Tanshinone IIA derivative and application thereof

Abstract

The invention discloses a tanshinone IIA derivative as well as a preparation method and application thereof, and provides a set of systematic chemical synthesis route for overcoming the defects that tanshinone IIA is poor in water solubility and low in bioavailability and the antitumor activity needs to be improved. A series of novel derivatives with various structures and general formula structures and pharmaceutical salts thereof are prepared. The core of the technical scheme is that after a specific functional group is introduced into the derivative, the water solubility and the stability of the compound are remarkably improved, and the derivative particularly shows excellent anti-colorectal cancer activity, can effectively inhibit tumor cell proliferation and tumor growth in an animal model, and does not have obvious toxic or side effects. The invention also provides a pharmaceutical composition containing the derivative and application of the pharmaceutical composition in preparation of medicines for preventing, relieving or treating colorectal cancer, and provides an important candidate compound for developing a high-efficiency and low-toxicity novel anti-colorectal cancer medicine.

Description

Technical Field

[0001] This invention relates to a tanshinone IIA derivative and its application, belonging to the technical field of preparation and application of tanshinone IIA derivatives. Background Technology

[0002] Tanshinone IIA is derived from the traditional Chinese medicine Danshen (Salvia miltiorrhiza). The most important and most active fat-soluble diterpenoid quinones extracted from the rhizome have a unique phenanthrenequinone structure and are key substances for the pharmacological effects of Salvia miltiorrhiza.

[0003] Modern pharmacological studies have shown that tanshinone IIA has a variety of cardiovascular protective effects, including protecting vascular endothelial cells, anti-arrhythmia, anti-atherosclerosis, improving microcirculation, protecting myocardium, inhibiting and relieving platelet aggregation, increasing coronary blood flow, and improving the body's tolerance to hypoxia. In addition, these compounds also exhibit broad anti-tumor activity, inhibiting various cancer cells such as liver cancer, lung cancer, breast cancer, and gastric cancer. Their mechanisms of action involve multiple aspects, including cell cycle regulation, inhibition of cell proliferation, induction of apoptosis, inhibition of tumor invasion and metastasis, inhibition of angiogenesis, and reversal of multidrug resistance in tumors. Recent studies have also found that tanshinone IIA imidazole derivatives designed and synthesized by introducing an imidazole ring into the parent structure can activate ROS release and regulate the PTEN / AKT signaling pathway, inhibiting the formation of invasive pseudopodia, thereby effectively inhibiting the proliferation and metastasis of cancer cells in a zebrafish xenograft model of triple-negative breast cancer (see the research results of Professor Mei Wenjie's team published in the Journal of Medicinal Chemistry, "Design and SAR of Withangulatin A Analogues that Act as Covalent TrxR Inhibitors through the Michael Addition Reaction Showing Potential in Cancer Treatment").

[0004] Although tanshinone IIA has a wide range of pharmacological activities, certain physicochemical properties of the drug itself severely limit its wider clinical application. These properties are mainly manifested in the following ways: tanshinone IIA has extremely high lipid solubility and extremely poor water solubility, leading to difficulties in drug dissolution and absorption, low bioavailability, and a short half-life, making it difficult to fully exert its efficacy. Compared with most antitumor drugs, the antitumor activity of tanshinone IIA still needs further improvement. Therefore, it is essential to optimize its structure or adopt novel delivery systems (see Li Na, Deng Qian, Jiang Jianjun, "Research Progress on the Antitumor Effect of Tanshinone IIA", *Chinese Journal of Clinical Research*, 2022, Vol. 14 Issue (18): 133-136).

[0005] To overcome these shortcomings, various methods have been explored in the existing technology, including in dosage form improvement, such as solid dispersions, inclusion technology, self-microemulsification drug release systems, preparation of ultrafine particles, and supercritical fluid antisolvent technology, to increase the in vitro dissolution rate and extent of drugs, thereby improving oral bioavailability; while the inclusion complex of tanshinone IIA for injection prepared using HP-β-CD as inclusion material has significantly improved water solubility.

[0006] In terms of structural modification, in addition to the aforementioned tanshinone IIA imidazole derivatives, existing technologies also involve the preparation and research of tanshinone IIA sulfonates. For example, East China University of Science and Technology developed "A continuous preparation method of sodium tanshinone IIA sulfonate based on a single-tube thin-film reactor" (application publication number: CN120349367A), and Shanghai Pharmaceutical First Biochemical Pharmaceutical Co., Ltd. applied for a patent for "related substances of sodium tanshinone IIA sulfonate and its purification method" (publication number CN119912516A), aiming to improve the quality standard of sodium tanshinone IIA sulfonate.

[0007] However, these existing technologies still have their limitations. For example, dosage form improvement may involve complex processes and high costs, and the long-term stability of some delivery systems still needs to be investigated; while structural modification improves activity, potential changes in toxicity must also be considered. Therefore, developing novel tanshinone IIA derivatives, formulations, or preparation processes that can comprehensively improve water solubility, stability, bioavailability, and pharmacological activity remains a pressing technical problem to be solved in this field. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention focuses on developing novel tanshinone IIA derivatives that comprehensively improve water solubility, stability, bioavailability, and pharmacological activity, thereby achieving better effects in the prevention, alleviation, and / or treatment of colorectal cancer. Therefore:

[0009] This invention first provides a method for preparing tanshinone IIA derivatives, comprising the following synthetic route:

[0010] ;

[0011] Right now:

[0012] a) Tanshinone IIA, acetic acid, 2,2,6,6-tetramethylpiperidine oxide (TEMPO) were mixed with chlorobenzene and reacted under heating conditions. After the reaction was completed, compound 1 was obtained by post-treatment.

[0013] b) Compound 1 was reacted with pyridine p-toluenesulfonate (PPTS) in toluene, and after the reaction was completed, compound 2 was obtained by post-treatment;

[0014] c) Compound 2 was reacted with selenium dioxide in 1,4-dioxane, and after the reaction was completed, compound 3 was obtained by post-treatment.

[0015] d) Compound 3 was reacted with N-bromosuccinimide (abbreviated as NBS) in dichloromethane. After the reaction was completed, post-treatment was performed to obtain tanshinone IIA derivative 4.

[0016] e) Compound 3 and paraformaldehyde were reacted in acetic acid under closed conditions, and the reaction was followed by alkali treatment to obtain tanshinone IIA derivative 6.

[0017] f) Tanshinone IIA derivative 6 was reacted with Des Martin periodate in dichloromethane to obtain tanshinone IIA derivative 10;

[0018] g) Tanshinone IIA derivative 10, hydrogen peroxide, disodium hydrogen phosphate buffer, and sodium chlorite were reacted in acetonitrile to obtain tanshinone IIA derivative 11.

[0019] h) Tanshinone IIA derivative 6 was reacted with thionyl chloride in dichloromethane to obtain tanshinone IIA derivative 8;

[0020] i-1) The compound 3, the amine compound or its hydrochloride salt, and paraformaldehyde were reacted in acetic acid to prepare tanshinone IIA derivatives 5-(1-2), 5-(5-9), 5-(11-17) and 5-(20-32);

[0021] i-2) Tanshinone IIA derivative 10, amine compounds or their hydrochlorides are subjected to a reducing amination reaction with sodium triacetoxyborohydride in 1,2-dichloroethane to obtain tanshinone IIA derivatives 5-(3-4), 5-10 and 5-(18-19).

[0022] i-3) Tanshinone IIA derivative 8, amine compounds or their hydrochloride salts are reacted with triethylamine in dichloromethane to prepare tanshinone IIA derivative 5-(33-39).

[0023] j-1) Tanshinone IIA derivative 6, organic acid acyl chloride and triethylamine were reacted in dichloromethane to prepare tanshinone IIA derivative 7-(1-12).

[0024] j-2) Tanshinone IIA derivative 6 and di(p-nitrobenzene) carbonate were reacted in dichloromethane in the presence of 4-dimethylaminopyridine and triethylamine, and then amine compounds were added to react to obtain tanshinone IIA derivative 7-(13-26).

[0025] k) Tanshinone IIA derivative 8 was reacted with sodium methoxide in a mixed solvent of dichloromethane and methanol to obtain tanshinone IIA derivative 9.

[0026] l) Tanshinone IIA derivative 11, amine compounds, triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) were reacted in dichloromethane to prepare tanshinone IIA derivative 12 series compounds 12-(1~13).

[0027] m) Tanshinone IIA derivative 11 was reacted with oxalyl chloride in dichloromethane under N,N-dimethylformamide catalysis to form acyl chloride, which was then reacted with methanol and triethylamine in dichloromethane to prepare tanshinone IIA derivative 13;

[0028] in:

[0029] R1 and R2 are each independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of cycloalkyl, 3-6 membered heterocyclic, benzene ring, or substituted benzene ring, wherein the substituent on the benzene ring is any one of F, Cl, Br, trifluoromethyl, amino, cyano, ester, nitro, methoxy, or hydroxyl, and the number of substituents is 1 to 3; or

[0030] R1 and R2 also form 3- to 6-membered rings with C, N, and O, in which the N atom on the ring interacts with the C atom. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocycles are linked, and the H atoms attached to the C atoms on the rings are C... 1-6 Alkyl, F, Cl, Br, benzene ring, 3-6 membered heterocyclic group, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl substitution;

[0031] R3 is H or is determined by at least one R a Group substitution, the R a The group is C 1-8 Alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, -C 1-8 Alkyl OC 1-8 Alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, N(C) 1-8 alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, nitro, C 1-8 Alkyl, hydroxyl or -COC 1-8 Any one of the alkyl groups;

[0032] R4 is selected from C 1-6 Alkyl, C2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups;

[0033] R5 and R6 are each independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups and N(C) 1-8 Any one of alkyl groups 2, wherein the carbon chain of the alkyl group is further linked by N and O, and the hydrogen of the alkyl group is C 1-6 Cycloalkyl, benzene ring, or aromatic heterocyclic substitution; or R1 and R2 may form 3- to 6-membered rings with C, N, and O, and the N atom on the ring may be substituted with C. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocyclic linkages;

[0034] R7 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups.

[0035] Further:

[0036] The structural formulas of the tanshinone IIA derivatives 5-(1-2), 5-(5-9), 5-(11-17), and 5-(20-32) are as follows:

[0037]

[0038] The structural formulas of the tanshinone IIA derivatives 5-(3-4), 5-10, and 5-(18-19) are as follows:

[0039]

[0040] The structural formulas of the tanshinone IIA derivatives 5-(33-39) are as follows:

[0041]

[0042] The structural formulas of the tanshinone IIA derivatives 7-(1-12) are as follows:

[0043]

[0044] The structural formulas of the tanshinone IIA derivatives 7-(13-26) are as follows:

[0045]

[0046] The structural formulas of the tanshinone IIA derivatives 12-(1-13) are as follows:

[0047]

[0048] Furthermore, the specific operating parameters in the above preparation method are as follows:

[0049] In step a), the reaction temperature is 100-130°C, and the molar ratio of tanshinone IIA, acetic acid and 2,2,6,6-tetramethylpiperidine oxide is 1:(1.5-3):(1-1.5).

[0050] In step b), the reaction temperature is 100–120 °C, and the molar ratio of compound 1 to toluenesulfonate is 1:(1–1.5).

[0051] In step c), the reaction temperature is 90–110 °C, and the molar ratio of compound 2 to selenium dioxide is 1:(1–1.1).

[0052] In step d), the reaction is carried out at 10–30 °C, and the molar ratio of compound 3 to N-bromosuccinimide is 1:(1–1.5).

[0053] In step e), the sealed condition is a tube-sealed reaction, the reaction temperature is 80-100°C, and the alkali used in the alkali treatment is potassium carbonate.

[0054] In step f), the reaction is carried out at 10–30°C, and the molar ratio of the tanshinone IIA derivative 6 to Des Martin periodate is 1:(1–1.5).

[0055] In step g), the volume concentration of hydrogen peroxide is 25-35%, the pH of the buffer solution is 1.5-2.5, and the reaction is carried out at room temperature;

[0056] In step h), the reaction is carried out at 10–30°C, and the molar ratio of tanshinone IIA derivative 6 to thionyl chloride is 1:(1–1.5).

[0057] In step i-1), the reaction temperature is 50-70°C, and the molar ratio of compound 3, amine compound and paraformaldehyde is 1:(1-1.5):(1-2).

[0058] In step i-2), the reductive amination reaction is carried out at 10-30°C, and the molar ratio of the tanshinone IIA derivative 10, the amine compound, and sodium triacetoxyborohydride is 1:(1-1.5):(1.5-2.5).

[0059] In step i-3), the reaction temperature is 20-40°C, and the molar ratio of the tanshinone IIA derivative 8, the amine compound, and triethylamine is 1:(1-1.5):(1.5-2.5).

[0060] In step j-1), the reaction is carried out in an ice bath at room temperature, and the molar ratio of the tanshinone IIA derivative 6, the organic acid acyl chloride and the triethylamine is 1:(1-1.5):(1.5-3).

[0061] In step j-2), the reaction is carried out in an ice bath at room temperature, and the molar ratio of the tanshinone IIA derivative 6, bis(p-nitrobenzene) carbonate, amine compound, 4-dimethylaminopyridine and triethylamine is 1:(1.5-2.5):(2-3):(0.05-0.15):(1-1.5).

[0062] In step k), the volume ratio of dichloromethane to methanol is 1:1, the reaction temperature is 0-20°C, and the molar ratio of tanshinone IIA derivative 8 to sodium methoxide is 1:(1.5-2.5).

[0063] In step 1), the reaction is carried out at 10–30 °C, and the molar ratio of the tanshinone IIA derivative 11, the amine compound, the triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate is 1:(1–1.5):(1–1.5):(1.2–1.8).

[0064] In step m), the reaction to form acyl chloride is carried out at 10–30 °C, and the molar ratio of the tanshinone IIA derivative 11, oxalyl chloride, methanol and triethylamine is 1:(4–6):(1.5–2.5):(1.5–2.5).

[0065] Furthermore, the optimized operating parameters in the above preparation process are as follows:

[0066] In step a), the reaction temperature is 120°C; the molar ratio of tanshinone IIA, acetic acid and 2,2,6,6-tetramethylpiperidine oxide is 1:2:1.2.

[0067] In step b), the reaction temperature is 110°C, and the molar ratio of compound 1 to toluenesulfonate is 1:1.2.

[0068] In step c), the reaction temperature is 100°C, and the molar ratio of compound 2 to selenium dioxide is 1:1.05;

[0069] In step d), the reaction is carried out at 20°C, and the molar ratio of compound 3 to N-bromosuccinimide is 1:1.2.

[0070] In step e), the reaction temperature is 90°C;

[0071] In step f), the reaction is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 6 to Des Martin periodate is 1:1.2.

[0072] In step g), the volume concentration of the hydrogen peroxide is 30%.

[0073] In step h), the reaction is carried out at 20°C, and the molar ratio of tanshinone IIA derivative 6 to thionyl chloride is 1:1.2.

[0074] In step i-1), the reaction temperature is 60°C, and the molar ratio of compound 3, amine compound and paraformaldehyde is 1:1.2:1.5;

[0075] In step i-2), the reductive amination reaction is carried out at 20°C, and the molar ratio of tanshinone IIA derivative 10, amine compound and sodium triacetoxyborohydride is 1:1.2:2.0.

[0076] In step i-3), the reaction temperature is 30°C, and the molar ratio of tanshinone IIA derivative 8, amine compound and triethylamine is 1:1.2:2.0.

[0077] In step j-1), the molar ratio of tanshinone IIA derivative 6, organic acid acyl chloride and triethylamine is 1:1.2:2;

[0078] In step j-2), the molar ratio of tanshinone IIA derivative 6, bis(p-nitrobenzene) carbonate, amine compound, 4-dimethylaminopyridine and triethylamine is 1∶2∶2.5∶0.1∶1.2;

[0079] In step k), the reaction temperature is 10°C, and the molar ratio of tanshinone IIA derivative 8 to sodium methoxide is 1:2.

[0080] In step 1), the reaction is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 11, the amine compound, the triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate is 1:1.2:1.2:1.5.

[0081] In step m), the reaction to form acyl chloride is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 11, oxalyl chloride, methanol and triethylamine is 1:5:2:2.

[0082] Preferably, in the above preparation method, the post-processing includes: washing with water first, then washing with saturated brine, then separating the organic layer and drying it with anhydrous sodium sulfate, then concentrating under reduced pressure to remove the organic solvent, and purifying the crude product by silica gel column chromatography.

[0083] Based on the above preparation method, the present invention also provides a tanshinone IIA derivative and its pharmaceutical salt, wherein:

[0084] The tanshinone IIA derivative was prepared by the above-described preparation method;

[0085] The pharmaceutical salt of the tanshinone IIA derivative is an addition salt formed by reacting a basic tanshinone IIA derivative with a basic nitrogen atom in its structure, prepared by the above preparation method, with a pharmaceutically acceptable inorganic or organic acid.

[0086] Optionally, the pharmaceutically acceptable inorganic acid is: hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid and / or nitric acid.

[0087] Optionally, the pharmaceutically acceptable organic acids are: formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethyl Sulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid and / or thiocyanate.

[0088] Based on this, the present invention also provides a composition comprising the above-mentioned tanshinone IIA derivative or its pharmaceutical salt, and an edible or pharmaceutically acceptable carrier or excipient.

[0089] The above-mentioned tanshinone IIA derivatives or their pharmaceutical salts, or compositions containing tanshinone IIA derivatives or their pharmaceutical salts, can be used in the preparation of foods or medicines for the prevention, relief and / or treatment of colorectal cancer.

[0090] Specifically, the above applications involve preparing oral tablets, capsules, granules, syrups, injectable powders, or solutions from the above-mentioned tanshinone IIA derivatives or their pharmaceutical salts, or from compositions containing tanshinone IIA derivatives or their pharmaceutical salts, or using them as functional additives in food, skincare products, cosmetics, and / or health products.

[0091] Compared with the prior art, the outstanding beneficial effects and significant progress of the present invention are as follows:

[0092] First, this invention breaks through the limitations of existing tanshinone IIA structural modifications, which are mostly concentrated on specific functional groups (such as sulfonation or the introduction of a single imidazole ring). Through an original multi-step synthetic route, it efficiently constructs a library of tanshinone IIA derivatives with diverse structures and rich substitution modes (including a series of tanshinone IIA derivatives such as 5, 7, and 12). While retaining the core phenanthrenequinone core of tanshinone IIA, these derivatives introduce alkyl, alkenyl, cycloalkyl, heterocyclic, and diverse amino and acyl side chains, greatly expanding the structural diversity and providing a solid chemical basis for screening highly active and selective candidate drugs. This fully demonstrates the systematic structural innovation and diversity of this invention.

[0093] Secondly, through structural modification, this invention not only improves the solubility of tanshinone IIA, but also significantly enhances its pharmacological activity through precise chemical modification of key active sites. This is confirmed in the following effect examples. In particular, this invention is the first to explicitly apply the prepared tanshinone IIA derivative to the prevention, alleviation, and / or treatment of colorectal cancer, and has confirmed that it can effectively inhibit the proliferation of colorectal cancer cells and the growth of tumors in animal models, without observing obvious toxic side effects. Compared with existing technologies that mainly focus on cardiovascular protection or broad-spectrum anti-tumor activity, this invention achieves targeted exploration and significant enhancement of the therapeutic potential in the specific refractory cancer field (colorectal cancer). Therefore, this invention has made a breakthrough in significantly improving pharmacological activity, especially for colorectal cancer.

[0094] Furthermore, the design and preparation of the derivatives of this invention directly address the core defects of tanshinone IIA, namely its extremely poor water solubility and low bioavailability. By introducing polar or ionizable groups (such as carboxylic acids, amino groups and their derivatives), the hydrophilicity of the derivatives is effectively improved. At the same time, reasonable structural modifications help to improve the metabolic stability of the compound in vivo, thereby potentially extending the half-life and improving bioavailability. This overcomes the problems of complex processes, high costs, or insufficient long-term stability that may be faced by existing dosage form improvement technologies, demonstrating the significant advantages of this invention in comprehensively optimizing the key properties of drugs.

[0095] Furthermore, existing structural modifications (such as sulfonates) may primarily improve solubility but offer limited activity enhancement, while the druggability parameters of certain highly active derivatives (such as imidazole derivatives) may not be fully optimized. In contrast, this invention, through a flexible synthetic strategy, achieves simultaneous optimization and balance of multiple druggability parameters, such as solubility, stability, cell membrane permeability, and target binding ability, within the same structural framework. This provides a better solution for developing candidate drugs that possess both potent antitumor activity and favorable pharmacokinetic properties, thus successfully addressing the challenge of both activity enhancement and druggability improvement.

[0096] This invention discloses in detail the specific methods, reaction conditions, and optimized parameters for the systematic synthesis of various end products from tanshinone IIA via key intermediate compounds 1, 2, 3, 6, 8, 10, and 11. The synthetic route is clear, the raw materials are readily available, the reaction conditions are relatively mild and controllable, and the post-processing steps are standardized. It has good reproducibility and potential for large-scale production, overcoming the shortcomings of some existing technologies that are complex or have harsh conditions. This invention demonstrates that it can provide an efficient and scalable preparation process.

[0097] In summary, this invention provides a class of novel tanshinone IIA derivatives and their pharmaceutical salts with reliable preparation methods. These derivatives not only theoretically improve the water solubility and stability of the parent compound through structural modification, but also achieve significant and specific inhibitory effects against colorectal cancer in terms of biological activity, with good safety profiles. Therefore, this invention addresses the bottlenecks in the clinical application of tanshinone IIA while providing valuable compound entities and a clear technical pathway for developing novel, highly effective, and low-toxicity anti-colorectal cancer drugs. It represents a significant advancement in this field, possessing outstanding substantive characteristics and beneficial effects, and thus has great potential for promotion and application. Attached Figure Description

[0098] To more clearly illustrate the technical solution of the present invention and the technical effects of implementing the present invention, the accompanying drawings used in the embodiments and effect examples of the present invention will be briefly introduced below.

[0099] It is obvious:

[0100] The accompanying drawings described below are only some of the drawings in the embodiments and effect examples of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort, but these other drawings are also within the scope of the drawings required for the embodiments of the present invention.

[0101] Figure 1 This is a collection of structural formulas for the tanshinone IIA derivative IIA5 series products provided in Example 9 of the present invention, wherein the product names are omitted in the figures. ;

[0102] Figure 2 This is a collection of structural formulas for the tanshinone IIA derivative IIA7 series products provided in Example 10 of the present invention, wherein the product names are omitted in the figures. ;

[0103] Figure 3 This is a collection of structural formulas for the tanshinone IIA derivative series IIA12 provided in Example 12 of the present invention, wherein the product names are omitted in the figures. ;

[0104] Figure 4 The image set of tumor tissue growth in SW620 colorectal tumor xenograft mice after different drug interventions is provided as Example 2 of the efficacy of the present invention, wherein n=6;

[0105] Figure 5 The tumor tissue volume curves in SW620 colorectal tumor xenograft mice after different drug interventions are provided in Example 2 of the present invention.

[0106] Figure 6 A bar chart showing the tumor tissue weight in SW620 colorectal tumor xenograft mice after different drug interventions, as provided in Example 2 of the present invention.

[0107] Figure 7 The body weight curves of SW620 colorectal tumor xenograft mice after different drug interventions are provided in Example 2 of the present invention.

[0108] Figure 8 An image set of protein expression levels related to LDHA, PDK1, and HK2 in tumor tissues of SW620 colorectal tumor xenograft mice after different drug interventions, provided as Example 2 of the present invention;

[0109] Figure 9 Bar chart showing the quantitative results of protein expression levels related to LDHA, PDK1, and HK2 in tumor tissues of SW620 colorectal tumor xenograft mice after different drug interventions, as provided in Example 2 of the present invention.

[0110] Figure 10 HE staining atlas of major organs in SW620 colorectal tumor xenograft mice after different drug interventions, provided as an example of the efficacy of the present invention (Example 2).

[0111] Note: * in the bar chart indicates a statistically significant difference. ; "**" indicates a statistically significant difference, that is "***" indicates an extremely significant statistical difference, that is... . Detailed Implementation

[0112] To make the technical solution, beneficial effects and significant progress of the present invention clearer and more comprehensive, the technical solution provided by the present invention will be clearly and completely described below through specific embodiments and their effects. Obviously, all embodiments and their effects described below are only some embodiments and effects of the present invention, and not all of them.

[0113] Based on the embodiments and effects provided by this invention, all other embodiments and effects obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0114] It should be noted that:

[0115] The terms "firstly," "secondly," etc., used in the claims, description, and examples and effects of the embodiments of this invention are only used to distinguish different objects and not to describe a specific order; furthermore, the term "comprising" and any variations thereof are intended to cover non-exclusive inclusion, for example, including not only a series of listed steps or units of a process, method, system, product, or device, but also optionally steps or units not listed, or optionally other operational steps or units inherent to these processes, methods, products, or devices.

[0116] What needs to be understood is:

[0117] In the description of the embodiments of the present invention, some basic operational terms commonly used in the art are used, such as "stirring" and "dissolving". These terms should be interpreted broadly, that is, they can refer to routine operations performed using various conventional equipment and instruments in the art, or operations performed using the latest equipment, such as program-controlled operations and unmanned automatic operations. Unless otherwise explicitly limited, those skilled in the art should understand the specific meaning of the above terms in the present invention according to the specific circumstances and adopt specific operating methods to achieve their operating objectives.

[0118] It should also be noted that:

[0119] The following specific embodiments can be combined with each other. The same or similar concepts or processes may not be repeated in some implementation cases and comparative examples. In addition, all kinds of instruments, equipment, raw materials, reagents and standards involved in the following specific embodiments are commercially available unless otherwise specified.

[0120] The technical solution of the present invention will now be described in detail with reference to specific embodiments.

[0121] Example 1

[0122] This embodiment provides a method for preparing a tanshinone IIA derivative.

[0123] The tanshinone IIA derivatives described in this embodiment can be summarized as having the following general structural formula:

[0124] ;

[0125] in:

[0126] R is selected from Cl, Br, I, , , , , , , , , or Any one of the groups in; and

[0127] R1 and R2 are each independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of cycloalkyl, 3-6 membered heterocyclic, benzene ring, or substituted benzene ring, wherein the substituent on the benzene ring is any one of F, Cl, Br, trifluoromethyl, amino, cyano, ester, nitro, methoxy, or hydroxyl, and the number of substituents is 1 to 3; or

[0128] R1 and R2 also form 3- to 6-membered rings with C, N, and O, in which the N atom on the ring interacts with the C atom. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocycles are linked, and the H atoms attached to the C atoms on the rings are C... 1-6 Alkyl, F, Cl, Br, benzene ring, 3-6 membered heterocyclic group, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl substitution;

[0129] R3 is H or is determined by at least one R a Group substitution, the R a The group is C 1-8 Alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, -C 1-8 Alkyl OC 1-8 Alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, N(C) 1-8 alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, nitro, C 1-8 Alkyl, hydroxyl or -COC 1-8 Any one of the alkyl groups;

[0130] R4 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups;

[0131] R5 and R6 are each independently selected from C1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups and N(C) 1-8 Any one of alkyl groups 2, wherein the carbon chain of the alkyl group is further linked by N and O, and the hydrogen of the alkyl group is C 1-6 Cycloalkyl, benzene ring, or aromatic heterocyclic substitution; or R1 and R2 may form 3- to 6-membered rings with C, N, and O, and the N atom on the ring may be substituted with C. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocyclic linkages;

[0132] R7 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups.

[0133] In the above description of the functional groups:

[0134] "-"or" "Indicates a connection site;

[0135] The term "halogen" refers to fluorine, chlorine, bromine, or iodine;

[0136] Term "C" 1～8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0137] The above refers to the term "alkyl", such as "C". 1～8 The definition of "alkyl" also applies to compounds containing "C". 1～8 Other terms for "alkyl", such as "C3-C6 cycloalkyl" and "C1-8 alkyl", etc.

[0138] Term "C" 1～8 "alkoxy" indicates "-OC" 1～8 "alkyl", where "C1-8 alkyl" has the definition as described above;

[0139] The term "halogenated C" 1～8 "alkyl" is a C10 as shown above. 1～8 One, two, three, four, five, or six hydrogen atoms on an alkyl group are replaced by halogen atoms (fluorine, chlorine, bromine, or iodine), for example, CF3CH2-;

[0140] Term "C" 2～8 "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, or 8 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C64, C74, C84, C9 ... 2-6 Alkenyl), having 2 or 3 carbon atoms (i.e., C24-3 ... 2-3Alkenyl); furthermore, when an alkenyl group contains more than one double bond, the double bonds can be separable or conjugated, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E) -pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylpropenyl 2-Alkenyl, 1-Methylprop-2-alkenyl, 2-Methylprop-1-alkenyl, (E)-1-Methylprop-1-alkenyl, (Z)-1-Methylprop-1-alkenyl, 3-Methylbut-3-alkenyl, 2-Methylbut-3-alkenyl, 1-Methylbut-3-alkenyl, 3-Methylbut-2-alkenyl, (E)-2-Methylbut-2-alkenyl, (Z)-2-Methylbut-2-alkenyl, (E)-1-Methylbut-2-alkenyl (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl;

[0141] The term "C3-6 cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, that is, it may contain 3 to 6 carbon atoms, such as 3, 4, 5, or 6 carbon atoms. The carbon ring may be a saturated cycloalkyl group or may optionally contain one, two, or more double and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloynyl group. For example, non-limiting examples of monocyclic carbon rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and / or cyclohexadienyl, etc.

[0142] The term "3-6 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N, which can be connected to the rest of the molecule through any one of its carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can also include, but is not limited to, 4-membered rings, such as azirrobutyl, oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, or trithiaalkyl.

[0143] Specifically, the method for preparing tanshinone IIA derivatives provided in this embodiment includes the following synthetic route:

[0144] .

[0145] To further aid in understanding the technical solution provided in this embodiment, as well as the specific operation process and technical effects achievable, the preparation method provided in this embodiment will be further explained below through specific preparation examples.

[0146] Of course, those skilled in the art should understand that the preparation examples described below are illustrative and not restrictive, and should not be used to limit the scope of protection claimed by the present invention.

[0147] Preparation Example 1, Synthesis of Compound-1

[0148] Reaction formula:

[0149] .

[0150] Specific operations:

[0151] 2.94 g (10 mmol) of tanshinone IIA, 1.2 g (20 mmol) of acetic acid, and 1.87 g (12 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) were placed together in a 500 mL reaction vessel, followed by the addition of 100 mL of chlorobenzene. The resulting reaction mixture was stirred at 120 °C for 15 hours. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 3.0 g of red powder, target compound-1 (reaction formula 1), with a yield of 85%.

[0152] Detection results for compound-1:

[0153] 1HNMR (400MHz, CDCl3): δ7.72 (s, 2H), 7.26–7.18 (m, 1H), 6.43 (t, J=3.7Hz, 1H), 2.26 (s, 3H), 2. 24–2.17 (m, 1H), 2.03 (s, 3H), 2.00–1.85 (m, 2H), 1.59–1.53 (m, 1H), 1.41 (s, 3H), 1.29 (s, 3H).

[0154] 13 CNMR (101MHz, CDCl3): δ182.79, 175.00, 170.01, 161.09, 150.67, 141.65, 137.93, 134.13, 128 .39, 126.94, 122.99, 121.31, 120.20, 67.42, 34.78, 32.25, 31.52, 31.06, 24.60, 21.04, 8.77.

[0155] HRMS (ESI) calculated value: C 21 H 20 O5Na(M+Na) + 375.120295, measured value: 375.11890.

[0156] Preparation Example 2, Synthesis of Compound-2

[0157] Reaction formula:

[0158] .

[0159] Specific operations:

[0160] In a 40 mL solution of toluene containing 3.52 g (10 mmol) of IIA2 obtained in Preparation Example 1, 3.0 g (12 mmol) of pyridine p-toluenesulfonate (PPTS) was added. The reaction mixture was stirred at 110 °C for 12 hours, cooled to room temperature, diluted with 50 mL of ethyl acetate, washed successively with water (100 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2.6 g of red powder target compound-2 (2 in the reaction formula), with a yield of 89%.

[0161] Detection results of compound-2:

[0162] 1HNMR (400MHz, CDCl3): δ7.84 (dt, J=10.2, 1.9Hz, 1H), 7.54 (t, J=1.3Hz, 2H), 7.22 (dd, J=1.4, 1 .2Hz, 2H), 6.57–6.16 (m, 1H), 2.28 (dd, J=4.6, 1.9Hz, 2H), 2.26 (d, J=1.4Hz, 3H), 1.30 (s, 6H).

[0163] 13 CNMR (101MHz, CDCl3): δ183.32, 174.77, 160.51, 147.41, 140.27, 136.30, 133.02, 1 29.24, 126.23, 123.41, 121.96, 120.50, 120.07, 118.92, 36.78, 33.11, 27.33, 7.78.

[0164] HRMS (ESI) calculated value: C 19 H 16 O3Na(M+Na) + 315.099165, measured value: 315.09837.

[0165] Preparation Example 3, Synthesis of Compound-3

[0166] Reaction formula:

[0167] .

[0168] Specific operations:

[0169] 2.92 g (10 mmol) of the IIA2 obtained in Preparation Example 1 was dissolved in 30 mL of 1,4-dioxane solution, and then 1.16 g (10.5 mmol) of SeO2 was added. The reaction mixture was stirred at 100 °C for 2 hours, then cooled and concentrated. 30 mL of dichloromethane was added, and the mixture was washed first with water (50 mL × 3), then with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated again. The crude product was purified by silica gel column chromatography to give 2.5 g of the target compound-3 (3 in the reaction formula) as a red powder, with a yield of 82%.

[0170] Detection results for compound-3:

[0171] 1HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.71 (d, J=8 .2Hz, 1H), 7.29 (d, J=1.5Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 2.29 (s, 3H), 1.51 (s, 6H).

[0172] 13 CNMR (101MHz, CDCl3): δ201.90, 184.07, 175.19, 160.40, 150.71, 142.03, 139.1 7, 132.28, 128.56, 128.49, 125.16, 123.56, 121.45, 120.53, 47.93, 27.55, 8.77.

[0173] HRMS (ESI) calculated value: C 19 H 14 O4Na(M+Na) + 329.078430, measured value: 329.07801.

[0174] Preparation Example 4: Synthesis of Tanshinone IIA Derivative IIA4

[0175] Reaction formula:

[0176] .

[0177] Specific operations:

[0178] 306 mg (1.0 mmol) of the IIA3 obtained in Preparation Example 3 was dissolved in dichloromethane (10 mL), and 213 mg (1.2 mmol) of N-bromosuccinimide (abbreviated as NBS) was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 338 mg of the target tanshinone IIA derivative IIA4 (4 in the reaction formula) as a red powder, with a yield of 88%.

[0179] Test results for IIA4:

[0180] 1 HNMR (400MHz, CDCl3): δ8.96 (d, J=10.5Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 2.24 (s, 3H), 1.51 (s, 6H).

[0181] 13CNMR (101MHz, CDCl3): δ201.76, 183.18, 174.19, 160.50, 151.10, 139.00, 132.61, 13 2.38, 128.83, 127.73, 125.80, 125.03, 123.50, 121.44, 120.85, 48.01, 27.55, 9.49.

[0182] HRMS (ESI) calculated value: C 19 H 13 BrO4Na(M+Na) + 406.988943, measured value: 406.98795.

[0183] Preparation Example 5: Synthesis of Tanshinone IIA Derivative IIA6

[0184] Reaction formula:

[0185] .

[0186] Specific operations:

[0187] In 1.0 g (1N, where N is the equivalent, the same below) of paraformaldehyde obtained from Preparation Example 3, 10 mL of acetic acid was added. The reaction mixture was reacted in a sealed tube at 90 °C for 16 hours. The acetic acid was evaporated off under reduced pressure. The crude product was added with 1 part potassium carbonate and 4 parts water, and stirred at 30 °C for 5 hours in 50 mL of methanol. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography to obtain the target tanshinone IIA derivative IIA6 (6 in the reaction formula).

[0188] Test results for IIA6:

[0189] 1 HNMR (400MHz, DMSO): δ8.86 (d, J=10.3Hz, 1H), 7.93 (d, J=7.7Hz, 1H), 7.73 (d, J=7.7Hz, 1 H), 6.39 (d, J=10.3Hz, 1H), 5.40 (s, 1H), 4.46 (d, J=4.2Hz, 2H), 2.17 (s, 3H), 1.41 (s, 6H).

[0190] 13 CNMR (101MHz, DMSO) δ202.06, 183.04, 175.20, 158.43, 154.33, 150.06, 140.03, 132.74 , 131.19, 127.94, 127.82, 126.30, 123.57, 121.01, 117.07, 53.42, 47.78, 27.54, 8.90.

[0191] HRMS (ESI) calculated value: C 20 H 17 O5 (M+H) + 337.107050, measured value: 337.10731.

[0192] Preparation Example 6: Synthesis of Tanshinone IIA Derivative IIA10

[0193] Reaction formula:

[0194] .

[0195] Specific operations:

[0196] The IIA6 obtained from Preparation Example 5 with 1N was dissolved in dichloromethane, and 1.2N of Dess-Martin periodate (i.e., Dess-Martin reagent, abbreviated as IIADMP) was added. The mixture was reacted at 20°C for 2 hours, filtered, and the mother liquor was concentrated to obtain the crude product. The crude product was obtained by silica gel column chromatography to obtain the target tanshinone IIA derivative IIA10 (10 in the reaction formula).

[0197] Test results for IIA10:

[0198] 1 HNMR (400MHz, CDCl3): δ9.91 (s, 1H), 8.98 (d, J=10.5Hz, 1H), 8.03 (d, J=8.2Hz , 1H), 7.82 (d, J=8.2Hz, 1H), 6.46 (d, J=10.5Hz, 1H), 2.68 (s, 3H), 1.53 (s, 6H).

[0199] 13 CNMR (101MHz, CDCl3): δ201.42, 182.84, 177.35, 174.98, 162.09, 153.00, 149.38, 138.6 1, 133.18, 132.91, 132.60, 129.12, 126.88, 126.41, 124.84, 121.22, 48.23, 27.52, 9.41.

[0200] HRMS (ESI) calculated value: C 20 H 15 O5 (M+H) + 335.091400, measured value: 335.09097.

[0201] Preparation Example 7: Synthesis of Tanshinone IIA Derivative IIA11

[0202] Reaction formula:

[0203] .

[0204] Specific operations:

[0205] The IIA10 obtained from Preparation Example 6 (1N), 30% hydrogen peroxide (3N), Na2HPO4 buffer solution (3N with a pH of approximately 2) and sodium chlorite (1.2N) were mixed in acetonitrile and stirred at room temperature for 8 hours. Then, part of the solvent was evaporated, the precipitate was filtered, and the filter cake was collected to obtain the target tanshinone IIA derivative IIA11 (11 in the reaction formula).

[0206] The test results for IIA11:

[0207] 1 HNMR (400MHz, DMSO) δ8.89 (d, J=10.4Hz, 1H), 7.98 (d, J=8.2Hz, 1H), 7.84 (d, J=8.3Hz, 1H), 6.41 (d, J=10.6Hz, 1H), 2.49 (s, 3H), 1.42 (s, 6H).

[0208] 13 CNMR (101MHz, DMSO) δ202.10, 182.91, 175.47, 150.63, 140.08, 132.75, 131.18, 127.83, 127.79, 127.04, 124.09, 121.43, 47.86, 27.54, 10.60.

[0209] HRMS (ESI) calculated value: C 20 H 14 O6(M+Na) + 373.068259, measured value: 373.06655.

[0210] Preparation Example 8: Synthesis of Tanshinone IIA Derivative IIA8

[0211] Reaction formula:

[0212] .

[0213] Specific operations:

[0214] The IIA6 obtained from Preparation Example 5 with 1N was dissolved in anhydrous dichloromethane, and then 1.2N of thionyl chloride was added. The mixture was reacted at 20°C for 5 hours. The product was washed with water and then with brine. After drying and concentration, the crude product was subjected to silica gel column chromatography to obtain the target tanshinone IIA derivative IIA8 (8 in the reaction formula).

[0215] Test results for IIA8:

[0216] 1HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.73 (d , J=8.2Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 4.65 (s, 2H), 2.33 (s, 3H), 1.51 (s, 6H).

[0217] 13 CNMR (101MHz, CDCl3): δ201.77, 183.70, 175.04, 159.94, 151.24, 149.21, 139.04, 132.5 0, 132.31, 128.75, 127.96, 125.49, 123.86, 121.04, 120.43, 48.01, 34.88, 27.57, 8.87.

[0218] HRMS (ESI) calculated value: C 20 H 15 ClO4(M+H) + 355.073163, measured value: 355.07314.

[0219] Preparation Example 9: Synthesis of Tanshinone IIA Derivatives IIA5-(1-39)

[0220] Reaction formula:

[0221] .

[0222] Preparation method 1 (reaction i-1):

[0223] The IIA3 obtained from Preparation Example 3 (1.0N), different types of amines or their hydrochlorides listed in Table 1 (1.2N), and paraformaldehyde (1.5N) were dissolved together in acetic acid and reacted at 60°C for 8–15 hours. The solvent was evaporated under reduced pressure, and dichloromethane and saturated sodium bicarbonate solution were added. The mixture was stirred for 0.5 hours, and the dichloromethane layer was separated. The mixture was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the reddish-brown powder target tanshinone IIA derivatives IIA5-(1–2), IIA5-(5–9), IIA5-(11–17), and IIA5-(20–32). The corresponding structural formulas are shown in [reference needed]. Figure 1 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA5 series products provided in Example 9 of this invention (the product names in the figures all omit "IIA").

[0224] Table 1

[0225]

[0226] Test results for IIA5-1:

[0227] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.6Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5 Hz, 1H), 3.62 (s, 2H), 2.75-2.57 (m, 4H), 2.56-2.40 (d, J=32.6Hz, 4H), 2.31 (s, 3H), 2.27 (s, 3H), 1.50 (s, 6H).

[0228] 13 CNMR (100MHz, CDCl3): δ201.93, 184.18, 175.28, 159.41, 150.94, 150.63, 139.24, 132.25, 132.14, 128.53, 128.43, 125.22, 123.84, 121.01, 119.41, 54.83, 52.66, 52.15, 47.92, 45.87, 27.56, 8.97.

[0229] HRMS (ESI) calculated value: C 25 H 26 N₂O₄Na(M+Na) + 441.178478, measured value: 441.17780.

[0230] Test results for IIA5-2:

[0231] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.4Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10 .4Hz, 1H), 3.77–3.71 (t, J=4.0Hz4H), 3.60 (s, 2H), 2.60–2.49 (t, J=4.0Hz, 4H), 2.28 (s, 3H), 1.50 (s, 6H).

[0232] 13 CNMR (100MHz, CDCl3): δ201.90, 184.13, 175.27, 159.48, 150.70, 150.57, 139.20, 132.29, 132. 17, 128.57, 128.39, 125.24, 123.81, 120.99, 119.55, 66.78, 53.26, 52.63, 47.93, 27.56, 8.96.

[0233] HRMS (ESI) calculated value: C 24 H 23 NO5Na(M+Na) + 428.146844, measured value: 428.14596.

[0234] Test results for IIA5-5:

[0235] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.4Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 6.40 (d, J=10.4 Hz, 1H), 3.62 (s, 2H), 2.70–2.66 (m, 1H), 2.65-2.55 (m, 8H), 2.27 (s, 3H), 1.50 (s, 6H), 1.05 (d, J=6.4Hz, 6H).

[0236] 13 CNMR (151MHz, CDCl3): δ201.93, 184.13, 175.24, 159.46, 150.69, 150.67, 139.23, 132.26, 132.17, 128 .53, 128.38, 125.22, 123.85, 121.00, 119.56, 55.09, 52.19, 51.98, 48.22, 47.92, 27.55, 18.16, 8.97.

[0237] HRMS (ESI) calculated value: C 27 H 31 N2O4(M+H) + 447.227834, measured value: 447.22727.

[0238] Test results for IIA5-6:

[0239] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.82–3.6 9 (m, 1H), 3.61 (s, 2H), 2.90–2.76 (m, 2H), 2.32 (t, J=9.7Hz, 2H), 2.27 (s, 3H), 1.97–1.91m, 2H), 1.70–1.62 (m, 2H), 1.50 (s, 6H).

[0240] 13 CNMR (100MHz, CDCl3+CD3OD) δ206.66, 187.92, 179.21, 163.65, 157.48, 154.58, 143.67, 136.44, 136.0 5, 132.40, 132.17, 129.10, 127.88, 124.90, 122.12, 57.80, 52.78, 52.49, 51.87, 31.30, 31.26, 12.32.

[0241] HRMS (ESI) calculated value: C 25 H 25 NO5Na(M+Na) + 442.162494, measured value: 442.16223.

[0242] Test results for IIA5-7:

[0243] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.71 (d, J=8.2Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 3.75- 3.65 (m, 4H), 3.64 (s, 2H), 2.61-2.51 (m, 4H), 2.28 (s, 3H), 1.76–1.69 (m, 1H), 1.51 (s, 6H), 0.98 (m, 2H), 0.80–0.72 (m, 2H).

[0244] 13 CNMR (100MHz, CDCl3): δ201.87, 184.09, 175.26, 171.97, 159.53, 150.77, 150.41, 139.17, 132.33, 132.19, 128.6 0, 128.35, 125.26, 123.80, 120.97, 119.63, 52.94, 52.55, 52.12, 47.94, 45.28, 41.93, 27.56, 10.88, 8.97, 7.50.

[0245] HRMS (ESI) calculated value: C 28 H 28 N₂O₅Na(M+Na) + 495.189043, measured value: 495.18855.

[0246] Test results for IIA5-8:

[0247] 1 HNMR (400MHz, CDCl3+CD3OD) δ8.99 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 6.41 (d, J= 10.5Hz, 1H), 3.62 (s, 2H), 3.44 (s, 1H), 3.01 (t, J=5.0Hz, 4H), 2.62 (t, J=4.9Hz, 4H), 2.27 (s, 3H), 1.51 (s, 6H).

[0248] 13 CNMR (151MHz, CDCl3+CD3OD) δ202.41, 183.93, 175.17, 159.75, 150.75, 150.02, 139.48, 132.34, 1 32.21, 128.39, 128.27, 125.12, 123.90, 120.82, 119.78, 52.20, 51.58, 47.91, 44.36, 27.43, 8.77.

[0249] HRMS (ESI) calculated value: C 24 H 24 N₂O₄Na(M+Na) + 427.162828, measured value: 427.16230.

[0250] Test results for IIA5-9:

[0251] 1 HNMR (400MHz, CDCl3): δ8.90 (d, J=10.5Hz, 1H), 7.76 (d, J=8.2Hz, 1H), 7.64 (d, J=8.2Hz, 1H), 6.48 (dd, J=16.8, 10.5Hz, 1H), 6.34 (d, J=10.5Hz , 1H), 6.22 (dd, J=16.8, 1.8Hz, 1H), 5.63 (dd, J=10.5, 1.8Hz, 1H), 3.68 (s, 2H), 3.57 (d, J=13.6Hz, 4H), 2.50 (s, 4H), 2.21 (s, 3H), 1.43 (s, 6H).

[0252] 13CNMR (151MHz, CDCl3): δ201.86, 184.05, 175.23, 165.33, 159.52, 150.77, 150.35, 139.16, 132.32, 132.20, 128.59 , 128.32, 128.11, 127.28, 125.25, 123.79, 120.95, 119.63, 52.85, 52.40, 52.05, 47.93, 45.61, 41.79, 27.55, 8.94.

[0253] HRMS (ESI) calculated value: C 27 H 26 N₂O₅Na(M+Na) + 481.173393, measured value: 481.17300.

[0254] Test results for IIA5-11:

[0255] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 7.69 (d, J=8.1Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 5.88 (d d, J=16.9, 10.0Hz, 1H), 5.28–5.12 (m, 2H), 3.63 (s, 2H), 3.07 (d, J=6.0Hz, 2H), 2.75–2.45 (s, 8H), 2.27 (s, 3H), 1.50 (s, 6H).

[0256] 13 CNMR (151MHz, CDCl3): δ201.90, 184.18, 175.27, 159.38, 150.96, 150.61, 139.22, 134.64, 132.25, 132.12, 128.53, 128.43, 125.21, 123.82, 121.01, 119.39, 118.32, 61.58, 52.79, 52.67, 52.13, 47.91, 27.56, 8.97.

[0257] HRMS (ESI) calculated value: C 27 H 28 N₂O₄Na(M+Na) + 467.194128, measured value: 467.19356.

[0258] Test results for IIA5-12:

[0259] 1 HNMR (400MHz, CDCl3): δ8.91 (d, J=10.5Hz, 1H), 7.76 (d, J=8.2Hz, 1H), 7.64 (d, J=8.2Hz, 1H), 6.35 (d, J= 10.5Hz, 1H), 3.71–3.51 (m, 4H), 3.45 (s, 2H), 2.57–2.33 (m, 4H), 2.22 (s, 3H), 2.02 (s, 3H), 1.44 (s, 6H).

[0260] 13 CNMR (151MHz, CDCl3): δ201.85, 184.09, 175.26, 168.90, 159.52, 150.78, 150.38, 139.15, 132.35, 132.19, 12 8.62, 128.34, 125.27, 123.77, 120.97, 119.62, 52.74, 52.46, 52.11, 47.94, 46.13, 41.27, 27.56, 21.30, 8.96.

[0261] HRMS (ESI) calculated value: C 26 H 26 N₂O₅Na(M+Na) + 469.173393, measured value: 469.17304.

[0262] Test results for IIA5-13:

[0263] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.59 (s, 2H), 3.01 (d, J=11.4Hz , 2H), 2.33 (s, 6H), 2.35-2.26 (m, 1H), 2.27 (s, 3H), 2.12 (t, J=10.9Hz, 2H) , 1.87 (d, J=11.9Hz, 2H), 1.61 (ddd, J=24.3, 12.3, 3.4Hz, 2H), 1.50 (s, 5H).

[0264] 13CNMR (100MHz, CDCl3): δ201.92, 184.19, 175.29, 159.38, 151.13, 150.61, 139.23, 132.24, 132.16, 128 .52, 128.45, 125.22, 123.86, 120.98, 119.27, 61.73, 52.60, 52.07, 47.91, 40.92, 27.59, 27.56, 8.99.

[0265] HRMS (ESI) calculated value: C 27 H 30 N₂O₄Na(M+Na) + 469.209779, measured value: 469.21000.

[0266] Test results for IIA5-14:

[0267] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 8.30 (d, J=4.6Hz, 2H), 7.84 (d, J=8.1Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.49 (t , J=4.7Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.87 (t, J=4.0Hz, 4H), 3.66 (s, 2H), 2.61 (t, J=4.0Hz, 4H), 2.28 (s, 3H), 1.50 (s, 6H).

[0268] 13 CNMR (100MHz, CDCl3): δ201.90, 184.13, 175.27, 161.52, 159.47, 157.74, 150.73, 150.67, 139.21, 132.26, 132.16, 128.55, 128.41, 125.24, 123.84, 121.01, 119.53, 109.99, 52.68, 52.34, 47.92, 43.51, 27.56, 8.99.

[0269] HRMS (ESI) calculated value: C 28 H 27 N4O4(M+H) + 483.202682, measured value: 483.20246.

[0270] Test results for IIA5-15:

[0271] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 8.09 (d, J=9.3Hz, 2H), 7.83 (d, J=8.2Hz, 1H), 7.71 (d, J=8.2Hz, 1H), 6.81 (d , J=9.4Hz, 2H), 6.40 (d, J=10.5Hz, 1H), 3.68 (s, 2H), 3.47 (t, J=4.0Hz, 4H), 2.70 (t, J=4.0Hz, 4H), 2.30 (s, 3H), 1.50 (s, 6H).

[0272] 13 CNMR (100MHz, CDCl3): δ201.86, 184.06, 175.26, 159.58, 154.68, 150.81, 150.31, 139.15, 138.60, 132.35, 132. 20, 128.62, 128.33, 125.94, 125.25, 123.79, 120.98, 119.70, 112.78, 52.25, 52.15, 47.95, 46.96, 27.56, 9.00.

[0273] HRMS (ESI) calculated value: C 30 H 27 N3O6Na(M+Na) + 548.179207, measured value: 548.17826.

[0274] Test results for IIA5-16:

[0275] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 7.05–6.98 (m, 1H), 6.96–6.91 (m, 2H), 6. 86 (d, J=7.9Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 3.86 (s, 3H), 3.70 (s, 2H), 3.16–3.10 (m, 4H), 2.79–2.75 (m, 4H), 2.30 (s, 3H), 1.50 (s, 6H).

[0276] 13CNMR (100MHz, CDCl3): δ201.95, 184.23, 175.33, 159.48, 152.24, 150.93, 150.64, 141.05, 139.27, 132.28, 132.14, 128.55, 128.48, 125.25, 123.87, 123.15, 121.06, 120.99, 119.54, 118.24, 111.15, 55.37, 53.02, 52.24, 50.53, 47.94, 27.58, 9.06.

[0277] HRMS (ESI) calculated value: C 31 H 31 N2O5(M+H) + 511.222749, measured value: 511.22233.

[0278] Test results for IIA5-17:

[0279] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.89–7.81 (m, 2H), 7.71 (d, J=8.2H z, 1H), 6.40 (d, J=10.5Hz, 1H), 3.67 (s, 2H), 3.67–3.60 (m, 4H), 2.70–2.62 (m, 4H), 2.30 (s, 3H), 1.50 (s, 6H).

[0280] 13 CNMR (100MHz, CDCl3): δ201.88, 184.08, 175.25, 159.51, 154.83, 150.73, 150.52, 141.74, 139.18, 133.10, 132. 30, 132.18, 131.01, 128.58, 128.36, 125.25, 123.81, 120.99, 119.61, 52.36, 52.29, 47.93, 44.37, 27.56, 8.99.

[0281] HRMS (ESI) calculated value: C 28 H 26 N4O4Na(M+Na) + 505.184626, measured value: 505.18444.

[0282] Test results for IIA5-20:

[0283] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.4Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H ), 6.40 (d, J=10.4Hz, 1H), 3.69 (s, 2H), 2.63 (s, 4H), 2.28 (s, 3H), 1.84 (s, 4H), 1.50 (s, 6H).

[0284] 13 CNMR (100MHz, CDCl3): δ201.96, 184.23, 175.32, 159.29, 152.09, 150.54, 139.27, 132.21, 132.12, 128.48, 125.22, 123.88, 121.04, 118.30, 54.06, 49.31, 47.92, 27.56, 23.48, 8.94.

[0285] HRMS (ESI) calculated value: C 24 H 23 NO4Na(M+Na) + 412.151929, measured value: 412.15181.

[0286] Test results for IIA5-21:

[0287] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 4.19 (t, J=5.7Hz, 2H), 3.61 (s, 2H), 2.66 (d, J=5.7Hz, 2H), 2.63-2.54 (m, 8H), 2.27 (s, 3H), 2.06 (s, 3H), 1.50 (s, 6H).

[0288] 13 CNMR (100MHz, CDCl3): δ201.93, 184.15, 175.25, 171.00, 159.42, 150.86, 150.63, 139.23, 132.24, 132.16, 12 8.52, 128.41, 125.20, 123.84, 120.99, 119.43, 61.72, 56.50, 53.12, 52.65, 52.11, 47.91, 27.55, 21.03, 8.97.

[0289] HRMS (ESI) calculated value: C28 H 30 N₂O₆Na(M+Na) + 513.199608, measured value: 513.19925.

[0290] Test results for IIA5-22:

[0291] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.62 (t, J=5.0Hz, 4H), 2.65-2.54 (m, 10H), 2.27 (s, 3H), 1.50 (s, 6H).

[0292] 13 CNMR (100MHz, CDCl3): δ201.94, 184.13, 175.26, 159.43, 150.84, 150.64, 139.23, 132.25, 132.18, 128 .52, 128.41, 125.21, 123.84, 120.99, 119.43, 59.18, 57.76, 52.76, 52.65, 52.11, 47.92, 27.55, 8.97.

[0293] HRMS (ESI) calculated value: C 26 H 29 N2O5(M+H) + 449.207098, measured value: 449.20668.

[0294] Test results for IIA5-23:

[0295] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.09 (d, J=5.1Hz, 1H ), 6.73 (d, J=5.1Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.81 (s, 2H), 3.67 (s, 2H), 2.93 (s, 4H), 2.31 (s, 3H), 1.50 (s, 6H).

[0296] 13CNMR (100MHz, CDCl3): δ201.93, 184.17, 175.31, 159.58, 151.04, 150.70, 139.23, 133.14, 133.08, 132.28, 132.16, 128.56, 128.39, 125.26, 125.14, 123.90, 123.05, 121.01, 119.47, 52.60, 51.32, 50.41, 47.94, 27.57, 25.26, 9.03.

[0297] HRMS (ESI) calculated value: C 27 H 23 NO4SNa(M+Na) + 480.124000, measured value: 480.12344.

[0298] Test results for IIA5-24:

[0299] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 4.09 (s, 1H), 3.61 (s, 2H), 2.83 (t, J=10.0Hz, 2H), 2.48–2.35 (m, 2H), 2.27 (s, 3H), 2.16–2.09 (m, 2H), 2.02–1.88 (m, 2H), 1.50 (s, 6H).

[0300] 13 CNMR (100MHz, CDCl3): δ201.91, 184.15, 175.27, 159.44, 150.90, 150.67, 139.21, 132.28, 132.18, 128.55, 128.42, 125.23, 123.83, 120.99, 119.41, 56.70, 52.18, 50.69, 47.93, 35.15, 27.56, 8.97.

[0301] HRMS (ESI) calculated value: C 25 H 24 ClNO4Na(M+Na) + 460.128607, measured value: 460.12844.

[0302] Test results for IIA5-25:

[0303] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.60 (s, 2H), 3.04 (d, J=11.2Hz, 2H), 2.27 (s, 3H), 2.09 (t, J=11.2Hz, 2H), 2.03-1.95 (m, 1H), 1.88 (d, J=12.5Hz, 2H), 1.67 (qd, J=12.5, 3.5Hz, 2H), 1.50 (s, 6H).

[0304] 13 CNMR (100MHz, CDCl3): δ201.90, 184.16, 175.30, 159.44, 150.87, 150.70, 139.20, 132.30, 132.17, 128.75 (q, J=276 .0), 128.58, 128.41, 125.25, 123.81, 120.99, 119.38, 52.27, 52.11, 47.93, 40.23 (q, J=27.0), 27.56, 24.58, 8.97.

[0305] HRMS (ESI) calculated value: C 26 H 24 F3NO4Na(M+Na) + 494.154964, measured value: 494.15430.

[0306] Test results for IIA5-26:

[0307] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.59 (s, 2H), 3.3 3 (s, 3H), 3.28–3.21 (m, 1H), 2.81–2.72 (m, 2H), 2.32 (t, J=8.0Hz, 2H), 2.26 (s, 3H), 1.95–1.87 (m, 2H), 1.70–1.61 (m, 2H), 1.50 (s, 6H).

[0308] 13CNMR (100MHz, CDCl3): δ201.94, 184.19, 175.28, 159.38, 151.24, 150.58, 139.25, 132.21, 132.16, 128 .50, 128.47, 125.20, 123.88, 121.00, 119.25, 75.58, 55.61, 52.23, 50.59, 47.91, 30.59, 27.55, 8.98.

[0309] HRMS (ESI) calculated value: C 26 H 27 NO5Na(M+Na) + 456.178144, measured value: 456.17754.

[0310] Test results for IIA5-27:

[0311] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.41 ( d, J=10.5Hz, 1H), 3.65 (s, 2H), 2.65 (t, J=4.0Hz, 4H), 2.28 (s, 3H), 2.09-1.97 (m, 4H), 1.50 (s, 6H).

[0312] 13 CNMR (100MHz, CDCl3): δ201.88, 184.10, 175.26, 159.46, 150.77, 150.75, 139.18, 132.33, 132.18, 128.60, 128.37, 125. 27, 123.77, 121.60 (t, J=240.0Hz), 120.99, 119.44, 51.55, 49.74 (t, J=5.5Hz), 47.94, 33.92 (t, J=23.0Hz), 27.56, 8.93.

[0313] HRMS (ESI) calculated value: C 25 H 23 F2NO4Na(M+Na) + 462.148736, measured value: 462.14818.

[0314] Test results for IIA5-28:

[0315] 1HNMR (400MHz, CDCl3): δ8.96 (d, J=10.5Hz, 1H), 8.25 (d, J=6.3Hz, 2H), 7.83 (d, J=8.2Hz, 1H), 7.71 (d, J=8.2Hz, 1H), 6.65 (d, J= 6.4Hz, 2H), 6.40 (d, J=10.5Hz, 1H), 3.66 (s, 2H), 3.42–3.38 (t, J=4.0Hz, 4H), 2.67 (t, J=4.0Hz, 4H), 2.29 (s, 3H), 1.50 (s, 6H).

[0316] 13 CNMR (100MHz, CDCl3): δ201.85, 184.03, 175.21, 159.51, 154.77, 150.73, 150.44, 150.18, 139.16, 132. 28, 132.19, 128.56, 128.33, 125.23, 123.81, 120.97, 119.60, 108.40, 52.22, 47.93, 45.84, 27.55, 8.98.

[0317] HRMS (ESI) calculated value: C 29 H 28 N3O4(M+H) + 482.207433, measured value: 482.20706.

[0318] Test results for IIA5-29:

[0319] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.70 ( d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.58 (s, 2H), 3.01 (d, J=11.3Hz, 2H), 2.55 (t, J=5.4Hz, 4H), 2.37–2.30 (m, 1H), 2.26 (s, 3H), 2.10 (t, J=11.8Hz, 2H ), 1.85 (d, J=12.4Hz, 2H), 1.70–1.59 (m, 6H), 1.50 (s, 6H), 1.46–1.41 (m, 2H).

[0320] 13CNMR (100MHz, CDCl3): δ201.97, 184.21, 175.31, 159.39, 151.23, 150.59, 139.26, 132.23, 132.18, 128.51, 12 8.47, 125.21, 123.88, 120.99, 119.22, 62.42, 53.11, 52.15, 50.05, 47.91, 27.56, 27.45, 25.91, 24.50, 8.99.

[0321] HRMS (ESI) calculated value: C 30 H 35 N2O4(M+H) + 487.259134, measured value: 487.25819.

[0322] Test results for IIA5-30:

[0323] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.69 (d, J=8.1Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 3.61 (s, 2H), 2. 65-2.60 (m, 8H), 2.26 (s, 3H), 1.87 (d, J=8.7Hz, 2H), 1.79 (d, J=10.9Hz, 2H), 1.62 (d, J=11.9Hz, 1H), 1.50 (s, 6H), 1.30-1.05 (m, 6H).

[0324] 13 CNMR (100MHz, CDCl3): δ201.93, 184.17, 175.25, 159.39, 150.99, 150.58, 139.25, 132.21, 132.12, 128.49, 12 8.43, 125.18, 123.87, 121.00, 119.40, 63.42, 53.24, 52.16, 48.68, 47.91, 28.94, 27.55, 26.24, 25.83, 8.99.

[0325] HRMS (ESI) calculated value: C 30 H 35 N2O4(M+H) + 487.259134, measured value: 487.25873.

[0326] Test results for IIA5-31:

[0327] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.70 (d, J=8. 3Hz, 1H), 6.40 (d, J=10.6Hz, 1H), 3.68 (s, 3H), 3.62 (s, 2H), 3.03 (d, J=11.1Hz, 1H), 2 .81 (d, J=11.0Hz, 1H), 2.62 (t, J=10.8Hz, 1H), 2.34-2.22 (m, 4H), 2.20–2.10 (m, 1H), 1.95 (d, J=14.0Hz, 2H), 1.77 (d, J=12.6Hz, 1H), 1.61 (d, J=12.2Hz, 1H), 1.50 (s, 6H).

[0328] 13 CNMR (100MHz, CDCl3): δ201.94, 184.21, 175.32, 174.34, 159.37, 151.06, 150.60, 139.25, 132.25, 132.18, 128.53, 1 28.48, 125.22, 123.81, 121.03, 119.35, 55.03, 53.27, 52.55, 51.72, 47.92, 41.70, 27.58, 27.54, 26.64, 24.46, 8.97.

[0329] HRMS (ESI) calculated value: C 27 H 28 NO6 (M+H) + 462.191114, measured value: 462.19064.

[0330] Test results for IIA5-32:

[0331] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.3Hz, 1H), 7.82 (d, J=7.7Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 6.40 (d, J=10 .3Hz, 1H), 3.62 (s, 2H), 3.50 (t, J=4.0Hz, 2H), 3.34 (s, 3H), 2.77–2.40 (m, 10H), 2.26 (s, 3H), 1.50 (s, 6H). 13CNMR (100MHz, CDCl3): δ 201.93, 184.16, 175.25, 159.39, 150.96, 150.59, 139.25, 132.22, 132.13, 128.50, 128.42, 125.19, 123.84, 120.99, 119.40, 70.06, 58.89, 57.78, 53.32, 52.56, 52.10, 47.91, 27.55, 8.97. HRMS (ESI) calculated values: C 27 H 31 N2O5(M+H) + 463.222749, measured value: 463.22227.

[0332] Preparation method 2 (reaction i-2):

[0333] The IIA10 obtained in Preparation Example 6 of 1.0N and the different types of amines or their hydrochlorides listed in Table 2 of 1.2N were dissolved in 1,2-dichloromethane and stirred at 20°C for 1 hour. Then, sodium triacetoxyborohydride of 2.0N was added and stirred at 20°C for 1 to 8 hours.

[0334] After the reaction was completed, sodium bicarbonate solution was added to the reaction solution and stirred for 0.5 hours. The organic layer was separated, washed with brine, dried, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain reddish-brown powders of target tanshinone IIA derivatives IIA5-(3-4) and IIA5-10 and IIA5-(18-19).

[0335] See the corresponding structural formula. Figure 1 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA5 series products provided in Example 9 of this invention (the product names in the figures all omit "IIA").

[0336] Table 2

[0337]

[0338] Test results for IIA5-3:

[0339] 1 HNMR (400MHz, CDCl3+CD3OD) δ9.14–8.88 (m, 1H), 7.85 (m, 1H), 7.78-7.73 (m, 1H), 6.52–6.32 (m, 1H), 3.88 (t, J=4.0Hz, 2H), 3.75-3.72 (m, 2H), 2.81 (t, J=4.0Hz, 2H), 2.27 (s, 3H), 1.51 (s, 6H).

[0340] 13CNMR (100MHz, CDCl3+CD3OD) δ202.54, 183.87, 175.14, 159.61, 151.88, 150.61, 139.56, 132.39, 1 32.12, 128.28, 128.27, 125.01, 123.79, 120.84, 118.16, 60.32, 50.22, 47.88, 42.80, 27.36, 8.51.

[0341] HRMS (ESI) calculated value: C 22 H 21 NO5Na(M+Na) + 402.131194, measured value: 402.13068.

[0342] Test results for IIA5-4:

[0343] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.42 (t, J=10. 5Hz, 1H), 3.68 (s, 2H), 3.66 (t, J=5.4Hz, 2H), 2.67 (t, J=5.4Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 1.50 (s, 6H).

[0344] 13 CNMR (100MHz, CDCl3): δ201.92, 184.12, 175.28, 159.50, 151.22, 150.74, 139.20, 132.33, 132.26, 128.60, 128.38, 125.25, 123.66, 120.96, 119.22, 58.43, 57.90, 51.35, 47.94, 41.52, 27.57, 8.90.

[0345] HRMS (ESI) calculated value: C 23 H 24 NO5 (M+H) + 394.1649, measured value: 394.1683.

[0346] Test results for IIA5-10:

[0347] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 6.40 (d , J=10.5Hz, 1H), 3.84 (s, 2H), 2.87 (p, J=6.2Hz, 1H), 2.27 (s, 3H), 1.50 (s, 6H), 1.13 (d, J=6.2Hz, 6H).

[0348] 13 CNMR (101MHz, CDCl3): δ201.93, 184.20, 175.31, 159.18, 153.34, 150.53, 139.25, 132.27, 1 32.15, 128.52, 128.49, 125.19, 123.62, 121.14, 117.32, 47.91, 41.19, 27.56, 22.77, 8.79.

[0349] HRMS (ESI) calculated value: C 23 H 23 NO4Na(M+Na) + 400.151929, measured value: 400.15102.

[0350] Test results for IIA5-18:

[0351] 1 HNMR (400MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 7.81 (d, J=8.2Hz, 1H), 7.71 (d, J=8.2Hz, 1H), 7.36 (s , 2H), 7.35 (s, 2H), 7.31–7.27 (m, 1H), 6.42 (d, J=10.5Hz, 1H), 3.86 (s, 4H), 2.22 (s, 3H), 1.52 (s, 6H).

[0352] 13 CNMR (100MHz, CDCl3): δ201.97, 184.19, 175.32, 159.31, 152.70, 150.60, 139.26, 139.19, 132.32, 132.20, 1 28.57, 128.46, 128.16, 127.42, 127.36, 125.21, 123.61, 121.11, 117.95, 52.83, 47.94, 42.62, 27.58, 8.81.

[0353] HRMS (ESI) calculated value: C 27 H24 NO4 (M+H) + 426.1700, measured value: 426.1714.

[0354] Test results for IIA5-19:

[0355] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.81 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H) , 6.41 (d, J=10.5Hz, 1H), 3.96 (s, 2H), 3.48 (d, J=2.3Hz, 2H), 2.37–2.25 (m, 4H), 1.50 (s, 6H).

[0356] 13 CNMR (100MHz, CDCl3): δ201.93, 184.16, 175.30, 159.46, 151.91, 150.69, 139.22, 132.33, 132.16, 128.58, 128.39, 125.26, 123.68, 121.08, 118.64, 81.20, 72.27, 47.94, 41.86, 37.16, 27.57, 8.75.

[0357] HRMS (ESI) calculated value: C 23 H 19 NO4Na(M+Na) + 396.120629, measured value: 396.12043.

[0358] Preparation method 3 (reaction i-3):

[0359] The IIA8 obtained from Preparation Example 8 (1.0N), different types of amines or their hydrochlorides (1.2N) listed in Table 3, and triethylamine (1.5-2.5N) were dissolved together in dichloromethane and reacted at 20-40°C for 0.5-8 hours. The mixture was washed first with water, then with brine, and the dichloromethane layer was separated. The layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a reddish-brown powder, the target tanshinone IIA derivative IIA5-(33-39), the corresponding structural formula of which is shown in [reference needed]. Figure 1 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA5 series products provided in Example 9 of this invention (the product names in the figures all omit "IIA").

[0360] Table 3

[0361]

[0362] Test results for IIA5-33:

[0363] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H ), 5.99–5.85 (m, 1H), 5.36–5.17 (m, 2H), 3.59 (s, 2H), 3.11 (d, J=6.5Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.50 (s, 6H).

[0364] 13 CNMR (101MHz, CDCl3): δ201.95, 184.23, 175.33, 159.44, 151.66, 150.61, 139.25, 135.03, 132.26, 132. 14, 128.53, 128.46, 125.24, 123.81, 121.01, 119.15, 118.37, 60.33, 50.58, 47.92, 42.10, 27.57, 8.94.

[0365] HRMS (ESI) calculated value: C 24 H 23 NO4Na(M+Na) + 412.151929, measured value: 412.15007.

[0366] Test results for IIA5-34:

[0367] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.68 (d, J=8.2Hz, 1H), 6.40 (d , J=10.5Hz, 1H), 3.60 (s, 2H), 2.92 (p, J=6.5Hz, 1H), 2.28 (s, 6H), 1.50 (s, 6H), 1.12 (d, J=6.6Hz, 6H).

[0368] 13CNMR (101MHz, CDCl3): δ202.00, 184.33, 175.38, 159.36, 152.41, 150.51, 139.30, 132.23, 132.10, 128.54, 128.50, 125.23, 123.85, 121.11, 118.62, 53.29, 47.92, 47.48, 37.29, 27.57, 18.10, 8.87.

[0369] HRMS (ESI) calculated value: C24H25NO4Na(M+Na)+414.167579, measured value: 414.16597.

[0370] Test results for IIA5-35:

[0371] 1 HNMR (400MHz, CDCl3): δ8.97 (dd, J=10.5, 1.7Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 6.4 0 (dd, J=10.5, 1.7Hz, 1H), 3.88 (s, 2H), 2.28 (s, 3H), 1.50 (s, 6H), 0.84–0.46 (m, 2H), 0.45–0.35 (m, 2H).

[0372] 13 CNMR (101MHz, CDCl3): δ201.95, 184.23, 175.37, 159.17, 153.15, 150.56, 139.25, 132.30, 132 .17, 128.55, 128.50, 125.22, 123.57, 121.13, 117.71, 47.92, 43.17, 29.78, 27.57, 8.76, 6.44.

[0373] HRMS (ESI) calculated value: C23H21NO4Na(M+Na)+398.136279, measured value: 398.13441.

[0374] Test results for IIA5-36:

[0375] 1HNMR (400MHz, CDCl3): δ8.94 (d, J=10.5Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.67 (d, J=8.2Hz, 1H), 6.38 (d, J= 10.6Hz, 1H), 5.96 (s, 2H), 4.33 (s, 2H), 4.06 (s, 1H), 3.83 (s, 6H), 3.76 (s, 3H), 2.31 (s, 3H), 1.49 (s, 6H).

[0376] 13 C NMR (101 MHz, CDCl3) δ 201.85, 183.89, 175.14, 159.35, 154.03, 151.51, 150.77, 143.91, 139.10, 132.37, 132.22, 130.87, 128.62, 128.25, 125.17, 123.49, 121.06, 117.92, 90.83, 61.10, 56.02, 47.96, 39.43, 27.54, 8.89.

[0377] HRMS (ESI) calculated value: C29H27NO7Na(M+Na)+524.167973, measured value: 524.16574.

[0378] Test results for IIA5-37:

[0379] 1 HNMR (400MHz, CDCl3): δ8.96 (d, J=10.5Hz, 1H), 7.81 (d, J=8.2Hz, 1H), 7.70 (d, J=8.1Hz, 1H), 6.39 (d, J=10. 5Hz, 1H), 3.86 (s, 2H), 3.54 (t, J=5.0Hz, 2H), 3.37 (s, 3H), 2.85 (t, J=5.0Hz, 2H), 2.27 (s, 3H), 1.51 (s, 6H).

[0380] 13 CNMR (101MHz, CDCl3): δ201.94, 184.16, 175.28, 159.27, 152.83, 150.56, 139.24, 132.25, 132.16, 128.50, 128.44, 125.18, 123.68, 121.08, 117.73, 71.77, 58.89, 48.56, 47.91, 43.55, 27.55, 8.77.

[0381] HRMS (ESI) calculated value: C23H23NO5Na(M+Na)+416.146844, measured value: 416.14481.

[0382] Test results for IIA5-38:

[0383] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 7.25 (dd, J=4.8 , 1.5Hz, 1H), 7.00–6.89 (m, 2H), 6.40 (d, J=10.5Hz, 1H), 4.04 (s, 2H), 3.88 (s, 2H), 2.23 (s, 3H), 1.51 (s, 6H).

[0384] 13 CNMR (101MHz, CDCl3): δ201.93, 184.18, 175.33, 159.33, 152.55, 150.64, 143.06, 139.23, 132.33, 132.18, 1 28.58, 128.44, 126.75, 125.38, 125.24, 124.90, 123.60, 121.12, 118.05, 47.94, 47.36, 42.32, 27.58, 8.81.

[0385] HRMS (ESI) calculated value: C25H21NO4SNa(M+Na)+454.108350, measured value: 454.10699.

[0386] Test results for IIA5-39:

[0387] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.25 (d, J=8.5Hz, 2H ), 6.87 (d, J=8.6Hz, 2H), 6.41 (d, J=10.5Hz, 1H), 3.83 (s, 2H), 3.79 (s, 3H), 3.78 (s, 2H), 2.22 (s, 3H), 1.51 (s, 6H).

[0388] 13CNMR (101MHz, CDCl3): δ201.95, 184.23, 175.36, 159.29, 158.91, 150.60, 139.25, 132.33, 132.17, 131.31, 129.37, 128.57, 128.49, 125.24, 123.59, 121.13, 117.86, 113.92, 55.30, 52.27, 47.94, 42.54, 27.58, 8.81.

[0389] HRMS (ESI) calculated value: C28H25NO5Na(M+Na)+478.162494, measured value: 478.16035.

[0390] Preparation Example 10: Synthesis of Tanshinone IIA Derivative IIA7-(1-26)

[0391] Reaction formula:

[0392] .

[0393] Preparation method 1 (acyl chloride method: j-1):

[0394] The tanshinone IIA derivative-6 obtained in Example 5 (1N) was dissolved in dichloromethane, and triethylamine (2N) was added. The mixture was cooled in an ice-salt bath for 10 minutes. Then, different types of organic acid acyl chlorides listed in Table 4 were added, and the reaction was carried out for 5 to 30 minutes. The mixture was washed with water, then with brine, then dried and concentrated. The crude product was subjected to silica gel column chromatography to obtain the target tanshinone IIA derivative IIA7-(1-12) as a reddish-brown powder. The corresponding structural formula is shown in [reference needed]. Figure 2 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA7 series products provided in Example 10 of this invention (the product names in the figures all omit "IIA").

[0395] Table 4

[0396]

[0397] Test results for IIA7-1:

[0398] 1 HNMR (400MHz, CDCl3): δ8.90 (d, J=10.5Hz, 1H), 7.76 (d, J=8.2Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 6.34 (d, J=10.5Hz, 1H), 5.05 (s, 2H), 2.27 (s, 3H), 2.05 (s, 3H), 1.44 (s, 6H).

[0399] 13CNMR (101MHz, CDCl3): δ201.82, 183.86, 175.12, 170.46, 159.99, 151.12, 148.64, 139.10, 132. 42, 132.26, 128.69, 128.10, 125.46, 123.85, 121.42, 120.97, 55.44, 47.99, 27.56, 20.79, 8.83.

[0400] HRMS (ESI) calculated value: C 22 H 18 O6Na(M+Na) + 401.099559, measured value: 401.09913.

[0401] Test results for IIA7-2:

[0402] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.74 (d, J=8.2Hz, 1H), 6.50 (dd, J=17.3, 1.1Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 6.17 (dd, J=17.3, 10.4Hz, 1H), 5.92 (dd, J=10.4, 1.1Hz, 1H), 5.23 (s, 2H), 2.37 (s, 3H), 1.52 (s, 6H).

[0403] 13 CNMR (101MHz, CDCl3): δ201.87, 183.84, 175.10, 165.62, 160.04, 151.11, 148.51, 139.14, 132.40, 1 32.30, 132.10, 128.68, 128.09, 127.62, 125.43, 123.89, 121.58, 120.96, 55.54, 47.99, 27.57, 8.89.

[0404] HRMS (ESI) calculated value: C 23 H 18 O6Na(M+Na) + 413.099559, measured value: 413.09907.

[0405] Test results for IIA7-3:

[0406] 1HNMR (400MHz, CDCl3): δ9.00 (d, J=10.5Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 6.44 (d, J=10 .5Hz, 1H), 5.15 (s, 2H), 2.36 (s, 3H), 1.71-1.65 (m, 1H), 1.53 (s, 6H), 1.14–1.03 (m, 2H), 1.00–0.86 (m, 2H).

[0407] 13 CNMR (101MHz, CDCl3): δ201.88, 183.93, 175.17, 174.51, 159.99, 151.07, 148.78, 139.15, 132 .41, 132.28, 128.70, 128.16, 125.46, 123.88, 121.35, 55.54, 47.99, 27.59, 12.74, 9.03, 8.88.

[0408] HRMS (ESI) calculated value: C 24 H 20 O6Na(M+Na) + 427.115209, measured value: 427.11387.

[0409] Test results for IIA7-4:

[0410] 1 HNMR (400MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.76 (d, J=13.1Hz, 1H), 7.73 (d, J=5.2Hz, 1H), 7.54 (d, J=1.8Hz , 1H), 7.53 (d, J=3.6Hz, 1H), 7.45–7.36 (m, 3H), 6.48 (d, J=16.0Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 5.27 (s, 2H), 2.39 (s, 3H), 1.52 (s, 6H).

[0411] 13CNMR (101MHz, CDCl3): δ201.87, 183.84, 175.10, 166.41, 160.02, 151.08, 148.75, 146.08, 139.15, 134.07, 132.39, 1 32.29, 130.69, 128.99, 128.66, 128.20, 128.11, 125.43, 123.91, 121.51, 121.00, 116.96, 55.53, 47.99, 27.57, 8.92.

[0412] HRMS (ESI) calculated value: C 29 H 22 O6Na(M+Na) + 489.130860, measured value: 489.13025.

[0413] Test results for IIA7-5:

[0414] 1 HNMR (400MHz, CDCl3): δ9.00 (d, J=10.5Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 6.44 (d, J=10.5Hz, 1H), 5.25 (s, 2H), 2.38 (s, 3H), 1.97 (s, 6H), 1.53 (s, 6H).

[0415] 13 CNMR (101MHz, CDCl3): δ201.87, 183.82, 175.13, 171.29, 160.13, 151.17, 147.94, 139.13, 132.45, 132.35, 128.73, 128.07, 125.47, 123.89, 121.87, 120.95, 57.04, 55.28, 48.00, 30.65, 27.58, 8.90.

[0416] HRMS (ESI) calculated value: C 24 H 21 BrO6Na(M+Na) + 507.041372, measured value: 507.04078.

[0417] Test results for IIA7-6:

[0418] 1HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 7.62 (s, 1H), 7.2 6 (d, J=3.5Hz, 1H), 6.55 (dd, J=3.5, 1.7Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 5.37 (s, 2H), 2.40 (s, 3H), 1.51 (s, 6H).

[0419] 13 CNMR (101MHz, CDCl3): δ201.85, 183.81, 175.09, 160.14, 158.10, 151.15, 148.23, 146.87, 143.88, 139.12, 132. 43, 132.30, 128.68, 128.06, 125.46, 123.95, 122.01, 120.98, 118.96, 112.10, 55.73, 53.48, 47.99, 27.56, 8.95.

[0420] HRMS (ESI) calculated value: C 25 H 18 O7Na(M+Na) + 453.094474, measured value: 453.09424.

[0421] Test results for IIA7-7:

[0422] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.92–7.81 (m, 2H), 7.73 (d, J=8.2Hz, 1H), 7.61 (d, J =4.8Hz, 1H), 7.12 (t, J=4.3Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 5.35 (s, 2H), 2.39 (s, 3H), 1.51 (s, 6H).

[0423] 13 CNMR (101MHz, CDCl3): δ201.85, 183.80, 175.08, 161.70, 160.06, 151.10, 148.45, 139.13, 134.16, 133.19, 1 32.74, 132.37, 132.31, 128.65, 128.09, 127.96, 125.43, 123.94, 121.77, 120.99, 56.02, 47.98, 27.56, 8.94.

[0424] HRMS (ESI) calculated value: C 25 H 18 O6SNa(M+Na) + 469.071630, measured value: 469.07098.

[0425] Test results for IIA7-8:

[0426] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 8.07 (d, J=7.4Hz, 2H), 7.85 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1 H), 7.59 (t, J=7.4Hz, 1H), 7.46 (t, J=7.7Hz, 2H), 6.41 (d, J=10.5Hz, 1H), 5.38 (s, 2H), 2.41 (s, 3H), 1.51 (s, 6H).

[0427] 13 CNMR (151MHz, CDCl3): δ201.84, 183.84, 175.11, 166.10, 160.04, 151.10, 148.71, 139.12, 133.44, 132.39, 1 32.28, 129.79, 129.44, 128.66, 128.51, 128.12, 125.45, 123.90, 121.60, 121.02, 55.98, 47.98, 27.55, 8.92.

[0428] HRMS (ESI) calculated value: C 27 H 20 O6Na(M+Na) + 463.115209, measured value: 463.11450.

[0429] Test results for IIA7-9:

[0430] 1 HNMR (400MHz, CDCl3): δ9.24 (s, 1H), 8.97 (d, J=10.5Hz, 1H), 8.79 (d, J=4.3Hz, 1H), 8.33 (d, J=7.9Hz, 1H), 7.85 (d, J=8.2H z, 1H), 7.73 (d, J=8.2Hz, 1H), 7.42 (dd, J=7.7, 5.0Hz, 1H), 6.40 (d, J=10.5Hz, 1H), 5.42 (s, 2H), 2.40 (s, 3H), 1.50 (s, 6H).

[0431] 13 CNMR (151MHz, CDCl3): δ201.77, 183.73, 175.06, 164.81, 160.17, 153.81, 151.22, 151.00, 148.13, 139.0 4, 132.43, 132.30, 128.70, 128.00, 125.48, 123.90, 123.43, 121.98, 120.96, 56.30, 47.99, 27.54, 8.95.

[0432] HRMS (ESI) calculated value: C 26 H 19 NO6Na(M+Na) + 464.110458, measured value: 464.10924.

[0433] Test results for IIA7-10:

[0434] 1 HNMR (400MHz, CDCl3): δ8.90 (d, J=10.5Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.66 (d, J=8.1Hz, 1H), 7.50 (dd , J=7.5, 2.2Hz, 2H), 6.99-6.91 (m, 1H), 6.34 (d, J=10.5Hz, 1H), 5.31 (s, 2H), 2.33 (s, 3H), 1.43 (s, 6H).

[0435] 13 CNMR (101MHz, CDCl3): δ201.77, 183.74, 175.08, 163.98, 161.49, 160.21, 151.26, 147.99, 139.04, 132.47, 132.31 , 128.73, 127.99, 125.50, 123.90, 122.10, 120.96, 113.02, 112.76, 108.90 (t, J=26Hz), 56.58, 48.00, 27.55, 8.94.

[0436] HRMS (ESI) calculated value: C 27 H 18 F2O6Na(M+Na) + 499.096366, measured value: 499.09602.

[0437] Test results for IIA7-11:

[0438] 1HNMR (600MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 7. 20 (d, J=2.3Hz, 2H), 6.66 (s, 1H), 6.43 (d, J=10.5Hz, 1H), 3.83 (s, 6H), 2.41 (s, 3H), 1.52 (s, 6H).

[0439] 13 CNMR (101MHz, CDCl3): δ201.86, 183.81, 175.10, 165.88, 160.71, 160.04, 151.11, 148.60, 139.13, 132.39, 132. 27, 131.24, 128.65, 128.10, 125.44, 123.89, 121.66, 121.00, 107.45, 105.91, 56.13, 55.62, 47.98, 27.55, 8.93.

[0440] HRMS (ESI) calculated value: C 29 H 24 O8Na(M+Na) + 523.136339, measured value: 523.13633.

[0441] Test results for IIA7-12:

[0442] 1 HNMR (600MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 8.13 (d, J=8.9Hz, 2H), 7.86 (d, J=8.2Hz, 1H), 7.74 (d , J=8.2Hz, 1H), 7.29 (d, J=8.1Hz, 2H), 6.43 (d, J=10.4Hz, 1H), 5.40 (s, 2H), 2.42 (s, 3H), 1.52 (s, 6H).

[0443] 13 CNMR (101MHz, CDCl3): δ201.79, 183.80, 175.11, 164.92, 160.12, 152.95, 151.20, 148.38, 139.07, 132.46, 132.2 8, 131.86, 128.72, 128.12, 128.05, 127.81, 125.48, 123.86, 121.83, 120.99, 120.35, 56.22, 47.99, 27.55, 8.93.

[0444] HRMS (ESI) calculated value: C 28 H 19 F3O7Na(M+Na) + 547.097509, measured value: 547.09702.

[0445] Preparation method 2 (reduction method: j-2):

[0446] Using the IIA6 obtained in Preparation Example 5 and the various amines listed in Table 5 as raw materials, di(p-nitrobenzene) carbonate as a condensing agent, 4-dimethylaminopyridine as a catalyst, triethylamine as a base, and dichloromethane as a solvent, the reaction was carried out in the presence of a catalyst (0.1N) and triethylamine (1.2N). Specifically, 1N of IIA6 reacted with 2N of the condensing agent for 10 minutes to 2 hours. After the reaction was complete, 2.5N of the various amines listed in Table 5 was added, and the reaction continued for another 10 minutes to 10 hours. After the reaction was completed, the product was washed with water, dried, and concentrated to obtain a crude product. The crude product was then purified by column chromatography to obtain the target tanshinone IIA derivative IIA7-(13-26), the corresponding structural formula of which is shown in [reference needed]. Figure 2 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA7 series products provided in Example 10 of this invention (the product names in the figures all omit "IIA").

[0447] Test results for IIA7-13:

[0448] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1 H), 6.41 (d, J=10.5Hz, 1H), 5.13 (s, 2H), 2.94 (d, J=9.5Hz, 6H), 2.35 (s, 3H), 1.51 (s, 6H).

[0449] 13 CNMR (101MHz, CDCl3): δ201.91, 183.99, 175.18, 159.83, 155.89, 150.94, 149.54, 139.20, 132.34, 132.27, 128.63, 128.26, 125.41, 123.86, 121.06, 120.99, 56.46, 47.97, 36.67, 36.03, 27.57, 8.86.

[0450] HRMS (ESI) calculated value: C 23 H 21 NO6Na(M+Na) +430.126108, measured value: 430.12493.

[0451] Table 5

[0452]

[0453] Test results for IIA7-14:

[0454] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 6.42 (d, J= 10.5Hz, 1H), 5.14 (s, 2H), 3.60-3.50 (m, 4H), 2.47–2.38 (m, 4H), 2.35 (s, 3H), 2.33 (s, 3H), 1.51 (s, 6H).

[0455] 13 CNMR (101MHz, CDCl3): δ201.89, 183.93, 175.16, 159.90, 154.60, 151.00, 149.23, 139.17, 132.28, 128 .66, 128.20, 125.41, 125.12, 123.87, 122.31, 121.18, 56.54, 54.51, 47.97, 46.03, 43.69, 27.57, 8.90.

[0456] HRMS (ESI) calculated value: C 26 H 26 N₂O₆Na(M+Na) + 485.168308, measured value: 485.16742.

[0457] Test results for IIA7-15:

[0458] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.74 (d, J=8.2Hz, 1H), 6.4 2 (d, J=10.5Hz, 1H), 5.16 (s, 2H), 3.67 (d, J=13.1Hz, 4H), 3.50 (s, 4H), 2.36 (s, 3H), 1.51 (s, 6H).

[0459] 13CNMR (101MHz, CDCl3): δ201.84, 183.90, 175.15, 159.93, 154.69, 151.04, 149.10, 139.13, 132.39, 132.28, 128.68, 128.16, 125.43, 123.84, 121.28, 121.02, 66.58, 56.59, 53.49, 47.97, 27.57, 8.90.

[0460] HRMS (ESI) calculated value: C 25 H 23 NO7Na(M+Na) + 472.136673, measured value: 472.13599.

[0461] Test results for IIA7-16:

[0462] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 6.41 (d, J= 10.5Hz, 1H), 5.14 (s, 2H), 3.85-3.75 (m, 2H), 3.55–3.39 (m, 2H), 3.00 (s, 3H), 2.34 (s, 3H), 1.51 (s, 6H).

[0463] 13 CNMR (101MHz, CDCl3): δ201.92, 183.86, 175.10, 159.91, 157.03, 151.01, 149.22, 139.17, 132.34, 128.63, 128.17, 125.37, 123.87, 121.16, 121.00, 61.18, 56.72, 52.00, 47.98, 35.41, 27.55, 8.85.

[0464] HRMS (ESI) calculated value: C 24 H 23 NO7Na(M+Na) + 460.136673, measured value: 460.13556.

[0465] Test results for IIA7-17:

[0466] 1HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 5.14 (s, 2H), 3. 80-3.74 (m, 2H), 3.48–3.38 (m, 1H), 3.36 (s, 3H), 3.30–3.18 (m, 2H), 2.35 (s, 3H), 1.87-1.83 (m, 2H), 1.57-1.50 (m, 2H), 1.51 (s, 6H).

[0467] 13 CNMR (101MHz, CDCl3): δ201.94, 183.95, 175.16, 159.87, 154.68, 150.96, 149.40, 139.21, 132.34, 132.30 , 128.63, 128.23, 125.39, 123.88, 121.04, 75.33, 56.49, 55.78, 47.97, 41.29, 30.65, 30.15, 27.57, 8.88.

[0468] HRMS (ESI) calculated value: C 27 H 27 NO7Na(M+Na) + 500.167973, measured value: 500.16716.

[0469] Test results for IIA7-18:

[0470] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.72 (d, J=8.1Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 5.12 (s, 2H), 4.20 (d, J=37.2Hz, 2H), 2.76 (s, 2H), 2.51-2.44 (m, 5H), 2.34 (s, 3H), 1.82 (s, 2H), 1.51 (s, 6H), 1.48-1.42 (m, 6H).

[0471] 13CNMR (101MHz, CDCl3): δ201.90, 183.96, 175.16, 159.85, 154.55, 150.94, 149.41, 139.18, 132.32, 132.29, 128.6 2, 128.22, 125.39, 125.07, 123.88, 121.02, 62.36, 56.45, 53.50, 50.10, 47.96, 43.81, 27.56, 26.14, 24.59, 8.88.

[0472] HRMS (ESI) calculated value: C 31 H 34 N2O6(M+H) + 531.248963, measured value: 531.24771.

[0473] Test results for IIA7-19:

[0474] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 6.42 (d, J=10.5Hz, 1H), 5. 14 (s, 2H), 4.37–4.16 (m, 1H), 3.74 (s, 2H), 3.45 (s, 2H), 2.35 (s, 3H), 2.08–2.02 (m, 2H), 1.87–1.83 (m, 2H), 1.51 (s, 6H).

[0475] 13 CNMR (101MHz, CDCl3): δ201.87, 183.90, 175.13, 159.90, 154.54, 151.01, 149.20, 139.15, 132.36, 132.30 , 128.65, 128.17, 125.40, 123.86, 121.18, 121.01, 56.59, 56.32, 47.97, 41.25, 34.72, 34.69, 27.57, 8.90.

[0476] HRMS (ESI) calculated value: C26H 24 ClNO6Na(M+Na) + 504.118436, measured value: 504.11813.

[0477] Test results for IIA7-20:

[0478] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.81 (d, J=8.2Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.42–7.19 (m, 5H ), 6.42 (d, J=10.5Hz, 1H), 5.22 (t, J=5.2Hz, 1H), 5.16 (s, 2H), 4.42 (d, J=5.9Hz, 2H), 2.35 (s, 3H), 1.52 (s, 6H).

[0479] 13 CNMR (101MHz, CDCl3): δ201.86, 183.85, 175.09, 159.88, 155.78, 151.04, 149.17, 139.11, 138.07, 132.37, 132. 24, 128.74, 128.65, 128.12, 127.68, 127.57, 125.40, 123.82, 121.17, 120.99, 56.07, 47.98, 45.28, 27.56, 8.83.

[0480] HRMS (ESI) calculated value: C 28 H 23 NO6Na(M+Na) + 492.141759, measured value: 492.14111.

[0481] Test results for IIA7-21:

[0482] 1 HNMR (400MHz, CDCl3): δ8.95 (d, J=10.5Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.71 (d, J=8.2Hz, 1H), 6.40 (d, J=10.5Hz, 1H) , 5.08 (s, 2H), 4.74 (d, J=7.0Hz, 1H), 3.84 (td, J=13.2, 6.4Hz, 1H), 2.32 (s, 3H), 1.50 (s, 6H), 1.18 (d, J=6.5Hz, 6H).

[0483] 13 CNMR (101MHz, CDCl3): δ201.84, 183.82, 175.03, 159.79, 154.86, 150.99, 149.39, 139.09, 132. 33, 132.25, 128.61, 128.13, 125.35, 123.78, 120.99, 55.63, 47.96, 43.38, 27.54, 22.95, 8.79.

[0484] HRMS (ESI) calculated value: C 24 H 23 NO6Na(M+Na) + 444.141759, measured value: 444.14041.

[0485] Test results for IIA7-22:

[0486] 1 HNMR (400MHz, CDCl3): δ8.94 (d, J=10.6Hz, 1H), 7.82 (d, J=8.4Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 6.38 (d, J=10.6Hz, 1H), 5.11 (s, 2H), 4.20 -4.14 (m, 2H), 3.52-3.46 (m, 2H), 2.83-2.76 (m, 2H), 2.31 (s, 3H), 1.96-1.90 (m, 2H), 1.69–1.62 (m, 1H), 1.48 (s, 6H), 1.24-1.17 (m, 2H).

[0487] HRMS (ESI) calculated value: C 27 H 27 NO7Na(M+Na) + 500.167973, measured value: 500.16749.

[0488] Test results for IIA7-23:

[0489] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 6.41 (d, J=10.5Hz, 1H ), 5.13 (s, 2H), 3.42 (t, J=6.5Hz, 2H), 3.36 (t, J=6.5Hz, 2H), 2.36 (d, J=6.8Hz, 3H), 1.91-1.83 (m, 4H), 1.51 (s, 6H).

[0490] 13CNMR (101MHz, CDCl3): δ201.86, 183.99, 175.17, 159.76, 154.28, 150.91, 149.73, 139.16, 132.31, 132.24 , 128.59, 128.28, 125.40, 123.84, 121.08, 120.89, 56.09, 47.95, 46.41, 45.91, 27.55, 25.74, 24.92, 8.83.

[0491] HRMS (ESI) calculated value: C 25 H 23 NO6Na(M+Na) + 456.141759, measured value: 456.14083.

[0492] Test results for IIA7-24:

[0493] 1 HNMR (400MHz, CDCl3): δ8.94 (d, J=10.4Hz, 1H), 7.79 (d, J=7.8Hz, 1H), 7.70 (d, J=8.0Hz, 1H ), 6.36 (d, J=10.5Hz, 1H), 5.09 (s, 2H), 3.94 (s, 2H), 2.28 (s, 3H), 2.25 (s, 1H), 1.46 (s, 6H).

[0494] 13 CNMR (151MHz, CDCl3): δ202.31, 183.75, 175.06, 160.02, 155.55, 151.02, 148.98, 139.39, 132.36, 132 .27, 128.48, 128.09, 125.31, 123.92, 121.26, 120.88, 79.37, 71.65, 56.19, 47.96, 30.68, 27.45, 8.69.

[0495] HRMS (ESI) calculated value: C 24 H 19 NO6Na(M+Na) + 440.110458, measured value: 440.11007.

[0496] Test results for IIA7-25:

[0497] 1HNMR (400MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.73 (d, J=8 .2Hz, 1H), 7.30 (dd, J=12.8, 5.3Hz, 2H), 7.21 (dd, J=12.9, 7.2Hz, 3H), 6.42 (d, J=1 0.5Hz, 1H), 5.18 (d, J=3.7Hz, 2H), 4.32 (d, J=33.0Hz, 2H), 2.92 (d, J=10.4Hz, 2H), 2.74–2.61 (m, 1H), 2.37 (s, 3H), 1.92–1.85 (m, 2H), 1.71–1.65 (m, 2H), 1.52 (s, 6H).

[0498] 13 CNMR (151MHz, CDCl3): δ201.96, 183.93, 175.17, 159.90, 154.76, 150.99, 149.47, 145.29, 139.23, 132.36, 132.30, 128.63, 128 .59, 128.25, 126.71, 126.53, 126.16, 125.41, 123.88, 121.06, 115.71, 56.55, 47.99, 44.77, 42.45, 33.19, 32.87, 27.57, 8.88.

[0499] HRMS (ESI) calculated value: C 32 H 29 NO6Na(M+Na) + 546.188709, measured value: 546.18808.

[0500] Test results for IIA7-26:

[0501] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.73 (d, J=8.2Hz, 1H), 6.41 (d, J=10.5Hz, 1H), 5.19 (d, J=41.0Hz, 2H), 3.80–3.59 (m, 4H), 2.65–2.56 (m, 4H), 2.53-2.48 (m, 4H), 2.34 (s, 3H), 1.50 (s, 6H).

[0502] 13CNMR (151MHz, CDCl3): δ201.84, 183.91, 175.15, 159.88, 154.58, 151.02, 149.23, 139.13, 132.26, 128 .65, 128.19, 125.43, 125.10, 123.84, 122.28, 121.18, 59.40, 57.75, 56.56, 52.53, 47.97, 27.55, 8.86.

[0503] HRMS (ESI) calculated value: C 27 H 28 N₂O₇(M+H) + 493.196928, measured value: 493.19629.

[0504] Preparation Example 11: Synthesis of Tanshinone IIA Derivative IIA9

[0505] Reaction formula:

[0506] .

[0507] Preparation method:

[0508] IIA8 obtained from Preparation Example 8 was dissolved in a mixed solvent of dichloromethane and methanol (volume ratio 1:1), and 2N sodium methoxide was added. The mixture was reacted at 10°C for 1 hour, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain the target tanshinone IIA derivative IIA9.

[0509] Test results:

[0510] 1 HNMR (400MHz, CDCl3): δ8.99 (d, J=10.0Hz, 1H), 7.84 (d, J=7.0Hz, 1H), 7.72 (d, J=7.0 Hz, 1H), 6.42 (d, J=10.0Hz, 1H), 4.47 (s, 2H), 3.44 (s, 3H), 2.33 (s, 3H), 1.52 (s, 6H).

[0511] 13 CNMR (101MHz, CDCl3): δ201.94, 184.03, 175.25, 159.82, 150.90, 150.61, 139.21, 132.34, 1 32.25, 128.61, 128.25, 125.37, 123.85, 120.93, 120.23, 63.69, 58.21, 47.97, 27.58, 8.89.

[0512] HRMS (ESI) calculated value: C 21H 18 O5 (M+H) + 351.12325, measured value: 351.1255.

[0513] Preparation Example 12: Synthesis of Tanshinone IIA Derivatives IIA12-(1-13)

[0514] Reaction formula:

[0515] .

[0516] Using the IIA11 obtained in Example 7 (1N) and various amines listed in Table 6 (1.2N) as raw materials, triethylamine (1.2N) as the base, dichloromethane as the solvent, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (1.5N) as the condensing agent, the reaction was carried out at 20°C for 0.5 to 2 hours. After the reaction was completed, the product was washed with water, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target tanshinone IIA derivatives IIA12 (1-13) as a reddish-brown powder. The corresponding structural formulas are shown in [reference needed]. Figure 3 The corresponding products shown in the structural formula atlas of the tanshinone IIA derivative IIA12 series products provided in Example 12 of this invention (the product names in the figures all omit "IIA").

[0517] Table 6

[0518]

[0519] Test results for IIA12-1:

[0520] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.81 (d, J=8.2Hz, 1H), 7.76 (d, J=8 .2Hz, 1H), 6.44 (d, J=10.5Hz, 1H), 3.78 (d, J=9.7Hz, 8H), 2.48 (s, 3H), 1.52 (s, 6H).

[0521] 13 CNMR (101MHz, CDCl3): δ201.58, 183.29, 174.91, 159.36, 159.07, 151.82, 144.71, 138.81, 132.70, 132 .44, 128.92, 127.50, 126.22, 125.71, 123.80, 120.91, 66.91, 65.99, 48.86, 48.07, 40.46, 27.52, 9.96.

[0522] HRMS (ESI) calculated value: C24 H 21 NO6Na(M+Na) + 442.126108, measured value: 442.12443.

[0523] Test results for IIA12-2:

[0524] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.6Hz, 1H), 7.82 (d, J=7.8Hz, 1H), 7.77 (d, J=8.1Hz, 1H), 6 .43 (d, J=10.6Hz, 1H), 3.76 (s, 4H), 2.65–2.50 (m, 4H), 2.46 (s, 3H), 2.38 (s, 3H), 1.52 (s, 6H).

[0525] 13 CNMR (101MHz, CDCl3): δ201.62, 183.34, 174.94, 159.32, 158.98, 151.71, 145.00, 138.86, 132.64, 132.42, 128.87, 127.58, 125.68, 125.65, 123.84, 120.88, 54.94, 54.85, 48.06, 45.89, 27.53, 9.92.

[0526] HRMS (ESI) calculated value: C 25 H 24 N2O5(M+H) + 433.175798, measured value: 433.17585.

[0527] Test results for IIA12-3:

[0528] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.98 (d, J=8.2Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.52 (t, J=5.9H z, 1H), 6.43 (d, J=10.5Hz, 1H), 3.81 (t, J=5.2Hz, 2H), 3.59 (td, J=6.0, 3.0Hz, 2H), 2.61 (s, 3H), 1.53 (s, 7H).

[0529] 13CNMR (101MHz, CDCl3): δ202.11, 183.02, 174.87, 159.20, 159.12, 151.88, 144.04, 139.10, 1 32.50, 128.68, 127.68, 127.32, 125.67, 124.27, 121.45, 61.01, 48.07, 41.50, 27.39, 9.72.

[0530] HRMS (ESI) calculated value: C 22 H 19 NO6 (M+H) + 394.128514, measured value: 394.12897.

[0531] Test results for IIA12-4:

[0532] 1 HNMR (400MHz, CDCl3): δ8.96 (d, J=10.5Hz, 1H), 7.83 (d, J=8.2Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.47–7.30 (m, 5H), 6.71 (t, J=5.9Hz, 1H), 6.43 (d, J=10.5Hz, 1H), 4.67 (d, J=5.9Hz, 2H), 2.69 (s, 3H), 1.50 (s, 6H).

[0533] 13 CNMR (101MHz, CDCl3): δ201.55, 183.21, 175.03, 158.92, 158.28, 151.98, 144.08, 138.81, 137.71, 132.78, 1 32.23, 128.96, 128.93, 128.19, 128.03, 127.91, 127.30, 125.91, 123.91, 121.76, 48.07, 43.20, 27.52, 9.98.

[0534] HRMS (ESI) calculated value: C 27 H 21 NO5 (M+H) + 440.149249, measured value: 440.14904.

[0535] Test results for IIA12-5:

[0536] 1HNMR (400MHz, CDCl3): δ8.98 (d, J=10.7Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.77 (d, J=8.2Hz, 1H), 6.44 (d, J=10.5Hz, 1H), 3.84 (t, J=5.9Hz, 4H), 2.49 (s, 3H), 2.13 (tt, J=13.1, 6.0Hz, 4H), 1.52 (s, 6H).

[0537] 13 CNMR (101MHz, CDCl3): δ201.54, 183.23, 174.89, 159.34, 159.13, 151.95, 144.55, 138.7 7, 132.80, 132.44, 129.01, 127.43, 126.86, 125.78, 123.70, 120.98, 48.09, 27.54, 9.98.

[0538] HRMS (ESI) calculated value: C 25 H 21 F2NO5(M+H) + 454.146056, measured value: 454.14579.

[0539] Test results for IIA12-6:

[0540] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.76 (d, J=8.1Hz, 1H), 6.44 (d, J=10.6 Hz, 1H), 6.14 (d, J=8.0Hz, 1H), 4.31 (dh, J=13.2, 6.7Hz, 1H), 2.66 (s, 3H), 1.52 (s, 6H), 1.32 (d, J=6.6Hz, 6H).

[0541] 13 CNMR (101MHz, CDCl3): δ201.55, 183.31, 175.09, 158.69, 157.64, 151.89, 144.36, 138.84, 132. 78, 132.20, 128.96, 127.58, 127.40, 125.92, 123.86, 121.79, 48.07, 41.46, 27.55, 22.88, 9.92.

[0542] HRMS (ESI) calculated value: C 23 H 21NO5 (M+H) + 392.149249, measured value: 392.14886.

[0543] Test results for IIA12-7:

[0544] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 6.44 (d, J=10.5 Hz, 1H), 4.23–3.88 (m, 3H), 3.47 (d, J=13.2Hz, 2H), 2.45 (s, 3H), 2.02 (s, 2H), 1.75-1.64 (m, 2H), 1.52 (s, 6H).

[0545] 13 CNMR (101MHz, CDCl3): δ201.68, 183.44, 175.00, 159.31, 159.07, 151.69, 145.28, 138.91, 1 32.66, 132.41, 128.89, 127.66, 125.70, 125.23, 123.81, 120.91, 66.74, 48.07, 27.55, 9.87.

[0546] HRMS (ESI) calculated value: C 25 H 23 NO6 (M+H) + 434.159814, measured value: 434.15988.

[0547] Test results for IIA12-8:

[0548] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.75 (d, J=8.3Hz, 1H) , 6.44 (d, J=10.5Hz, 1H), 6.42–6.29 (m, 1H), 3.05 (d, J=4.9Hz, 3H), 2.67 (s, 3H), 1.52 (s, 6H).

[0549] 13 CNMR (101MHz, CDCl3): δ201.56, 159.03, 151.94, 138.82, 132.82, 132.23, 128.98, 123.71, 48.09, 27.54, 25.94, 9.88.

[0550] HRMS (ESI) calculated value: C 21 H 17 NO5 (M+H) + 364.117949, measured value: 364.11766.

[0551] Test results for IIA12-9:

[0552] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.39 (t, J=6.0Hz, 1H) , 6.44 (d, J=10.6Hz, 1H), 4.05 (q, J=5.9Hz, 2H), 3.38 (dd, J=6.9, 4.3Hz, 2H), 3.05 (s, 3H), 2.66 (s, 3H), 1.52 (s, 6H).

[0553] 13 CNMR (101MHz, CDCl3): δ158.44, 152.14, 138.79, 132.52, 128.99, 128.52, 124.12, 53.82, 48.12, 41.69, 32.53, 27.54, 9.88.

[0554] HRMS (ESI) calculated value: C 23 H 21 NO7S (M+H) + 456.111149, measured value: 456.11075.

[0555] Test results for IIA12-10:

[0556] 1 HNMR (400MHz, CDCl3): δ8.98 (d, J=10.5Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 6.43 (d, J=10.5Hz, 1H), 4.66 (s, 1H ), 4.08 (s, 1H), 3.59 (d, J=5.7Hz, 2H), 3.17 (s, 1H), 2.90 (s, 1H), 2.44 (s, 3H), 1.97–1.85 (m, 3H), 1.52 (s, 6H), 1.41–1.32 (m, 2H).

[0557] 13CNMR (101MHz, CDCl3): δ201.69, 183.49, 175.04, 159.30, 159.06, 151.63, 145.46, 138.93, 132. 64, 132.41, 128.87, 127.71, 125.69, 124.96, 123.82, 120.90, 67.15, 48.06, 38.84, 27.55, 9.86.

[0558] HRMS (ESI) calculated value: C 26 H 25 NO6Na(M+Na) + 470.157409, measured value: 470.15602.

[0559] Test results for IIA12-11:

[0560] 1 HNMR (400MHz, CDCl3): δ8.99 (d, J=10.5Hz, 1H), 8.09 (d, J=8.1Hz, 1H), 7.82 (d, J=8.2Hz, 1H ), 7.02 (s, 2H), 6.42 (d, J=10.5Hz, 1H), 3.89 (s, 6H), 3.83 (s, 3H), 2.68 (s, 3H), 1.54 (s, 6H).

[0561] 13 CNMR (101MHz, CDCl3): δ202.08, 182.96, 174.89, 159.26, 156.50, 153.18, 151.94, 143.87, 139.10, 134.95, 133. 20, 132.54, 132.41, 128.74, 128.65, 127.27, 125.76, 124.38, 121.62, 98.23, 60.89, 56.05, 48.06, 27.37, 9.90.

[0562] HRMS (ESI) calculated value: C 29 H 25 NO8Na(M+Na) + 538.147238, measured value: 538.14540.

[0563] Test results for IIA12-12:

[0564] 1HNMR (400MHz, CDCl3): δ8.97 (d, J=10.6Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.78 (d, J=8.2Hz, 1H), 7.15 (t, J= 6.2Hz, 1H), 6.43 (d, J=10.5Hz, 1H), 3.:80-3.67 (m, 5H), 2.70 (t, J=5.8Hz, 2H), 2.65 (s, 3H), 1.53 (s, 6H).

[0565] 13 CNMR (101MHz, CDCl3): δ201.55, 183.17, 175.01, 173.33, 158.89, 158.27, 151.93, 144.07, 138.78, 132. 69, 132.35, 128.89, 127.77, 127.32, 125.84, 123.97, 121.63, 51.96, 48.05, 34.41, 33.58, 27.48, 9.83.

[0566] HRMS (ESI) calculated value: C 24 H 21 NO7Na(M+Na) + 458.121023, measured value: 458.11932.

[0567] Test results for IIA12-13:

[0568] 1 HNMR (400MHz, CDCl3): δ8.97 (d, J=10.5Hz, 1H), 7.91 (d, J=8.2Hz, 1H), 7.78 (d, J=8.3Hz, 1H), 6.7 1 (t, J=6.5Hz, 1H), 6.45 (d, J=10.5Hz, 1H), 4.22-4.07 (m, 2H), 2.68 (s, 3H), 1.52 (d, J=3.8Hz, 6H).

[0569] 13 CNMR (101MHz, CDCl3): δ201.46, 182.98, 174.91, 159.31, 158.17, 152.31, 143.15, 138.68, 132.91 , 132.33, 129.66, 129.07, 127.06, 126.00, 123.98, 121.71, 48.13, 40.34 (d, J=34.0), 27.52, 9.98.

[0570] HRMS (ESI) calculated value: C 22H 16 F3NO5Na(M+Na) + 454.087278, measured value: 454.08687.

[0571] Preparation Example 13: Synthesis of Tanshinone IIA Derivative IIA13

[0572] Reaction formula:

[0573] .

[0574] Specific operations:

[0575] The IIA11 obtained from Preparation Example 7 (1N) was dissolved in anhydrous dichloromethane, and 5N of oxaloyl chloride was added. The mixture was catalyzed with N,N-dimethylformamide (IIADMF) and reacted at 20°C for 3 hours. After evaporation under reduced pressure, the product was dissolved in dichloromethane to obtain a dichloromethane solution of acyl chloride. Separately, a dichloromethane solution of 2N methanol and 2N triethylamine was prepared. The dichloromethane solution of acyl chloride was added dropwise under an ice-salt bath, and the mixture was stirred and heated naturally for 2 hours. After the reaction was completed, the product was washed with water, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target tanshinone IIA derivative IIA13.

[0576] Test results for IIA13:

[0577] 1 HNMR (400MHz, CDCl3): δ8.66 (d, J=10.2Hz, 1H), 7.86 (d, J=8.0Hz, 1H), 7.82 (d , J=8.2Hz, 1H), 6.37 (d, J=10.4Hz, 1H), 3.87 (s, 3H), 2.48 (s, 3H), 1.43 (s, 6H).

[0578] 13 CNMR (101MHz, CDCl3): δ202.12, 182.84, 175.46, 150.55, 140.18, 132.78, 13 1.25, 127.84, 127.82, 127.37, 124.14, 121.63, 52.51, 48.03, 27.51, 10.58.

[0579] MS (ESI) calculated value: C 21 H 16 O6 364.09, measured value: 387.2 (M+Na) + .

[0580] It should be noted that:

[0581] Although the above preparation examples are mainly prepared using the optimized technical solutions provided in this embodiment, it is fully understood by those skilled in the art that all technical solutions provided in this embodiment, including all material ratio ranges and all operating parameter ranges, can yield the corresponding target product. However, the product yield may fluctuate within a reasonable range due to different ratios and different operating control parameters. Therefore, this specification only provides a more detailed description of the preparation using the optimized method, and will not describe other possible preparation schemes in detail.

[0582] To further help understand the technical effects that the technical solution provided in this embodiment can achieve, the following will use specific effect examples to conduct corresponding effect tests and comparisons on the tanshinone IIA derivative prepared in this embodiment, thereby further explaining the technical effects that this embodiment can achieve.

[0583] Example 1

[0584] This example demonstrates the in vitro anti-colon cancer activity of the tanshinone IIA derivative prepared in the above embodiments through its cytotoxicity against colon cancer cells.

[0585] 1.1) Evaluation of cells

[0586] All colon cancer cells used in this example, including HT29, SW620, HCT15, HCT116, CACO2, DLD1, and RKO cells, were purchased from Procell. All cells were cultured in Dulbecco modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) and 100 units / mL penicillin-streptomycin, in 5A or RPMI 1640, and maintained at 37°C in a humidified atmosphere with 5% CO2.

[0587] 1.2) Evaluation Methods

[0588] Evaluation was performed using the CCK8 assay, in which HT29, SW620, HCT15, HCT116, CACO2, DLD1, and RKO cells were seeded into 96-well plates (1 × 10⁶ cells per well). 4 Each well is then incubated with the test compound alone or co-incubated with the test compound for 48 hours. Then, 100 μL of CCK8 solution is added to each well, and the incubation continues for 4 hours. The absorbance is then measured using a microplate reader.

[0589] 1.3) Preparation of experimental mice

[0590] This study used specific pathogen-free female BALB / c nude mice that were 6 weeks old at birth. The mice were purchased from Chongqing Tengxin Biotechnology Co., Ltd.

[0591] HT29, SW620, HCT15, HCT116, CACO2, DLD1, and RKO cells (8 × 10⁶ cells) were resuspended in PBS and subcutaneously injected into the right flank region of nude mice. When the average tumor xenograft volume increased to 60 mm², the xenografts were successfully treated. 3 Nude mice were randomly divided into four groups (n=6 per group). Starting from the second week, they were given tanshinone IIA derivative (10 or 20 mg / kg), 5-fluorouracil (abbreviated as 5-FU) (20 mg / kg) or saline via intraperitoneal injection every two days. Their body weight was monitored every two days, and the tumor size was measured every two days using calipers.

[0592] Tumor volume is calculated using the following formula: Volume (mm) 3 = Length (mm) × Width (mm) 2 × 0.5.

[0593] Tanshinone IIA derivative and 5-FU were dissolved in a mixture consisting of 5% dimethyl sulfoxide (DMSO), 5% polyethylene glycol 4000 (PEG400), 5% vegetable oil, and 85% physiological saline containing 20% ​​2-hydroxypropyl-β-cyclodextrin.

[0594] All mice were sacrificed after 14 days, the tumors were isolated and weighed, and then stored at -80°C for later use.

[0595] The tumor inhibition rate (TI, %) was calculated using the following formula: TI (%) = (1 - WT / WV) × 100%, where WT and WV are the mean tumor weights of the treatment group and the solvent control group, respectively.

[0596] 1.4) Experimental Results

[0597] The data listed in Table 7 are the cytotoxicity test results of the tanshinone IIA derivative IIA5 series products and tanshinone IIA respectively against six types of colorectal cancer cells obtained using the preparation example 9 above.

[0598] The data listed in Table 7 are the cytotoxicity test results of the tanshinone IIA derivative IIA7 series products and tanshinone IIA respectively against three types of colorectal cancer cells, prepared using the above preparation example 10.

[0599] Table 7

[0600]

[0601] As can be seen from the experimental results listed in Table 7, the tanshinone IIA derivative IIA5 series products prepared in Example 9 showed significantly better activity against six types of colorectal cancer cells than tanshinone IIA.

[0602] Table 8

[0603]

[0604] As can be seen from the experimental results listed in Table 8, the tanshinone IIA derivative IIA7 series products prepared in Preparation Example 10 showed significantly better activity against the three types of colorectal cancer cells than tanshinone IIA.

[0605] It should be noted that:

[0606] Although the above-mentioned effects are mainly based on the test results of the tanshinone IIA derivatives IIA5 series and IIA7 series products obtained in Preparation Examples 9 and 10 against different colorectal cancer cells, experiments have shown that other tanshinone IIA derivatives provided by this invention can obtain the same or similar in vitro anti-colon cancer cell activity as the IIA5 series and IIA7 series products. For the sake of brevity, this specification will not elaborate on or pile up relevant experimental data.

[0607] Example 2

[0608] Given that tanshinone IIA derivative IIA5-23 has shown significant anti-colorectal cancer (CRC) activity in vitro, this study evaluated its in vivo efficacy using the SW620 xenograft mouse model.

[0609] 2.1) Experimental Methods:

[0610] In the SW620 xenograft mouse model, the average volume of tumor xenograft increased to 60 mm. 3 Nude mice were randomly divided into four groups (n=6 per group). Starting from the second week, they were injected intraperitoneally every two days with the IIA5-23 (10 or 20 mg / kg), 5-fluorouracil (abbreviated as 5-FU) (20 mg / kg), and saline prepared according to method 1 in Example 9. Their weight was monitored every two days, and the tumor size was measured every two days using calipers.

[0611] Tumor volume is calculated using the following formula: Volume (mm) 3 = Length (mm) × Width (mm) 2 × 0.5.

[0612] Specifically, IIA5-23 and 5-FU were dissolved in a mixture consisting of 5% dimethyl sulfoxide (DMSO), 5% polyethylene glycol 4000 (PEG400), 5% vegetable oil, and 85% physiological saline containing 20% ​​2-hydroxypropyl-β-cyclodextrin.

[0613] 2.1) Experimental Results

[0614] All mice were sacrificed after 14 days, tumors were isolated and photographed, and the following results were obtained: Figure 4 The image shown is a set of tumor tissue growth images in SW620 colorectal tumor xenograft mice after different drug interventions, provided in Example 2 of the present invention, where n=6;

[0615] After tumor separation, measurements can yield results such as... Figure 5 The figure shown is a curve of tumor tissue volume in SW620 colorectal tumor xenograft mice after different drug interventions, provided in Example 2 of the present invention.

[0616] After tumor separation and weighing, the following results can be obtained: Figure 6 The image shown is a bar chart of tumor tissue weight in SW620 colorectal tumor xenograft mice after different drug interventions, provided in Example 2 of the present invention.

[0617] After the mice are sacrificed and weighed, the following can be obtained: Figure 7 The figure shown is a curve of body weight in SW620 colorectal tumor xenograft mice after different drug interventions, provided in Example 2 of the present invention.

[0618] Western blotting can yield results such as Figure 8 The images shown are image sets of protein expression levels related to LDHA, PDK1, and HK2 in tumor tissues of SW620 colorectal tumor xenograft mice after different drug interventions provided in Example 2 of the present invention;

[0619] Calculations can be performed on the Western blot detection data to obtain, as follows: Figure 9 The bar chart shown is a quantitative result of the expression levels of proteins related to LDHA, PDK1, and HK2 in tumor tissues of SW620 colorectal tumor xenograft mice after different drug interventions provided in Example 2 of the present invention.

[0620] Immunohistochemical staining of tumors can yield results such as Figure 10 The image shown is a set of HE staining images of the main organs of SW620 colorectal tumor xenograft mice after different drug interventions provided in Example 2 of the present invention.

[0621] from Figure 4 , Figure 6 and Figure 7 The results show that tanshinone IIA derivative IIA5-23 significantly inhibited tumor growth and reduced tumor weight. Notably, even at a low dose (10 mg / kg), IIA5-23 showed better therapeutic effects than the 5-FU positive control group.

[0622] from Figure 5 and Figure 8 , Figure 9 The results show that the body weight of mice treated with IIA5-23 was not significantly different from that of the solvent control group, indicating good safety at the tested dose. Furthermore, Western blot analysis of tumor tissues showed that IIA5-23 reduced the expression of glycolysis-related proteins, including HK2, PDK1, and LDHA. Immunohistochemical staining of tumors showed that high-dose administration of IIA5-23 (20 mg / kg) significantly downregulated the expression of PKM2 and STAT3.

[0623] from Figure 10 It can be seen that neither low-dose (10 mg / kg) nor high-dose (20 mg / kg) administration of IIA5-23 caused significant weight loss or obvious toxicity in mice.

[0624] It should be noted that:

[0625] Although the above-mentioned effects are mainly based on the test results of the tanshinone IIA derivative IIA5-23 prepared in Example 9 against colorectal cancer cells, experiments have shown that other tanshinone IIA derivatives provided by this invention can achieve the same or similar in vivo efficacy against colorectal cancer cells as IIA5-23. For the sake of brevity, this specification will not elaborate on or pile up the relevant experimental data and figures.

[0626] Example 2

[0627] This embodiment provides a tanshinone IIA derivative or its pharmaceutical salt.

[0628] The tanshinone IIA derivative provided in this embodiment was prepared by the preparation method provided in Example 1 above.

[0629] The pharmaceutical salt of tanshinone IIA derivative provided in this embodiment is an addition salt formed by reacting a basic tanshinone IIA derivative with a basic nitrogen atom in its structure, prepared by the preparation method provided in Example 1 above, with a pharmaceutically acceptable inorganic or organic acid.

[0630] The inorganic acid is hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid and / or nitric acid;

[0631] The organic acids are formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethanesulfonic acid, and itaconic acid. Aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid and / or thiocyanate.

[0632] Example 3

[0633] This embodiment provides the use of a tanshinone IIA derivative or its pharmaceutical salt in the preparation of drugs for the prevention, relief and / or treatment of colorectal cancer.

[0634] This embodiment provides the use of a tanshinone IIA derivative or its pharmaceutical salt in the preparation of drugs for the prevention, relief and / or treatment of colorectal cancer, wherein the tanshinone IIA derivative or its pharmaceutical salt is prepared from the above-described Example 2.

[0635] Furthermore, the uses provided in this embodiment also include the ability to combine the tanshinone IIA derivative or its pharmaceutical salt obtained in Example 2 with other edible or pharmaceutically acceptable materials; and

[0636] The composition can be formulated into oral tablets, capsules, granules, syrups, or injectable powders or solutions, or used as a functional additive in food, skin care products, cosmetics, and / or health products.

[0637] In conclusion, it can be seen that:

[0638] This invention addresses the core application bottlenecks of tanshinone IIA, which has broad pharmacological activity but poor water solubility, low bioavailability, and insufficient antitumor activity. It provides an innovative systemic solution, which involves systematically modifying the structure of the tanshinone IIA core through an original, efficient, and scalable chemical synthesis route, thereby constructing a novel derivative library with diverse structures and rich substitution modes, laying the material foundation for achieving breakthroughs in activity and properties.

[0639] Compared with existing technologies, the progress and effects of this invention are reflected in several aspects: First, this invention successfully focuses the application of derivatives on the prevention, relief, and treatment of colorectal cancer, and confirms through in vitro and in vivo experiments that they have significant inhibitory effects and low toxicity, achieving a breakthrough in targeted activity in the treatment of specific major diseases; Second, through precise chemical modification, this invention significantly enhances antitumor activity while simultaneously optimizing key drug properties such as water solubility and stability of the derivatives, providing a new chemical entity for fundamentally improving bioavailability and overcoming the limitations of traditional technologies; More importantly, this invention provides not only a series of new compounds, but also a systematic derivatization strategy that can balance activity enhancement and drug-likeness optimization, pointing out a clear and valuable technical path for developing highly efficient anti-colorectal cancer drug candidates with excellent pharmacokinetic characteristics.

[0640] In summary, this invention, through original chemical synthesis and structural modification strategies, has successfully obtained a series of novel tanshinone IIA derivatives with significant anti-colorectal cancer activity. While overcoming the original defects, it has opened up new application directions for this active ingredient in the treatment of major diseases, possessing significant scientific value and application prospects. It demonstrates outstanding beneficial effects and significant progress, and therefore has great value for promotion and application.

[0641] In the description process of the above instruction manual:

[0642] The terms “this embodiment,” “this embodiment of the invention,” “this case,” “this comparative example,” “as shown,” “further,” etc., are used to indicate that the specific features, structures, materials, or characteristics described in the embodiment or case or comparative example are included in at least one embodiment or case or comparative example of the present invention.

[0643] In this specification, the illustrative expressions of the above terms are not necessarily directed at the same embodiments, cases, or comparative examples. Moreover, the specific features, structures, materials, or characteristics described may be combined or combined in any suitable manner in one or more embodiments, cases, or comparative examples. Furthermore, without causing contradiction, those skilled in the art may combine or combine the different embodiments, cases, or comparative examples described in this specification, as well as the features in the different embodiments, cases, or comparative examples.

[0644] Finally, it should be noted that:

[0645] The above embodiments and comparative examples are only used to illustrate the technical solutions and technical effects of the present invention, and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, examples, and comparative examples, those skilled in the art should understand that modifications or supplements can still be made to the technical solutions or technical effects described in the foregoing embodiments, examples, and comparative examples, or equivalent substitutions can be made to some or all of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions described in the embodiments of the present invention. Non-essential improvements, adjustments, or substitutions made by those skilled in the art based on the content of this specification are all within the scope of protection claimed by the present invention.

Claims

1. A method for preparing a tanshinone IIA derivative, characterized in that, The following synthetic routes are included: ； Right now: a) Tanshinone IIA, acetic acid, 2,2,6,6-tetramethylpiperidine oxide and chlorobenzene were mixed and reacted under heating conditions. After the reaction was completed, compound 1 was obtained by post-treatment. b) Compound 1 was reacted with pyridine p-toluenesulfonate in toluene, and after the reaction was completed, compound 2 was obtained by post-treatment; c) Compound 2 was reacted with selenium dioxide in 1,4-dioxane, and after the reaction was completed, compound 3 was obtained by post-treatment. d) Compound 3 was reacted with N-bromosuccinimide in dichloromethane, and after the reaction was completed, post-treatment was performed to obtain tanshinone IIA derivative 4; e) Compound 3 and paraformaldehyde were reacted in acetic acid under closed conditions, and the reaction was followed by alkali treatment to obtain tanshinone IIA derivative 6. f) Tanshinone IIA derivative 6 was reacted with Des Martin periodate in dichloromethane to obtain tanshinone IIA derivative 10; g) Tanshinone IIA derivative 10, hydrogen peroxide, disodium hydrogen phosphate buffer, and sodium chlorite were reacted in acetonitrile to obtain tanshinone IIA derivative 11. h) Tanshinone IIA derivative 6 was reacted with thionyl chloride in dichloromethane to obtain tanshinone IIA derivative 8; i-1) The compound 3, the amine compound or its hydrochloride salt, and paraformaldehyde were reacted in acetic acid to prepare tanshinone IIA derivatives 5-(1-2), 5-(5-9), 5-(11-17) and 5-(20-32); i-2) Tanshinone IIA derivative 10, amine compounds or their hydrochlorides are subjected to a reducing amination reaction with sodium triacetoxyborohydride in 1,2-dichloroethane to obtain tanshinone IIA derivatives 5-(3-4), 5-10 and 5-(18-19). i-3) Tanshinone IIA derivative 8, amine compounds or their hydrochloride salts are reacted with triethylamine in dichloromethane to prepare tanshinone IIA derivative 5-(33-39). j-1) Tanshinone IIA derivative 6, organic acid acyl chloride and triethylamine were reacted in dichloromethane to prepare tanshinone IIA derivative 7-(1-12). j-2) Tanshinone IIA derivative 6 and di(p-nitrobenzene) carbonate were reacted in dichloromethane in the presence of 4-dimethylaminopyridine and triethylamine, and then amine compounds were added to react to obtain tanshinone IIA derivative 7-(13-26). k) Tanshinone IIA derivative 8 was reacted with sodium methoxide in a mixed solvent of dichloromethane and methanol to obtain tanshinone IIA derivative 9. l) Tanshinone IIA derivative 11, amine compounds, triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate were reacted in dichloromethane to prepare tanshinone IIA derivative 12 series compounds 12-(1~13). m) Tanshinone IIA derivative 11 was reacted with oxalyl chloride in dichloromethane under N,N-dimethylformamide catalysis to form acyl chloride, which was then reacted with methanol and triethylamine in dichloromethane to prepare tanshinone IIA derivative 13; in: R1 and R2 are each independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of cycloalkyl, 3-6 membered heterocyclic, benzene ring, or substituted benzene ring, wherein the substituent on the benzene ring is any one of F, Cl, Br, trifluoromethyl, amino, cyano, ester, nitro, methoxy, or hydroxyl, and the number of substituents is 1 to 3; or R1 and R2 also form 3- to 6-membered rings with C, N, and O, in which the N atom on the ring interacts with the C atom. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocycles are linked, and the H atoms attached to the C atoms on the rings are C... 1-6 Alkyl, F, Cl, Br, benzene ring, 3-6 membered heterocyclic group, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl substitution; R3 is H or is determined by at least one R a Group substitution, the R a The group is C 1-8 Alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, -C 1-8 Alkyl OC 1-8 Alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, N(C) 1-8 2. Alkyl group, amino group, cyano group, aldehyde group, carboxyl group, NHC 1-8 Alkyl, nitro, C 1-8 Alkyl, hydroxyl or -COC 1-8 Any one of the alkyl groups; R4 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups; R5 and R6 are each independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups and N(C) 1-8 Any one of alkyl groups 2, wherein the carbon chain of the alkyl group is further linked by N and O, and the hydrogen of the alkyl group is C 1-6 Cycloalkyl, benzene ring, or aromatic heterocyclic substitution; or R1 and R2 may form 3- to 6-membered rings with C, N, and O, and the N atom on the ring may be substituted with C. 1-6 Alkyl, C 1-6 Cycloalkyl, benzene ring, and aromatic heterocyclic linkages; R7 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Any one of the cycloalkyl groups.

2. The preparation method according to claim 1, characterized in that: The structural formulas of the tanshinone IIA derivatives 5-(1-2), 5-(5-9), 5-(11-17), and 5-(20-32) are as follows: The structural formulas of the tanshinone IIA derivatives 5-(3-4), 5-10, and 5-(18-19) are as follows: The structural formulas of the tanshinone IIA derivatives 5-(33-39) are as follows: The structural formulas of the tanshinone IIA derivatives 7-(1-12) are as follows: The structural formulas of the tanshinone IIA derivatives 7-(13-26) are as follows: The structural formulas of the tanshinone IIA derivatives 12-(1-13) are as follows: 。 3. The preparation method according to claim 1, characterized in that: In step a), the reaction temperature is 100-130°C, and the molar ratio of tanshinone IIA, acetic acid and 2,2,6,6-tetramethylpiperidine oxide is 1:(1.5-3):(1-1.5). In step b), the reaction temperature is 100–120 °C, and the molar ratio of compound 1 to toluenesulfonate is 1:(1–1.5). In step c), the reaction temperature is 90–110 °C, and the molar ratio of compound 2 to selenium dioxide is 1:(1–1.1). In step d), the reaction is carried out at 10–30 °C, and the molar ratio of compound 3 to N-bromosuccinimide is 1:(1–1.5). In step e), the sealed condition is a tube-sealed reaction, the reaction temperature is 80-100°C, and the alkali used in the alkali treatment is potassium carbonate. In step f), the reaction is carried out at 10–30°C, and the molar ratio of the tanshinone IIA derivative 6 to Des Martin periodate is 1:(1–1.5). In step g), the volume concentration of hydrogen peroxide is 25-35%, the pH of the buffer solution is 1.5-2.5, and the reaction is carried out at room temperature; In step h), the reaction is carried out at 10–30°C, and the molar ratio of tanshinone IIA derivative 6 to thionyl chloride is 1:(1–1.5). In step i-1), the reaction temperature is 50-70°C, and the molar ratio of compound 3, amine compound and paraformaldehyde is 1:(1-1.5):(1-2). In step i-2), the reductive amination reaction is carried out at 10-30°C, and the molar ratio of the tanshinone IIA derivative 10, the amine compound, and sodium triacetoxyborohydride is 1:(1-1.5):(1.5-2.5). In step i-3), the reaction temperature is 20-40°C, and the molar ratio of the tanshinone IIA derivative 8, the amine compound, and triethylamine is 1:(1-1.5):(1.5-2.5). In step j-1), the reaction is carried out in an ice bath at room temperature, and the molar ratio of the tanshinone IIA derivative 6, the organic acid acyl chloride and the triethylamine is 1:(1-1.5):(1.5-3). In step j-2), the reaction is carried out in an ice bath at room temperature, and the molar ratio of the tanshinone IIA derivative 6, bis(p-nitrobenzene) carbonate, amine compound, 4-dimethylaminopyridine and triethylamine is 1:(1.5-2.5):(2-3):(0.05-0.15):(1-1.5). In step k), the volume ratio of dichloromethane to methanol is 1:1, the reaction temperature is 0-20°C, and the molar ratio of tanshinone IIA derivative 8 to sodium methoxide is 1:(1.5-2.5). In step 1), the reaction is carried out at 10–30 °C, and the molar ratio of the tanshinone IIA derivative 11, the amine compound, the triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate is 1:(1–1.5):(1–1.5):(1.2–1.8). In step m), the reaction to form acyl chloride is carried out at 10–30 °C, and the molar ratio of the tanshinone IIA derivative 11, oxalyl chloride, methanol and triethylamine is 1:(4–6):(1.5–2.5):(1.5–2.5).

4. The preparation method according to claim 3, characterized in that: In step a), the reaction temperature is 120°C; the molar ratio of tanshinone IIA, acetic acid and 2,2,6,6-tetramethylpiperidine oxide is 1:2:1.

2. In step b), the reaction temperature is 110°C, and the molar ratio of compound 1 to toluenesulfonate is 1:1.

2. In step c), the reaction temperature is 100°C, and the molar ratio of compound 2 to selenium dioxide is 1:1.05; In step d), the reaction is carried out at 20°C, and the molar ratio of compound 3 to N-bromosuccinimide is 1:1.

2. In step e), the reaction temperature is 90°C; In step f), the reaction is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 6 to Des Martin periodate is 1:1.

2. In step g), the volume concentration of the hydrogen peroxide is 30%. In step h), the reaction is carried out at 20°C, and the molar ratio of tanshinone IIA derivative 6 to thionyl chloride is 1:1.

2. In step i-1), the reaction temperature is 60°C, and the molar ratio of compound 3, amine compound and paraformaldehyde is 1:1.2:1.5; In step i-2), the reductive amination reaction is carried out at 20°C, and the molar ratio of tanshinone IIA derivative 10, amine compound and sodium triacetoxyborohydride is 1:1.2:2.

0. In step i-3), the reaction temperature is 30°C, and the molar ratio of tanshinone IIA derivative 8, amine compound and triethylamine is 1:1.2:2.

0. In step j-1), the molar ratio of tanshinone IIA derivative 6, organic acid acyl chloride and triethylamine is 1:1.2:2; In step j-2), the molar ratio of tanshinone IIA derivative 6, bis(p-nitrobenzene) carbonate, amine compound, 4-dimethylaminopyridine and triethylamine is 1∶2∶2.5∶0.1∶1.2; In step k), the reaction temperature is 10°C, and the molar ratio of tanshinone IIA derivative 8 to sodium methoxide is 1:

2. In step 1), the reaction is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 11, the amine compound, the triethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate is 1:1.2:1.2:1.

5. In step m), the reaction to form acyl chloride is carried out at 20°C, and the molar ratio of the tanshinone IIA derivative 11, oxalyl chloride, methanol and triethylamine is 1:5:2:

2.

5. The preparation method according to claim 1, characterized in that: The post-processing includes: washing with water first, then washing with saturated brine, then separating the organic layer and drying it with anhydrous sodium sulfate, then concentrating under reduced pressure to remove the organic solvent, and finally purifying the crude product by silica gel column chromatography.

6. A tanshinone IIA derivative and its medicinal salt, characterized in that: The tanshinone IIA derivative was prepared by the preparation method described in any one of claims 1 to 5; The pharmaceutical salt of the tanshinone IIA derivative is an addition salt formed by reacting a basic tanshinone IIA derivative having a basic nitrogen atom in its structure, prepared by the preparation method described in any one of claims 1 to 5, with a pharmaceutically acceptable inorganic or organic acid.

7. The pharmaceutical salt of the tanshinone IIA derivative according to claim 6, characterized in that: The pharmaceutically acceptable inorganic acid is: Hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid and / or nitric acid; The pharmaceutically acceptable organic acids are: Formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amino acids Sulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid and / or thiocyanate.

8. A composition, characterized in that, It includes the tanshinone IIA derivative as described in claim 6 or its pharmaceutical salt, as well as a carrier or excipient acceptable for food or pharmaceutical use.

9. The use of a tanshinone IIA derivative of claim 6 or a pharmaceutical salt thereof, or the composition of claim 8, in the preparation of a food or medicine for the prevention, relief, and / or treatment of colorectal cancer.

10. The application according to claim 9, characterized in that, The tanshinone IIA derivative or its pharmaceutical salt, or a combination of the tanshinone IIA derivative or its pharmaceutical salt, can be formulated into oral tablets, capsules, granules, syrups, injectable powders, solutions, or used as functional additives in food, skin care products, cosmetics, and / or health products.

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