Tanshinone iia derivative, preparation method and application thereof

Abstract

The application discloses a compound shown in formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and belongs to the technical field of pharmacy. A Mannich reaction is used as a key synthesis step to realize the skeleton transition of tanshinone IIA, incorporate a piperidine ring and a side chain on the D ring (furan ring) of tanshinone IIA, greatly improve the chemical space of tanshinone IIA, improve the physical and chemical properties and drug-like properties, and adjust the side chain to improve the pharmacokinetic characteristics of tanshinone IIA derivatives. Compared with tanshinone IIA, the compound has obvious improved pharmacological activity in the treatment of heart failure, anti-inflammation and tumor inhibition, and has good drug-making characteristics.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmacy, and particularly relates to a tanshinone IIA derivative, a preparation method thereof and application thereof. BACKGROUND

[0002] Tanshinone is an extract from the root of Salvia miltiorrhiza Bunge, which is the main liposoluble active ingredient of Salvia miltiorrhiza Bunge and contains an o-quinone or a p-quinone structure. Tanshinone is mainly divided into tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone and 15, 16-dihydrotanshinone according to its different chemical structures. Among them, tanshinone IIA (PubChem CID: 164676) is the monomer compound with the highest content, which has antioxidant, antibacterial, anti-inflammatory and immunomodulatory activities. Tanshinone IIA has a wide range of pharmacological effects and is used in the treatment of various cardiovascular and cerebrovascular diseases in clinical practice. There are also many reports that tanshinone IIA has antitumor activity and anti-mycobacterium activity. However, tanshinone IIA has too high liposolubility and is almost insoluble in water, resulting in poor metabolic stability and extremely low bioavailability in the body. Therefore, one of the best methods to fully exert its therapeutic effect is to modify and modify tanshinone IIA to enhance the pharmacodynamic strength of the compound and improve its water solubility so as to be made into various drug dosage forms and improve the bioavailability. There is tanshinone IIA sodium sulfonate, which solves the water solubility problem of the compound by introducing a water-soluble sulfonic acid group into tanshinone IIA. However, due to the strong acidity of the sulfonic acid group, the pH value of the injection is low, the product is highly irritating, and the patient suffers a lot. Moreover, the stability of tanshinone IIA sodium sulfonate is poor, and the sulfonic acid group is easily removed to form tanshinone IIA during storage of the drug, which may precipitate in the injection.

[0003]

[0004] In addition to tanshinone IIA sodium sulfonate, various structural modifications of tanshinone IIA derivatives and their biological activity evaluation have been reported. Since the 2-position of the furan ring of tanshinone IIA is an electron-rich site, most of the work is to introduce substituents at the 2-position of the furan ring by acylation and Mannich reaction. Huang introduced a tetrahydrothiophene [2, 3-C] pyridine substituent at the 2-position of the furan ring by Mannich reaction, which can increase the water solubility of the compound and inhibit ADP-induced platelet aggregation and thrombus formation (patent CN110066310A, 2019). Song introduced a five- or six-membered saturated nitrogen-containing heterocyclic ring at this position and prepared the corresponding hydrochloride salt to solve the water solubility problem, and some compounds could inhibit the calcium ion channel of HEK293 cells with a half-inhibitory rate IC 50less than 5 micromole; in addition, some compounds can resist endothelial cell damage induced by oxidized low-density lipoprotein ox-LDL (Patent: CN110016069A, 2019); Tan reported derivatives methylated at this position, which can significantly inhibit calcium chloride-induced ventricular fibrillation (Patent: CN109369771A, 2019); Sun reported phosphorylation reaction at this position, and the phosphorylated derivatives can protect the brain tissue of cerebral ischemia-reperfusion rats, reduce the area of cerebral infarction, and the effect is equivalent to edaravone (Patent: CN107540725A, 2018). However, these analogs, although having improved water solubility and / or biological activity to some extent compared with tanshinone IIA, still need new structure tanshinone drugs with significantly improved pharmacodynamics and drugability. SUMMARY

[0005] Based on the above analysis, the natural product tanshinone IIA has problems such as too high fat solubility, low bioavailability, and poor drugability. In view of this, the present application realizes the skeleton transition of tanshinone IIA by a new chemical synthesis method, incorporates a piperidine ring and a side chain on the D ring (furan ring) of tanshinone IIA by taking Mannich reaction as a key synthesis step, greatly improves the chemical space of tanshinone IIA, improves the physicochemical properties and drug-like properties, and can adjust the side chain to improve the pharmacokinetic properties of tanshinone IIA derivatives. Through activity testing and drugability evaluation, compared with tanshinone IIA, the compounds have significantly improved pharmacological activity in the treatment of heart failure, anti-inflammatory, and tumor inhibition, and have good drugability characteristics.

[0006] To achieve the above-mentioned purposes of the application, the technical solutions of the present application are as follows:

[0007] In one aspect, the present application provides a compound represented by formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0008]

[0009] wherein R is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or halogen.

[0010] Further, the substituted substituents are selected from one or more of halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxy, ester, aryl, heterocyclyl, alkyl monosubstituted aminyl, alkyl disubstituted aminyl, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, alkylcarbonylimine, cycloalkylcarbonylimine, heterocyclylcarbonylimine, aminylcarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphonic acid group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, carboxyalkylcarbonyloxy.

[0011] Still further, R is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C1-C10 carbonyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C12 heterocyclyl, substituted or unsubstituted C5-C12 heteroaryl, or halogen;

[0012] Still further, R is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C1-C10 carbonyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C12 heterocyclyl, substituted or unsubstituted C5-C12 heteroaryl, or halogen;

[0013] Still further, R is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C1-C10 carbonyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C12 heterocyclyl, substituted or unsubstituted C5-C12 heteroaryl, or halogen;

[0014] The substituents of the substituents are selected from one or more of halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxy, ester, phenyl, heterocyclyl, C1-C6 alkyl monosubstituted aminyl, C1-C6 alkyl disubstituted aminyl, C1-C6 alkoxy, C1-C6 alkylcarbonyloxy, C1-C6 cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, C1-C6 alkoxycarbonyl, C1-C6 cycloalkoxycarbonyl, heterocyclyloxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 cycloalkylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, C1-C6 alkoxycarbonylamido, C1-C6 alkylmercapto, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxy C1-C6 alkoxycarbonyl, carboxy C1-C6 alkoxy, carboxy C1-C6 alkylcarbonyloxy.

[0015] Still further, the compound of formula (I) is selected from:

[0016]

[0017]

[0018] Unless otherwise indicated, the term "alkyl" as used herein includes both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, and includes all isomers unless otherwise indicated, "alkenyl" is a branched or straight chain aliphatic hydrocarbon group containing a carbon-carbon double bond (an olefinic bond), and "alkynyl" is a branched or straight chain aliphatic hydrocarbon group containing a carbon-carbon triple bond (an acetylenic bond). Commonly used abbreviations for alkyl groups are represented, for example, by "Me" or CH3for methyl, "Et" or CH2CH3for ethyl, "Pr" or CH2CH2CH3for propyl, "Bu" or CH2CH2CH2CH3for butyl, and the like.

[0019] The term "carbonyl" is an organic functional group (C=0) formed by the linkage of two atoms, carbon and oxygen, through a double bond.

[0020] The terms "cycloalkyl" and "cycloalkenyl" refer to hydrocarbon groups having a saturated or unsaturated ring of carbon atoms in a single ring system.

[0021] The term "aryl" refers to aromatic mono and polycarbocyclic ring systems wherein the individual carbocyclic rings are fused or linked by single bonds, and in the case of polycarbocyclic rings, as long as one of the carbocyclic rings is aromatic, and generally includes phenyl, naphthyl, and biphenylidene.

[0022] The term "heterocyclyl" refers to a ring structure composed of carbon atoms and non-carbon atoms, such as nitrogen, oxygen, and sulfur. The heterocyclyl group can be a monocyclic heterocyclyl group having 4-8 ring atoms, or a bicyclic heterocyclyl group having 7-11 ring atoms. In the bicyclic heterocyclyl group, only one ring need be heterocyclyl, the other can be aromatic or non-aromatic, and can contain heteroatoms or not. In addition, the bicyclic heterocyclyl group can be fused, spiro, or bridged. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

[0023] The term "heteroaryl" refers to an aromatic ring group containing 1-4 heteroatoms as ring members. The heteroatoms are nitrogen, oxygen, or sulfur. The heteroaryl group can be a monocyclic heteroaryl group having 5-7 ring atoms, or a bicyclic heteroaryl group having 7-11 ring atoms. In the bicyclic heteroaryl group, only one ring need be heteroaromatic, the other can be aromatic or non-aromatic, and can contain heteroatoms or not. In addition, the bicyclic heteroaryl group can be fused, spiro, or bridged. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, and the like.

[0024] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (or fluorinated (F), chlorinated (Cl), brominated (Br), and iodinated (I)).

[0025] In the present application, "C1-C8 alkyl" refers to straight or branched chain alkyl groups having a specified number of carbon atoms (1-8), including all isomers, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, and the like. "C2-C8 alkenyl" refers to straight or branched chain alkyl groups having a specified number of carbon atoms (2-8), including all isomers, including but not limited to ethenyl, allyl, and the like. "C3-C8 cycloalkyl or cycloalkenyl" refers to hydrocarbyl groups having a 3-8 carbon atom monocyclic ring system, saturated or unsaturated, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclohexenyl, and the like. Similarly, the terms "C1-C10 alkyl", "C2-C10 alkenyl", "C1-C8 carbonyl", "C3-C8 cycloalkenyl", "C6-C10 aryl", "C5-C10 heterocyclyl", "C5-C10 heteroaryl", and the like have analogous meanings.

[0026] All ranges recited herein are inclusive of the endpoints. For example, "1-4" includes 1, 2, 3, 4.

[0027] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be readily prepared from an inorganic or organic acid. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include salts of primary, secondary, and tertiary amines, including those derived from natural and synthetic sources. Pharmaceutically acceptable organic non-toxic bases from which salts can be prepared include arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present application is basic, its corresponding salt can be readily prepared from an inorganic or organic acid. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. In the present application, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, lithium, sodium, potassium, calcium, magnesium, lysine are preferred.

[0028] The term "solvate" means a complex of variable stoichiometry formed by a solute (i.e. a compound of Formula I) or a pharmaceutically acceptable salt thereof and a solvent, which can be an organic or inorganic molecule, which does not interfere with the biological activity of the solute. Examples of solvents include, but are not limited to, water, ethanol, and acetic acid. When the solvent is water, the solvate is a hydrate. Hydrates include, but are not limited to, monohydrates, hemihydrates, monohemihydrates, dihydrates, and trihydrates.

[0029] The term "prodrug" is a functional derivative of a compound of the present application that is readily convertible into the desired compound in vivo. In the present application, preferred are prodrug forms of derivatives of various derivatives after reduction of quinone to diphenol, other substituents.

[0030] In another aspect, the present application provides a method for preparing the above-mentioned compound, comprising the following synthetic route:

[0031]

[0032] Further, step b is specifically: reacting compound A, formaldehyde and R-NH2 to obtain compound B. Wherein, R has the same definition as the foregoing.

[0033] Further, the reaction is carried out in the presence of a solvent and under heating. Further, the solvent is selected from at least one of methanol, acetonitrile, acetic acid, and most preferably acetic acid. Further, the heating temperature is 40-120°C. Further, the reaction time is 3-24 hours.

[0034] Further, step c is specifically: reacting compound B and palladium-carbon under hydrogen to obtain the tanshinone IIA derivative of formula (I).

[0035] Further, the reaction is carried out in the presence of a solvent and under heating. Further, the solvent is selected from at least one of methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, and most preferably methanol. Further, the heating temperature is 40-60°C. Further, the reaction time is 3-10 hours.

[0036] Further, compound A can be prepared according to the following steps: reacting tanshinone I and palladium-carbon under hydrogen, when the reaction system changes from red to colorless, transferring the reaction system to argon, adding anhydrous potassium carbonate and benzyl halide to obtain compound A.

[0037] Further, the reaction is carried out in the presence of a solvent and under heating. Further, the solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, toluene, and most preferably N,N-dimethylacetamide. Further, the heating temperature is 40-100°C. Further, the reaction time is 5-24 hours.

[0038] In another aspect, the present application provides a pharmaceutical composition comprising an effective amount of the compound of formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and one or more pharmaceutically acceptable carriers, diluents, excipients.

[0039] In the pharmaceutical composition, the term "composition" includes a product comprising the active ingredient and the inert ingredient (pharmaceutically acceptable excipient) of the constituent carrier, and any product directly or indirectly obtained by the combination, complexation or aggregation of two or more ingredients, or the decomposition of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present application includes any composition prepared by mixing the compound of formula I, other active ingredients and pharmaceutically acceptable excipients.

[0040] The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, lozenges, granules, and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.

[0041] When the compound of the present application is administered in combination with other therapeutic agents, the same dosage forms as described above can be used. When the drugs are administered in physical combination, the dosage form and route of administration should be selected according to the compatibility of the combined drugs. The compound of the present application can be administered as the sole active ingredient or in combination with a second active ingredient.

[0042] The term "effective amount" means an amount of a compound sufficient to significantly improve the condition without causing serious side effects. The effective amount is determined according to the age, condition, course of treatment, etc. of the subject.

[0043] The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler or gel materials, which are suitable for human use, and must be of sufficient purity and low toxicity. "Compatibility" here means that the components of the composition can be mixed with the compound of the present application and among themselves without significantly reducing the pharmaceutical efficacy of the compound. Examples of pharmaceutically acceptable carriers include sugars (such as glucose, sucrose, lactose, etc.), starches (such as corn starch, potato starch, etc.), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0044] In another aspect, the present application provides the use of a compound represented by formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above pharmaceutical composition in the preparation of a drug for inhibiting tumors.

[0045] Preferably, the compound is selected from S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-10, S-11, S-12, S-13, S-14, S-15, S-16, S-17, S-18, S-19, S-20, S-21, S-22, S-23, S-24, S-25, S-28, S-29, S-31, S-32, S-33, S-34, S-35, S-36, S-37, S-38, S-39, S-40; preferably S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-10, S-11, S-12, S-13, S-14, S-15, S-16, S-19, S-20, S-21, S-22, S-23, S-24, S-25, S-29, S-31, S-32, S-33, S-34, S-35, S-36, S-39, S-40; further preferably S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-23, S-24, S-25, S-31, S-32, S-33, S-34, S-35, S-36, S-39, S-40; further preferably S-1, S-2, S-3, S-5, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-23, S-25, S-31, S-32, S-33, S-34, S-40; further preferably S-1, S-2, S-3, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-31, S-32, S-33, S-40; further preferably S-2, S-6, S-10, S-11, S-13, S-14, S-22, S-31; further preferably S-13, S-22, most preferably S-13.

[0046] In still another aspect, the present application provides use of a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitro oxide, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the pharmaceutical composition as described above in the preparation of a drug for treating heart failure.

[0047] Preferably, the compound is selected from S-7, S-8. Most preferably S-8.

[0048] Finally, the present application provides a use of the compound of formula (I) or its stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as described above in the preparation of an anti-inflammatory drug.

[0049] Preferably, the compound is selected from S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-11, S-12, S-13, S-14, S-15, S-16, S-18, S-19, S-20, S-22, S-23, S-24, S-28, S-29, S-30, S-31, S-32, S-33, S-34, S-36, S-38, S-39, S-40; preferably S-2, S-3, S-9, S-13, S-14, S-15, S-16, S-24, S-29, S-32, S-36, S-39, S-40; further preferably S-14, S-15, S-36, S-39; most preferably S-36.

[0050] The term "heart failure" refers to a syndrome of reduced cardiac output due to primary cardiac damage, which cannot meet the metabolic needs of tissues under normal venous return.

[0051] The term "anti-inflammatory" refers to the treatment of infectious or non-infectious inflammation, pneumonia, bacterial infection, mycoplasma infection, asthma, rheumatoid arthritis, psoriasis, atopic dermatitis, allergic rhinitis, prostatitis, inflammatory bowel disease, diabetes, etc.

[0052] The term "tumor" includes, but is not limited to, lymphoma, bladder cancer, bone cancer, childhood brain stem glioma, adult brain tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, craniopharyngioma, ependymal cell tumor, breast cancer, bronchial tumor, central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, colon cancer, colorectal cancer, esophageal cancer, eye cancer, gallbladder cancer, stomach cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, intestinal cancer, thyroid cancer, etc. In the present application, it is preferably selected from leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, cervical cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, melanoma, prostate cancer, osteosarcoma, glioma.

[0053] The term "infectious disease" refers to a disease caused by infection of bacteria, viruses, fungi or mycoplasma, chlamydia, etc.

[0054] The present application has the following advantages:

[0055] This invention utilizes a novel chemical synthesis method, employing the Mannich reaction as a key synthetic step, to achieve a skeletal transition of tanshinone IIA. This involves incorporating a piperidine ring and side chain onto the D ring (furan ring) of tanshinone IIA, thereby significantly enhancing its chemical steric dimensionality, improving its physicochemical properties and drug-likeness, and modulating the side chain to improve the pharmacokinetic characteristics of the tanshinone IIA derivative. Activity testing results indicate that this tanshinone IIA derivative possesses higher tumor-suppressive activity, anti-inflammatory activity, and therapeutic effects for heart failure. Attached Figure Description

[0056] Figure 1 The results of tests show that representative compounds inhibit the release of inflammatory factors.

[0057] Figure 2 The representative compound, doxorubicin, caused heart failure in zebrafish.

[0058] Figure 3 The results showed that treatment with doxorubicin, a representative compound, induced heart failure in C57 mice. Detailed Implementation

[0059] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed in this application. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and these should also fall within the scope of protection claimed in this application. Unless otherwise specified, all chemical reagents used in the embodiments of this invention are obtained through conventional commercial means.

[0060] In the following examples, the hydrogen nuclear magnetic resonance spectrum of the compound ( 1 ¹H NMR was measured using a Bruker-AV-500 NMR spectrometer; ESI-MS was performed using an Agilent G1946D mass spectrometer. All reaction solvents were redistilled before use, and all anhydrous solvents were dried according to standard methods. The room temperature was 25°C. Unless otherwise specified, all reactions were carried out under argon protection and monitored by TLC, and post-processing involved drying with saturated brine and anhydrous sodium sulfate. Unless otherwise specified, the products were purified by silica gel (200-300 mesh) column chromatography. Tanshinone IIA was purchased from Beijing Solarbio Science & Technology Co., Ltd., catalog number IT0530.

[0061] Synthetic routes for compounds of general formula (I) (preparation of A-series compounds):

[0062]

[0063] Example 1

[0064] Preparation of 10, 11-dibenzyl protected tanshinone IIA (2)

[0065] Tanshinone IIA (2.94 g, 10 mmol) was weighed into a two-necked flask, dissolved in 25 mL of DMF, 0.294 g of palladium-carbon (10% carbon supported palladium) was added, and the reaction was carried out under hydrogen gas at room temperature. When the red color in the two-necked flask disappeared, the solution in the flask was transferred to another two-necked flask filled with cesium carbonate (13.04 g, 40 mmol) under argon protection using a syringe (note that this process cannot be exposed to air, and the syringe and two-necked flask were previously replaced with argon), and then benzyl chloride (5.06 g, 40 mmol) was added at room temperature using a syringe. After the addition was completed, the reaction was warmed to 75°C, and the reaction was carried out for 4 h. After the specified reaction time was reached, the reaction solution was filtered through celite and washed with EA. The organic layer was extracted with saturated brine three times to remove DMF. The organic layer was collected, dried over anhydrous sodium sulfate, and rotary evaporated to remove EA. Purification was carried out by silica gel column chromatography [developing agent: V(PE):V(EA)=150:1] to obtain the target product compound 2 (2.84 g, white solid, yield: 59.8%). 1 H NMR (500 MHz, CDC13) δ 8.06 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.50 - 7.40 (m, 6H), 7.33 - 7.27 (m, 2H), 7.24 - 7.17 (m, 3H), 5.15 (s, 2H), 4.96 (s, 2H), 3.47 (t, J = 6.2 Hz, 2H), 2.29 (d, J = 1.3 Hz, 3H), 1.84 - 1.75 (m, 2H), 1.74 - 1.67 (m, 2H), 1.37 (s, 6H); m / z (ESI-MS): 477.23 [M+H] + .

[0066] Preparation of 2-(7,8-bis(benzyloxy))-3,3-dimethyl-3,5,6,9,10,12-hexahydrophenanthro[2',1':4,5]furo[2,3-c]pyridine-11(4H)-yl)acetate methyl ester (3a)

[0067] Into a pressure tube, intermediate 2 (1.90 g, 4 mmol) prepared above was taken, glycine methyl ester hydrochloride (2.0 g, 16 mmol), paraformaldehyde (0.96 g, 32 mmol) and glacial acetic acid 30 mL were added and heated to 90 °C for reaction, TLC was used for monitoring. The reaction was carried out for about 1.5 h, after the completion of the reaction as monitored by TLC, the glacial acetic acid was removed by rotary evaporation, the crude product was dissolved in EA 50 mL, the pH was made neutral by saturated aqueous sodium bicarbonate solution and washed with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate and the EA was removed by rotary evaporation. The crude product was purified by silica gel column chromatography [eluent: V(DCM):V(MeOH) = 100:1] to obtain 3a (1.39 g, white solid, yield: 59.0%). 1 H NMR (500 MHz, CDC13) δ 8.02 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.38 - 7.32 (m, 2H), 7.27 - 7.20 (m, 3H), 5.15 (s, 2H), 4.96 (s, 2H), 3.82 (t, J = 2.0 Hz, 2H), 3.77 (s, 3H), 3.51 (s, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.84 (m, 2H), 1.82 - 1.76 (m, 2H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 590.26 [M+H] + .

[0068] Preparation of S-1

[0069] Into a two necked flask, intermediate 3a (0.59 g, 1 mmol) prepared above was taken, palladium on carbon 0.06 g and EA 15 mL were added, the reaction was carried out under hydrogen gas condition (hydrogen gas was purged several times) at room temperature, TLC was used for monitoring. The monitoring method: a small amount of reaction solution was taken in a syringe, exposed to air, left for several seconds, observed whether the reaction solution turned to dark red color, TLC was used to monitor whether the starting material was completely consumed. After the completion of the reaction, the reaction solution was diluted with EA, filtered through celite, the sample was concentrated, purified by silica gel column chromatography to obtain the target product S-1 (0.34 g, red solid, yield: 83.2%). 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 3.82 (t, J = 2.0 Hz, 2H), 3.77 (s, 3H), 3.51 (s, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.84 (m J = 5.9, 3.7, 2.8 Hz, 2H), 1.82 - 1.76 (m, 2H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 408.17 [M+H] + .

[0070] Preparation of Example 2 S-2

[0071] Compound S-2 (0.31 g, red solid, yield: 73.6%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with 3-aminopropanoic acid methyl ester hydrochloride (2.23 g, 16 mmol). 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.82 - 2.78 (m, 4H), 2.61 (t, J = 7.2 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 422.20 [M+H] + .

[0072] Preparation of Example 3 S-3

[0073] Compound S-3 (0.36 g, red solid, yield: 82.7%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with 4-aminobutanoic acid methyl ester hydrochloride (2.46 g, 16 mmol). 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.66 (s, 3H), 3.59 (t, J = 1.9 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.78 (m, 4H), 2.63 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.91 (p, J = 7.2 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 436.20 [M+H] + .

[0074] Preparation of Example 4 S-4

[0075] Compound S-4 (0.34 g, red solid, yield: 80.8%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with L-alanine methyl ester hydrochloride (2.23 g, 16 mmol). 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.84 (t, J = 2.0 Hz, 2H), 3.75 (s, 3H), 3.61 (q, J = 7.1 Hz, 1H), 3.17 (t, J = 6.4 Hz, 2H), 2.99 - 2.94 (m, 1H), 2.87 - 2.82 (m, 1H), 2.81 - 2.77 (m, 2H), 1.82 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H), 1.31 (s, 6H); m / z (ESI-MS): 422.19 [M+H] + .

[0076] Preparation of Example 5 S-5

[0077] Compound S-5 (0.31 g, red solid, yield: 66.9%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with L-isoleucine methyl ester hydrochloride (2.90 g, 16 mmol). 1H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.80 - 3.72 (2H), 3.72 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 3.11 (d, J = 10.7 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.81 - 2.68 (m, 3H), 2.05 - 1.94 (m, 1H), 1.83 - 1.76 (m, 2H), 1.75 - 1.71 (m, 1H), 1.68 - 1.62 (m, 2H), 1.31 (s, 6H), 1.24 - 1.12 (m, 1H), 0.92 - 0.89 (m, 6H); m / z (ESI-MS): 464.23 [M+H] + .

[0078] Preparation of Example 6 S-6

[0079] Compound S-6 (0.32 g, red solid, yield: 71.3%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with L-valine methyl ester hydrochloride (2.68 g, 16 mmol). 1 H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.80 - 3.72 (2H), 3.72 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 3.11 (d, J = 10.7 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.81 - 2.68 (m, 3H), 2.05 - 1.94 (m, 1H), 1.83 - 1.76 (m, 2H), 1.75 - 1.71 (m, 1H), 1.68 - 1.62 (m, 2H), 1.31 (s, 6H), 1.24 - 1.12 (m, 1H), 0.92 - 0.89 (m, 6H); m / z (ESI-MS): 464.23 [M+H] + .

[0080] Preparation of Example 7 S-7

[0081] Compound S-7 (0.43 g, red solid, yield: 86.5%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with L-phenylalanine methyl ester hydrochloride (3.45 g, 16 mmol). 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.24 - 7.20 (m, 3H), 3.93 - 3.82 (m, 2H), 3.72 (dd, J = 9.0, 6.2 Hz, 1H), 3.64 (s, 3H), 3.21 (d, J = 9.1 Hz, 1H), 3.18 - 3.15 t, 6.6 Hz, 2H), 3.07 - 3.01 (m, 2H), 2.86 (m, 1H), 2.77 (m, 1H), 1.79 (m, 2H), 1.67 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 498.22 [M+H] + .

[0082] Preparation of Example 8 S-8

[0083] Compound S-8 (0.45 g, red solid, yield: 87.7%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride (3.70 g, 16 mmol) with L-tyrosine methyl ester hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.24 - 7.20 (m, 3H), 3.93 - 3.82 (m, 2H), 3.72 (dd, J = 9.0, 6.2 Hz, 1H), 3.64 (s, 3H), 3.21 (d, J = 9.1 Hz, 1H), 3.18 - 3.15 t, 6.6 Hz, 2H), 3.07 - 3.01 (m, 2H), 2.86 (m, 1H), 2.77 (m, 1H), 1.79 (m, 2H), 1.67 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 498.22 [M+H] + .

[0084] Preparation of Example 9 S-9

[0085] Compound S-9 (0.36 g, red solid, yield: 73.0%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride (3.70 g, 16 mmol) with L-tyrosine methyl ester hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.90 - 3.72 (m, 2H), 3.74 (s, 3H), 3.63 (s, 3H), 3.51 (dd, J = 8.6, 6.8 Hz, 1H), 3.17 (t, J = 6.5 Hz, 2H), 3.03 - 2.97 (m, 1H), 2.80 - 2.72 (m, 3H), 2.45 (td, J = 7.2, 2.9 Hz, 2H), 2.16 - 2.09 (m, 2H), 1.82 - 1.76 (m, 2H), 1.67 - 1.62 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 494.21 [M+H] + .

[0086] Preparation of Example 10 S-10

[0087] Compound S-10 (0.24 g, red solid, yield: 50.1%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride (3.16 g, 16 mmol) with L-aspartic acid dimethyl ester hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.90 - 3.72 (m, 2H), 3.74 (s, 3H), 3.63 (s, 3H), 3.51 (dd, J = 8.6, 6.8 Hz, 1H), 3.17 (t, J = 6.5 Hz, 2H), 3.03 - 2.97 (m, 1H), 2.80 - 2.72 (m, 3H), 2.45 (td, J = 7.2, 2.9 Hz, 2H), 1.82 - 1.76 (m, 2H), 1.67 - 1.62 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 480.19 [M+H] + .

[0088] Preparation of Example 11 S-11

[0089] Compound S-11 (0.38 g, red solid, yield: 82.0%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride (3.16 g, 16 mmol) with L-leucine methyl ester hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.83 (t, J = 2.1 Hz, 2H), 3.72 (s, 3H), 3.53 (t, J = 7.5 Hz, 1H), 3.17 (t, J = 6.4 Hz, 2H), 3.01 - 2.92 (m, 1H), 2.86 - 2.69 (m, 3H), 1.84 - 1.75 (m, 2H), 1.71 - 1.63 (m, 5H), 1.31 (s, 6H), 0.94 (dd, J = 15.5, 6.5 Hz, 6H); m / z (ESI-MS): 464.24 [M+H] + .

[0090] Preparation of Example 12 S-12

[0091] Compound S-12 (0.34 g, red solid, yield: 80.8%) was prepared in the same preparation method as compound S-1 by replacing glycine methyl ester hydrochloride with D-alanine methyl ester hydrochloride (2.23 g, 16 mmol). 1 H NMR (500 MHz, CDC13) δ 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.83 (t, J = 2.1 Hz, 2H), 3.72 (s, 3H), 3.53 (t, J = 7.5 Hz, 1H), 3.17 (t, J = 6.4 Hz, 2H), 3.01 - 2.92 (m, 1H), 2.86 - 2.69 (m, 3H), 1.84 - 1.75 (m, 2H), 1.71 - 1.63 (m, 5H), 1.31 (s, 6H), 0.94 (dd, J = 15.5, 6.5 Hz, 6H); m / z (ESI-MS): 464.24 [M+H] + .

[0092] Synthetic route of compound of general formula (I) (preparation of compounds of series B):

[0093]

[0094] Example 13

[0095] Preparation of 2-(7,8-di(benzyloxy)-3,3-dimethyl-3,5,6,9,10,12-hexahydrofuro[2',1':4,5]cyclo- penta[c]pyrindin-11(4H)-yl)ethyl-1-ol (4a)

[0096] The 3a (1.18 g, 2 mmol) prepared in the above step was weighed into a flask, and LiAlH4(0.32 g, 8 mmol) was added portionwise. The reaction was allowed to proceed at room temperature for about 15 min. EA 100 mL was added to quench the reaction, and a small amount of 4N NaOH aqueous solution was added. After the white precipitate was completely removed, the organic layer was collected by filtration with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography [V(DCM):V(MeOH) = 100:1] to obtain the alcohol compound 4a (0.96 g, white solid, yield: 85.6%). 1 H NMR (500 MHz, CDC13) δ 8.02 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.38 - 7.32 (m, 2H), 7.27 - 7.20 (m, 3H), 5.15 (s, 2H), 4.96 (s, 2H), 3.82 (t, J = 2.0 Hz, 2H), 3.69 (t, J = 1.9 Hz, 2H), 3.51 (s, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.84 (m, 2H), 1.82 - 1.76 (m, 2H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 562.28 [M+H] + .

[0097] Preparation of S-13

[0098] The 4a (0.56 g, 1 mmol) prepared in the above step was weighed into a flask, and palladium-carbon 0.056 g and THF 15 mL were added. The reaction was allowed to proceed under hydrogen gas (hydrogen gas was replaced several times) at room temperature. TLC was used to monitor the reaction. The monitoring method was as follows: a small amount of reaction solution was taken with a syringe, exposed to air, and allowed to stand for several seconds. The reaction solution was observed to see if it turned dark red, and TLC was used to monitor whether the starting material was completely consumed. After the reaction was completed, the reaction solution was diluted with DCM, filtered through diatomite, and concentrated. The sample was purified by silica gel column chromatography [V(DCM):V(MeOH) = 100:1] to obtain the target product S-13 (0.28 g, red solid, yield: 73.9%). 1H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 5.3 Hz, 2H), 3.68 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 5.1 Hz, 2H), 2.80 (m, 4H), 1.84 - 1.75 (m, 2H), 1.69 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 380.18 [M+H] + .

[0099] Preparation of Example 14 S-14

[0100] Compound S-14 (0.30 g, red solid, yield: 76.3%) was prepared in the same preparation method as compound S-13, using methyl 3-aminopropanoate hydrochloride (2.23 g, 16 mmol) instead of methyl glycinate hydrochloride. 1 H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 5.3 Hz, 2H), 3.68 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 5.1 Hz, 2H), 2.80 (m, 4H), 1.84 - 1.75 (m, 2H), 1.69 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 380.18 [M+H] + .

[0101] Preparation of Example 15 S-15

[0102] Compound S-15 (0.29 g, red solid, yield: 71.3%) was prepared in the same preparation method as compound S-13, using methyl 4-aminobutanoate hydrochloride (2.46 g, 16 mmol) instead of methyl glycinate hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.66 (s, 2H), 3.62 (t, J = 5.1 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.84 (s, 4H), 2.66 (t, J = 5.7 Hz, 2H), 1.78 - 1.82 (m, 2H), 1.78 - 1.71 (m, 4H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 408.20 [M+H] + .

[0103] Preparation of Example 16 S-16

[0104] Compound S-16 (0.30 g, red solid, yield: 76.3%) was prepared in the same preparation method as compound S-13, using L-alanine methyl ester hydrochloride (2.23 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.66 (s, 2H), 3.62 (t, J = 5.1 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.84 (s, 4H), 2.66 (t, J = 5.7 Hz, 2H), 1.78 - 1.82 (m, 2H), 1.78 - 1.71 (m, 4H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 408.20 [M+H] + .

[0105] Preparation of Example 17 S-17

[0106] Compound S-17 (0.26 g, red solid, yield: 59.8%) was prepared in the same preparation method as compound S-13, using L-isoleucine methyl ester hydrochloride (2.90 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.61 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 3.80 - 3.72 (2H), 3.4 (m, 2H), 3.17 (t, J = 6.4 Hz, 2H), 3.12 (d, J = 10.7 Hz, 1H), 2.95 - 2.83 (m, 1H), 2.82 - 2.69 (m, 3H), 2.03 - 1.96 (m, 1H), 1.84 - 1.76 (m, 2H), 1.74 - 1.71 (m, 1H), 1.71 - 1.64 (m, 2H), 1.32 (s, 6H), 1.23 - 1.11 (m, 1H), 0.92 - 0.89 (m, 6H); m / z (ESI-MS): 464.23 [M+H] + ; m / z (ESI-MS): 436.24 [M+H] + .

[0107] Preparation of Example 18 S-18

[0108] Compound S-18 (0.27 g, red solid, yield: 64.1%) was prepared in the same manner as compound S-13 using L-valine methyl ester hydrochloride (2.68 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, CDC13) δ 7.61 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 3.80 - 3.72 (2H), 3.4 (m, 2H), 3.17 (t, J = 6.4 Hz, 2H), 3.12 (d, J = 10.7 Hz, 1H), 2.95 - 2.83 (m, 1H), 2.82 - 2.69 (m, 3H), 2.03 - 1.96 (m, 1H), 1.84 - 1.76 (m, 2H), 1.74 - 1.71 (m, 1H), 1.71 - 1.64 (m, 2H), 1.32 (s, 6H), 1.23 - 1.11 (m, 1H), 0.92 - 0.89 (m, 6H); m / z (ESI-MS): 464.23 [M+H] + .

[0109] Preparation of Example 19 S-19

[0110] Compound S-19 (0.36 g, red solid, yield: 76.8%) was prepared in the same manner as compound S-13 using L-phenylalanine methyl ester hydrochloride (3.45 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 6.6 Hz, 1H), 3.89 - 3.71 (m, 2H), 3.54 - 3.49 (m, 2H), 3.18 (m, 3H), 3.08 - 2.99 (m, 2H), 2.87 - 2.72 (m, 3H), 2.52 (dd, J = 13.6, 9.2 Hz, 1H), 1.83 - 1.77 (m, 2H), 1.68 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 470.23 [M+H] + .

[0111] Preparation of Example 20 S-20

[0112] Compound S-20 (0.31 g, red solid, yield: 63.9%) was prepared in the same preparation method as compound S-13, using L-tyrosine methyl ester hydrochloride (3.70 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, Methanol-d4) δ 7.62 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.11 - 7.05 (m, 2H), 6.75 - 6.69 (m, 2H), 3.80 (bs, 2H), 3.66 (dd, J = 11.6, 7.8 Hz, 1H), 3.57 (dd, J = 11.5, 4.3 Hz, 1H), 3.08 (t, J = 6.4 Hz, 2H), 3.06 - 2.99 (m, 2H), 2.94 - 2.84 (m, 2H), 2.69 - 2.64 (m, 2H), 2.60 (dd, J = 13.8, 8.5 Hz, 1H), 1.84 - 1.76 (m, 2H), 1.69 - 1.64 (m, 2H), 1.32 (d, J = 4.0 Hz, 6H); m / z (ESI-MS): 486.22 [M+H] + .

[0113] Preparation of Example 21 S-21

[0114] Compound S-21 (0.27 g, red solid, yield: 61.8%) was prepared in the same preparation method as compound S-13, using L-glutamic acid dimethyl ester hydrochloride (3.38 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 3.86 - 3.72 (m, 2H), 3.71 - 3.65 (m, 3H), 3.55 (dd, J = 11.0, 9.3 Hz, 1H), 3.17 (t, J = 6.4 Hz, 2H), 3.02 - 2.87 (m, 2H), 2.83 - 2.73 (m, 3H), 1.83 - 1.77 (m, 2H), 1.75 - 1.69 (m, 1H), 1.68 - 1.64 (m, 3H), 1.31 (s, 6H); m / z (ESI-MS): 438.22 [M+H] + .

[0115] Preparation of Example 22 S-22

[0116] Compound S-22 (0.24 g, red solid, yield: 56.7%) was prepared in the same preparation method as compound S-13 using L-aspartic acid dimethyl ester hydrochloride (3.16 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 3.86 - 3.72 (m, 2H), 3.71 - 3.65 (m, 3H), 3.55 (dd, J = 11.0, 9.3 Hz, 1H), 3.17 (t, J = 6.4 Hz, 2H), 3.02 - 2.87 (m, 2H), 2.83 - 2.73 (m, 3H), 1.83 - 1.77 (m, 2H), 1.75 - 1.69 (m, 1H), 1.68 - 1.64 (m, 3H), 1.31 (s, 6H); m / z (ESI-MS): 424.20 [M+H] + .

[0117] Preparation of Example 23 S-23

[0118] Compound S-23 (0.31 g, red solid, yield: 78.9%) was prepared in the same preparation method as compound S-13 using D-alanine methyl ester hydrochloride (2.23 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 3.84 (t, J = 2.0 Hz, 2H), 3.74 (s, 3H), 3.59 (q, J = 7.1 Hz, 1H), 3.22 (t, J = 6.4 Hz, 2H), 2.99 - 2.94 (m, 1H), 2.86 - 2.84 (m, 1H), 2.81 - 2.77 (m, 2H), 1.82 - 1.79 (m, 2H), 1.67 - 1.63 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H), 1.31 (s, 6H); m / z (ESI-MS): 394.19 [M+H] + .

[0119] Synthesis route of compound of general formula (I) (preparation of compounds of series C):

[0120]

[0121] Example 24

[0122] Preparation of 7,8-di(benzyloxy)-3,3,11-trimethyl-3,4,5,6,9,10,11,12- octahydrophenanthro[2',l':4,5]furo[2,3-c]pyrindine (5a)

[0123] The intermediate 2 prepared in Example 1 (1.90 g, 4 mmol) was weighed into a pressure tube, methylamine hydrochloride (1.08 g, 16 mmol), paraformaldehyde (0.96 g, 32 mmol) and glacial acetic acid 30 mL were added, and the oil bath was heated to 90 °C for reaction. The reaction was observed, and when the solution color changed to dark red, TLC was used to monitor the reaction. After about 3 h, when TLC monitoring showed that the raw material reacted completely, after most of the glacial acetic acid was removed by rotary evaporation, the crude product was dissolved in EA 50 mL, and after the pH value was adjusted to neutral with saturated brine, saturated brine was added for washing. The organic layer was collected, dried over anhydrous sodium sulfate, and then rotary evaporation was performed to remove EA. The crude product was purified by silica gel column chromatography [eluent: V(PE):V(EA) = 4:1], to obtain the target product intermediate 5a (1.03 g, white solid, yield: 48.5%). 1H NMR (500 MHz, CDC13) δ 8.02 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.38 - 7.32 (m, 2H), 7.27 - 7.20 (m, 3H), 5.15 (s, 2H), 4.96 (s, 2H), 3.55 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.81 (d, J = 5.3 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H), 2.52 (s, 3H), 1.82 - 1.76 (m, 2H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 532.28 [M+H] + .

[0124] Preparation of S-24

[0125] The 5a (0.53 g, 1 mmol) prepared in the above step was weighed in a two-necked flask, palladium on carbon 0.06 g and THF 15 mL were added, and the reaction was carried out under hydrogen (hydrogen was replaced for several times) at room temperature, and TLC was used for monitoring. The monitoring method was that a small amount of reaction solution was taken out with a syringe, exposed to air, and left to stand for several seconds to observe whether the reaction solution turned dark red, and TLC was used to monitor whether the raw material was completely consumed. After the reaction was completed, the reaction solution was diluted with DCM, filtered through diatomite, the sample was concentrated, and column chromatography on silica gel was used for purification to obtain the target product S-24 (0.29 g, red solid, yield: 83.1%). 1 H NMR (500 MHz, CDC13) δ 8.02 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.38 - 7.32 (m, 2H), 7.27 - 7.20 (m, 3H), 5.15 (s, 2H), 4.96 (s, 2H), 3.55 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.81 (d, J = 5.3 Hz, 2H), 2.71 (t, J = 5.6 Hz, 2H), 2.52 (s, 3H), 1.82 - 1.76 (m, 2H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 532.28 [M+H] + .

[0126] Preparation of S-25

[0127] S-25 (0.31 g, red solid, yield: 67.1%) was prepared in the same method as that for preparing S-24 in Example 24, with N-(3-aminopropyl)morpholine hydrochloride (3.17 g, 16 mmol) instead of methylamine hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.60 (t, J = 1.8 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.81 - 2.75 (m, 4H), 2.64 (t, J = 7.4 Hz, 2H), 2.47 (s, 4H), 2.47 - 2.40 (m, 2H), 1.83 - 1.76 (m, 4H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 463.25 [M+H] + .

[0128] Preparation of Example 26 S-26

[0129] S-26 (0.38 g, red solid, yield: 86.2%) was prepared in the same manner as in the preparation of S-24 using 2-(methylsulfonyl)ethylamine hydrochloride (2.55 g, 16 mmol) instead of methylamine hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.60 (t, J = 1.8 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.81 - 2.75 (m, 4H), 2.64 (t, J = 7.4 Hz, 2H), 2.47 (s, 4H), 2.47 - 2.40 (m, 2H), 1.83 - 1.76 (m, 4H), 1.68 - 1.63 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 463.25 [M+H] + .

[0130] Synthetic route of the compound of general formula (I) (preparation of compounds of series D):

[0131]

[0132] Example 27

[0133] Preparation of 2-(7,8-bis(benzyloxy)-3,3-dimethyl-3,5,6,9,10,12-hexahydrofuro[2,3- c]phenanthridin-11(4H)-yl)-N-methylformamide (7a)

[0134] Into a flask, 3a (1.47 g, 2.5 mmol) prepared in Example 1 was weighed and dissolved in THF 15 mL. Lithium hydroxide (0.24 g, 10 mmol) was weighed and dissolved in 15 mL of deionized water. The aqueous lithium hydroxide solution was added to the flask, and the reaction was heated to 70 °C and refluxed overnight. After the reaction was complete, glacial acetic acid was added to adjust the pH to pH = 6-7. EA 100 mL and saturated brine 100 mL were added to extract, and the organic layer was collected. The organic layer was washed once more with saturated brine 100 mL. The organic layer was collected, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to obtain white solid 6a. The next step reaction was carried out without purification. 6a was transferred to a flask, and methylamine hydrochloride (0.34 g, 5 mmol), DIPEA (0.65 g, 5 mmol), and HATU (1.9 g, 5 mmol) were added. DCM 25 mL was added, and the reaction was carried out at room temperature overnight. After the reaction was complete, DCM 100 mL was added to dilute the reaction solution, and saturated brine 100 mL was added to wash. The organic layer was collected, dried over anhydrous sodium sulfate, and rotary evaporated to remove the solvent. After purification by silica gel column chromatography, 7a (0.95 g, white solid, yield: 64.6%) was obtained. 1 H NMR (500 MHz, CDC13) δ 8.02 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.63 - 7.49 (m, 5H), 7.39 - 7.33 (m, 2H), 7.28 - 7.20 (m, 3H), 5.15 (s, 2H), 4.97 (s, 2H), 3.65 (t, J = 1.9 Hz, 2H), 3.28 (s, 2H), 3.19 (t, J = 6.4 Hz, 2H), 2.91 (d, J = 5.0 Hz, 3H), 2.86 (m, 2H), 2.83 (td, J = 5.0, 2.4 Hz, 2H), 1.84 - 1.78 (m, 2H), 1.69 - 1.65 (m, 2H), 1.32 (s, 6H); m / z (ESI-MS): 589.30 [M+H] + .

[0135] Preparation of S-27

[0136] Into a flask, 7a (0.59 g, 1 mmol) prepared in the above step was weighed, and palladium on carbon 0.06 g and THF 15 mL were added. The reaction was carried out under hydrogen gas (hydrogen gas was replaced several times) at room temperature, and TLC was used to monitor the reaction. The monitoring method was as follows: a small amount of reaction solution was taken out using a syringe, exposed to air, and left to stand for several seconds. Whether the reaction solution turned dark red was observed, and TLC was used to monitor the reaction. After the reaction was complete, DCM was added to dilute the reaction solution, and the reaction solution was filtered through celite. The sample was concentrated, and the target product S-27 (0.35 g, dark red solid, yield: 86.2%) was obtained by silica gel column chromatography.1 H NMR (500 MHz, Chloroform-d) δ 7.56 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 3.65 (t, J = 1.9 Hz, 2H), 3.27 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.90 (d, J = 5.0 Hz, 3H), 2.85 (m, 2H), 2.80 (td, J = 5.0, 2.4 Hz, 2H), 1.84 - 1.78 (m, 2H), 1.68 - 1.65 (m, 2H), 1.32 (s, 6H); m / z (ESI-MS): 407.19 [M+H] + .

[0137] Preparation of Example 28 S-28

[0138] Compound S-28 (0.35 g, dark red solid, yield: 83.3%) was prepared in the same preparation method as S-27 using methyl 3-aminopropanoate hydrochloride (2.23 g, 16 mmol) instead of methyl glycinate hydrochloride. 1 H NMR (500 MHz, Chloroform-d) δ 7.56 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 3.65 (t, J = 1.9 Hz, 2H), 3.27 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.90 (d, J = 5.0 Hz, 3H), 2.85 (m, 2H), 2.80 (td, J = 5.0, 2.4 Hz, 2H), 1.84 - 1.78 (m, 2H), 1.68 - 1.65 (m, 2H), 1.32 (s, 6H); m / z (ESI-MS): 407.19 [M+H] + .

[0139] Preparation of Example 29 S-29

[0140] Compound S-29 (0.36 g, dark red solid, yield: 82.9%) was prepared in the same preparation method as S-27 using methyl 4-aminobutanoate hydrochloride (2.46 g, 16 mmol) instead of methyl glycinate hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 3.61 (s, 2H), 3.16 (t, J = 6.4 Hz, 2H), 2.80 (7H), 2.67 (t, J = 6.8 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 6.9 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.69 - 1.62 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 435.22 [M+H] + .

[0141] Example 30

[0142] Preparation of S-30

[0143] Compound S-30 (0.34 g, dark red solid, yield: 81.0%) was prepared in the same preparation method as S-27 using L-alanine methyl ester hydrochloride (2.23 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, CDC13) δ 7.59 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 3.61 (s, 2H), 3.16 (t, J = 6.4 Hz, 2H), 2.80 (7H), 2.67 (t, J = 6.8 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 6.9 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.69 - 1.62 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 435.22 [M+H] + .

[0144] Example 31

[0145] Preparation of S-31

[0146] Compound S-31 (0.33 g, dark red solid, yield: 71.4%) was prepared in the same preparation method as S-27 using L-leucine methyl ester hydrochloride (2.90 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.56 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.06 (q, J = 5.0 Hz, 1H), 3.78 - 3.61 (m, 2H), 3.30 - 3.27 (m, 1H), 3.16 (t, J = 6.4 Hz, 2H), 2.86 (d, J = 4.9 Hz, 3H), 2.83 (t, J = 5.7 Hz, 2H), 2.79 - 2.74 (m, 2H), 1.84 - 1.76 (m, 4H), 1.69 - 1.63 (m, 2H), 1.51 (m, 1H), 1.32 (d, J = 4.4 Hz, 6H), 0.98 (dd, J = 9.6, 6.4 Hz, 6H); m / z (ESI-MS): 463.25 [M+H] + .

[0147] Example 32

[0148] Preparation of S-32

[0149] Compound S-32 (0.39 g, dark red solid, yield: 78.6%) was prepared in the same preparation method as S-27 using L-phenylalanine methyl ester hydrochloride (3.44 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, CDC13) δ 7.56 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.06 (q, J = 5.0 Hz, 1H), 3.78 - 3.61 (m, 2H), 3.30 - 3.27 (m, 1H), 3.16 (t, J = 6.4 Hz, 2H), 2.86 (d, J = 4.9 Hz, 3H), 2.83 (t, J = 5.7 Hz, 2H), 2.79 - 2.74 (m, 2H), 1.84 - 1.76 (m, 4H), 1.69 - 1.63 (m, 2H), 1.51 (m, 1H), 1.32 (d, J = 4.4 Hz, 6H), 0.98 (dd, J = 9.6, 6.4 Hz, 6H); m / z (ESI-MS): 463.25 [M+H] + .

[0150] Example 33

[0151] Preparation of S-33

[0152] Compound S-33 (0.38 g, dark red solid, yield: 74.2%) was prepared in the same preparation method as S-27 using L-tyrosine methyl ester hydrochloride (3.70 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 3.67 (s, 3H), 3.50 (dd, J = 14.3, 6.1 Hz, 1H), 3.14 (bs, 2H), 2.98 (dd, J = 14.2, 7.3 Hz, 1H), 2.90 - 2.76 (m, 5H), 2.75 - 2.64 (m, 2H), 1.83 - 1.76 (m, 2H), 1.68 - 1.64 (m, 2H), 1.31 (d, J = 3.9 Hz, 6H); m / z (ESI-MS): 513.23 [M+H] + .

[0153] Example 34

[0154] Preparation of S-34

[0155] Compound S-34 (0.33 g, red solid, yield: 78.6%) was prepared in the same preparation method as S-13 using D-alanine methyl ester hydrochloride (2.23 g, 16 mmol) instead of glycine methyl ester hydrochloride. 1 H NMR (500 MHz, CDC13) δ 7.56 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 3.72 - 3.59 (dd, 2H), 3.34 (q, J = 7.0 Hz, 1H), 3.15 (t, J = 6.4 Hz, 2H), 2.88 (d, J = 5.0 Hz, 3H), 2.81 - 2.70 (m, 4H), 1.85 - 1.78 (m, 2H), 1.67 - 1.64 (m, 2H), 1.36 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 3.2 Hz, 6H); m / z (ESI-MS): 421.20 [M+H] + .

[0156] Example 35

[0157] Preparation of S-35

[0158] Compound S-35 (0.31 g, dark red solid, yield: 67.1%) was prepared in the same preparation method as S-27 using morpholine (0.44 g, 5 mmol) instead of methylamine hydrochloride. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.73 (s, J = 1.9 Hz, 2H), 3.72 - 3.59 (m, 8H), 3.46 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.87 (d, J = 5.1 Hz, 2H), 2.85 - 2.78 (t, 2H), 1.83 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 463.22 [M+H] + .

[0159] Example 36

[0160] Preparation of S-36

[0161] Compound S-36 (0.30 g, dark red solid, yield: 63.0%) was prepared in the same preparation method as S-30 by condensation of morpholine (0.44 g, 5 mmol) instead of methylamine hydrochloride with carboxylic acid. 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 3.73 (s, J = 1.9 Hz, 2H), 3.72 - 3.59 (m, 8H), 3.46 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.87 (d, J = 5.1 Hz, 2H), 2.85 - 2.78 (t, 2H), 1.83 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 463.22 [M+H] + .

[0162] Example 37

[0163] Preparation of S-37

[0164] Compound S-37 (0.32 g, dark red solid, yield: 67.4%) was prepared in the same preparation method as S-27 by using N-methylpiperazine (0.50 g, 5 mmol) instead of methylamine hydrochloride. 1H NMR (500 MHz, CDC13) δ 7.61 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 2.2 Hz, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.0 Hz, 2H), 3.46 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.86 (d, J = 5.3 Hz, 2H), 2.81 (m, 2H), 2.40 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H), 1.83 - 1.76 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 476.25 [M+H] + .

[0165] Example 38

[0166] Preparation of S-38

[0167] Compound S-38 (0.29 g, dark red solid, yield: 59.3%) was prepared in the same preparation method as S-30 by replacing methylamine hydrochloride with N-methylpiperazine (0.50 g, 5 mmol). 1 H NMR (500 MHz, CDC13) δ 7.61 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 2.2 Hz, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 5.0 Hz, 2H), 3.46 (s, 2H), 3.17 (t, J = 6.4 Hz, 2H), 2.86 (d, J = 5.3 Hz, 2H), 2.81 (m, 2H), 2.40 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H), 1.83 - 1.76 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 476.25 [M+H] + .

[0168] Example 39

[0169] Preparation of S-39

[0170] Compound S-39 (0.29 g, dark red solid, yield: 69.0%) was prepared in the same preparation method as S-27 by replacing methylamine hydrochloride with dimethylamine hydrochloride (0.41 g, 5 mmol). 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 3.74 (s, J = 1.9 Hz, 2H), 3.46 (s, 2H), 3.17 (m, 8H), 2.87 (d, J = 5.1 Hz, 2H), 2.85 - 2.78 (t, 2H), 1.83 - 1.77 (m, 2H), 1.67 - 1.64 (m, 2H), 1.31 (s, 6H); m / z (ESI-MS): 421.20 [M+H] + .

[0171] Example 40

[0172] Preparation of S-40

[0173] S-1 prepared in Example 1 (0.2 g, 0.5 mmol) was weighed into 15 mL EA, and a freshly prepared ethyl hydrogen chloride acetate solution was added dropwise while stirring in an ice bath. Precipitates were generated during the dropwise addition, and after the precipitates were completely generated, excess EA and ethyl hydrogen chloride acetate solution were removed by rotary evaporation. A light red solid was obtained, 20 mL of EA was added for washing, and the filter cake was obtained by filtration, and EA was used for washing again (20 mL x 3), and the filter cake was collected to obtain S-40. 1 H NMR (500 MHz, DMSO) δ 7.82 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 4.45 (s, 2H), 4.24 (s, 2H), 3.76 (s, 3H), 3.48 (bs, 2H), 3.07 (t, J = 6.3 Hz, 2H), 2.93 (s, 2H), 1.75 - 1.71 (m, 2H), 1.65 - 1.59 (m, 2H), 1.29 (s, 6H); m / z (ESI-MS): 408.17 [M+H] + .

[0174] Anti-inflammatory activity test of detection example 1

[0175] Logarithmic phase growth RAW264.7 cells were plated in 96-well plates at a density of 1 x 105 cells per well. After the cells were incubated overnight to adhere, the compounds prepared with DMSO were added to make the final administration concentration 10 μM. Incubate in the cell incubator for 2 h. After 2 h, give LPS stimulation, and the final concentration of LPS stimulation is 50 ng / mL. After adding LPS, incubate in the cell incubator for 24 h, and then collect the cell supernatant for the next step of enzyme-linked immunosorbent assay (ELISA) test. The OD value at 450 nm was detected by a microplate reader. The control of the administration group and the LPS group is the relative protein content. The results are shown in Figure 1 .

[0176] The results show that in the LPS-stimulated RAW264.7 cells, most of the compounds of formula (I) can significantly reduce the release of cell inflammatory factors TNF-α and IL-6, and the anti-inflammatory activity is obviously improved compared with that of tanshinone II A, proving that the tanshinone II A derivative of formula (I) provided by the application has stronger anti-inflammatory activity.

[0177] Activity test for treating heart failure in detection example 2

[0178] 2.1 A transgenic zebrafish Tg(cmlc2:eGFP) labeled with green fluorescent protein was used to establish a heart failure model. Fertilized eggs were collected into a suitable culture dish, foreign matter and dead eggs were removed, and placed in E3 Buffer containing methylene blue for incubation at 27.5°C. After 12 hours, the E3 buffer containing 200 μM PTU was changed to inhibit the production of melanin. The time of spawning, i.e. the time of removing the baffle, was marked as zero hour (0 hour post fertilization, 0hpf). At 30hpf, the zebrafish were broken out of the eggs by adding a membrane breaker. At 30hpf, the zebrafish were moved to a 24-well plate, 5 zebrafish per well, and then 1 mL of E3 buffer containing 200 μM PTU was added. The control group was added with PTU-containing E3 Buffer, the model group was added with 65 mM doxorubicin for modeling, and iron trichloride (10 μM) was added to ensure the presence of iron. The positive drug group and the administration group were added with dexrazoxane and the test drug, respectively, at the same time as modeling. At 60hpf, the zebrafish were rinsed with PTU-containing E3 buffer for 3 times, and then the administration group and the positive drug group continued to be administered. At 100hpf, the zebrafish were anesthetized, and the zebrafish were moved into a 96-well plate, one fish per well. The position of the zebrafish was adjusted so that the right ventricle was on top, and a Leica inverted microscope camera was used to automatically take pictures at a speed of 50 frames per second for 2 seconds per well, and the shape of the heart was recorded. The results are shown in Figure 2 .

[0179] The results show that compounds S-7 and S-8 can significantly improve the heart failure of zebrafish caused by DOX. In the model group, the heart of the zebrafish was slender and irregularly deformed, while the heart toxicity of DOX was reversed, heart failure was treated, and the normal shape of the heart was maintained after administration of S-7 and S-8.

[0180] 2.2 Fifty healthy C57 male mice, weighing 21±2g, were provided by Shanghai Slek Experimental Animal Co., Ltd. The mice were randomly divided into 5 groups, 10 mice in each group, namely a blank group, a control group (administration: dexrazoxane), a model group, an experimental group 1 (low-dose group), and an experimental group 2 (high-dose group).

[0181] Blank group: from the first day of the experiment, daily gavage with blank CMC-Na; from the first day of the experiment, intraperitoneal injection of normal saline on the first day, the second day, and the fifth day;

[0182] Model group: from the first day of the experiment, daily gavage with blank CMC-Na, intraperitoneal injection of normal saline on the first day and the fifth day, and intraperitoneal injection of 15 mg / Kg DOX on the second day;

[0183] Experimental group 1: from the first day of the experiment, daily gavage with CMC-Na suspension of S-8, with a dose of 40 mg / Kg / d, for a total of 8 days of administration; and intraperitoneal injection of 15 mg / Kg DOX on the second day to establish the model; intraperitoneal injection of normal saline on the first day and the fifth day from the first day of the experiment;

[0184] Experimental group 2: from the first day of the experiment, daily gavage with CMC-Na suspension of S-8, with a dose of 80 mg / Kg / d, for a total of 8 days of administration; and intraperitoneal injection of 15 mg / Kg DOX on the second day to establish the model;

[0185] Control group: intraperitoneal injection of normal saline on the first day and the fifth day from the first day of the experiment; intraperitoneal injection of 60 mg / Kg of a normal saline solution of dexrazoxane on the first day from the first day of the experiment; intraperitoneal injection of 15 mg / Kg DOX on the second day; and intraperitoneal injection of 60 mg / Kg of a normal saline solution of dexrazoxane on the fifth day from the first day of the experiment.

[0186] Ultrasonic detection was performed on the eighth day. The results are shown in Figure 3 .

[0187] The results show that, compared with the model group, administration of S-8 can significantly improve the left ventricular dysfunction caused by DOX, including affecting diastolic septum, systolic septum, and ejection fraction.

[0188] Tumor inhibition activity test

[0189] Tumor cells in the logarithmic growth phase were seeded into 96-well plates and cultured overnight at 37°C in 5% carbon dioxide. The next day, the sample to be tested was dissolved using DMSO and added to the culture dish, with a final concentration of 10 μM per well of the sample to be tested. The cells were further cultured at 37°C in 5% carbon dioxide for 72 h. After 72 h, 20 μL of Reagent detection reagent was placed on the orbital shaker for 2 minutes, and then incubated at room temperature for 60 minutes to stabilize the luminescent signal. After 60 minutes, the absorbance value at 450 nm was detected on the enzyme marker. The inhibition rate of the compound on tumor cells was calculated according to the following formula:

[0190]

[0191] The results are as follows:

[0192] Table 1.

[0193]

[0194]

[0195] 1 The inhibition rate value is the mean ± standard deviation after concentration of 10 μM, parallel test twice

[0196] The above merely describes the preferred embodiments of the present application and is not used to limit the present application, any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, R is selected from substituted or unsubstituted C1-C8 alkyl groups; The substituent is selected from one or more of hydroxyl, phenyl, C1-C6 alkyl monosubstituted amino, C1-C6 alkyl disubstituted amino, C1-C10 alkoxycarbonyl, cyano, piperidinyl, and morpholino.

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

3. A method for preparing the compound according to any one of claims 1-2, comprising the following synthetic route: in, The R has the same definition as in any one of claims 1-2.

4. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, and excipients.

5. The use of the compound or pharmaceutically acceptable salt of any one of claims 1-2 or the pharmaceutical composition of claim 4 in the preparation of an antitumor drug.

6. The application according to claim 5, characterized in that, The compound is selected from:

7. The application according to claim 6, characterized in that, The compounds are selected from: S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-10, S-11, S-12, S-13, S-14, S-15, S-16, S-17, S-18, S-19, S-20, S-21, S-22, S-23, S-24, S-25, S-28, S-29, S-31, S-32, S-33, S-34, S-35, S-36, S-37, S-38, S-39, and S-40.

8. The application according to claim 7, characterized in that, The compounds are selected from: S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-10, S-11, S-12, S-13, S-14, S-15, S-16, S-19, S-20, S-21, S-22, S-23, S-24, S-25, S-29, S-31, S-32, S-33, S-34, S-35, S-36, S-39, and S-40.

9. The application according to claim 8, characterized in that, The compounds are selected from: S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-23, S-24, S-25, S-31, S-32, S-33, S-34, S-35, S-36, S-39, and S-40.

10. The application according to claim 9, characterized in that, The compounds are selected from: S-1, S-2, S-3, S-5, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-23, S-25, S-31, S-32, S-33, S-34, and S-40.

11. The application according to claim 10, characterized in that, The compounds are selected from: S-1, S-2, S-3, S-6, S-7, S-10, S-11, S-12, S-13, S-14, S-15, S-19, S-21, S-22, S-31, S-32, S-33, and S-40.

12. The application according to claim 11, characterized in that, The compounds are selected from: S-2, S-6, S-10, S-11, S-13, S-14, S-22, and S-31.

13. The application according to claim 12, characterized in that, The compounds are selected from S-13 and S-22.

14. The application according to claim 13, characterized in that, The compound is selected from S-13.

15. The use of the compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of a medicament for treating heart failure.

16. The application according to claim 15, characterized in that, The compound is selected from:

17. The application according to claim 16, characterized in that, The compounds are selected from S-7 and S-8.

18. The application according to claim 17, characterized in that, The compound is selected from S-8.

19. The use of the compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, in the preparation of an anti-inflammatory drug.

20. The application according to claim 19, characterized in that, The compound is selected from:

21. The application according to claim 20, characterized in that, The compounds are selected from: S-2, S-3, S-4, S-5, S-6, S-7, S-8, S-9, S-11, S-12, S-13, S-14, S-15, S-16, S-18, S-19, S-20, S-22, S-23, S-24, S-28, S-29, S-30, S-31, S-32, S-33, S-34, S-36, S-38, S-39, and S-40.

22. The application according to claim 21, characterized in that, The compounds are selected from: S-2, S-3, S-9, S-13, S-14, S-15, S-16, S-24, S-29, S-32, S-36, S-39, and S-40.

23. The application according to claim 22, characterized in that, The compounds are selected from: S-14, S-15, S-36, and S-39.

24. The application according to claim 23, characterized in that, The compound is selected from S-36.

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