1.22 (d,J = 4.0 Hz, 2H), 1.20 (s, 2H), 0.99 (dd, J = 6.8, 2.9 Hz, 2H), 0.97– 0.92 (m, 1H), 0.90 – 0.83 (m, 2H), 0.80 (s, 1H). HRMS (ESI): m / z calcd forC 45 H 53 F3N7O3S + [M+H] + : 828.3877; found 828.3876.

[0125] (10) Preparation of compound M3

[0126] The structure of compound M3 is as follows:

[0127] Compound M3; Its preparation process is as follows:

[0128] The specific preparation method is as follows: Compound M3 is obtained by following the synthesis steps of compound M1. Compared with compound M1, only propargylamine is replaced with pent-4-yn-1-amine to obtain compound J3. Then, compound L and compound J3 are reacted to obtain compound M3.

[0129] In the above reaction, the structure of compound J3 is as follows:

[0130] Compound J3;

[0131] The results of the detection of compound M3 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.57 (s, 1H), 7.14 – 7.06 (m, 2H), 6.89 – 6.81 (m, 2H), 6.74 (d, J = 0.7 Hz, 1H), 6.20 (t, J= 1.0 Hz, 1H), 5.78 (s, 1H), 4.48 – 4.36 (m, 4H), 3.28 – 3.21(m, 1H), 3.21 – 3.14 (m, 1H), 2.85 (s, 2H), 2.52 (s, 1H), 2.42 (dt, J = 17.9,1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 2.06 – 1.90 (m, 4H),1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.71 (d, J = 13.0 Hz, 1H), 1.58 (d, J =17.1 Hz, 3H), 1.50 (d, J = 8.2 Hz, 4H), 1.39 – 1.29 (m, 2H), 1.24 (d, J = 13.0Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ178.21, 172.88, 171.30, 158.13, 146.69, 142.47, 138.95, 136.87, 135.57,133.83, 133.64, 128.90, 126.04, 125.66, 125.33, 124.79, 124.48, 122.31,119.43, 117.70, 106.85, 71.91, 66.95, 57.41, 50.36, 49.09, 48.85, 42.83,40.58, 37.98, 34.11, 34.10, 33.53, 31.29, 29.56, 28.12, 27.75, 23.78, 23.57,22.03, 20.48, 16.96. HRMS (ESI): m / z calcd for C 46 H 55 F3N7O3S + [M+H] + : 842.4034;found 842.4035.

[0132] (11) Preparation of compound M4

[0133] The structure of compound M4 is as follows:

[0134] Compound M4; Its preparation process is as follows:

[0135] The specific preparation method is as follows: Compound M4 is obtained by following the synthesis steps of compound M1. Compared with compound M1, only propargylamine is replaced with pent-4-yn-1-amine to obtain compound J4. Then, compound L and compound J4 are reacted to obtain compound M4.

[0136] In the above reaction, the structure of compound J4 is as follows:

[0137] Compound J4;

[0138] The results of the detection of compound M4 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ8.13 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.69 (dd, J = 7.5, 2.1 Hz, 1H),7.57 (s, 1H), 7.14 – 7.06 (m, 2H), 6.89 – 6.81 (m, 2H), 6.68 (d, J = 0.7 Hz, 1H), 6.20 (t, J = 1.0 Hz, 1H), 5.78 (s, 1H), 4.48 – 4.36 (m, 4H), 3.14 (d, J =12.4 Hz, 1H), 3.10 – 3.02 (m, 1H), 2.90 – 2.77 (m, 2H), 2.52 (s, 1H), 2.42(dt, J = 17.9, 1.0 Hz, 1H), 2.30 – 2.21 (m, 2H), 2.17 – 2.06 (m, 2H), 1.96 (s,1H), 1.86 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.71 (d, J= 13.0 Hz, 1H), 1.67 –1.54 (m, 11H), 1.49 (s, 1H), 1.39 – 1.29 (m, 2H), 1.24 (d, J = 13.0 Hz, 1H), 1.15 – 1.06 (m, 9H), 0.77 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 178.26,172.88, 171.30, 158.13, 146.69, 143.15, 138.95, 136.87, 135.57, 133.83,133.64, 128.43, 126.04, 125.66, 125.33, 124.79, 124.48, 122.31, 119.43,117.70, 106.85, 71.91, 66.95, 57.41, 50.36, 49.09, 48.85, 41.53, 40.58,37.98, 36.29, 34.10, 33.53, 31.29, 30.80, 30.15, 29.56, 26.25, 23.78, 23.57,22.03, 20.48, 16.96. HRMS (ESI): m / z calcd for C 47 H 57 F3N7O3S + [M+H] + : 856.4190;found 856.4193.

[0139] (12) Preparation of compound M5

[0140] The structure of compound M5 is as follows:

[0141] Compound M5; its preparation process is as follows:

[0142] The specific preparation method is as follows: Compound M5 is obtained by following the synthesis steps of compound M1. Compared with compound M1, only propargylamine is replaced with pent-4-yn-1-amine to obtain compound J5. Then, compound L and compound J5 are reacted to obtain compound M5.

[0143] In the above reaction, the structure of compound J5 is as follows:

[0144] Compound J5;

[0145] The results of the detection of compound M5 are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ7.99 – 7.93 (m, 2H), 7.83 (dd, J = 8.3, 1.8 Hz, 1H), 7.47 (s, 1H), 7.22 (s,1H), 7.20 (s, 1H), 7.01 (d, J = 8.6 Hz, 2H), 5.81 (dd, J = 14.6, 8.7 Hz, 1H),5.29 (s, 1H), 4.74 (q, J = 5.5 Hz, 2H), 4.40 (td, J = 5.0, 2.7 Hz, 2H), 3.24 (dq, J = 15.2, 8.5, 7.5 Hz, 2H), 2.84 (dt, J = 7.0, 3.5 Hz, 1H), 2.72 (td, J = 7.6, 2.2Hz, 2H), 2.41 – 2.22 (m, 1H), 2.21 – 2.00 (m, 2H), 2.00 – 1.87 (m, 2H), 1.87– 1.74 (m, 4H), 1.74 – 1.57 (m, 6H), 1.55(s, 6H), 1.53 – 1.50 (m, 2H), 1.39(dd, J = 8.4, 5.5 Hz, 2H), 1.25 (s, 3H), 1.23 (s, 1H), 1.21 (d, J = 1.6 Hz, 3H), 1.18 (d, J = 11.2 Hz, 2H), 1.01 – 0.94 (m, 2H), 0.88 – 0.80 (m, 2H). 13 C NMR (100MHz, Chloroform- d ) δ 180.19, 178.33, 175.01, 158.66, 147.05, 145.73, 137.19,135.21, 133.71 (q, J F-C = 301.2 Hz), 133.56 (q, JF-C = 33.3 Hz), 132.21, 130.90,128.37, 127.14 (q, J F-C = 4.9, 4.4 Hz), 126.89, 124.08, 123.92, 121.83, 115.68,114.80, 110.18, 66.82, 66.33, 49.45, 47.22, 45.57, 39.59, 38.60, 38.02,37.34, 37.09, 33.45, 30.00, 29.38, 29.33, 28.91, 26.37, 25.44, 25.21, 23.97,23.64, 21.11, 18.78, 16.55. HRMS (ESI): m / z calcd for C 48 H 59 F3N7O3S + [M+H] + :870.4347; found 870.4343.

[0146] Example 2

[0147] In this embodiment, the protein degrading agents with rosin acid as the hydrophobic group (the protein degrading agents prepared in Example 1, E4-E7, H1-H3, M1-M5) were evaluated using Western blotting to assess their ability to degrade AR and AR-V7 in the human prostate cancer cell line 22Rv1. The AR protein degrading agent SARD279, as reported in the literature, was used as a positive control. All compounds used were at a concentration of 10 μM. The degradation efficiency results are shown in Table 1.

[0148] Table 1. Degradation efficiency of compounds on AR and AR-V7 in human prostate cancer cell line 22Rv1

[0149]

[0150] The table shows that all compounds possess a certain ability to degrade AR and AR-V7. Compounds H1, M1, M2, M3, and M5 exhibited degradation efficiencies comparable to or relatively higher than the positive control drug SARD279. Further evaluation of the degradation effects of H1, M1, M2, M3, and M5 was conducted using three concentration gradients of 0, 1, and 10 μM to determine whether these preferred compounds could degrade AR and AR-V7 in a concentration-dependent manner. Results are shown below. Figure 1The results showed that compounds H1, M1, M2, M3, and M5 could all degrade AR and AR-V7 in a concentration-dependent manner, with compound M2 exhibiting the highest degradation efficiency. Therefore, compound M2 was selected as the preferred compound for further evaluation.

[0151] Example 3

[0152] This embodiment evaluates the anti-tumor cell proliferation experiment of the protein degrading agent with rosin acid as the hydrophobic group (the compound synthesized in Example 1). The experiment was carried out in the human prostate cancer cell line 22Rv1, with the AR protein degrading agent SARD279 reported in the literature as a positive control. After incubation with 1 μM of the drug for 6 days, the cells were counted. The results are shown in Table 2. It was found that the cell number decreased to varying degrees, and the cell number of compound M2 decreased the most significantly, which is consistent with the degradation efficiency results in Example 13.

[0153] To more intuitively compare the differences in compound activity, the remaining cell percentage was divided into four categories: 80% < percentage < 100% (*), 50% < percentage < 80% (**), and 50% > percentage (***). Specific test results are shown in Table 2 below.

[0154] Table 2. Count of the survival rate of compounds in human prostate cancer cell line 22Rv1

[0155] Compound numbering Remaining cell count E4 * E5 * E6 * E7 * H1 ** H2 * H3 * M1 *** M2 *** M3 ** M4 * M5 ** SARD279 ***

[0156] Example 4

[0157] This embodiment evaluates the bioavailability of compound M2.

[0158] Protein degraders, such as hydrophobic tag degraders, often have limited in vivo efficacy due to their metabolic instability and low bioavailability. Previous reports indicated that the AR hydrophobic tag protein degrader SARD279 exhibited some protein degradation effects, but suffered from poor solubility and bioavailability. This invention optimizes the hydrophobic tag type and linker type, selecting compound M2, which has good solubility and is expected to achieve higher in vivo oral bioavailability. SARD279 was used as a positive control for in vivo oral bioavailability evaluation.

[0159] The specific method for evaluating oral bioavailability was as follows: After fasting overnight, three rats were administered the drug by gavage (20 mg / kg), and three rats were administered the drug via tail vein (5 mg / kg). Blood samples were then collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h, and placed in pre-heparinized tubes. After gently tapping the tubes several times to thoroughly mix the blood with the heparin sodium, the tubes were centrifuged (4 ℃, 3000 rpm, 10 min) to obtain plasma. 50 μL of plasma sample was taken, and 50 μL of diluent (50% methanol / water) and 250 μL of methanol precipitant were added. The mixture was vortexed and centrifuged (4 ℃, 12000 rpm, 10 min). The supernatant was then sealed through a membrane and sent for LC-MS / MS analysis.

[0160] Parameters were analyzed using WinNonlin software (see Table 3). The results showed that compound M2 had good oral bioavailability of 15.4%, while the positive control SARD279 had an oral bioavailability of 0.04%.

[0161] Table 3 Dynamic parameters

[0162]

[0163] Example 5

[0164] In this embodiment, the in vivo efficacy of compound M2 was evaluated. 22Rv1 cells were used to establish a xenograft model, and SARD279, as reported in the literature, was used as a positive control.

[0165] The specific method was as follows: 22Rv1 was injected into nu / nu immunodeficient mice. When the average tumor diameter reached 3 mm, the mice were randomly divided into a control group (n=5), a compound M2 oral administration group (50 mpk, n=5), a compound M2 intravenous administration group (10 mpk, n=5), a SARD279 oral administration group (50 mpk, n=5), and a SARD279 intravenous administration group (10 mpk, n=5), and administered the drugs for 18 days. There were no significant fluctuations in body weight between the administration groups and the control group, and the mice showed no significant abnormalities, indicating that compound M2 had good safety. The tumor weight and volume in the administration groups were significantly lower than those in the control group. The tumor inhibition rate ((1 - tumor weight in administration group / tumor weight in control group) * 100%) is shown in Table 4. These results indicate that compound M2 has a stronger in vivo oral efficacy compared to SARD279.

[0166] Table 4. 22Rv1 cell xenograft model TGI

[0167] Group M2 IV M2 PO SARD279 IV SARD279 PO TGI 71.1% 72.6% 62.1% 0%

[0168] Although the description of the invention has been quite detailed and particularly of several described embodiments, it is not intended to limit it to any of these details or embodiments or any particular embodiment, but should be considered as providing a broad possible interpretation of the claims by referring to the appended claims and taking into account the prior art, thereby effectively covering the intended scope of the invention. Furthermore, the invention has been described above with respect to embodiments foreseeable by the inventors in order to provide a useful description, and non-substantial modifications to the invention that have not yet been foreseen may still represent equivalent modifications.

Claims

1. A protein degrading agent with rosin acid as a hydrophobic group, characterized in that, Its structural formula is one of the following compounds: E6, E7, H1, H2, M1, M2, M3, and M5: Compound E6 Compound E7 Compound H1, Compound H2, Compound M1, Compound M2, Compound M3, Compound M5.

2. The protein degrading agent with rosin acid as a hydrophobic group according to claim 1, characterized in that, The molecular structure of the degrading agent is shown below: 。 3. A method for preparing a protein degrading agent with rosin acid as a hydrophobic group as described in any one of claims 1-2, characterized in that, Its preparation route is Route 1, Route 2, or Route 3: Route 1: ； Route 2: ； Route 3: 。 4. The use of the protein degrading agent with rosin acid as a hydrophobic group as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the preparation of AR degrading agents.

5. The application according to claim 4, characterized in that, The AR degrading agent can be used to prepare drugs for the treatment and / or prevention of cancers associated with AR abnormalities or resistance to conventional AR inhibitors.

6. The application according to claim 5, characterized in that, The relevant cancer is prostate cancer.

7. A pharmaceutical composition, characterized in that, Includes the protein degrading agent with rosin acid as a hydrophobic group as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition comprises one or more pharmaceutically acceptable excipients or carriers.

Images