A proteolytic targeting chimera, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application belongs to the technical field of chemical medicine synthesis, and particularly relates to a proteolysis targeting chimera, a preparation method, a pharmaceutical composition and purposes thereof. The structural formula of the proteolysis targeting chimera is shown in formula Ia or formula Ib; the preparation process is simple and easy to operate; the proteolysis targeting chimera or pharmaceutically acceptable salt thereof prepared has the effect of efficiently degrading CDK2 / 4 / 6 / 9 and has high selectivity; and experimental results show that the compound can induce the targeted degradation of CDK2 / 4 / 6 / 9 protein by using the ubiquitin-proteasome system, inhibit the downstream signal pathway, realize the selective degradation of CDK2 / 4 / 6 / 9 at the protein level, cell level and animal level, and has a good effect of resisting the proliferation of prostate cancer cells.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis technology, specifically relating to a protein hydrolysis targeted chimera, its preparation method, pharmaceutical composition, and uses. Background Technology

[0002] Castration-resistant prostate cancer (CRPC) is the leading cause of death among prostate cancer patients. The persistent action of the androgen receptor (AR) renders CRPC patients insensitive to both traditional and novel endocrine therapies targeting the AR signaling axis. Cyclin-dependent kinases (CDKs) synergistically regulate cell cycle progression and transcription with cyclin chaperones. Numerous studies have demonstrated direct interactions between various CDKs and AR. Androgens, closely associated with the development and progression of prostate cancer (PCa), can overactivate cell cycle-related CDK4 / 6, stimulating their overexpression and reducing sensitivity to CDK inhibitors. In metastatic castration-resistant prostate cancer (mCRPC), c-Myc expression is frequently upregulated, and CDK4 / 6 are direct transcriptional targets of c-Myc. CDK2 and CDK4 / 6 exhibit synergistic effects, and CDK2 can also mediate AR phosphorylation. Furthermore, studies have shown that CDK9 is also directly associated with AR and can mediate AR phosphorylation. Phosphorylation of serine 81 (S81) on the AR may play an important role in regulating the core function of the AR. Therefore, CDK2 / 4 / 6 / 9 may be a potential target for treating AR signaling axis-driven CRPC.

[0003] Proteolytic targeting chimeras (PROTACs) are an emerging drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade and clear target proteins. Due to their "event-driven mechanism," PROTACs offer advantages such as targeting undrug-resistant proteins, overcoming drug resistance, and requiring low dosages, providing new avenues for drug research and development. However, the clinical progress of many PROTAC molecules has not been smooth, and most PROTAC molecules do not meet the five principles of drug-likeness, possessing high molecular weight and large polar surface area. Summary of the Invention

[0004] This invention utilizes protein hydrolysis-targeted chimeric (PROTAC) technology. Through molecular-protein docking analysis, the selective CDK4 / 6 inhibitor Ribociclib is modified, and then linked to a CRBN ligand (i.e., thalidomide) via a specific rigid linker molecule, resulting in a series of PROTAC molecules targeting CDK2 / 4 / 6 / 9, with structural formulas shown in Formula Ia or Formula Ib:

[0005] The Linker in Equation Ia can be any of the following structures:

[0006]

[0007] The Linker in Equation Ib can be any of the following structures:

[0008]

[0009] This invention reveals that the synthesized proteolytic targeting chimeric compounds exhibit significant effects in inducing the degradation of CDK2 / 4 / 6 / 9 proteins. Compound A12, in particular, demonstrates even more pronounced effects.

[0010]

[0011] In a second aspect, the present invention also provides a method for preparing the above-mentioned compound A12, the synthetic route of which is shown below:

[0012]

[0013] A third aspect of the invention is to provide the use of the above-described protein hydrolysis-targeting chimera or its solvates, and pharmaceutically acceptable salts, in the preparation of remedies for treating and / or preventing CDK2 / 4 / 6 / 9-related diseases, including cancer, particularly prostate cancer, and more particularly castration-resistant prostate cancer.

[0014] A fourth aspect of the invention also provides a pharmaceutical composition whose main active ingredient is the aforementioned protein hydrolysis-targeting chimera or a pharmaceutically acceptable salt thereof. Depending on the specific needs, the dosage form of the pharmaceutical composition may be a liquid or solid formulation, such as tablets, capsules, powders, granules, pellets, pastes, and powders. The pharmaceutical composition may also include one or more pharmaceutically acceptable excipients or carriers, such as at least one of carbohydrates, polymers, lipids, and minerals.

[0015] The beneficial effects of this invention are as follows: the protein hydrolysis targeted chimera proposed in this invention has the effect of highly efficient targeted degradation of CDK2 / 4 / 6 / 9 and has high selectivity. It has also achieved good therapeutic effects in in vivo animal models, providing a new means for the treatment and / or prevention of CDK2 / 4 / 6 / 9 related diseases, especially prostate cancer. Detailed Implementation

[0016] The following will provide a clear and complete description of the concept and technical effects of the present invention in conjunction with embodiments, so as to fully understand the purpose, solution and effects of the present invention. It should be noted that, unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other.

[0017] Example 1

[0018] A protein hydrolysis-targeting chimera (compound A1) has the following synthetic route:

[0019]

[0020] The specific process is as follows:

[0021] (1) Specific preparation process of intermediate 11a:

[0022]

[0023] Compound 10a (3.70 g, 8.86 mmol, 1.0 eq) was dissolved in 90 mL of MeOH, and 10% palladium on carbon (350 mg) was added. The mixture was purged with argon five times, followed by purging with hydrogen five times. The reaction was carried out overnight at room temperature under hydrogen atmosphere, and the reaction progress was monitored by TLC (PE:EA = 1:1). After the reaction was complete, the palladium on carbon was removed by diatomaceous earth filtration. The filtrate was concentrated under reduced pressure to obtain compound 11a (white solid, 2.46 g, 98%). HRMS (ESI) predicted value C 15 H 30 N3O2 + [M+H] + : 284.2333, measured value: 284.2339.

[0024] (2) Specific preparation process of intermediate 12a:

[0025]

[0026] Compound 7a (500 mg, 1.81 mmol, 1.0 eq) was dissolved in 10 mL of DMSO. Compound 11a (513 mg, 1.81 mmol, 1.0 eq) and N,N-diisopropylethylamine (702 mg, 5.43 mmol, 3.0 eq) were added, and the mixture was reacted overnight at 90 °C. The reaction progress was monitored by TLC (DCM:MeOH = 18:1). After the reaction was complete, the system was cooled to room temperature, and 30 mL of water was added, resulting in the precipitation of a solid. The solid was filtered through filter paper, and the filter cake was purified by silica gel column chromatography (DCM:MeOH = 40:1) to obtain compound 12a (yellow solid, 791 mg, 81%). HRMS (ESI) predicted value C 28 H 38 N5O6 + [M+H] + : 540.2817, measured value: 540.2820.

[0027] (3) Specific preparation process of compound A1:

[0028]

[0029] Compound 12a (300 mg, 0.56 mmol, 1.05 eq) was placed in a reaction flask, and 4 mL of 4M hydrochloric acid / 1,4-dioxane solution was added. The reaction was carried out at room temperature for 30 min to remove the Boc protecting group. The reaction was monitored by TLC. After the reaction was complete, the solution was concentrated and evaporated to dryness for later use. Compound 4 (208 mg, 0.53 mmol, 1.0 eq) was dissolved in 6 mL of N,N-dimethylformamide, and HATU (242 mg, 0.64 mmol, 1.2 eq) and N,N-diisopropylethylamine (137 mg, 1.06 mmol, 2.0 eq) were added. The mixture was stirred for 15 min, and then the Boc-deprotected 12a was added to the reaction system. The reaction was carried out at room temperature overnight and monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, 15 mL of water was added to the system, and the mixture was extracted with EA (10 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 45:1) to give compound A1 (yellow solid, 226 mg, 50%). HRMS (ESI) predicted value C 44 H 51 N 10 O6 + [M+H] + : 815.3988, measured value: 815.3972.

[0030] Example 2

[0031] A protein hydrolysis-targeting chimera (compound A2) has the following synthetic route:

[0032]

[0033] The specific process is as follows:

[0034] (1) Specific preparation process of intermediate 13a:

[0035]

[0036] Compound 4 (1.00 g, 2.55 mmol, 1.0 eq) was dissolved in 25 mL of acetonitrile. HATU (1.16 g, 3.05 mmol, 1.2 eq) and N,N-diisopropylethylamine (658 mg, 5.075 mmol, 2.0 eq) were added, and the mixture was stirred for 15 min. Then, compound 11 (720 mg, 2.55 mmol, 1.0 eq) was added, and the mixture was reacted overnight at room temperature. The reaction was monitored by TLC (DCCM:MeOH = 20:1). After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 60:1) to give compound 13a (white solid, 1.44 g, 86%). HRMS (ESI) predicted value C 36 H 51 N8O4 + [M+H] + : 659.4028, measured value: 659.4031.

[0037] (2) Specific preparation process of intermediate 14a:

[0038]

[0039] Compound 13a (1.00 g, 1.516 mmol) was dissolved in 4 mL of 4 M hydrochloric acid / 1,4-dioxane and reacted at room temperature for 1 h to obtain compound 14a. The reaction solution was concentrated and used directly in subsequent reactions.

[0040] (3) Specific preparation process of compound A2:

[0041]

[0042] Compound 14a (200 mg, 0.358 mmol, 1.0 eq) was dissolved in 4 mL of N,N-dimethylformamide, followed by the addition of compound 7a (109 mg, 0.393 mmol, 1.1 eq) and N,N-diisopropylethylamine (138 mg, 1.074 mmol, 3.0 eq). The reaction was carried out overnight at 90 °C, and the reaction progress was monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, the system was cooled to room temperature, and then 10 mL of water was added. The system was extracted with EA (10 mL × 3), and the organic phase was collected. The organic phase was back-extracted with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 45:1) to give compound A2 (yellow solid, 166 mg, 57%). HRMS (ESI) predicted value C 44 H 51 N 10 O6 + [M+H] +: 815.3988, measured value: 815.3978.

[0043] Example 3

[0044] A protein hydrolysis-targeting chimera (compound A3) has the following synthetic route:

[0045]

[0046] The specific process is as follows:

[0047] (1) Specific preparation process of intermediate 15a:

[0048]

[0049] Compound 12b (500 mg, 1.13 mmol, 1.0 eq) was dissolved in 6 mL of 4 M hydrochloric acid / 1,4-dioxane. The reaction was carried out at room temperature to remove Boc. After the reaction was complete, the reaction solution was concentrated, and then N,N-dimethylformamide (8 mL) and triethylamine (343 mg, 3.39 mmol, 3.0 eq) were added. Bromoacetyl chloride (186 mg, 1.187 mmol, 1.05 eq) was slowly added dropwise at 0 °C. The reaction was carried out at 0 °C for 30 min, and the reaction progress was monitored by TLC (DCM:MeOH = 18:1). After the reaction was complete, 20 mL of water was added to the system, and the mixture was extracted with EA (15 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 15a (yellow solid, 283 mg, 54%). HRMS (ESI) predicted value C 19 H 20 BrN4O5 + [M+H] + 463.0612, 465.0592, Measured values: 463.0614, 465.0596.

[0050] (2) Specific preparation process of intermediate 13b:

[0051]

[0052] The synthesis method was the same as for compound 13a, using N-Boc-piperazine (500 mg, 2.68 mmol, 1.0 eq) as the starting material, which underwent amide condensation with compound 4 to give compound 13b (white solid, 1.34 g, 89%). HRMS (ESI) predicted value C 30 H 40 N7O4 + [M+H] +: 562.3137, measured value: 562.3140.

[0053] (3) Specific preparation process of intermediate 14b:

[0054]

[0055] Compound 13b (1.00 g, 1.78 mmol) was dissolved in 10 mL of 4 M hydrochloric acid / 1,4-dioxane and reacted at room temperature for 1 h to obtain compound 14b. The reaction solution was concentrated and used directly in subsequent reactions.

[0056] (4) Specific preparation process of compound A3:

[0057]

[0058] Compound 14b (230 mg, 0.5 mmol, 1.0 eq) was dissolved in 8 mL of N,N-dimethylformamide, and triethylamine (151 mg, 1.5 mmol, 3.0 eq) and 15a (234 mg, 0.5 mmol, 1.0 eq) were added. The reaction was carried out at room temperature for 4 h, and the reaction progress was monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, 20 mL of water was added to the system, and the mixture was extracted with EA (15 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 45:1) to give compound A3 (yellow solid, 270 mg, 64%). HRMS (ESI) predicted value C 45 H 51 N 11 O7 + [M+H] + : 844.3890, measured value: 844.3902.

[0059] Example 4

[0060] A protein hydrolysis-targeting chimera (compound A4) has the following synthetic route:

[0061]

[0062] The specific process is as follows:

[0063] (1) Specific preparation process of intermediate 16a:

[0064]

[0065] Compound 12b (1.00 g, 2.26 mmol, 1.0 eq) was dissolved in 10 mL of 4 M hydrochloric acid / 1,4-dioxane. The reaction was carried out at room temperature to remove Boc. After the reaction was complete, the reaction solution was concentrated, and then N,N-dimethylformamide (15 mL), triethylamine (687 mg, 6.76 mmol, 3.0 eq), and tert-butyl bromoacetate (440 mg, 2.26 mmol, 1.0 eq) were added. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC (DCM:MeOH = 20:1). After the reaction was complete, 40 mL of water was added to the system, and the mixture was extracted with EA (30 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 60:1) to give compound 16a (yellow solid, 857 mg, 83%). HRMS (ESI) predicted value C 23 H 29 N4O6 + [M+H] + : 457.2082, measured value: 457.2085.

[0066] (2) Specific preparation process of intermediate 17a:

[0067]

[0068] Compound 16a (850 mg, 1.86 mmol) was dissolved in 8 mL of DCM, and then 8 mL of trifluoroacetic acid was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the solution was concentrated and used directly in the next step.

[0069] (3) Specific preparation process of compound A4:

[0070]

[0071] Compound 17a (200 mg, 0.50 mmol, 1.0 eq) was dissolved in 5 mL of N,N-dimethylformamide, followed by the addition of HATU (228 mg, 0.60 mmol, 1.2 eq) and N,N-diisopropylethylamine (194 mg, 1.50 mmol, 3.0 eq). The mixture was stirred for 15 min, and then compound 14b (230 mg, 0.50 mmol, 1.0 eq) was added. The reaction was allowed to proceed overnight at room temperature, and the reaction progress was monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, 15 mL of water was added to the system, and the mixture was extracted with EA (10 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 45:1) to give compound A4 (yellow solid, 219 mg, 52%). HR MS (ESI) predicted value C44 H 50 N 11 O7 + [M+H] + : 844.3890, measured value: 844.3896.

[0072] Example 5

[0073] A protein hydrolysis-targeting chimera (compound A5) has the following synthetic route:

[0074]

[0075] The specific process is as follows:

[0076] (1) Specific preparation process of intermediate 12c:

[0077]

[0078] Compound 7b (1.20 g, 3.56 mmol, 1.0 eq) was dissolved in 30 mL of N,N-dimethylformamide. Then, N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.21 g, 3.915 mmol, 1.1 eq), potassium phosphate (1.89 g, 8.9 mmol, 2.5 eq), and bis(diphenylphosphine)ferrocene palladium dichloride (261 mg, 0.356 mmol, 0.1 eq) were added sequentially. Argon gas was purged three times, and the reaction was carried out overnight at 90 °C. The reaction was monitored by TLC (PE:EA = 1:3). After the reaction was complete, 70 mL of water was added to the system, and the mixture was extracted with EA (50 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:1) to give compound 12c (white solid, 1.19 g, 76%). HRMS (ESI) predicted value C 23 H 26 N3O6 + [M+H] + : 440.1817, measured value: 440.1821.

[0079] (2) Specific preparation process of intermediate 15b:

[0080]

[0081] Starting with compound 12c (400 mg, 0.91 mmol, 1.0 eq), compound 15b (white solid, 221 mg, 53%) was synthesized using the same method as 15a. HRMS (ESI) predicted value C 20 H 19 BrN3O5+ [M+H] + : 460.0503, measured value: 460.0506.

[0082] (3) Specific preparation process of compound A5:

[0083]

[0084] The synthetic method was the same as that for compound A3. Compounds 15b (200 mg, 0.43 mmol, 1.0 eq) and 14b underwent nucleophilic substitution to give compound A5 (white solid, 223 mg, 61%). HRMS (ESI) predicted value C 45 H 49 N 10 O7 + [M+H] + : 841.3781, measured value: 841.3775.

[0085] Example 6

[0086] A protein hydrolysis-targeting chimera (compound A6) has the following synthetic route:

[0087]

[0088] The specific process is as follows:

[0089] (1) Specific preparation process of intermediate 19:

[0090]

[0091] Compound 12c (400 mg, 0.91 mmol, 1.0 eq) was dissolved in 10 mL of MeOH, and 10% palladium on carbon (40 mg) was added. The mixture was purged with argon five times, followed by purging with hydrogen five times. The reaction was carried out overnight at room temperature under hydrogen atmosphere, and the reaction progress was monitored by TLC (PE:EA = 1:3). After the reaction was complete, the palladium on carbon was removed by diatomaceous earth filtration, and the filtrate was concentrated to obtain compound 19 (white solid, 379 mg, 95%). HRMS (ESI) predicted value C 23 H 28 N3O6 + [M+H] + : 442.1973, measured value: 442.1977.

[0092] (2) Specific preparation process of intermediate 15c:

[0093]

[0094] Starting with compound 19 (350 mg, 0.79 mmol, 1.0 eq), compound 15c was synthesized using the same method as compound 15a to obtain a white solid (186 mg, 51%). HRMS (ESI) predicted value C 20 H 21 BrN3O5 + [M+H] + : 462.0660, Measured value: 462.0662.

[0095] (3) Specific preparation process of compound A6:

[0096]

[0097] The synthetic method was the same as that for compound A3. Compound 15c (150 mg, 0.32 mmol, 1.0 eq) and compound 14b underwent nucleophilic substitution to give compound A6 (white solid, 142 mg, 52%). HRMS (ESI) predicted value C 45 H 51 N 10 O7 + [M+H] + : 843.3937, measured value: 843.3934.

[0098] Example 7

[0099] A protein hydrolysis-targeting chimera (compound A7) has the following synthetic route:

[0100]

[0101] The specific process is as follows:

[0102] (1) Specific preparation process of intermediate 21:

[0103]

[0104] 2-Bromo-4'-nitroacetophenone (20) (1.00 g, 4.09 mmol, 1.0 eq) was dissolved in 40 mL of acetonitrile, and N-Boc-piperazine (839 mg, 4.5 mmol, 1.1 eq) was added. The reaction was carried out at room temperature for 1.5 h, and the reaction progress was monitored by TLC (PE:EA = 2:1). After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (PE:EA = 8:1) to give compound 21 (orange-yellow solid, 1.23 g, 86%). HRMS (ESI) predicted value C 17 H 24 N3O5 + [M+H] + 350.1711, measured value: 350.1714.

[0105] (2) Specific preparation process of intermediate 22a:

[0106]

[0107] Compound 21 (500 mg, 1.43 mmol, 1.0 eq) was dissolved in 14 mL of MeOH, and palladium on carbon (50 mg) was added. The mixture was then purged with argon five times and hydrogen five times. The reaction was carried out at 0 °C for 1 h, and the reaction progress was monitored by TLC (PE:EA = 2:1). After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 8:1) to obtain compound 22a (white solid, 365 mg, 80%). HRMS (ESI) predicted value C 17 H 26 N3O3 + [M+H] + : 320.1969, measured value: 320.1965.

[0108] (3) Specific preparation process of intermediate 13c:

[0109]

[0110] The synthesis method was the same as that for compound 3a. Compound 22a (350 mg, 1.09 mmol, 1.0 eq) and compound 2 underwent Buchwald-Hartwig coupling to give compound 13c (white solid, 523 mg, 83%). HRMS (ESI) predicted value C 31 H 42 N7O4 + [M+H] + : 576.3293, measured value: 576.3297.

[0111] (4) Specific preparation process of intermediate 14c:

[0112]

[0113] Compound 13c (500 mg, 0.869 mmol, 1.0 eq) was dissolved in 6 mL of 4 M hydrochloric acid / 1,4-dioxane solution. After the reaction was complete, the solution was concentrated to obtain 14c, which was directly used in subsequent reactions.

[0114] (5) Specific preparation process of compound A7:

[0115]

[0116] The synthesis method was the same as that for compound A3. Compound 14c (150 mg, 0.315 mmol, 1.0 eq) and compound 15a underwent a nucleophilic substitution reaction to give compound A7 (yellow solid, 165 mg, 61%). HRMS (ESI) predicted value C 45 H 52 N 11 O7 + [M+H] + : 858.4046, measured value: 858.4040.

[0117] Example 8

[0118] A protein hydrolysis-targeting chimera (compound A8) has the following synthetic route:

[0119]

[0120] The synthesis method was the same as that for compound A3. Compound 14a (150 mg, 0.268 mmol, 1.0 eq) and compound 15a underwent a nucleophilic substitution reaction to give compound A8 (yellow solid, 154 mg, 61%). HRMS (ESI) predicted value C 50 H 61 N 12 O7 + [M+H] + : 941.4781, measured value: 941.4785.

[0121] Example 9

[0122] A protein hydrolysis-targeting chimera (compound A9) has the following synthetic route:

[0123]

[0124] The synthesis method was the same as that for compound A4. Compound 14a (150 mg, 0.268 mmol, 1.0 eq) and compound 17a underwent amide condensation to give compound A9 (yellow solid, 121 mg, 48%). HRMS (ESI) predicted value C 50 H 61 N 12 O7 + [M+H] + : 941.4781, measured value: 941.4778.

[0125] Example 10

[0126] A protein hydrolysis-targeting chimera (compound A10) has the following synthetic route:

[0127]

[0128] The specific process is as follows:

[0129] (1) Specific preparation process of intermediate 15d:

[0130]

[0131] The synthetic method was the same as that for compound 15a. Compound 12a (1.50 g, 2.78 mmol, 1.0 eq) was reacted with bromoacetyl chloride after the removal of the Boc to give compound 15d (yellow solid, 763 mg, 49%). HRMS (ESI) predicted value C 25 H 31 BrN5O5 + [M+H] + : 560.1504, measured value: 560.1506.

[0132] (2) Specific preparation process of compound A10:

[0133]

[0134] The synthetic method was the same as that for compound A3. Compound 15d (150 mg, 0.267 mmol, 1.0 eq) and compound 14b underwent a nucleophilic substitution reaction to give compound A10 (yellow solid, 141 mg, 56%). HRMS (ESI) predicted value C 50 H 61 N 12 O7 + [M+H] + : 941.4781, measured value: 941.4778.

[0135] Example 11

[0136] A protein hydrolysis-targeting chimera (compound A11) has the following synthetic route:

[0137]

[0138] The specific process is as follows:

[0139] (1) Specific preparation process of intermediate 23:

[0140]

[0141] Compound 12a (300 mg, 0.556 mmol, 1.0 eq) was dissolved in 6 mL of 4 M hydrochloric acid / 1,4-dioxane solution. After the reaction was complete, the reaction solution was concentrated, and then dichloroethane:MeOH (6 mL: 2 mL), compound 8 (130 mg, 0.611 mmol, 1.1 eq), glacial acetic acid (0.2 mL), and sodium triacetoxyborohydride (235 mg, 1.112 mmol, 2.0 eq) were added. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC (DCM:MeOH = 14:1). After the reaction was complete, the reaction was quenched by adding 15 mL of saturated sodium bicarbonate solution at 0 °C. The mixture was extracted with DCM (20 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 45:1) to give compound 23 (yellow solid, 258 mg, 73%). HRMS (ESI) predicted value C 34 H 49 N6O6 + [M+H] + : 637.3709, measured value: 637.3712.

[0142] (2) Specific preparation process of compound A11:

[0143]

[0144] Compound 23 (200 mg, 0.313 mmol, 1.0 eq) was dissolved in 4 mL of 4 M hydrochloric acid / 1,4-dioxane solution. After the reaction was complete, the reaction solution was concentrated for later use. Compound 4 (123 mg, 0.313 mmol, 1.0 eq) was dissolved in 4 mL of N,N-dimethylformamide. HATU (143 mg, 0.376 mmol, 1.2 eq) and N,N-diisopropylethylamine (121 mg, 0.941 mmol, 3.0 eq) were added. The mixture was stirred at room temperature for 15 min, and then the Boc-depleted compound 23 was added. The reaction was carried out overnight at room temperature and monitored by TLC (DCM:MeOH = 9:1). After the reaction was complete, 10 mL of water was added to the system, and the mixture was extracted with EA (8 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 30:1) to give compound A11 (yellow solid, 123 mg, 43%). HRMS (ESI) predicted value C 50 H 62 N 11 O6 + [M+H] + : 912.4880, measured value: 912.4878.

[0145] Example 12

[0146] A protein hydrolysis-targeting chimera (compound A12) has the following synthetic route:

[0147]

[0148] The specific process is as follows:

[0149] (1) Specific preparation process of intermediate 24a:

[0150]

[0151] The synthesis method was the same as that for compound 10. Compound 14c (200 mg, 0.42 mmol, 1.0 eq) and compound 8 were subjected to reductive amination to give compound 24a (white solid, 217 mg, 77%). HRMS (ESI) predicted value C 37 H 53 N8O4 + [M+H] + : 673.4185, measured value: 673.4186.

[0152] (2) Specific preparation process of compound A12:

[0153]

[0154] Compound 24a (200 mg, 0.297 mmol, 1.0 eq) was dissolved in 4 mL of 4M hydrochloric acid / 1,4-dioxane. After the reaction was complete, the reaction solution was concentrated, and then N,N-dimethylformamide (4 mL), triethylamine (90 mg, 0.891 mmol, 3.0 eq), and compound 15a (137 mg, 0.297 mmol, 1.0 eq) were added. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC (DCM:MeOH = 9:1). After the reaction was complete, 15 mL of water was added to the system, and the mixture was extracted with EA (10 mL × 3). The organic phase was collected, back-extracted with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 30:1) to give compound A12 (yellow solid, 164 mg, 58%). HRMS (ESI) predicted value C 51 H 63 N 12 O7 + [M+H] + : 955.4938, measured value: 955.4943.

[0155] Example 13

[0156] A protein hydrolysis-targeting chimera (compound A13) has the following synthetic route:

[0157]

[0158] The specific process is as follows:

[0159] (1) Specific preparation process of intermediate 22b:

[0160]

[0161] Compound 21 (500 mg, 1.43 mmol, 1.0 eq) was dissolved in 14 mL of MeOH, and palladium on carbon (50 mg) was added. Argon and hydrogen atmospheres were successively purged, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC (PE:EA = 2:1). After the reaction was complete, palladium on carbon was filtered off, and the mixture was purified by silica gel column chromatography (PE:EA = 6:1) to give compound 22b (white solid, 395 mg, 86%). HRMS (ESI) predicted value C 50 H 62 N 11 O6 + [M+H] + 322.2126, measured value: 322.2129.

[0162] (2) Specific preparation process of intermediate 13d:

[0163]

[0164] The synthesis method was the same as that for compound 3a. Compound 22b (300 mg, 0.933 mmol, 1.0 eq) and compound 2 underwent Buchwald-Hartwig coupling to give compound 13d (white solid, 426 mg, 79%). HRMS (ESI) predicted value C 31 H 44 N7O4 + [M+H] + : 578.3450, measured value: 578.3447.

[0165] (3) Specific preparation process of intermediate 24b:

[0166]

[0167] The synthesis method was the same as that for compound 23. Compound 13d (200 mg, 0.346 mmol, 1.0 eq), after Boc removal, underwent reductive amination with compound 8 to give compound 24b (white solid, 182 mg, 78%). HRMS (ESI) predicted value C 37 H 55 N8O4 + [M+H] + : 675.4341, Measured value: 675.4345.

[0168] (4) Specific preparation process of compound A13:

[0169]

[0170] The synthesis method was the same as that for compound A12. Compound 24b (150 mg, 0.222 mmol, 1.0 eq) was debocized and then reacted with compound 15a via a nucleophilic substitution reaction to give compound A13 (yellow solid, 117 mg, 55%). HRMS (ESI) predicted value C 51 H 65 N 12 O7 + [M+H] + : 957.5094, measured value: 957.5100.

[0171] Example 14

[0172] A protein hydrolysis-targeting chimera (compound A14) has the following synthetic route:

[0173]

[0174] The specific process is as follows:

[0175] (1) Specific preparation process of intermediate 11b:

[0176]

[0177] The synthesis method was the same as that for compound 11a. Compound 10b (1.50 g, 3.586 mmol) was deprotected by the Cbz protecting group to give compound 11b (white solid, 965 mg, 95%). HRMS (ESI) predicted value C 15 H 30 N3O2 + [M+H]+: 284.2333, Measured value: 284.2335.

[0178] (2) Specific preparation process of intermediate 26a:

[0179]

[0180] The synthesis method was the same as that for compound A4. Compound 11b (500 mg, 1.764 mmol, 1.0 eq) and compound 17a were amide condensed to give compound 26a (yellow solid, 893 mg, 76%). HRMS (ESI) predicted value C 34 H 48 N7O7 + [M+H] + : 666.3610, measured value: 666.3607.

[0181] (3) Specific preparation process of intermediate 27:

[0182]

[0183] The synthesis method was the same as that of compound 14a. After the reaction was completed, the reaction solution was concentrated and used directly in subsequent reactions without further purification.

[0184] (4) Specific preparation process of compound A14:

[0185]

[0186] Compound 3b (200 mg, 0.49 mmol, 1.0 eq) was dissolved in 6 mL of MeOH, and 2 mL of an aqueous solution containing LiOH (23 mg, 0.98 mmol, 2.0 eq) was added to hydrolyze the ester bond. After the reaction was complete, the pH was adjusted to neutral with 1 M hydrochloric acid aqueous solution. The mixture was concentrated under reduced pressure, and then N,N-dimethylformamide (6 mL), HATU (223 mg, 0.588 mmol, 1.2 eq), and N,N-diisopropylethylamine (127 mg, 0.98 mmol, 2.0 eq), along with compound 27 (276 mg, 0.49 mmol, 1.0 eq) were added. The mixture was reacted overnight at room temperature. After the reaction was complete, 15 mL of water was added to the system, and the mixture was extracted with EA (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 40:1) to give compound A14 (yellow solid, 190 mg, 42%). HRMS (ESI) predicted value C 50 H 61 N 12 O7 + [M+H] + : 941.4781, measured value: 941.4778.

[0187] Example 15

[0188] A protein hydrolysis-targeting chimera (compound A15) has the following synthetic route:

[0189]

[0190] The specific process is as follows:

[0191] (1) Specific preparation process of intermediate 28a:

[0192]

[0193] Compound 10b (500 mg, 1.197 mmol, 1.0 eq) was dissolved in 8 mL of 4 M hydrochloric acid / 1,4-dioxane solution and reacted at room temperature for 30 min, with TLC monitoring the reaction progress (PE:EA = 1:1). After the reaction was complete, the reaction solution was concentrated, and then acetonitrile (20 mL), trans-4-(tert-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (308 mg, 1.197 mmol, 1.0 eq), HATU (546 mg, 1.437 mmol, 1.2 eq), and N,N-diisopropylethylamine (464 mg, 3.592 mmol, 3.0 eq) were added. The reaction was carried out at room temperature for 6 h, with TLC monitoring the reaction progress (DCM:MeOH = 19:1). After the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (DCM:MeOH = 60:1) to give compound 28a (white solid, 580 mg, 87%). HRMS (ESI) predicted value C 31 H 49 N4O5 + [M+H] + : 557.3698, measured value: 557.3701.

[0194] (2) Specific preparation process of intermediate 29a:

[0195]

[0196] Compound 28a (500 mg, 0.897 mmol, 1.2 eq) was dissolved in 8 mL of 4 M hydrochloric acid / 1,4-dioxane solution and reacted at room temperature for 30 min. The reaction progress was monitored by TLC (DCM:MeOH = 19:1). After the reaction was complete, the reaction solution was concentrated. Then, NMP (8 mL), compound 2 (218 mg, 0.747 mmol, 1.0 eq), and N,N-diisopropylethylamine (289 mg, 2.242 mmol, 3.0 eq) were added, and the mixture was refluxed at 140 °C for 24 h. The reaction progress was monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, the system was cooled to room temperature, and then 20 mL of water was added. Extraction was performed using EA (15 mL × 3), and the organic phase was collected. Back-extraction with saturated sodium chloride solution was performed (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was achieved by silica gel column chromatography (DCM:MeOH = 60:1) to give compound 29a (white solid, 282 mg, 53%). HRMS (ESI) predicted value C 40 H 57 N8O4 + [M+H] + : 713.4498, measured value: 713.4496.

[0197] (3) Specific preparation process of compound A15:

[0198]

[0199] Compound 29a (260 mg, 0.364 mmol, 1.0 eq) was dissolved in 6 mL of MeOH. 30 mg of 10% palladium on carbon was added, and argon and hydrogen were successively purged. The reaction was carried out overnight at room temperature under hydrogen atmosphere, monitored by TLC (DCM:MeOH = 15:1). After the reaction was complete, the palladium on carbon was filtered off, the filtrate was concentrated, and then 5 mL of N,N-dimethylformamide, compound 15a (168 mg, 0.364 mmol, 1.0 eq), and triethylamine (74 mg, 0.728 mmol, 2.0 eq) were added. The reaction progress was monitored by TLC (DCM:MeOH = 12:1). After the reaction was complete, 15 mL of water was added to the system, and the mixture was extracted with EA (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 40:1) to give compound A15 (yellow solid, 196 mg, 56%). HRMS (ESI) predicted value C 51 H 69 N 12 O7 + [M+H] + : 961.5407, measured value: 961.5422.

[0200] Example 16

[0201] A protein hydrolysis-targeting chimera (compound A16) has the following synthetic route:

[0202]

[0203] The specific process is as follows:

[0204] (1) Specific preparation process of intermediate 28b:

[0205]

[0206] The synthesis method was the same as that for compound 28a. Compound 10b (400 mg, 0.958 mmol, 1.0 eq) was debonded (Boc removed) and then condensed with Bo c-trans-4-aminocyclohexanecarboxylic acid via an amide condensation to give compound 28b (white solid, 463 mg, 89%). HRMS (ESI) predicted value C 30 H 47 N4O5 + [M+H] + : 543.3541, measured value: 543.3544.

[0207] (2) Specific preparation process of intermediate 29b:

[0208]

[0209] The synthesis method was the same as that for compound 29a. Compound 28b (450 mg, 0.829 mmol, 1.2 eq) was debocized and then reacted with compound 2 via a nucleophilic substitution reaction to give compound 29b (white solid, 260 mg, 54%). HRMS (ESI) predicted value C 39 H 55 N8O4 + [M+H] + : 699.4341, measured value: 699.4345.

[0210] (3) Specific preparation process of compound A16:

[0211]

[0212] The synthesis method was the same as that for compound A15. Compound 29 (200 mg, 0.286 mmol, 1.0 eq), after the removal of Cbz, reacted with compound 15a via a nucleophilic substitution reaction to give compound A16 (yellow solid, 141 mg, 52%). HRMS (ESI) predicted value C 50 H 67 N 12 O7 + [M+H] + : 947.5251, measured value: 947.5260.

[0213] Example 17

[0214] A protein hydrolysis-targeting chimera (compound A18) has the following synthetic route:

[0215]

[0216] The specific process is as follows:

[0217] (1) Specific preparation process of intermediate 32b:

[0218]

[0219] The synthetic method was the same as that for compound 32a. 1-Boc-4-aminopiperidine (2d) (410 mg, 2.049 mmol, 1.2 eq) was reacted with compound 1 via a substitution reaction to give compound 32b (white solid, 538 mg, 69%). HRMS (ESI) predicted value C 24 H 37 N6O3 + [M+H] + : 457.2922, measured value: 457.2925.

[0220] (2) Specific preparation process of compound A18:

[0221]

[0222] The synthesis method was the same as that for compound A11. Compound 32b (200 mg, 0.437 mmol, 1.0 eq), after the removal of the Boc, was condensed with compound 31 via amide condensation to give compound A18 (yellow solid, 206 mg, 49%). HRMS (ESI) predicted value C 50 H 68 N 13 O7 + [M+H] + : 962.5360, measured value: 962.5361.

[0223] Example 18

[0224] A protein hydrolysis-targeting chimera (compound B1) has the following synthetic route:

[0225]

[0226] The specific process is as follows:

[0227] (1) Specific preparation process of intermediate 15e:

[0228]

[0229] The synthesis method was the same as that for compound 15a. Compound 12d (400 mg, 0.91 mmol, 1.0 eq) was debocized and then condensed with bromoacetyl chloride via an amide to give compound 15e (yellow solid, 225 mg, 54%). HRMS (ESI) predicted value C 19 H 20 BrN4O5 + [M+H] + : 463.0612, measured value: 463.0615.

[0230] (2) Specific preparation process of compound B1:

[0231]

[0232] The synthesis method was the same as that for compound A3. Compounds 15e (150 mg, 0.324 mmol, 1.0 eq) and 14a were nucleophilically substituted to give compound B1 (yellow solid, 167 mg, 55%). HRMS (ESI) predicted value C 50 H 61 N 12 O7 + [M+H] +: 941.4781, measured value: 941.4791.

[0233] Example 19

[0234] A protein hydrolysis-targeting chimera (compound B2) has the following synthetic route:

[0235]

[0236] The specific process is as follows:

[0237] (1) Specific preparation process of intermediate 16b:

[0238]

[0239] The synthesis method was the same as that for compound 16a. Compound 12d (300 mg, 0.678 mmol, 1.0 eq) was debocized and then nucleophilically substituted with tert-butyl bromoacetate to give compound 16b (yellow solid, 244 mg, 79%). HRMS (ESI) predicted value C 23 H 29 N4O6 + [M+H] + : 457.2082, measured value: 457.2086.

[0240] (2) Specific preparation process of intermediate 17b:

[0241]

[0242] Using compound 16b as a starting material, the same synthesis method as compound 17a was used directly in the next step.

[0243] (3) The specific preparation process of compound B2:

[0244]

[0245] The synthesis method was the same as that for compound A4. Compounds 17b and 14a were amide condensed to give compound B2 (yellow solid, 169 mg, 48%). HRMS (ESI) predicted value C. 50 H 61 N 12 O7 + [M+H] + : 941.4781, measured value: 941.4787.

[0246] Comparative Example 1

[0247] A protein hydrolysis-targeting chimera (compound A17) has the following synthetic route:

[0248]

[0249] The specific process is as follows:

[0250] (1) Specific preparation process of intermediate 26b:

[0251]

[0252] The synthesis method was the same as that for compound A3. Compound 11b (800 mg, 2.822 mmol, 1.0 eq) and compound 15a were subjected to a nucleophilic substitution reaction to give compound 26b (yellow solid, 1.43 g, 76%). HRMS (ESI) predicted value C 34 H 48 N7O7 + [M+H] + : 666.3610, measured value: 666.3612.

[0253] (2) Specific preparation process of intermediate 30:

[0254]

[0255] The synthesis method was the same as that for compound 16a. Compound 26b (1.30 g, 1.95 mmol, 1.0 eq) was reacted with tert-butyl bromoacetate via a nucleophilic substitution reaction after the removal of the Boc, yielding compound 30 (yellow solid, 1.03 g, 78%). HRMS (ESI) predicted value C 35 H 50 N7O7 + [M+H] + : 680.3767, measured value: 680.3764.

[0256] (3) Specific preparation process of intermediate 31:

[0257]

[0258] Using compound 30 as a starting material, the same synthesis method as compound 17a was used, and the unpurified compound was directly used in subsequent reactions.

[0259] (4) Specific preparation process of intermediate 32a:

[0260]

[0261] Compound 1 (500 mg, 1.707 mmol, 1.0 eq) was dissolved in 15 mL of NMP, and then (S)-1-Boc-3-aminopiperidine (2c) (410 mg, 2.049 mmol, 1.2 eq) and N,N-diisopropylethylamine (662 mg, 5.123 mmol, 3.0 eq) were added. The mixture was refluxed at 140 °C for 18 h, and the reaction progress was monitored by TLC (DCM:MeOH = 20:1). After the reaction was complete, the system was cooled to room temperature, and then 40 mL of water was added. The mixture was extracted with EA (25 mL × 3), and the organic phase was collected. The organic phase was back-extracted with saturated sodium chloride solution (25 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 60:1) to give compound 32a (white solid, 506 mg, 65%). HRMS (ESI) predicted value C 24 H 37 N6O3 + [M+H] + : 457.2922, measured value: 457.2924.

[0262] (5) Specific preparation process of compound A17:

[0263]

[0264] The synthesis method was the same as that for compound A11. Compound 32a (200 mg, 0.437 mmol, 1.0 eq), after Boc removal, was amide-condensed with compound 31 to give compound A17 (yellow solid, 189 mg, 45%). HRMS (ESI) predicted value C 50 H 68 N 13 O7 + [M+H] + : 962.5360, measured value: 962.5357.

[0265] Compound performance testing

[0266] 1. Determination of the cell viability of the compound

[0267] Nineteen PROTAC molecules from Examples 1-19 and one PROTAC molecule from Comparative Example 1 were evaluated using the CCK-8 assay to assess their in vitro antiproliferative activity against prostate cancer cell lines PC3 and DU145. Ten concentration gradients of PROTAC molecules were established, with a maximum concentration of 10 μM, followed by 3-fold serial dilutions and a minimum concentration of 0 μM. These were co-incubated with PC-3 and DU145 cells for 72 h. Cell viability was assessed using the MTT assay, and data were processed using GraphPad Prism9 to calculate the IC50. 50 Values. The results are shown in Table 1:

[0268] Table 1. Cellular antiproliferative activity of PROTAC molecules

[0269]

[0270]

[0271] Wherein, +: >1000nM; ++: 1000-100nM; +++: <100nM.

[0272] As shown in Table 1, all PROTAC compounds in Examples 1-19 exhibited some inhibitory activity against the selected PCa cell lines, especially in androgen-independent PC3 cells, while the PROTAC compound in Comparative Example 1 showed lower activity. Further activity evaluations were performed on several other cell lines, A1-A13 and B1-B2, and the results are shown in Table 2.

[0273] Table 2. Cellular antiproliferative activity of PROTAC molecules

[0274]

[0275] Wherein, +: >100nM; ++: 10-100nM; +: <10nM.

[0276] As shown in Table 2, most of the tested molecules exhibited varying degrees of inhibitory effects on MV-4-11, LNCap, Vcap, and RM-1, indicating that the tested molecules have the potential to inhibit the proliferation of these tumor cells.

[0277] 2. Determination of the degradation activity of the compound

[0278] The degradation effects of some PROTAC compounds from Examples 1-19 on CDK2 / 4 / 6 / 9 proteins in PC3 cells were evaluated using Western blotting experiments. Western blotting analysis of CDK2 / 4 / 6 / 9 protein levels in cells showed that these compounds exhibited good degradation capabilities for CDK2 / 4 / 6 / 9 proteins.

[0279] Table 3. Determination of the degradation activity of PROTAC molecules on different CDKs

[0280]

[0281]

[0282] Among them, +++: >80%; ++: 50%-80%; +: <50%.

[0283] 3. Determination of the CDKs kinase inhibition rate of the compound

[0284] HTRF kinase assay: Kinase activity was tested using the ADP-Glo ​​method. The test concentrations of compounds A12 and Ribociclib were set at 100 nM, and the results are shown in Table 4. Compared with Ribociclib, compound A12 significantly improved the inhibitory activity against CDK9 and CDK2, while maintaining significant inhibitory effects on CDK4 / 6, effectively targeting CDK2 / 4 / 6 / 9 simultaneously.

[0285] Table 4. Inhibition rates of compounds A12 and Ribociclib on CDK kinases

[0286]

[0287] Among them, ++++: >90%; +++: 70%-90%; ++: 50%-70%; +: <50%.

[0288] 4. Compound-based animal tumor inhibition experiments

[0289] To evaluate the in vivo antitumor activity of active PROTAC molecules, animal experiments were conducted in two xenograft tumor models in mice (PC3, DU145). As shown in Table 5, PROTAC molecules exhibited antitumor activity, with a more significant inhibitory effect on the PC-3 model.

[0290] Table 5 Animal Experiments

[0291]

[0292] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. Any embodiment that achieves the technical effects of the present invention using the same means should fall within the protection scope of the present invention. Within the protection scope of the present invention, various modifications and variations can be made to the technical solutions and / or implementation methods.

Claims

1. A protein hydrolysis-targeting chimera, characterized in that, The structural formula is shown as formula Ia or formula Ib: Linker in Formula Ia is any one of the following structures: Linker in said Formula lb is any one of the following structures:

2. The proteolysis targeting chimera of claim 1, wherein, The structural formula is shown as A12:

3. A method of producing a proteolysis targeting chimera of claim 2, wherein, The synthetic route is shown as follows:

4. Use of the proteolysis targeting chimera or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of a medicament for the treatment and / or prevention of cancer, which is prostate cancer.

5. A pharmaceutical composition, characterized by, The main active ingredient is the proteolysis targeting chimera or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

6. The pharmaceutical composition of claim 5, wherein, The dosage form of the pharmaceutical composition is a liquid preparation or a solid preparation.

7. The pharmaceutical composition of claim 6, wherein, The dosage form is one of a tablet, a capsule, a powder, a granule, a dripping pill, a paste and a powder.

8. The pharmaceutical composition of claim 5, wherein, The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or carriers.

9. The pharmaceutical composition of claim 8, wherein, The excipients include at least one of a carbohydrate, a polymer, a lipid and a mineral.

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