Steroidal compounds and methods of manufacture and use

Abstract

The present invention discloses a steroidal compound and its preparation and use, the structure of which is represented by Formula I, in which the definitions of each substituent are as described in the specification and claims. The steroidal compound of the present invention is a steroidal compound with excellent dual functions of AR antagonistic and AR decomposing activity, and has the characteristics of good drug-likeness and good safety, and can be used for the treatment of AR signal pathway related diseases. [Case 1] JPEG2025501370000074.jpg3467

Description

[Technical field]

[0001] The present invention belongs to the field of pharmacology, and relates to the fields of drug synthesis and pharmacology. More specifically, the present invention relates to a steroid-based compound with a dual mechanism of action of degrading and antagonizing androgen receptor, a method for its preparation and its use in treating patients with diseases related to the androgen receptor (AR) signal pathway, including prostate cancer, castration-resistant prostate cancer, SARS-CoV-2 infectious disease, and late-stage breast cancer. [Background technology]

[0002] Prostate cancer (PCa) is a common malignant tumor of the male urogenital system that is androgen-dependent. Its onset, development, metastasis and progression are closely related to androgen and its receptor signaling pathways. Therefore, androgen deprivation therapy (ADT) is the main treatment for early-stage PCa. However, after 18-24 months of ADT treatment, patients may develop fatal castration resistant prostate cancer (CRPC) as they adapt to low levels of androgen in the body. Over the past two decades, there has been significant progress in the treatment of CRPC patients. Among them, abiraterone acetate, an inhibitor of the CYP17A1 enzyme (an enzyme that synthesizes male hormones), and the second-generation AR antagonists enzalutamide, apalutamide, and darolutamide have been approved for use in the frontline treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer (nmCRPC), and have shown good therapeutic effects.

[0003] However, abiraterone acetate and second-generation AR antagonists still show acquired drug resistance after 9-15 months of clinical treatment, which can be divided into AR-associated drug resistance and AR alternative pathway activation drug resistance. AR-associated drug resistance includes: 1) AR gene amplification and overexpression. Approximately 80% of CRPC patients show high AR expression levels, which allows tumors to adapt to low levels of androgen and subsequently grow and proliferate; 2) expression of point mutations and truncated mutants in the AR ligand-binding domain. Among CRPC patients treated with enzalutamide and abiraterone, approximately 12-48% have AR mutations. Among them, F876L mutation causes enzalutamide and abirateramide to change from AR antagonist activity to AR agonist activity, which in turn promotes tumor growth, and L701H and T877A mutations cause abiraterone to develop drug resistance and become ineffective. Approximately 50% of patients treated with enzalutamide or abiraterone develop truncated variants. AR-V567 and AR-V7 are the two most common truncated variants, which partially or completely delete the ligand-binding domain of AR, respectively, rendering all current AR antagonists unable to bind to AR and exert their effects, resulting in drug resistance and ineffectiveness. AR alternative pathway-driven drug resistance is a condition in which the expression of glucocorticoid receptor (GR) is increased in CRPC patients and competes with AR to bind to response elements, making patients independent of the AR signaling pathway and promoting the transcription of downstream tumor-related genes, leading to the worsening of the disease.

[0004] The five-year survival rate of CRPC patients is less than 30%, and current treatments for CRPC patients are ineffective in controlling the disease. Therefore, new therapeutic strategies are urgently needed in clinical practice for the treatment of CRPC patients and drug-resistant CRPC.

[0005] The entry (infection) of SARS-CoV-2 (new coronavirus, COVID-19) into host cells mainly depends on the mediation of two proteases, namely type II transmembrane serine protease (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 adheres to the cell membrane via ACE2, and TMPRSS2 completes the hydrolysis of the spike protein at the S1 / S2 site of the SARS-CoV-2 spike protein, thereby initiating the fusion and entry of SARS-CoV-2 into the host cell and completing the entry / infection of the host cell. In addition, since TMPRSS2 and ACE2 proteins are positively regulated by the human androgen receptor signaling pathway, AR antagonists or AR degraders can suppress the function of AR and downregulate the expression of TMPRSS2 and ACE2 at the transcriptional level, thereby blocking the entry of SARS-CoV-2 into host cells and fundamentally blocking the infection of the new coronavirus, see Figure 1.

[0006] Clinical studies have also shown that therapeutic strategies targeting the AR signaling pathway can effectively treat COVID-19 patients and significantly reduce mortality. Proxalutamide, an AR antagonist from Suzhou Kintor Pharmaceutical Limited, has already completed phase II proof of concept for the treatment of COVID-19 patients with AR antagonists and has shown remarkable clinical anti-COVID-19 efficacy, and is currently undergoing phase III clinical research in many countries. The drug was already approved for emergency use in Paraguay in July 2021.

[0007] As mentioned above, the AR signaling pathway plays an important role in many diseases, including prostate cancer and novel coronavirus pneumonia, and research and development of AR antagonists or AR decomposition agents is expected to be used more effectively in the treatment of AR signaling pathway-related diseases. Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide a steroid compound having the dual functions of excellent AR antagonistic and AR degrading activity at the same time, which can more thoroughly block the AR signal pathway compared to existing antagonists and can be more suitably used for treating diseases related to the AR signal pathway. [Means for solving the problem]

[0009] In a first aspect of the present invention, there is provided a compound represented by general formula (I), or an enantiomer, diastereomer, stereoisomer, prodrug, deuterated product, hydrate, solvate, racemate, or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, A is [ka] -SO- or a C1-C3 alkylene group. B is hydrogen, substituted or unsubstituted C 1-6 Alkyl groups, substituted or unsubstituted C 3-8 Cycloalkyl groups, substituted or unsubstituted 4-8 membered heterocycloalkyl groups, substituted or unsubstituted C 6-10 an aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group. X is selected from a substituted or unsubstituted 5- to 12-membered heteroaryl group, and a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group. Each of the above substitutions is independently selected from deuterium, hydroxyl, carboxyl, amino, mercapto, C 1-6 Alkyl group, C 1-6 Alkoxy group, sulfonic group, halogen, cyano group, NO2, C 1-6 Haloalkyl group, -SO-C 1-6 Alkyl group, -SO2-C 1-6 Alkyl group, -CONH-C 1-6 Alkyl group, -NHCO-C 1-6 Alkyl group, C 3-6 It is substituted with one or more groups selected from the group consisting of cycloalkyl groups. The heteroatoms of the heterocycloalkyl group and the heteroaryl group are selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0010] In another preferred embodiment, the compound of formula I has the formula: [ka]

[0011] In another preferred embodiment, A is [ka] -SO-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0012] In another preferred embodiment, B is hydrogen, substituted or unsubstituted C 1-4 Alkyl groups, substituted or unsubstituted C 3-6 a cycloalkyl group, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 7-membered heteroaryl group;

[0013] The substitutions are deuterium, hydroxyl, carboxyl, amino, mercapto, C 1-4 Alkyl group, C 1-4 Alkoxy group, sulfonic group, F, Cl, Br, CN, NO2, C 1-4 Haloalkyl group, -SO-C 1-4 Alkyl group, -SO2-C 1-4 Alkyl group, -CONH-C 1-4 Alkyl group, -NHCO-C 1-4 Alkyl group, C 3-6 cycloalkyl groups, The heteroatoms in the heterocycloalkyl group and heteroaryl group are selected from O, N and S, and the number of heteroatoms is 1, 2 or 3.

[0014] In another preferred embodiment, B is [ka] or a phenyl group, which is optionally substituted with one, two or three groups selected from the group consisting of deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxy, amino, F, Cl, Br, cyano, NO2, -SOCH3, -SOCH2CH3, -SOCH(CH3)2, -SO2CH3, -SO2CH2CH3, and -SO2CH(CH3)2.

[0015] In another preferred embodiment, X is selected from a substituted or unsubstituted 5- to 9-membered heteroaryl group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, The substitutions are deuterium, hydroxyl, carboxyl, amino, mercapto, C 1-4 Alkyl group, C 1-4 Alkoxy group, sulfonic group, F, Cl, Br, CN, NO2, C 1-4 Haloalkyl group, -SO-C 1-4 Alkyl group, -SO2-C 1-4 Alkyl group, -CONH-C 1-4 Alkyl group, -NHCO-C 1-4 Alkyl group, C 3-6 cycloalkyl groups, The heteroatoms in the heterocycloalkyl group and heteroaryl group are selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0016] In another preferred embodiment, X is a nitrogen-containing heteroaryl group selected from pyridyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyrimidinyl, and pyridazyl groups, and the above groups are deuterium, hydroxyl, carboxyl, amino, mercapto, C 1-4 Alkyl group, C 1-4 Alkoxy group, sulfonic group, F, Cl, Br, CN, NO2, C 1-4 Haloalkyl group, -SO-C 1-4 Alkyl group, -SO2-C 1-4Alkyl group, -CONH-C 1-4 Alkyl group, -NHCO-C 1-4 Alkyl group, C 3-6 It is substituted with one, two or three groups selected from the group consisting of cycloalkyl groups.

[0017] In another preferred embodiment, X is [ka] and the above groups are optionally substituted with one or two groups selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, cyano, nitro, carboxy, fluorine, chlorine, bromine, -CONHCH3, and -NHCOCH3.

[0018] In another preferred embodiment, the pharmaceutically acceptable salt is composed of a compound of formula (I) and an organic or inorganic acid, an organic or inorganic base. The pharmaceutically acceptable salt includes, but is not limited to, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., and organic acid salts such as formate, acetate, propionate, maleate, fumarate, succinate, tartrate, citrate, acidic amino acid salt, alkylsulfonate (e.g., methanesulfonate, ethanesulfonate, etc.), arylsulfonate (e.g., benzenesulfonate, p-toluenesulfonate, etc.). The pharmaceutically acceptable salt includes, but is not limited to, inorganic base salts such as sodium salt, potassium salt, magnesium salt, calcium salt, and organic base salts including ethylenediamine salt, meglumine salt, tromethamine salt, etc.

[0019] The compound of the present invention represented by the general formula (I), its optical isomer or a pharma- ceutically acceptable salt thereof may exist in the form of a solvate, for example, a hydrate or an alcohol solvate, and these solvates are also included within the scope of the present invention.

[0020] In another preferred embodiment, the compound or a pharma- ceutically acceptable salt thereof is selected from the following: [ka] [ka] [ka]

[0021] In a second aspect of the present invention there is provided a method for preparing a compound according to the first aspect, the method comprising the steps of: [ka] a) reacting intermediate I-1 with methanesulfonyl chloride to obtain intermediate I-2; b) reacting intermediate I-2 with azidotrimethylsilane and boron trifluoride ethyl etherate to give intermediate I-3; c) reacting intermediate I-3 with lithium aluminum hydride to give intermediate I-4; d) reacting intermediate I-4 with an acid chloride to give the desired compound I; or e) The intermediate I-4 is subjected to a condensation reaction with a carboxylic acid to obtain the target compound I. (In each formula, X, A and B are defined as above.)

[0022] In another preferred embodiment, in step a, intermediate I-1 is dissolved in a polar aprotic solvent in the presence of an organic base, and then reacted with methanesulfonyl chloride at room temperature for 2-6 h under the catalysis of 4-dimethylaminopyridine to obtain intermediate I-2. The organic base can be triethylamine, N,N-diisopropylethylamine, the polar aprotic solvent can be 1,4-dioxane, toluene, tetrahydrofuran, dichloromethane, and the most preferred solvent is dichloromethane.

[0023] In another preferred embodiment, in step b, intermediate I-2 is dissolved in dry dichloromethane solution, and then 3-6 equivalents of azidotrimethylsilane and 4-8 equivalents of boron trifluoride ethyl ether are added in sequence, and reacted at room temperature for 12-24 hours to obtain intermediate I-3 with the configuration maintained, where the optimal equivalent ratio of azidotrimethylsilane is 3 equivalents, and the optimal equivalent ratio of boron trifluoride ethyl ether is 4 equivalents.

[0024] In another preferred embodiment, in step c, intermediate I-3 is dissolved in a polar aprotic solvent, and 1.5 equivalents of lithium aluminum hydride are added to the solvent and reacted at room temperature for 2-6 h to obtain intermediate I-4. The polar aprotic solvent may be 1,4-dioxane, toluene, tetrahydrofuran, dichloromethane, and the most preferred solvent is tetrahydrofuran.

[0025] In another preferred embodiment, in step d, intermediate I-4 is dissolved in a polar aprotic solvent in the presence of an organic base, and then reacted with various acid chlorides (isonicotinic acid chloride hydrochloride, nicotinic acid chloride hydrochloride, pyridine-3-sulfonic acid chloride hydrochloride, etc.) at room temperature for 6-12 h under the catalysis of 4-dimethylaminopyridine to obtain target compound I. The organic base can be triethylamine, N,N-diisopropylethylamine, the polar aprotic solvent can be 1,4-dioxane, toluene, tetrahydrofuran, dichloromethane, and the most suitable solvent is dichloromethane.

[0026] In another preferred embodiment, in step e, intermediate I-4 is dissolved in N,N-dimethylformamide and condensed with various carboxylic acids (such as pyridazine-4-carboxylic acid, 4-fluoropyridine-3-carboxylic acid, etc.) under the action of condensing agent 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) at room temperature for 8-12 hours to obtain target compound I. The reaction temperature is 0-50°C, and the optimal temperature is room temperature.

[0027] In another preferred embodiment, compound II-1 is subjected to Suzuki coupling reaction with a boronic acid or boronic ester to obtain the intermediate I-1. [ka] (In the formula, X is defined as above.)

[0028] In another preferred embodiment, compound II-1 is dissolved in a mixture of 1,4-dioxane and water, and then reacted with various boronic acids or boronic acid esters (pyrimidine-5-boronic acid, 5-methylpyridine-3-boronic acid, 5-methoxypyrimidine-3-boronic acid pinacol ester, etc.) under the catalysis of bis(triphenylphosphine)palladium dichloride at 100°C to obtain corresponding compound I-1. The volume ratio of 1,4-dioxane to water is 5:1-2:1, the optimal volume ratio is 3:1, the reaction temperature is 80-110°C, the optimal reaction temperature is 100°C.

[0029] In another preferred embodiment, the method for preparing the intermediate I-1 comprises the steps of: [ka] i) subjecting compound II-2 to an addition-elimination reaction to obtain compound II-3; ii) removing the aldehyde group from compound II-3 to obtain compound II-4; iii) Compound II-4 is hydrolyzed to give intermediate I-1. (In the formula, X is defined as above.)

[0030] In another preferred embodiment, in step i, compound II-2 is dissolved in a polar solvent, and then undergoes addition-elimination reaction with various aromatic heterocyclic compounds (such as 1,2,3-triazole, imidazole, 4-methylimidazole, 4-ethylimidazole, etc.) under the action of an inorganic base at 80° C. to obtain the corresponding compound II-3. The polar solvent can be acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and the inorganic base can be sodium carbonate, potassium carbonate, cesium carbonate, and the most suitable inorganic base is potassium carbonate.

[0031] In another preferred embodiment, in step ii, compound II-3 is dissolved in dry N,N-dimethylformamide, and reacted with a stoichiometric amount of palladium carbon for 18-72 h to remove the aldehyde group to obtain compound II-4. The reaction temperature may be 140-170°C, and the optimal reaction temperature is 160°C.

[0032] In another preferred embodiment, in step iii, compound II-4 is dissolved in a polar protic solvent, and then potassium hydroxide is added to hydrolyze the acetate ester at room temperature to obtain the corresponding compound I-1. The polar protic solvent can be methanol or ethanol.

[0033] In addition, the compound represented by formula (I) according to the present invention can be prepared by a person skilled in the art by combining various methods familiar to a person skilled in the art of organic synthesis or medicinal chemistry under the teaching of the above-mentioned methods, and the compound of the present invention can be synthesized by combining the above-mentioned methods with synthetic methods known in the art or modifications thereof that will be understood by a person skilled in the art, and is not limited to the above-mentioned methods.

[0034] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: A compound of general formula (I) according to the first aspect, or an enantiomer, diastereomer, stereoisomer, prodrug, deuterated form, hydrate, solvate, racemate or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable carrier.

[0035] In a fourth aspect of the present invention, there is provided a use of a compound of general formula (I) according to the first aspect or a pharmaceutical composition according to the third aspect for the manufacture of a medicament for preventing and / or treating a disease associated with the AR signaling pathway. In another preferred embodiment, the disease associated with the AR signal pathway is selected from prostate cancer, castration-resistant prostate cancer, breast cancer, SARS-CoV-2 infectious disease, osteoporosis, and digestive system diseases.

[0036] Of course, it is understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced with any homologous, equivalent or similar purpose substitute feature. Due to space limitations, we will not explain each one here. [Brief description of the drawings]

[0037] [Figure 1] Figure 1 shows SARS-CoV-2 virus infection of host cells mediated by the AR-ACE2 / TMPRSS2 signaling pathway. [Diagram 2] FIG. 2 shows the effect of compounds on internal gonadal weight gain, where (A) is seminal vesicle weight and (B) is prostate weight. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The inventors of this patent have conducted extensive and in-depth research to design and synthesize a series of steroid compounds with the general structural formula of formula (I), and performed in vitro AR antagonistic activity, AR decomposition activity, mutant AR antagonistic activity and cell proliferation inhibitory activity assays, as well as system bioactivity assays such as in vivo rat gonad weight increase and mouse in vivo xenograft tumor assays, which showed that the compounds of the present invention have excellent antitumor activity and are safer and more effective AR decomposition / antagonists; at the same time, the rat in vivo pharmacokinetics experiment of the compounds of the present invention showed that such compounds have high plasma exposure, excellent pharmacokinetic properties and drug-like properties. All these results prove that the compounds of the present invention are useful for treating AR signal pathway-related diseases, including prostate cancer, COVID-19 patients, etc. Based on this, the present invention has been completed.

[0039] term In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, the halogen is F, Cl, Br or I. In the present invention, the term "C 1-6 " means having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C 1-4 " means having 1, 2, 3 or 4 carbon atoms, and so on.

[0040] In the present invention, the term "alkyl group" refers to a saturated linear or branched hydrocarbon moiety consisting only of carbon and hydrogen atoms, for example, the term "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl groups, preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0041] As used herein, the term "alkylene group" refers to a straight or branched chain saturated aliphatic group having a specified number of carbon atoms and having at least two other groups attached thereto, i.e., a divalent hydrocarbon group. The two groups attached to the alkylene group may be attached to the same or different atoms in the alkylene group. For example, a straight chain alkylene group is -(CH2) n - divalent radical, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0042] In the present invention, the term "alkoxy group" refers to -O-(C 1-6 For example, the term "C 1-6 The term "alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.

[0043] In the present invention, the term "cycloalkyl group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which may contain fused, bridged or spiro ring systems, typically having 3 to 15 carbon atoms. For example, the term "C 3-8 The term "cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3-6 "Cycloalkyl group" has an analogous meaning.

[0044] As used herein, the term "heterocycloalkyl group" refers to a saturated or unsaturated non-aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) ring heteroatom (e.g., N, O, or S), such as, for example, a tetrahydropyridyl group, a pyrrolinyl group, a dihydropyridyl group, a dihydrofuryl group, a dihydrothienyl group, or a morpholyl group.

[0045] In the present invention, the term "4-8 membered" means that the number of atoms forming the closed ring skeleton itself in the closed ring system group defined thereby (e.g., aryl group, heteroaryl group, heterocycloalkyl group, etc.) is 4, 5, 6, 7 or 8, and the number varies depending on the number of rings in the closed ring system group, the degree of saturation, and the properties of the atoms constituting the ring, etc. This also explains the meaning of other terms with similar notations, such as "3- to 6-membered" and "4- to 6-membered".

[0046] In the present invention, the term "aryl group" refers to a hydrocarbon group moiety with one or more aromatic rings. For example, the term "C 6-10 The term "aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and containing no heteroatoms in the ring, such as a phenyl group or a naphthyl group.

[0047] In the present invention, the term "heteroaryl group" refers to an aromatic ring system consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen and sulfur, which may be a monocyclic, bicyclic, tricyclic or higher ring system, and is connected to the rest of the molecule by a single bond through an atom in the aromatic ring.Typically, examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazyl, indolyl, indazolyl, isoindazolyl, benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzopyridazyl, quinazolinyl, quinoxalinyl and the like.

[0048] Unless otherwise stated, the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups described herein may be substituted or unsubstituted, and possible substituents include hydroxy, amino, nitro, cyano, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, These include, but are not limited to, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylaminosulfonyl, arylaminosulfonyl, C1-C10 alkylimino, C1-C10 alkylsulfonylimino, arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidyl, ureido, cyano, aryl, thioacyl, acyloxy, carboxy, and carboxylate. Meanwhile, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may also be interchangeably condensed.

[0049] In the present invention, the substitution can be mono- or poly-substitution, and the poly-substitution can be di-, tri-, tetra- or penta-substitution. The di-substitution means having two substituents, and the other expressions are the same.

[0050] compound The present invention provides a steroid compound with a dual mechanism of action of simultaneously degrading and antagonizing AR, which antagonizes AR while promoting AR degradation, thereby achieving complete blockage of the androgen receptor signaling pathway. This has better therapeutic effects than existing monofunctional AR antagonists, monofunctional AR degraders or monofunctional androgen synthase inhibitors, and can be used to treat CRPC and even prostate cancer patients at all stages, solve the increasingly serious problem of drug resistance in PCa patients, and can also be used to treat diseases such as new coronavirus pneumonia, thereby achieving better treatment than diseases related to the AR signaling pathway.

[0051] The structures of the compounds of the present invention are as follows: [ka] (In the formula, each substituent is defined as above.)

[0052] Drug Composition The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount and a pharma- ceutically acceptable carrier. The "active ingredient" according to the present invention is a compound of formula (I) according to the present invention.

[0053] The "active ingredient" and the pharmaceutical composition according to the present invention are used to manufacture a drug for treating AR signal pathway-related diseases. The "active ingredient" and the pharmaceutical composition according to the present invention are useful as AR decomposition agents or antagonists. The AR signal pathway-related diseases are selected from prostate cancer, SARS-CoV-2 infectious diseases, castration-resistant prostate cancer, breast cancer, osteoporosis, and digestive system diseases. "Safe and effective amount" refers to the amount of active ingredient that is sufficient to significantly improve the condition without causing serious side effects.

[0054] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be applicable to humans and have sufficient purity and sufficiently low toxicity. "Compatible" refers to the ability of each component in the composition to be blended with and among the active components of the present invention without significantly reducing the effectiveness of the active components. Some examples of pharmaceutically acceptable vehicles include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tallow, glyceryl ... R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water.

[0055] The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, but representative modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral administration (intravenous, intramuscular, or subcutaneous administration), and the like. The compounds of the present invention may be administered alone or in combination with other therapeutic agents (eg, anti-tumor agents).

[0056] When using pharmaceutical compositions, a safe and effective amount of the compounds of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage administered is a pharma- ceutical effective amount. Of course, the specific dosage should take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only.

[0058] Of course, it is understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be freely replaced with any homologous, equivalent or similar purpose alternative feature. Any improvements made to the present invention without creative labor by these techniques known to those skilled in the art, such as prodrugs or precursor drugs (hydroxyl groups, carboxy groups, NH, etc. in the structure of the compound of the present invention can be prepared into prodrugs by conventional methods), deuteration, salt formation, solvates, etc., are all within the scope of protection of this patent.

[0059] The purpose of the following specific examples is to enable those skilled in the art to more clearly understand and practice the present invention. They are merely illustrative and representative of the present invention, without being considered as limitations on the scope of the present invention. Those skilled in the art will recognize that there are other synthetic routes to form the compounds of the present invention, and the following are non-limiting examples.

[0060] All reactions were monitored by thin layer chromatography (TLC) on silica gel F-254 TLC plates. Column chromatography was performed on silica gel (200-300 mesh). The structures of the compounds were confirmed by nuclear magnetic resonance (NMR). The solvents used for the measurements were deuterated dimethylmethylsulfoxide (DMSO-d6) or deuterated chloroform (CDCl3). 1 H and 13C NMR measurements were performed on a Bruker 400, Bruker 500 or Bruker 600 NMR spectrometer. Chemical shifts (δ) are given in parts per million (ppm) and coupling constants (J) are given in Hertz (Hz). Mass spectrometry measurements were performed on a Finnigan MAT95 mass spectrometer for electron ionization (EI), a Krats MS 80 mass spectrometer for electrospray ionization (ESI) and a 1290-6545 UHPLC-QTOF Drug Small Molecule Structure Analysis High Resolution Mass Spectrometer for high resolution. All final compounds were purified to >95% purity by analytical high performance liquid chromatography (PLATISIL ODS 250 mm × 4.6 mm, 5 μm particle size) using acetonitrile / water, acetonitrile / buffer (0.1% trifluoroacetic acid / water) or methanol / buffer (0.1% trifluoroacetic acid / water) as mobile phases.

[0061] Example 1: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridine-3-sulfonamide (Compound 1) [ka]

[0062] (3S,10R,13S)-10,13-Dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (45) Abiraterone (44) (1 g, 2.86 mmol) and 4-dimethylaminopyridine (35 mg, 0.286 mmol) were added together in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (1.19 mL, 8.58 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.5 mL, 5.72 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, then filtered, the organic phase was concentrated with silica gel, and purified by automated chromatography (20-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 705 mg of pale yellow solid 45 was obtained, with a yield of 57.6%. 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.24 (dd, J = 7.6, 4.9 Hz, 1H), 6.01 (s, 1H), 5.49 (d, J = 4.5 Hz, 1H), 4.56 (dq, J = 16.2, 5.3 Hz, 1H), 3.04 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H).

[0063] 3-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)pyridine (46) Compound 45 (470 mg, 1.1 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.22 mL, 1.65 mmol) and boron trifluoride ethyl etherate (0.27 mL, 2.2 mmol) were added in sequence in a plastic charging apparatus, and after the addition was completed, the mixture was stirred at room temperature for 16 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane, the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated by silica gel, and purified by automated chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 120 mg of compound 46 was obtained as a white solid, with a yield of 29.1%. 1 H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 1.8 Hz, 1H), 8.48 (dd, J = 4.8, 1.4 Hz, 1H), 7.67 (dt, J = 7.9, 1.9 Hz, 1H), 7.24 (dd, J = 7.9, 4.8 Hz, 1H), 6.02 (dd, J = 3.1, 1.7 Hz, 1H), 5.45 (d, J = 5.1 Hz, 1H), 3.24 (ddd, J = 10.5, 9.2, 4.1 Hz, 1H), 1.09 (s, 3H), 1.07 (s, 3H).

[0064] (3S,10R,13S)-10,13-Dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (47) Compound 46 (253 mg, 0.68 mmol) was dissolved in dry tetrahydrofuran and stirred in an ice bath, then 1 M lithium aluminum hydride in tetrahydrofuran (1 mL, 1 mmol) was slowly added dropwise using a plastic charger. After completion of the addition, the mixture was stirred at room temperature for 1.5 h and the reaction was monitored for completion by TLC. After completion of the reaction, the system was placed in an ice bath, quenched with ice water, and extracted with ethyl acetate. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated by silica gel, and purified by automated chromatography (5-10% methanol / dichloromethane) to obtain the desired product. Finally, 113 mg of compound 47 was obtained as a white solid, with a yield of 48.1%. 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 1.7 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.8, 4.8 Hz, 1H), 6.01 (s, 1H), 5.39 (d, J = 5.1 Hz, 1H), 1.07 (s, 6H).

[0065] N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridine-3-sulfonamide (Compound 1) Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (60 μL, 0.42 mmol) was added and stirred for a certain period of time. Finally, pyridine-3-sulfonyl chloride hydrochloride (40 mg, 0.17 mmol) was added and stirred at room temperature for 4 h. The reaction was monitored for completion by TLC. After the reaction was completed, the mixture was extracted with dichloromethane and water. The organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic chromatography (30-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 45 mg of compound 1 was obtained as a white solid, with a yield of 64.1%. 1 H NMR (400 MHz, DMSO) δ 8.97 (d, J = 2.1 Hz, 1H), 8.82 (dd, J = 4.8, 1.5 Hz, 1H), 8.58 (s, 1H), 8.43 (d, J = 3.5 Hz, 1H), 8.23 ​​- 8.17 (m, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.65 (dd, J = 8.0, 4.8 Hz, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 6.11 (s, 1H), 5.21 (d, J = 4.8 Hz, 1H), 2.90 (dd, J = 11.6, 4.7 Hz, 1H), 0.99 (s, 3H), 0.95 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 153.36, 148.26, 147.61, 147.27, 140.99, 138.94, 134.70, 133.75, 132.57, 129.44, 124.76, 123.82, 121.51, 57.43, 53.99, 50.04, 47.07, 37.64, 36.55, 34.97, 31.72, 31.26, 30.27, 29.51, 20.73, 19.27, 16.68. HRMS (ESI) (M+H)+ m / z calculated value C 29 H 36 N3O2S 490.2523, Measured: 490.2513.

[0066] Example 2: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)isonicotinamide (compound 2) [ka]

[0067] Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (60 μL, 0.42 mmol) was added and stirred for a certain period of time. Finally, isonicotinic acid chloride hydrochloride (30 mg, 0.17 mmol) was added and stirred at room temperature for 6 h. The reaction was monitored for completion by TLC. After the reaction was completed, the system was concentrated with silica gel and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 34 mg of compound 2 was obtained as a white solid, with a yield of 52.3%. 1 H NMR (600 MHz, CDCl3) δ 8.69 (d, J = 5.8 Hz, 2H), 8.59 (s, 1H), 8.43 (d, J = 4.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 5.8 Hz, 2H), 7.22 (dd, J = 7.8, 4.9 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 5.99 (s, 1H), 5.43 (d, J = 5.1 Hz, 1H), 3.94 - 3.86 (m, 1H), 1.05 (s, 3H), 1.02 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 164.77, 151.48, 150.52, 147.43, 141.95, 140.29, 134.23, 133.07, 129.49, 123.21, 122.05, 120.90, 57.45, 50.44, 50.29, 47.32, 39.14, 37.75, 36.78, 35.09, 31.81, 31.47, 30.40, 29.01, 20.77, 19.30, 16.58. HRMS (ESI) (MH) - m / z calculated value C 30 H 34 N3O 452.2707, Found: 452.2703.

[0068] Example 3: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)nicotinamide (compound 3) [ka]

[0069] Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (60 μL, 0.42 mmol) was added and stirred for a certain period of time. Finally, nicotinic acid chloride hydrochloride (30 mg, 0.17 mmol) was added and stirred at room temperature for 3 h. The reaction was monitored for completion by TLC. After the reaction was completed, the system was concentrated with silica gel and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 44 mg of compound 3 was obtained as a white solid, with a yield of 67.7%. 1H NMR (500 MHz, CDCl3) δ 8.98 (d, J = 1.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.64 (d, J = 1.7 Hz, 1H), 8.47 (dd, J = 4.8, 1.4 Hz, 1H), 8.14 - 8.10 (m, 1H), 7.67 (dt, J = 7.9, 1.8 Hz, 1H), 7.39 (dd, J = 7.8, 4.9 Hz, 1H), 7.24 (dd, J = 7.9, 4.8 Hz, 1H), 6.24 (d, J = 7.8 Hz, 1H), 6.02 (dd, J = 3.1, 1.7 Hz, 1H), 5.48 - 5.45 (m, 1H), 3.95 (tdd, J = 12.1, 8.1, 4.3 Hz, 1H), 1.11 (s, 3H), 1.07 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 151.60, 151.12, 147.30, 147.27, 147.22, 139.85, 134.61, 133.35, 128.85, 122.97, 122.59, 121.47, 56.98, 49.87, 49.82, 46.84, 38.76, 37.29, 36.30, 34.72, 31.30, 30.99, 29.92, 28.61, 20.28, 18.81, 16.02. + m / z calculated value C 30 H 36 N3O 454.2853, Found: 454.2849.

[0070] Example 4: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 4) [ka]

[0071] Compound 47 (50 mg, 0.143 mmol) and pyridazine-4-carboxylic acid (20 mg, 0.161 mmol) were placed in a flask, and then dried N,N-dimethylformamide was added as a solvent and stirred at room temperature. Then, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (74 mg, 0.195 mmol) was added and stirred for a certain period of time. Finally, N,N-diisopropylethylamine (43 μL, 0.29 mmol) was added and stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic chromatography (30-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 29 mg of compound 4 was obtained as a pale yellow solid, with a yield of 44.6%. 1 H NMR (600 MHz, DMSO) δ 9.50 (dd, J = 2.1, 1.3 Hz, 1H), 9.39 (dd, J = 5.3, 1.1 Hz, 1H), 8.82 (d, J = 7.9 Hz, 1H), 8.77 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.96 (dd, J = 5.3, 2.3 Hz, 1H), 7.72 (dd, J = 8.0, 5.3 Hz, 1H), 6.33 (d, J = 1.0 Hz, 1H), 5.36 (d, J = 5.0 Hz, 1H), 3.73 - 3.65 (m, 1H), 1.03 (s, 3H), 1.01 (s, 3H). 13C NMR (151 MHz, DMSO) δ 162.66, 152.40, 149.28, 142.67, 141.30, 139.28, 132.89, 132.01, 125.99, 124.67, 121.33, 117.45, 57.47, 50.30, 50.05, 47.07, 38.54, 37.88, 36.86, 34.55, 32.02, 31.26, 30.26, 28.23, 20.83, 19.46, 16.53. - m / z calculated value C 29 H 33 N4O 453.266, Found: 453.2654.

[0072] Example 5: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)-4-fluoronicotinamide (compound 5) [ka]

[0073] Compound 47 (50 mg, 0.143 mmol) and 4-fluoropyridine-3-carboxylic acid (22 mg, 0.143 mmol) were placed in a flask, and then dried N,N-dimethylformamide was added as a solvent and stirred at room temperature. Then, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (74 mg, 0.195 mmol) was added and stirred for a certain period of time. Finally, N,N-diisopropylethylamine (43 μL, 0.29 mmol) was added and stirred at room temperature for 10 h. The completion of the reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 36 mg of compound 5 was obtained as a white solid, with a yield of 53.2%. 1 H NMR (600 MHz, CDCl3) δ 8.88 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.78 (dd, J = 7.8, 5.6 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.33 (s, 1H), 5.48 (d, J = 4.8 Hz, 1H), 3.96 (d, J = 5.8 Hz, 1H), 1.12 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ 160.23, 148.55, 146.44, 140.98, 140.24, 139.80, 139.02, 136.70, 134.88, 126.03, 124.91, 121.83, 57.41, 50.61, 50.09, 47.44, 39.00, 37.68, 36.78, 34.89, 32.18, 31.32, 30.25, 28.87, 20.67, 19.31, 16.61;+ m / z calculated value C 30 H 35 FN3O 472.2759, measured value: 472.2763.

[0074] Example 6: N-((3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridine-3-sulfonamide (compound 6) [ka]

[0075] (3S,10R,13S)-10,13-Dimethyl-17-(1H-benzo[d]imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (49) Galeterone (48) (1.645 g, 4.24 mmol) and 4-dimethylaminopyridine (52 mg, 0.424 mmol) were added together in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (1.8 mL, 12.72 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.7 mL, 8.4 mmol) was slowly added, and after the addition was complete, the mixture was stirred at room temperature for 8 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.64 g of compound 49 was obtained as a pale yellow solid, with a yield of 83.2%. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.86 - 7.82 (m, 1H), 7.52 - 7.49 (m, 1H), 7.35 - 7.30 (m, 2H), 6.00 (dd, J = 3.1, 1.7 Hz, 1H), 5.50 (d, J = 5.2 Hz, 1H), 4.57 (tdd, J = 11.4, 7.1, 4.7 Hz, 1H), 3.04 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H).

[0076] 3-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-benzo[d]imidazole (50) Compound 49 (979 mg, 2.1 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.41 mL, 3.15 mmol) and boron trifluoride ethyl etherate (0.52 mL, 4.2 mmol) were added in sequence in a plastic charging apparatus, and the mixture was stirred at room temperature overnight after the dropwise addition was completed, and the reaction was monitored for completion by TLC. Then, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane, and the organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated on silica gel, and purified by automated chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 266 mg of compound 50 was obtained as a white solid, with a yield of 30.7%. 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.60 - 7.52 (m, 3H), 6.24 (dd, J = 3.0, 1.6 Hz, 1H), 5.47 (d, J = 5.0 Hz, 1H), 3.25 (dt, J = 11.5, 6.3 Hz, 1H), 1.08 (s, 3H), 1.05 (s, 3H).

[0077] (3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (51) Compound 50 (266 mg, 0.643 mmol) was dissolved in dry tetrahydrofuran and stirred in an ice bath, then 1 M lithium aluminum hydride in tetrahydrofuran (1 mL, 1 mmol) was slowly added dropwise using a plastic charger. After the addition was complete, the mixture was stirred at room temperature for 2 h and the reaction was monitored for completion by TLC. After the reaction was complete, the system was placed in an ice bath, quenched with ice water, and extracted with ethyl acetate. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated by placing silica gel in the organic phase, and purified by automated chromatography (5-10% methanol / dichloromethane) to obtain the desired product. Finally, 107 mg of compound 51 was obtained as a white solid, with a yield of 43.3%. 1 H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.28 (ddd, J = 15.0, 13.7, 6.6 Hz, 2H), 6.06 (s, 1H), 5.32 (d, J = 4.3 Hz, 1H), 0.99 (s, 3H), 0.97 (s, 3H).

[0078] N-((3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridine-3-sulfonamide (compound 6) Compound 51 (50 mg, 0.129 mmol) and 4-dimethylaminopyridine (2 mg, 0.013 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (54 μL, 0.39 mmol) was added and stirred for a certain period of time. Finally, pyridine-3-sulfonyl chloride (20 μL, 0.155 mmol) was slowly added. After the dropwise addition was completed, the mixture was stirred at room temperature for 6 h and the reaction completion was monitored by TLC. After the reaction was completed, the system was concentrated with silica gel and purified by automatic chromatography (30-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 35 mg of compound 6 was obtained as a white solid, with a yield of 51.3%. 1 H NMR (600 MHz, CDCl3) δ 9.09 (d, J = 1.9 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 7.99 (s, 1H), 7.81 - 7.78 (m, 1H), 7.48 - 7.42 (m, 2H), 7.31 - 7.26 (m, 2H), 5.97 (dd, J = 3.1, 1.6 Hz, 1H), 5.31 (d, J = 7.0 Hz, 2H), 3.16 - 3.08 (m, 1H), 0.97 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ 153.03, 147.92, 146.97, 141.52, 140.13, 138.18, 134.59, 134.42, 124.42, 123.74, 123.63, 122.76, 121.93, 119.94, 111.24, 55.75, 54.21, 50.36, 47.21, 40.28, 37.65, 36.59, 34.73, 30.96, 30.28, 30.23, 20.50, 19.15, 15.98. HRMS (ESI) (M+H) + m / z calculated value C 31 H 37 N4O2S 529.2632, Measured: 529.2635.

[0079] Example 7: (3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-N-(pyridin-4-ylmethyl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (compound 7) [ka]

[0080] Compound 51 (50 mg, 0.129 mmol) was placed in a flask, and dried N,N-dimethylformamide was added as a solvent and stirred at room temperature. Then potassium carbonate (36 mg, 0.261 mmol) was added and stirred for a certain period of time. Finally, 4-(bromomethyl)pyridine hydrochloride (33 mg, 0.130 mmol) was added. After the addition was completed, the system was slowly heated to 50°C and stirred overnight, and the reaction completion was monitored by TLC. After the reaction was completed, it was extracted with ethyl acetate and water, and the organic phase was collected and washed twice with saturated saline, then dried over anhydrous sodium sulfate, filtered, concentrated by adding silica gel to the system, and purified by automatic chromatography (2-5% methanol / dichloromethane) to obtain the desired product. Finally, 32 mg of compound 7 was obtained as a white solid, with a yield of 51.8%. 1 H NMR (600 MHz, CDCl3) δ 8.53 (dd, J = 4.6, 1.3 Hz, 2H), 7.94 (s, 1H), 7.81 - 7.77 (m, 1H), 7.48 - 7.45 (m, 1H), 7.30 (d, J = 5.6 Hz, 2H), 7.29 - 7.26 (m, 2H), 5.96 (dd, J = 2.9, 1.6 Hz, 1H), 5.38 - 5.35 (m, 1H), 3.87 (s, 2H), 1.03 (s, 3H), 0.99 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 149.92, 147.17, 143.22, 141.64, 134.55, 124.11, 123.41, 123.25, 122.50, 120.81, 120.17, 111.15, 57.65, 55.87, 50.56, 49.31, 47.23, 37.68, 37.24, 34.86, 31.09, 30.33, 30.29, 20.59, 19.33, 16.02. HRMS (ESI) (M+H) + m / z calculated value C 32 H 39 N4479.3169, Actual value: 479.3168.

[0081] Example 8: N-((3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)isonicotinamide (compound 8) [ka]

[0082] Compound 8 was synthesized in the same manner as in the synthesis of compound 2. Compound 51 (50 mg, 0.129 mmol) was added to obtain 24 mg of compound 8 as a white solid, with a yield of 37.8%. 1 H NMR (500 MHz, DMSO) δ 8.74 (d, J = 4.4 Hz, 2H), 8.65 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 5.9 Hz, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.41 - 7.32 (m, 2H), 6.15 (s, 1H), 5.39 (d, J = 4.6 Hz, 1H), 3.77 - 3.67 (m, 1H), 1.03 (s, 3H), 0.97 (s, 3H). 13C NMR (126 MHz, DMSO) δ 163.98, 149.94, 146.22, 141.55, 126.38, 124.68, 123.90, 121.98, 120.98, 118.70, 112.46, 55.72, 50.39, 50.16, 47.17, 38.65, 37.96, 36.86, 34.17, 30.86, 30.41, 28.34, 20.63, 19.41, 16.07. HRMS (ESI) (M+H) + m / z calculated value C 32 H 37 N4O 493.2962, Found: 493.2969.

[0083] Example 9: N-((3S,10R,13S)-17-(1H-benzo[d]imidazol-1-yl)-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 9) [ka]

[0084] Compound 9 was synthesized in the same manner as in the synthesis of compound 4. Compound 51 (50 mg, 0.129 mmol) was added to obtain 24 mg of compound 9 as a white solid, with a yield of 37.8%. 1H NMR (600 MHz, CDCl3) δ 9.53 (dd, J = 2.1, 1.2 Hz, 1H), 9.28 (dd, J = 5.2, 1.0 Hz, 1H), 7.94 (s, 1H), 7.86 (dd, J = 5.2, 2.3 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.49 - 7.44 (m, 1H), 7.30 - 7.25 (m, 2H), 7.18 (d, J = 7.9 Hz, 1H), 5.97 (dd, J = 2.8, 1.5 Hz, 1H), 5.43 (d, J = 5.0 Hz, 1H), 3.94 (tdd, J = 12.1, 8.1, 4.2 Hz, 1H), 1.01 (s, 3H), 0.99 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 162.79, 151.81, 148.56, 142.98, 141.55, 140.26, 134.53, 132.28, 124.39, 124.16, 123.54, 122.62, 121.80, 120.02, 111.22, 55.77, 50.74, 50.42, 47.22, 38.87, 37.72, 36.81, 34.81, 31.05, 30.30, 28.71, 20.56, 19.19, 16.01. HRMS (ESI) (M+H) + m / z calculated value C 31 H 36 N5O 494.2914, Found: 494.2917.

[0085] Example 10: N-((3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 10) [ka]

[0086] (3S,10R,13S)-10,13-Dimethyl-17-(pyrimidin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthrenequinone-3-ol (52) Compound II-1 (7 g, 17.6 mmol), pyrimidine-5-boronic acid (2.68 g, 21.6 mmol), potassium carbonate (7.45 g, 54.02 mmol) and bis(triphenylphosphine)palladium dichloride (1.28 g, 1.82 mmol) were added to a flask, followed by 60 mL of dioxane and 20 mL of water, stirring at room temperature, and then replacing with argon gas three times, slowly raising the temperature to 100 ° C. and reacting overnight, monitoring the completion of the reaction by TLC the next day, after the reaction was completed, it was extracted with ethyl acetate and water, the organic phase was collected, washed twice with saturated saline, further dried over anhydrous sodium sulfate, filtered, then concentrated with silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.2 g of yellow solid compound 52 was obtained, with a yield of 35.78%. 1 H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.72 (s, 2H), 6.10 (s, 1H), 5.38 (d, J = 5.1 Hz, 1H), 3.58 - 3.49 (m, 1H), 1.06 (s, 3H), 1.04 (s, 3H).

[0087] (3S,10R,13S)-10,13-Dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (53) Compound 52 (2.2 g, 6.28 mmol) and 4-dimethylaminopyridine (80 mg, 0.65 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (2.6 mL, 19.34 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (1 mL, 11.54 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, then filtered, the organic phase was concentrated with silica gel, and purified by automated chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 534 mg of compound 53 was obtained as a white solid, with a yield of 19.9%. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.74 (s, 2H), 6.13 (dd, J = 3.1, 1.7 Hz, 1H), 5.49 (d, J = 5.1 Hz, 2H), 4.60 - 4.51 (m, 1H), 3.04 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H).

[0088] 5-((3S,10R,13S)-3-Azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)pyrimidine (54) Compound 53 (534 mg, 1.24 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.5 mL, 3.77 mmol) and boron trifluoride ethyl etherate (0.6 mL, 4.83 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated on silica gel, and purified by automated chromatography (10-20% ethyl acetate / petroleum ether) to give the desired product. Finally, 231 mg of compound 54 was obtained as a white solid, with a yield of 49.4%.

[0089] (3S,10R,13S)-10,13-Dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (55) Compound 54 (231 mg, 0.615 mmol) was dissolved in dry tetrahydrofuran and stirred in an ice bath, then 1 M lithium aluminum hydride in tetrahydrofuran (0.9 mL, 0.9 mmol) was slowly added dropwise using a plastic charger, and the mixture was stirred at room temperature overnight and monitored for completion of the reaction by TLC. After completion of the reaction, the system was placed in an ice bath, quenched with ice water, and extracted with ethyl acetate. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated by placing silica gel in the organic phase, and purified by automated chromatography (5-8% methanol / dichloromethane) to obtain the desired product. Finally, 101 mg of compound 55 was obtained as a white solid, with a yield of 47.02%.

[0090] N-((3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 10) Compound 55 (43 mg, 0.123 mmol) was added to give 42 mg of compound 10 as a yellow solid, with a yield of 75%. 1 H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 9.41 (d, J = 5.3 Hz, 1H), 9.04 (s, 1H), 8.81 (s, 3H), 7.97 (dd, J = 5.2, 2.2 Hz, 1H), 6.28 (s, 1H), 5.37 (d, J = 4.1 Hz, 1H), 3.71 (dd, J = 11.8, 4.1 Hz, 1H), 1.04 (s, 3H), 1.01 (s,3H). 13 C NMR (126 MHz, DMSO) δ 162.21, 156.70, 153.81, 152.12, 148.82, 147.92, 140.88, 131.64, 131.25, 130.07, 124.07, 120.85, 56.89, 49.87, 49.61, 46.67, 38.17, 37.47, 36.37, 34.30, 31.52, 30.91, 29.88, 27.87, 20.35, 18.97, 16.08; + m / z calculated value C 28 H 34 N5O 456.2758, Found: 456.2762.

[0091] Example 11: N-((3S,10R,13S)-10,13-dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 11) [ka]

[0092] (3S,10R,13S)-16-Formyl-10,13-dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (56) Compound II-2 (2 g, 5.3 mmol) and potassium carbonate (2.56 g, 18.6 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 1,2,3-triazole (0.9 mL, 15.9 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.26 g of white solid compound 56 was obtained, with a yield of 58%. 1 H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.83 (d, J = 1.1 Hz, 1H), 5.41 (d, J = 4.9 Hz, 1H), 4.59 (dt, J = 10.8, 6.1 Hz, 1H), 2.03 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H).

[0093] (3S,10R,13S)-10,13-Dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (57) Compound 56 (2 g, 4.89 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 1 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was allowed to proceed for 3 days, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and then dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (20-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 720 mg of compound 57 was obtained as a yellow solid, with a yield of 38.6%. 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.0 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 5.96 (dd, J = 3.1, 1.7 Hz, 1H), 5.41 (d, J = 5.0 Hz, 1H), 4.61 (dt, J = 11.4, 4.4 Hz, 1H), 2.03 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H).

[0094] (3S,10R,13S)-10,13-Dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (58) Compound 57 (720 mg, 1.88 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.4 g, 7.3 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 4 h and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then dried directly by rotary evaporation to obtain the target compound. 554 mg of compound 58 was obtained as a yellow solid, with a yield of 86.4%.1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.71 (s, 1H), 5.97 (s, 1H), 5.38 (d, J = 4.7 Hz, 1H), 3.54 (m, 1H), 1.13 (s, 3H), 1.07 (s, 3H).

[0095] (3S,10R,13S)-10,13-Dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (59) Compound 58 (550 mg, 1.62 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.7 mL, 5.04 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.25 mL, 3.3 mmol) was slowly added, and after the dropwise addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the desired product. Finally, 500 mg of white solid 59 was obtained, with a yield of 74%. 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.73 (s, 1H), 5.98 (s, 1H), 5.47 (d, J = 5.1 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.03 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H).

[0096] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-1,2,3-triazole (60) Compound 59 (100 mg, 0.24 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (47 μL, 0.26 mmol) and boron trifluoride ethyl etherate (59 μL, 0.48 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated on silica gel, and purified by automated chromatography (10-20% ethyl acetate / petroleum ether) to give the desired product. Finally, 63 mg of white solid 60 was obtained, with a yield of 72.16%. 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.74 (s, 1H), 5.99 (dd, J = 3.1, 1.8 Hz, 1H), 5.45 (d, J = 5.1 Hz, 1H), 3.24 (ddd, J = 10.4, 8.8, 4.1 Hz, 1H), 1.15 (s, 3H), 1.08 (s, 3H).

[0097] (3S,10R,13S)-10,13-Dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (61) Compound 60 (63 mg, 0.173 mmol) was dissolved in dry tetrahydrofuran and stirred at room temperature. After adding 1 M lithium aluminum hydride in tetrahydrofuran (0.3 mL, 0.3 mmol), the reaction was allowed to proceed for 2 hours, and the completion of the reaction was monitored by TLC. The reaction was quenched with saturated ammonium chloride solution, then extracted with ethyl acetate, the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated to dryness by rotary evaporation to give the desired product. Finally, 30 mg of compound 61 was obtained as a white solid in a yield of 51.2%.1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.81 (d, J = 0.9 Hz, 1H), 6.12 (s, 1H), 5.27 (s, 1H), 1.05 (s, 3H), 0.99 (s, 3H).

[0098] N-((3S,10R,13S)-10,13-dimethyl-17-(1H-1,2,3-triazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carbamide (compound 11) Compound 61 (50 mg, 0.148 mmol) was added to give 58 mg of compound 11 as a white solid, with a yield of 88.3%. 1 H NMR (400 MHz, DMSO) δ 9.55 - 9.53 (m, 1H), 9.43 (dd, J = 5.3, 1.0 Hz, 1H), 8.85 (d, J = 7.9 Hz, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.00 (dd, J = 5.3, 2.3 Hz, 1H), 7.83 (d, J = 0.9 Hz, 1H), 6.15 (s, 1H), 5.39 (d, J = 4.5 Hz, 1H), 3.79 - 3.67 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 162.12, 152.10, 148.82, 133.25, 124.13, 123.46, 120.75, 118.75, 67.03, 55.84, 49.84, 45.88, 38.16, 37.41, 36.39, 34.25, 30.48, 29.64, 29.49, 27.84, 25.14, 20.08, 18.86, 15.51. HRMS (ESI) (M+H) + m / z calculated value C 26 H 33 N6O 445.271, Found: 445.2722.

[0099] Example 12: N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)nicotinamide (compound 12) [ka]

[0100] (3S,10R,13S)-16-Formyl-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl acetate (62) Compound II-2 (7.90 g, 20.96 mmol) and potassium carbonate (7.24 g, 52.40 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-methylimidazole (2.06 g, 25.09 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 7.0 g of compound 62 was obtained as a yellow solid, with a yield of 79%. 1 H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.54 (d, J = 1.1 Hz, 1H), 6.84 (s, 1H), 5.43 (d, J = 5.2 Hz, 1H), 4.62 (tt, J = 10.5, 5.4 Hz, 1H), 2.29 (d, J = 0.6 Hz, 3H), 2.06 (s, 3H), 1.08 (s, 6H).

[0101] (3S,10R,13S)-10,13-Dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (63) Compound 62 (6.30 g, 14.91 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 5 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 18 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 3.0 g of compound 63 was obtained as a yellow solid, with a yield of 50.6%. 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.75 (s, 1H), 5.60 (s, 1H), 5.40 (d, J = 4.8 Hz, 1H), 4.60 (tt, J = 10.8, 5.3 Hz, 1H), 2.22 (s, 3H), 2.02 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H).

[0102] (3S,10R,13S)-10,13-Dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (64) Compound 63 (1.80 g, 4.56 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (1.01 g, 18.24 mmol) was added, and after the addition was complete, the mixture was stirred at room temperature for 4 h and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then dried directly by rotary evaporation to obtain the target compound. 1.6 g of compound 64 was obtained as a yellow solid, with a yield of 99.5%. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 0.9 Hz, 1H), 6.78 (s, 1H), 5.63 (dd, J = 3.0, 1.7 Hz, 1H), 5.40 (d, J = 5.2 Hz, 1H), 3.61 - 3.50 (m, 1H), 2.25 (s, 3H), 1.07 (s, 3H), 1.01 (s, 3H).

[0103] (3S,10R,13S)-10,13-Dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (65) Compound 64 (1.06 g, 3.01 mmol) and 4-dimethylaminopyridine (37 mg, 0.30 mmol) were added together in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (1.25 mL, 9.03 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.47 mL, 6.01 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 10 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.05 g of compound 65 was obtained as a yellow solid, with a yield of 81.4%. 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.80 (s, 1H), 5.69 (d, J = 1.3 Hz, 1H), 5.47 (d, J = 4.8 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.04 (s, 3H), 2.28 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H).

[0104] 1-((3S,10R,13S)-3-Azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-4-methyl-1H-imidazole (66) Compound 65 (1.95 g, 4.53 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (3.6 mL, 27.18 mmol) and boron trifluoride ethyl ether (5.6 mL, 45.30 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.55 g of white solid 66 was obtained, with a yield of 90.64%. 1 H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 6.84 (s, 1H), 5.92 - 5.88 (m, 1H), 5.42 (d, J = 4.9 Hz, 1H), 3.27 - 3.17 (m, 1H), 2.39 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0105] (3S,10R,13S)-10,13-Dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (67) Compound 66 (1.55 g, 4.11 mmol) was dissolved in 16 mL of tetrahydrofuran, 16 mL of methanol and 4 mL of water and stirred at room temperature, then weighed triphenylphosphine (3.23 g, 12.33 mmol) was added, then the temperature was slowly raised to 60°C, and the mixture was stirred at this temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 350 mg of white solid 67, with a yield of 24.3%. 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.78 (s, 1H), 5.63 (dd, J = 3.0, 1.7 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 2.25 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0106] N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)nicotinamide (compound 12) Compound 67 (55 mg, 0.156 mmol) was added to give 55 mg of compound 12 as a brown solid, with a yield of 77%. 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 1.7 Hz, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.18 - 8.14 (m, 1H), 7.73 (s, 1H), 7.48 (dd, J = 7.9, 4.9 Hz, 1H), 7.05 (s, 1H), 5.73 (s, 1H), 5.36 (d, J = 4.0 Hz, 1H), 3.77 - 3.65 (m, 1H), 2.09 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.90, 151.73, 148.40, 141.15, 137.05, 134.95, 134.73, 123.31, 120.51, 116.43, 114.56, 55.84, 49.81, 49.50, 45.37, 38.36, 37.53, 36.40, 34.09, 30.38, 29.68, 29.17, 28.01, 20.13, 18.95, 15.64, 13.35; + m / z calculated value C 29 H 37 N4O 445.271, Found: 445.2722.

[0107] Example 13: N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 13) [ka]

[0108] Compound 67 (55 mg, 0.156 mmol) was added to give 46 mg of compound 13 as a pale yellow solid, with a yield of 64.3%. 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 9.41 (d, J = 4.4 Hz, 1H), 8.82 (d, J = 7.8 Hz, 1H), 7.97 (dd, J = 5.2, 2.2 Hz, 1H), 7.68 (s, 1H), 7.02 (s, 1H), 5.71 (s, 1H), 5.36 (d, J = 3.3 Hz, 1H), 3.71 (d, J = 7.2 Hz, 1H), 2.08 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 162.20, 152.08, 148.82, 140.88, 134.77, 124.12, 120.74, 116.14, 114.38, 55.82, 54.92, 49.86, 49.79, 45.39, 38.15, 37.42, 36.36, 34.08, 30.46, 29.66, 29.10, 27.85, 20.18, 18.92, 15.64, 13.47. HRMS (ESI) (M+H) + m / z calculated value C 28 H 36 N5O 458.2914, Found: 458.2912.

[0109] Example 14: N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)isonicotinamide (compound 14) [ka]

[0110] Compound 67 (55 mg, 0.156 mmol) was added to give 52 mg of compound 14 as a white solid, with a yield of 72.8%. 1H NMR (500 MHz, DMSO) δ 8.72 (dd, J = 4.4, 1.6 Hz, 2H), 8.59 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.75 (dd, J = 4.5, 1.6 Hz, 2H), 7.10 (s, 1H), 5.79 - 5.76 (m, 1H), 5.39 (d, J = 4.9 Hz, 1H), 3.78 - 3.68 (m, 1H), 2.12 (d, J = 0.5 Hz, 3H), 1.06 (s, 3H), 0.99 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 164.19, 150.62, 148.26, 142.08, 137.21, 135.12, 121.64, 121.01, 115.15, 56.30, 50.35, 50.10, 45.87, 38.67, 37.96, 36.85, 34.47, 30.92, 30.14, 29.64, 28.30, 20.63, 19.40, 16.08, 13.65. HRMS (ESI) (M+H) + m / z calculated value C 29 H 37 N4O 457.2962, Found: 457.2959.

[0111] Example 15: N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)-3-fluoroisonicotinamide (compound 15) [ka]

[0112] Compound 67 (100 mg, 0.285 mmol) was added to give 89 mg of compound 15 as a brown solid, with a yield of 65.9%. 1H NMR (600 MHz, DMSO) δ 8.68 (s, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.53 (d, J = 4.7 Hz, 1H), 7.71 (s, 1H), 7.57 - 7.54 (m, 1H), 7.06 (s, 1H), 5.74 (s, 1H), 5.40 (d, J = 4.6 Hz, 1H), 3.68 (dt, J = 16.9, 8.6 Hz, 1H), 2.11 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 161.60, 148.38, 146.64, 141.34, 139.13, 137.71, 135.23, 123.72, 121.12, 116.60, 114.86, 56.29, 50.20, 50.15, 45.85, 38.65, 37.86, 36.79, 34.52, 30.93, 30.11, 29.62, 28.37, 20.65, 19.39, 16.11, 13.93. + m / z calculated value C 29 H 36 FN4O 457.2868, measured value: 457.2874.

[0113] Example 16: N-((3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 16) [ka]

[0114] (3S,10R,13S)-16-Formyl-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (68) Compound II-2 (6 g, 15.92 mmol) and potassium carbonate (4.39 g, 31.83 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, imidazole (1.08 g, 15.86 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.27 g of compound 68 was obtained as a yellow solid, with a yield of 34.97%. 1 H NMR (400 MHz, CDCL3) δ 9.72 (s, 1H), 7.61 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 5.40 (d, J = 4.6 Hz, 1H), 4.58 (dt, J = 10.8, 5.7 Hz, 1H), 2.01 (s, 3H), 1.05 (s, 6H).

[0115] (3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl acetate (69) Compound 68 (2.27 g, 5.56 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 2.27 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C. and reacted for 20 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 875 mg of compound 69 was obtained as a yellow solid, with a yield of 41.47%. It was directly used in the reaction of the next step.

[0116] (3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (70) Compound 69 (860 mg, 2.26 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.37 g, 6.78 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 4 h, and the completion of the reaction was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, and then the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then dried directly by rotary evaporation to obtain the target compound. 730 mg of compound 70 was obtained as a yellow solid, with a yield of 95.4%. It was then used in the next step.

[0117] (3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (71) Compound 70 (105 mg, 0.31 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added together in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (129 μL, 0.93 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (48 μL, 0.62 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel in the system and purified by automated chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 111 mg of compound 71 was obtained as a white solid, with a yield of 86.3%. 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.69 (dd, J = 3.0, 1.6 Hz, 1H), 5.46 (d, J = 5.1 Hz, 1H), 4.58 - 4.48 (m, 1H), 3.02 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H).

[0118] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-1H-imidazole (72) Compound 71 (44 mg, 0.106 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.15 mL, 1.13 mmol) and boron trifluoride ethyl ether (0.15 mL, 1.21 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated on silica gel, and purified by automated chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 10 mg of white solid 72 was obtained, with a yield of 26.04%. 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.39 (s, 1H), 7.16 (s, 1H), 6.01 (s, 1H), 5.45 (d, J = 4.9 Hz, 1H), 3.24 (dt, J = 16.1, 5.8 Hz, 1H), 1.08 (s, 3H), 1.05 (s, 3H).

[0119] (3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (73) Compound 72 (157 mg, 0.432 mmol) was dissolved in 6 mL of tetrahydrofuran, 6 mL of methanol and 1.5 mL of water and stirred at room temperature, then weighed triphenylphosphine (453 mg, 1.73 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, some of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 80 mg of white solid 73, with a yield of 54.9%. 1 H NMR (400 MHz, DMSO) δ 8.10 (s, 2H), 7.84 (s, 1H), 7.36 (s, 1H), 7.00 (s, 1H), 5.83 (s, 1H), 5.41 (d, J = 4.8 Hz, 1H), 1.01 (s, 3H), 0.99 (s, 3H).

[0120] N-((3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carbamide (compound 16) Compound 73 (35 mg, 0.104 mmol) was added to give 28 mg of compound 16 as a white solid, with a yield of 61%. 1H NMR (500 MHz, DMSO) δ 9.56 (d, J = 0.7 Hz, 1H), 9.42 (d, J = 5.2 Hz, 1H), 9.25 (s, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.05 (dd, J = 5.3, 2.3 Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 6.26 (d, J = 1.3 Hz, 1H), 5.39 (d, J = 4.6 Hz, 1H), 3.78 - 3.69 (m, 1H), 1.06 (s, 3H), 1.02 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 162.64, 152.53, 149.31, 146.43, 141.41, 132.14, 124.63, 121.57, 121.42, 121.00, 56.29, 50.40, 50.17, 46.07, 38.55, 37.87, 36.83, 33.43, 30.80, 30.04, 29.95, 28.19, 20.35, 19.37, 15.66. HRMS (ESI) (M+H) + m / z calculated value C 27 H 34 N5O 444.2758, Found: 444.2757.

[0121] Example 17: N-((3S,10R,13S)-17-(1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 17) [ka]

[0122] Compound 73 (35 mg, 0.104 mmol) was added to give 17 mg of compound 17 as a white solid, with a yield of 37%. 1H NMR (500 MHz, DMSO) δ 9.33 (s, 1H), 8.88 (d, J = 6.0 Hz, 2H), 8.79 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 6.2 Hz, 2H), 7.95 (s, 1H), 7.87 (s, 1H), 6.29 (s, 1H), 5.40 (d, J = 4.4 Hz, 1H), 3.79 - 3.69 (m, 1H), 1.07 (s, 3H), 1.03 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.24, 147.80, 146.19, 141.47, 134.57, 125.71, 123.31, 121.65, 121.00, 56.29, 50.33, 50.17, 46.03, 38.55, 37.88, 36.84, 33.44, 30.79, 30.04, 29.99, 28.25, 20.34, 19.37, 15.63. HRMS (ESI) (M+H) + m / z calculated value C 28 H 35 N4O 443.2805, Measured: 443.2812.

[0123] Example 18: N-((3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 18) [ka]

[0124] (3S,10R,13S)-16-formyl-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (74) Compound II-2 (4 g, 10.61 mmol) and potassium carbonate (2.15 g, 15.59 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-ethylimidazole (1 g, 10.4 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the reaction completion was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 3.386 g of brown solid compound 74 was obtained, with a yield of 73%. 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 7.54 (s, 1H), 6.81 (s, 1H), 5.42 (s, 1H), 4.66 - 4.55 (m, 1H), 2.63 (q, J = 7.5 Hz, 2H), 2.04 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H), 1.01 (s, 3H), 0.88 (s, 3H).

[0125] (3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (75) Compound 74 (3.386 g, 5.56 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 1.5 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 36 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and then dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (1-4% methanol / dichloromethane) to obtain the desired product. Finally, 1.264 g of compound 75 was obtained as a yellow solid, with a yield of 39.9%. 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 1.2 Hz, 1H), 6.76 (d, J = 0.9 Hz, 1H), 5.41 (d, J = 3.8 Hz, 1H), 4.67 - 4.56 (m, 1H), 2.63 (q, J = 7.5 Hz, 2H), 2.05 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H), 1.01 (s, 3H), 0.88 (s, 3H).

[0126] (3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (76) Compound 75 (1.26 g, 3.08 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.52 g, 9.27 mmol) was added, and the mixture was stirred at room temperature for 4 h after the addition was complete, and the reaction was monitored for completion by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 537 mg of compound 76 was obtained as a yellow solid, with a yield of 47.5%. 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 0.8 Hz, 1H), 6.78 (s, 1H), 5.64 (dd, J = 3.0, 1.7 Hz, 1H), 5.41 (d, J = 5.2 Hz, 1H), 3.56 (dt, J = 15.5, 5.4 Hz, 1H), 2.63 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H), 1.08 (s, 3H), 1.02 (s, 3H).

[0127] (3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (77) Compound 76 (537 mg, 1.47 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were added together in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.6 mL, 4.41 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.24 mL, 2.94 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 489 mg of compound 77 was obtained as a yellow solid, with a yield of 75.1%. 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 6.77 (s, 1H), 5.67 - 5.64 (m, 1H), 5.48 (d, J = 5.1 Hz, 1H), 4.59 - 4.50 (m, 1H), 3.04 (s, 3H), 2.63 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0128] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-ethyl-1H-imidazole (78) Compound 77 (900 mg, 2.02 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.8 mL, 6.06 mmol) and boron trifluoride ethyl ether (1 mL, 8.08 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 156 mg of white solid 78 was obtained, with a yield of 19.7%. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 1.3 Hz, 1H), 6.84 (s, 1H), 5.94 (dd, J = 3.1, 1.7 Hz, 1H), 5.44 (d, J = 5.0 Hz, 1H), 3.25 (ddd, J = 15.9, 11.6, 4.1 Hz, 1H), 2.87 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H), 1.08 (s, 3H), 1.04 (s, 3H).

[0129] (3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (79) Compound 78 (150 mg, 0.383 mmol) was dissolved in 8 mL of tetrahydrofuran and 3 mL of water and stirred at room temperature, then weighed triphenylphosphine (390 mg, 1.49 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 75 mg of white solid 79, with a yield of 53.57%. 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 6.73 (s, 1H), 5.58 (s, 1H), 5.31 (d, J = 5.0 Hz, 1H), 2.57 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H), 1.01 (s, 3H), 0.97 (s, 3H).

[0130] N-((3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 18) Compound 79 (75 mg, 0.205 mmol) was added to give 57 mg of compound 18 as a white solid, with a yield of 59.07%. 1H NMR (600 MHz, DMSO) δ 8.68 (dd, J = 4.5, 1.4 Hz, 2H), 8.54 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 4.5, 1.5 Hz, 2H), 7.67 (s, 1H), 7.00 (s, 1H), 5.71 (s, 1H), 5.35 (d, J = 4.8 Hz, 1H), 3.73 - 3.65 (m, 1H), 2.44 (dd, J = 15.0, 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 2H), 1.02 (s, 3H), 0.95 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 164.18, 150.62, 148.49, 144.30, 142.07, 141.59, 135.19, 121.72, 121.04, 116.48, 113.77, 56.31, 50.26, 50.10, 45.86, 38.68, 37.95, 36.85, 34.56, 30.90, 30.14, 29.62, 28.36, 21.55, 20.69, 19.40, 16.13, 13.99; (M+H) + m / z calculated value C 30 H 39 N4O 471.3118, Found: 471.3125.

[0131] Example 19: N-((3S,10R,13S)-17-(4-ethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 19) [ka]

[0132] Compound 79 (32 mg, 0.08 mmol) was added to give 10 mg of compound 19 as a white solid, with a yield of 24.3%. 1H NMR (500 MHz, DMSO) δ 9.56 (s, 1H), 9.43 (d, J = 5.1 Hz, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.04 (s, 1H), 7.50 (s, 1H), 6.11 (s, 1H), 5.40 (s, 1H), 3.78 - 3.70 (m, 1H), 2.62 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H), 1.07 (s, 3H), 1.02 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 162.57, 152.59, 149.25, 147.01, 141.43, 138.76, 134.10, 132.08, 124.62, 122.40, 121.06, 116.21, 56.33, 50.32, 50.18, 45.96, 38.57, 37.92, 36.84, 33.82, 30.83, 30.01, 29.82, 28.26, 20.38, 19.34, 19.02, 15.80, 13.24. HRMS (ESI) (M+H) + m / z calculated value C 29 H 38 N5O 472.3071, Found: 472.3066.

[0133] Example 20: N-((3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 20) [ka]

[0134] (3S,10R,13S)-16-formyl-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (80) Compound II-2 (7 g, 18.57 mmol) and potassium carbonate (3.8 g, 27.55 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 5-isopropylimidazole (1.98 g, 17.97 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.28 g of brown solid compound 80 was obtained, with a yield of 27.3%. 1 H NMR (400 MHz, CDCL3) δ 9.76 (s, 1H), 7.54 (s, 1H), 6.78 (s, 1H). 5.42 (d, J = 5.0 Hz, 1H), 4.60 - 4.54 (m, 1H), 2.96 - 2.80 (m, 2H), 2.04 (s, 3H), 1.26 (t, J = 6.1 Hz, 6H), 1.08 (s, 3H), 0.96 (s, 3H).

[0135] (3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (81) Compound 80 (2.28 g, 5.06 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 1 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 24 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.13 g of yellow solid compound 81 was obtained, with a yield of 52.8%. 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 0.8 Hz, 1H), 6.96 (s, 1H), 5.43 (d, J = 5.0 Hz, 1H), 4.65 - 4.54 (m, 1H), 2.96 - 2.80 (m, 2H), 2.04 (s, 3H), 1.26 (t, J = 6.1 Hz, 6H), 1.08 (s, 3H), 0.96 (s, 3H).

[0136] (3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (82) Compound 81 (1 g, 2.37 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.45 g, 8.02 mmol) was added, and the mixture was stirred at room temperature for 4 h after the addition was completed, and the reaction was monitored for completion by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automated chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 426 mg of compound 82 was obtained as a white solid, with a yield of 47.3%. 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 1.2 Hz, 1H), 6.75 (s, 1H), 5.64 (dd, J = 3.1, 1.7 Hz, 1H), 5.42 - 5.39 (m, 1H), 3.60 - 3.51 (m, 1H), 2.91 (dt, J = 13.7, 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.08 (s, 3H), 1.03 (s, 3H).

[0137] (3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (83) Compound 82 (426 mg, 1.12 mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.47 mL, 3.45 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.18 mL, 2.21 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel in the system and purified by automated chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 490 mg of compound 83 was obtained as a white solid, with a yield of 95.5%. 1 H NMR (400 MHz, DMSO) δ 7.56 (s, 1H), 6.74 (s, 1H), 5.63 (s, 1H), 5.46 (s, 1H), 4.59 - 4.49 (m, 1H), 3.02 (s, 3H), 2.90 (dt, J = 13.7, 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H), 1.08 (s, 3H), 1.01 (s, 3H).

[0138] 1-((3S,10R,13S)-3-Azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-4-isopropyl-1H-imidazole (84) Compound 83 (490 mg, 1.07 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.45 mL, 3.4 mmol) and boron trifluoride ethyl etherate (0.53 mL, 4.28 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 151 mg of white solid 84 was obtained, with a yield of 34.87%. 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 6.74 (s, 1H), 5.67 - 5.65 (m, 1H), 5.41 (d, J = 4.9 Hz, 1H), 3.21 (ddd, J = 10.2, 8.7, 4.7 Hz, 1H), 2.88 (dq, J = 13.8, 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H), 1.04 (s, 3H), 1.00 (s, 3H).

[0139] (3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (85) Compound 84 (151 mg, 0.372 mmol) was dissolved in 6 mL of tetrahydrofuran and 4 mL of water and stirred at room temperature, then weighed triphenylphosphine (390 mg, 1.49 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 100 mg of white solid 85, with a yield of 70.77%. 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 6.72 (s, 1H), 5.60 (s, 1H), 5.34 (d, J = 5.0 Hz, 1H), 2.86 (dq, J = 13.6, 6.8 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H), 1.03 (s, 3H), 0.99 (s, 3H).

[0140] N-((3S,10R,13S)-17-(4-isopropyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 20) Compound 85 (100 mg, 0.264 mmol) was added to give 63 mg of compound 20 as a white solid, with a yield of 49.2%. 1H NMR (500 MHz, DMSO) δ 9.28 (d, J = 1.5 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.84 (d, J = 5.7 Hz, 2H), 8.00 (d, J = 6.2 Hz, 2H), 7.68 (s, 1H), 6.30 - 6.27 (m, 1H), 5.39 (d, J = 5.0 Hz, 1H), 3.75 (qd, J = 12.4, 5.0 Hz, 1H), 3.03 (dq, J = 14.0, 7.0 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H), 1.07 (s, 3H), 1.04 (s, 3H). 13C NMR (126 MHz, DMSO) δ 163.32, 158.66, 148.22, 146.41, 144.36, 141.55, 141.00, 133.74, 124.80, 122.97, 120.92, 116.31, 56.36, 50.34, 50.16, 45.99, 38.56, 37.91, 36.85, 33.45, 30.80, 30.04, 29.89, 28.24, 25.20, 21.77, 20.41, 19.37, 15.63. HRMS (ESI) (M+H)+ m / z calculated value C 31 H 41 N4O 485.3275, Found: 485.3279.

[0141] Example 21: N-((3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 21) [ka]

[0142] (3S,10R,13S)-16-Formyl-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (86) Compound II-2 (10 g, 26.53 mmol) and potassium carbonate (5.49 g, 39.8 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-nitroimidazole (3 g, 26.53 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 7 g of compound 86 was obtained as a gray-green solid, with a yield of 58.3%. 1 H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 5.44 (d, J = 5.1 Hz, 1H), 4.63 (ddd, J = 16.0, 11.1, 5.1 Hz, 1H), 2.77 (dd, J = 15.7, 6.0 Hz, 1H), 2.06 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H).

[0143] (3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (87) Compound 86 (7 g, 15.44 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 3.5 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 39 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.07 g of compound 87 was obtained as a yellow solid, with a yield of 16.3%. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 1.3 Hz, 1H), 5.96 - 5.92 (m, 1H), 5.43 (d, J = 5.1 Hz, 1H), 4.68 - 4.57 (m, 1H), 2.06 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H).

[0144] (3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (88) Compound 87 (1.07 g, 2.52 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.45 g, 8.02 mmol) was added, and the mixture was stirred at room temperature for 4 h after the addition was completed, and the reaction was monitored for completion by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automated chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 910 mg of compound 88 was obtained as a white solid, with a yield of 94.3%. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.4 Hz, 1H), 5.95 (dd, J = 3.0, 1.6 Hz, 1H), 5.40 (d, J = 5.1 Hz, 1H), 3.61 - 3.51 (m, 1H), 1.08 (s, 3H), 1.05 (s, 3H).

[0145] (3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (89) Compound 88 (910 mg, 2.375 mmol) and 4-dimethylaminopyridine (30 mg, 0.245 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (1 mL, 7.34 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.4 mL, 4.91 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 1.02 g of compound 89 was obtained as a yellow-green solid, with a yield of 93.1%. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 5.95 (dd, J = 3.1, 1.7 Hz, 1H), 5.48 (d, J = 4.8 Hz, 1H), 4.60 - 4.51 (m, 1H), 3.04 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H).

[0146] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-nitro-1H-imidazole (90) Compound 89 (1.02 g, 2.21 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.88 mL, 6.65 mmol) and boron trifluoride ethyl etherate (1.1 mL, 8.88 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 714 mg of yellow solid 90 was obtained, with a yield of 78.63%. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.4 Hz, 1H), 5.95 (dd, J = 3.2, 1.7 Hz, 1H), 5.45 (d, J = 5.1 Hz, 1H), 3.30 - 3.20 (m, 1H), 1.08 (s, 3H), 1.05 (s, 3H).

[0147] (3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (91) Compound 90 (713 mg, 1.75 mmol) was dissolved in 20 mL of tetrahydrofuran and 10 mL of water and stirred at room temperature, then weighed triphenylphosphine (1.8 g, 6.86 mmol) was added, and the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, collected and combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 75 mg of white solid 91, the yield was 11.2%, and it was directly used in the next step.

[0148] N-((3S,10R,13S)-17-(4-nitro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carbamide (compound 21) Compound 91 (75 mg, 0.196 mmol) was added to give 68 mg of compound 21 as a white solid, with a yield of 70.8%. 1 H NMR (500 MHz, DMSO) δ 9.54 (dd, J = 2.1, 1.3 Hz, 1H), 9.43 (dd, J = 5.3, 1.1 Hz, 1H), 8.82 (d, J = 7.9 Hz, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.99 (dd, J = 5.3, 2.3 Hz, 1H), 6.17 (d, J = 1.2 Hz, 1H), 5.39 (d, J = 4.8 Hz, 1H), 3.79 - 3.68 (m, 1H), 1.06 (s, 3H), 1.01 (s, 3H). 13C NMR (126 MHz, DMSO) δ 162.69, 159.92, 152.51, 149.26, 148.07, 146.98, 141.37, 136.23, 132.03, 124.59, 123.21, 121.03, 120.00, 56.22, 50.32, 50.15, 46.07, 38.59, 37.87, 36.83, 33.78, 30.84, 30.08, 29.91, 28.37, 20.49, 19.38, 15.78. (ESI) (M+H) + m / z calculated value C 27 H 33 N6O3489.2609, Found: 489.2603.

[0149] Example 22: N-((3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 22) [ka]

[0150] (3S,10R,13S)-16-formyl-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (92) Compound II-2 (3.6 g, 9.55 mmol) and potassium carbonate (3.96 g, 28.7 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-trifluoromethylimidazole (1.56 g, 11.46 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.2 g of compound 92 was obtained as a yellow solid, with a yield of 48.4%. 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.67 (s, 1H), 7.45 (s, 1H), 5.43 (d, J = 5.1 Hz, 1H), 4.63 (dq, J = 15.9, 5.2 Hz, 1H), 2.73 (dd, J = 15.5, 6.1 Hz, 1H), 2.06 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H).

[0151] (3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (93) Compound 92 (2.2 g, 4.62 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 2 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160°C, and the reaction was carried out for 38 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and then dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 725 mg of white solid compound 93 was obtained, with a yield of 35.0%. 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.36 (s, 1H), 5.80 (s, 1H), 5.41 (d, J = 4.8 Hz, 1H), 4.66 - 4.56 (m, 1H), 2.04 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H).

[0152] (3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (94) Compound 93 (720 mg, 1.61 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.36 g, 6.02 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 4 h and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 650 mg of compound 94 was obtained as a pale yellow solid, with a yield of 99.5%. 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.36 (s, 1H), 5.80 (s, 1H), 5.39 (s, 1H), 3.61 - 3.48 (m, 1H), 1.06 (s, 3H), 1.00 (s, 3H).

[0153] (3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (95) Compound 4 (650 mg, 1.60 mmol) and 4-dimethylaminopyridine (20 mg, 0.164 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.66 mL, 4.84 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.25 mL, 3.06 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.747 g of compound 95 was obtained as a pale yellow solid, with a yield of 96.4%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.39 (s, 1H), 5.84 (d, J = 1.3 Hz, 1H), 5.48 (d, J = 5.0 Hz, 1H), 4.56 (tdd, J = 11.3, 7.0, 4.7 Hz, 1H), 3.04 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H).

[0154] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-trifluoromethyl-1H-imidazole (96) Compound 95 (650 mg, 1.34 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (1.06 mL, 8.01 mmol) and boron trifluoride ethyl ether (1.66 mL, 13.4 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 570 mg of yellow solid 96 was obtained, with a yield of 98.4%. 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.38 (s, 1H), 5.82 (dd, J = 3.0, 1.6 Hz, 1H), 5.45 (d, J = 5.0 Hz, 1H), 3.24 (ddd, J = 11.4, 8.8, 4.0 Hz, 1H), 1.07 (s, 3H), 1.03 (s, 3H).

[0155] (3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (97) Compound 96 (650 mg, 1.51 mmol) was dissolved in 6 mL of tetrahydrofuran and 6 mL of water and stirred at room temperature, then weighed triphenylphosphine (435 mg, 1.66 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 355 mg of white solid 97, with a yield of 58.1%. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 7.72 (s, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 5.49 (d, J = 3.6 Hz, 1H), 3.13 (s, 1H), 1.10 (s, 3H), 1.03 (s, 3H).

[0156] N-((3S,10R,13S)-17-(4-trifluoromethyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carbamide (compound 22) Compound 97 (100 mg, 0.247 mmol) was added to give 96 mg of compound 22 as a white solid, with a yield of 76.2%. 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.36 (d, J = 5.0 Hz, 1H), 7.92 (dd, J = 5.1, 1.9 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 6.98 (d, J = 7.9 Hz, 1H), 5.83 (d, J = 1.1 Hz, 1H), 5.46 (d, J = 4.9 Hz, 1H), 4.03 - 3.91 (m, 1H), 1.09 (s, 3H), 1.02 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 162.60, 152.55, 149.22, 147.44, 141.36, 137.99, 131.95, 124.58, 121.15, 56.25, 50.30, 50.23, 45.96, 38.60, 37.87, 36.83, 33.99, 31.43, 30.87, 30.10, 29.78, 28.29, 22.53, 20.52, 19.38, 15.88, 14.35. HRMS (ESI) (M+H) + m / z calculated value C 28 H 31 F3N5O 510.2486, measured value: 510.2489.

[0157] Example 23: N-((3S,10R,13S)-17-(4-methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 23) [ka]

[0158] (3S,10R,13S)-16-formyl-17-(4-methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl acetate (98) Compound II-2 (4.2 g, 11.14 mmol) and potassium carbonate (4.6 g, 33.35 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-methoxyimidazole (1.09 g, 11.1 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (10-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2 g of compound 98 was obtained as a yellow solid, with a yield of 41.08%. 1 H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.31 (d, J = 1.5 Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.63 (ddd, J = 15.9, 10.7, 5.3 Hz, 1H), 3.88 (s, 3H), 2.06 (s, 3H), 1.09 (d, J = 1.9 Hz, 6H).

[0159] (3S,10R,13S)-17-(4-Methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl acetate (99) Compound 98 (2.6 g, 5.93 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 2.6 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160°C, and the reaction was carried out for 30 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and then dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 0.45 g of compound 99 was obtained as a yellow solid, with a yield of 18.75%. 1 H NMR (400 MHz, DMSO) δ 7.28 (s, 1H), 6.34 (s, 1H), 5.61 (s, 1H), 5.40 (d, J = 4.2 Hz, 1H), 4.66 - 4.55 (m, 1H), 3.81 (d, J = 0.5 Hz, 3H), 2.03 (s, 3H), 1.06 (s, 3H), 1.00 (s, 3H).

[0160] (3S,10R,13S)-17-(4-Methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (100) Compound 99 (0.45 g, 1.10 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (0.246 g, 4.38 mmol) was added, and the mixture was stirred at room temperature for 4 h after the addition was completed, and the reaction was monitored for completion by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automated chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 330 mg of compound 100 was obtained as a yellow solid, with a yield of 81.88%. 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 1.3 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.63 (d, J = 1.2 Hz, 1H), 5.40 (d, J = 5.1 Hz, 1H), 3.84 (s, 3H), 3.55 (ddd, J = 15.7, 11.0, 4.5 Hz, 1H), 1.07 (s, 3H), 1.02 (s, 3H).

[0161] (3S,10R,13S)-17-(4-Methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl methanesulfonate (101) Compound 100 (330 mg, 0.896 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.4 mL, 2.936 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.14 mL, 1.72 mmol) was slowly added, and after the addition was complete, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. The mixture was then quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.38 g of compound 101 was obtained as an orange-yellow solid, with a yield of 95.2%. 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 1.4 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.64 (dd, J = 3.0, 1.6 Hz, 1H), 5.48 (d, J = 5.0 Hz, 1H), 4.60 - 4.50 (m, 1H), 3.84 (s, 3H), 3.04 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0162] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-methoxy-1H-imidazole (102) Compound 101 (0.4 g, 0.896 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.54 mL, 4.08 mmol) and boron trifluoride ethyl ether (1.74 mL, 14 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 300 mg of yellow solid 102 was obtained, with a yield of 84.98%. 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 6.37 (s, 1H), 5.65 (s, 1H), 5.44 (d, J = 4.8 Hz, 1H), 3.84 (s, 3H), 3.23 (dt, J = 10.2, 4.7 Hz, 1H), 1.07 (s, 3H), 1.03 (s, 3H).

[0163] (3S,10R,13S)-17-(4-Methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (103) Compound 102 (300 mg, 0.763 mmol) was dissolved in 10 mL of tetrahydrofuran and 50 mL of water and stirred at room temperature, then weighed triphenylphosphine (0.6 g, 2.29 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, some of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 50 mg of pale yellow solid 103, with a yield of 11.2%. 1 H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.37 (s, 1H), 5.63 (s, 1H), 5.36 (d, J = 4.8 Hz, 1H), 3.83 (s, 3H), 2.63 (td, J = 11.3, 5.6 Hz, 1H), 1.05 (s, 3H), 1.02 (s, 3H).

[0164] N-((3S,10R,13S)-17-(4-methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)isonicotinamide (compound 23) Compound 103 (61 mg, 0.166 mmol) was added to give 52 mg of compound 23 as a white solid, with a yield of 66.67%. 1H NMR (500 MHz, DMSO) δ 8.81 (d, J = 4.9 Hz, 1H), 8.71 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 3.5 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.56 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 5.89 (s, 1H), 5.39 (d, J = 4.7 Hz, 1H), 3.76 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.68, 155.36, 149.08, 143.72, 141.49, 132.66, 132.04, 130.36, 129.17, 122.53, 121.04, 96.85, 57.74, 56.39, 50.23, 45.86, 38.62, 37.97, 36.76, 34.30, 30.82, 30.02, 29.58, 28.31, 20.55, 19.30, 15.97. HRMS (ESI) (M+H) + m / z calculated value C 29 H 37 N4O2473.2911, Measured: 473.2917.

[0165] Example 24: N-((3S,10R,13S)-17-(4-methoxy-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 24) [ka]

[0166] Compound 103 (70 mg, 0.191 mmol) was added to give 58 mg of compound 24 as a white solid, with a yield of 64.4%. 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 9.31 (d, J = 5.0 Hz, 1H), 7.93 - 7.90 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 6.36 (s, 1H), 5.64 (s, 1H), 5.43 (d, J = 4.3 Hz, 1H), 4.01 - 3.89 (m, 1H), 3.80 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 162.84, 157.25, 151.79, 148.64, 148.55, 140.32, 132.36, 130.58, 124.22, 121.70, 118.09, 95.87, 56.87, 56.16, 50.86, 50.32, 46.09, 38.77, 37.72, 36.77, 34.83, 30.89, 30.12, 29.66, 28.62, 20.56, 19.13, 15.93; (M+H) + m / z calculated value C 28 H 36 N5O2474.2864, Found: 474.2875.

[0167] Example 25: N-((3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carboxamide (compound 25) [ka]

[0168] (3S,10R,13S)-16-formyl-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (104) Compound II-2 (3.8 g, 10.08 mmol) and potassium carbonate (4.07 g, 29.5 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-cyanoimidazole (1.03 g, 11.06 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 3.64 g of yellow solid compound 104 was obtained, with a yield of 82.4%. 1 H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.66 (s, 2H), 5.43 (d, J = 5.0 Hz, 1H), 4.66 - 4.57 (m, 1H), 2.74 (dd, J = 15.6, 6.1 Hz, 1H), 2.05 (s, 3H), 1.09 (s, 6H).

[0169] (3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl acetate (105) Compound 104 (3.6 g, 8.31 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 3.6 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 30 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.8 g of yellow solid compound 105 was obtained, with a yield of 53.57%. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 1.1 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 5.86 (dd, J = 3.2, 1.7 Hz, 1H), 5.43 (d, J = 5.1 Hz, 1H), 4.63 (ddd, J = 15.9, 11.1, 5.1 Hz, 1H), 2.06 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H).

[0170] (3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (106) Compound 105 (0.315 g, 0.78 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (43 mg, 0.78 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 4 h, and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, and further dried over anhydrous sodium sulfate. After filtration, the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 175 mg of compound 106 was obtained as a white solid, with a yield of 62.05%. 1 H NMR (400 MHz, DMSO) δ 8.37 (d, J = 0.9 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 6.04 (s, 1H), 5.31 (d, J = 4.4 Hz, 1H), 4.65 (d, J = 4.5 Hz, 1H), 3.27 (td, J = 10.8, 5.5 Hz, 1H), 0.99 (s, 3H), 0.97 (s, 3H).

[0171] (3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (107) Compound 106 (175 mg, 0.482 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.2 mL, 1.64 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (75 μL, 0.856 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 5 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.21 g of compound 107 was obtained as a pale yellow solid, with a yield of 99%. 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.59 (d, J = 1.0 Hz, 1H), 5.87 (dd, J = 3.1, 1.7 Hz, 1H), 5.48 (d, J = 4.9 Hz, 1H), 4.55 (tdd, J = 11.5, 7.2, 4.7 Hz, 1H), 3.04 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0172] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-cyano-1H-imidazole (108) Compound 107 (0.21 g, 0.48 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.19 mL, 1.42 mmol) and boron trifluoride ethyl ether (0.3 mL, 2.42 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 110 mg of yellow solid 108 was obtained, with a yield of 59.45%. 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.59 (d, J = 1.0 Hz, 1H), 5.86 (dd, J = 3.1, 1.7 Hz, 1H), 5.45 (d, J = 5.1 Hz, 1H), 3.24 (td, J = 12.4, 5.9 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H).

[0173] (3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (109) Compound 108 (110 mg, 0.283 mmol) was dissolved in 6 mL of tetrahydrofuran and 3 mL of water and stirred at room temperature, then weighed triphenylphosphine (90 mg, 0.343 mmol) was added, then the temperature was slowly raised to 60 ° C. and stirred at that temperature overnight, and the completion of the reaction was monitored by TLC. Then, some of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, collected and combined with the organic phase, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 60 mg of white solid 109, with a yield of 58.2%. It was directly put into the next step.

[0174] N-((3S,10R,13S)-17-(4-cyano-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-yl)pyridazine-4-carbamide (compound 25) Compound 109 (60 mg, 0.166 mmol) was added to give 25 mg of compound 25 as a yellow solid, with a yield of 32.5%. 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 9.36 (s, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 6.78 (s, 1H), 5.85 (s, 1H), 5.44 (d, J = 4.6 Hz, 1H), 3.96 (s, 1H), 1.07 (s, 3H), 0.99 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 162.68, 152.00, 148.45, 147.18, 140.19, 137.62, 132.40, 126.60, 124.25, 122.79, 121.64, 114.77, 114.44, 56.11, 50.66, 50.26, 46.32, 38.92, 37.69, 36.78, 34.57, 30.88, 30.11, 29.94, 28.69, 20.60, 19.31, 15.88. (ESI) (M+H) + m / z calculated value C 28 H 33 N6O 469.271, Found: 469.2706.

[0175] Example 26: N-((3S,10R,13S)-10,13-dimethyl-17-(4-(methylaminoformyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)pyridazine-4-carboxamide (compound 26) [ka]

[0176] 1-((3S,10R,13S)-3-acetoxy-16-formyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate ethyl (110) Compound II-2 (2 g, 5.3 mmol) and potassium carbonate (1.1 g, 7.97 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, imidazole-4-carboxylate ethyl (0.75 g, 5.35 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature for 1 h, and the reaction completion was monitored by TLC. After the reaction was completed, the mixture was extracted with acetic acid, and the organic phase was collected and washed twice with saturated saline, and then dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 1.97 g of white solid compound 110 was obtained, with a yield of 77.25%. 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 5.43 (d, J = 4.8 Hz, 1H), 4.67 - 4.56 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.73 (dd, J = 15.5, 6.2 Hz, 1H), 2.06 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.09 (s, 3H).

[0177] 1-((3S,10R,13S)-3-Acetoxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate ethyl (111) Compound 110 (317 mg, 0.66 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature, then 0.3 g of palladium carbon was added, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 160 ° C., and the reaction was carried out for 18 hours, and the completion of the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added, and the mixture was stirred for a certain period of time, and then filtered through diatomaceous earth. The filtrate was collected, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 108 mg of white solid compound 111 was obtained, with a yield of 36.24%. 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 1.1 Hz, 1H), 7.65 (d, J = 1.0 Hz, 1H), 5.83 (d, J = 1.3 Hz, 1H), 5.43 (d, J = 5.0 Hz, 1H), 4.63 (ddd, J = 16.0, 10.8, 5.3 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0178] 1-((3S,10R,13S)-3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-N-methyl-1H-imidazole-4-carboxamide (112) Compound 111 (0.75 g, 1.66 mmol) was placed in a sealed tube, and 10 mL of alcoholic solution of methylamine was added. The sealed tube was reacted at 50° C. overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was cooled to room temperature, extracted with ethyl acetate and water, the organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automated chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 408 mg of compound 112 was obtained as a white solid, with a yield of 62.29%. 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 1.3 Hz, 1H), 7.55 (d, J = 1.3 Hz, 1H), 7.17 (d, J = 4.4 Hz, 1H), 5.79 (dd, J = 3.1, 1.7 Hz, 1H), 5.39 (d, J = 5.2 Hz, 1H), 3.61 - 3.51 (m, 1H), 2.99 (d, J = 5.0 Hz, 3H), 1.07 (s, 3H), 1.02 (s, 3H).

[0179] (3S,10R,13S)-10,13-Dimethyl-17-(4-(methylaminoformyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (113) Compound 112 (408 mg, 1.03 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.43 mL, 3.28 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (160 μL, 2.06 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 4 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.46 g of compound 113 was obtained as a pale yellow solid, with a yield of 94.26%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.71 (s, 1H), 7.39 (s, 1H), 5.86 (dd, J = 3.0, 1.6 Hz, 1H), 5.48 (d, J = 4.7 Hz, 1H), 4.56 (ddd, J = 14.2, 11.4, 4.8 Hz, 1H), 3.04 (s, 3H), 3.00 (d, J = 5.0 Hz, 3H), 1.09 (s, 3H), 1.03 (s, 3H).

[0180] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-N-methyl-1H-imidazole-4-carboxamide (114) Compound 113 (0.46 g, 0.97 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.5 mL, 3.55 mmol) and boron trifluoride ethyl etherate (0.6 mL, 4.84 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated on silica gel, and purified by automated chromatography (30-60% ethyl acetate / petroleum ether) to give the desired product. Finally, 219 mg of white solid 114 was obtained, with a yield of 53.68%. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 1.3 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.22 (d, J = 4.4 Hz, 1H), 5.81 (dd, J = 3.1, 1.7 Hz, 1H), 5.44 (d, J = 5.1 Hz, 1H), 3.24 (ddd, J = 9.9, 8.7, 3.9 Hz, 1H), 2.99 (d, J = 5.0 Hz, 3H), 1.07 (s, 3H), 1.02 (s, 3H).

[0181] 1-((3S,10R,13S)-3-amino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-N-methyl-1H-imidazole-4-carboxamide (115) Compound 114 (219 mg, 0.52 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water and stirred at room temperature, then weighed triphenylphosphine (205 mg, 0.78 mmol) was added, and the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at which time a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, collected and combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 58 mg of white solid 115, with a yield of 28.3%. It was directly used in the next step.

[0182] N-((3S,10R,13S)-10,13-dimethyl-17-(4-(methylaminoformyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl)pyridazine-4-carboxamide (compound 26) Compound 115 (58 mg, 0.147 mmol) was added to give 53 mg of compound 26 as a white solid, with a yield of 72.1%. 1 H NMR (500 MHz, DMSO) δ 9.52 - 9.50 (m, 1H), 9.41 (dd, J = 5.3, 1.0 Hz, 1H), 8.79 (d, J = 7.9 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.88 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 1.1 Hz, 1H), 5.96 (s, 1H), 5.37 (d, J = 4.6 Hz, 1H), 3.76 - 3.65 (m, 1H), 2.72 (d, J = 4.8 Hz, 3H), 1.03 (s, 3H), 0.97 (s, 3H). 13C NMR (126 MHz, DMSO) δ 162.69, 162.63, 152.55, 149.27, 147.76, 141.36, 137.68, 136.34, 132.12, 124.59, 121.17, 120.30, 119.79, 56.20, 50.32, 50.22, 46.06, 38.61, 37.88, 36.84, 34.28, 30.89, 30.12, 29.73, 28.30, 25.92, 20.58, 19.39, 15.98. HRMS (ESI) (M+H) + m / z calculated value C 28 H 41 N2O6501.2959, Measured: 501.2954.

[0183] Example 27: 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazine-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylic acid (compound 27) [ka]

[0184] 1-((3S,10R,13S)-3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate methyl (116) Compound 111 (2.14 g, 4.73 mmol) was placed in a flask, and 20 mL of a methanolic solution of sodium methoxide was added. The mixture was stirred at room temperature overnight and monitored for completion by TLC. After completion of the reaction, the mixture was neutralized with a 4 M methanolic solution of hydrochloric acid. When the solution turned from yellow to colorless, it was extracted with dichloromethane and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solution was rotary evaporated to obtain the desired product. Finally, 1.85 g of compound 116 was obtained as a yellow solid in a yield of 98.9%. 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 1.2 Hz, 1H), 7.94 (s, 1H), 6.00 (s, 1H), 5.28 (d, J = 4.4 Hz, 1H), 4.65 (s, 1H), 3.74 (s, 3H), 3.25 (s, 1H), 0.97 (s, 3H), 0.95 (s, 3H).

[0185] 1-((3S,10R,13S)-10,13-dimethyl-3-((methylsulfonyl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate methyl (117) Compound 116 (105 mg, 0.25 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.1 mL, 0.75 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (39 μL, 0.5 mmol) was slowly added, and after the addition was complete, the mixture was stirred at room temperature for 4 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 117 mg of compound 117 was obtained as a white solid, with a yield of 97.8%. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 2H), 5.83 (s, 1H), 5.45 (d, J = 4.9 Hz, 1H), 4.54 (d, J = 5.0 Hz, 1H), 3.91 (s, 3H), 3.02 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H).

[0186] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate methyl (118) Compound 117 (0.11 g, 0.23 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (92 μL, 0.69 mmol) and boron trifluoride ethyl etherate (143 μL, 1.15 mmol) were added in sequence in a plastic charging apparatus, and after the addition was completed, the mixture was stirred at room temperature overnight and the reaction was monitored for completion by TLC. Then, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane, the organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated with silica gel, and purified by automated chromatography (30-60% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 66 mg of white solid 118 was obtained, with a yield of 68.7%. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.68 (s, 1H), 5.84 (s, 1H), 5.44 (d, J = 5.0 Hz, 1H), 3.93 (s, 3H), 3.28 - 3.19 (m, 1H), 1.07 (s, 3H), 1.02 (s, 3H).

[0187] 1-((3S,10R,13S)-3-amino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate methyl (119) Compound 118 (55 mg, 0.13 mmol) was dissolved in 6 mL of tetrahydrofuran and 6 mL of water and stirred at room temperature, then weighed triphenylphosphine (51 mg, 0.19 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 29 mg of white solid 119, with a yield of 55.8%. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.63 (s, 1H), 5.82 (s, 1H), 5.38 (s, 1H), 3.92 (d, J = 2.1 Hz, 3H), 1.06 (s, 3H), 1.01 (s, 3H).

[0188] 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazine-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylate methyl (120) Compound 119 (24 mg, 0.06 mmol) was added to give 22 mg of compound 120 as a white solid, with a yield of 73.3%. 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 9.31 (d, J = 5.2 Hz, 1H), 7.93 (dd, J = 5.0, 1.8 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.29 (s, 1H), 5.83 (s, 1H), 5.44 (d, J = 4.6 Hz, 1H), 3.95 (qd, J = 12.3, 6.4 Hz, 1H), 3.89 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0189] 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazine-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-1H-imidazole-4-carboxylic acid (compound 27) Compound 120 (50 mg, 0.1 mmol) was dissolved in 5 mL of methanol and 5 mL of tetrahydrofuran and stirred at room temperature. After adding 1 mL of 2 M sodium hydroxide solution, the mixture was reacted at room temperature for 2 h, and the reaction completion was monitored by TLC. After that, a part of the solution was removed by rotary evaporation, and then the pH was adjusted to be acidic with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 33 mg of white solid 27 was obtained, and the yield was 67.8%. 1 H NMR (500 MHz, DMSO) δ 9.54 (s, 1H), 9.43 (d, J = 4.7 Hz, 1H), 8.82 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 6.00 (s, 1H), 5.39 (s, 1H), 3.73 (s, 1H), 1.05 (s, 3H), 0.99 (s, 3H). 13C NMR (126 MHz, DMSO) δ 163.85, 162.63, 152.54, 149.22, 147.59, 141.49, 137.45, 134.15, 132.11, 124.58, 124.28, 121.15, 120.50, 56.23, 50.32, 50.22, 46.00, 38.60, 37.88, 36.83, 34.25, 30.81, 30.18, 29.80, 28.22, 21.45, 20.56, 19.31, 15.90. HRMS (ESI) (M+H) + m / z calculated value C 28 H 34 N5O3488.2656, Found: 488.2657.

[0190] Example 28: 4-Fluoro-N-((3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)benzamide (compound 28) [ka]

[0191] (3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-16-formyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl acetate (121) Compound II-2 (4.38 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were added together in a flask, and then dried N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-fluoroimidazole (1 g, 11.62 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.8 g of brownish yellow solid compound 121 was obtained, with a yield of 36.3%. 1 H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.25 (s, 1H), 6.69 (dd, J = 8.1, 1.6 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 4.67 - 4.58 (m, 1H), 2.06 (s, 3H), 1.09 (s, 6H).

[0192] (3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (122) Compound 1,3-bis(diphenylphosphino)propane (0.48 g, 1.16 mmol) and carbonylbis(triphenylphosphine)rhodium(I) chloride (0.48 g, 0.69 mmol) were dissolved in dry xylene, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 80°C and stirred for half an hour, and then compound 121 (1 g, 2.35 mmol) was added, the reaction temperature was raised to 135°C, and the reaction was stirred at that temperature and reacted overnight. After the reaction was completed, the reaction system was cooled to room temperature, and then extracted with ethyl acetate and water, the organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 230 mg of compound 122 was obtained as a white solid, with a yield of 24.62%. 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.72 (s, 1H), 5.43 (d, J = 5.1 Hz, 1H), 4.63 (tt, J = 10.7, 5.1 Hz, 1H), 2.06 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0193] (3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (123) Compound 122 (0.22 g, 0.55 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (50 mg, 0.9 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 1 h and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate. After filtration, the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 167 mg of compound 123 was obtained as a white solid, with a yield of 84.77%. 1 H NMR (600 MHz, CDCl3) δ 7.14 (s, 1H), 6.50 (dd, J = 8.1, 1.4 Hz, 1H), 5.62 (dd, J = 3.0, 1.7 Hz, 1H), 5.33 - 5.29 (m, 1H), 3.50 - 3.44 (m, 1H), 0.99 (s, 3H), 0.93 (s, 3H).

[0194] (3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (124) Compound 123 (160 mg, 0.449 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.2 mL, 1.64 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (150 μL, 1.71 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 2 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.29 g of compound 124 was obtained as a yellow solid, which was directly used in the next step.

[0195] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-fluoro-1H-imidazole (125) Compound 124 (0.29 g, 0.68 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.3 mL, 2.24 mmol) and boron trifluoride ethyl ether (0.34 mL, 2.42 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (5-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 146 mg of compound 125 was obtained as a white solid, with a yield of 56.59%. 1 H NMR (600 MHz, CDCl3) δ 7.16 (s, 1H), 6.50 (dd, J = 8.1, 1.1 Hz, 1H), 5.63 (dd, J = 3.0, 1.6 Hz, 1H), 5.36 (d, J = 5.3 Hz, 1H), 3.18 - 3.12 (m, 1H), 0.98 (s, 3H), 0.93 (s, 3H).

[0196] (3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (126) Compound 125 (140 mg, 0.367 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water and stirred at room temperature, then weighed triphenylphosphine (145 mg, 0.553 mmol) was added, then the temperature was slowly raised to 60 ° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, some of the solvent was removed by rotary evaporation, 20 mL of ethyl acetate was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at which time a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of ethyl acetate, collected and combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 72 mg of white solid compound 126, with a yield of 55.38%. It was directly put into the next step.

[0197] 4-Fluoro-N-((3S,10R,13S)-17-(4-fluoro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)benzamide (compound 28) Compound 126 (47 mg, 0.132 mmol) was added to give 47 mg of compound 28 as a white solid, with a yield of 74.6%. 1 H NMR (600 MHz, DMSO) δ 8.28 (d, J = 8.0 Hz, 1H), 7.89 (dd, J = 8.7, 5.6 Hz, 2H), 7.54 (s, 1H), 7.25 (t, J = 8.8 Hz, 2H), 7.09 (dd, J = 8.2, 1.6 Hz, 1H), 5.83 (s, 1H), 5.33 (d, J = 4.7 Hz, 1H), 3.72 - 3.64 (m, 1H), 1.01 (s, 3H), 0.95 (s, 3H). 13C NMR (151 MHz, DMSO) δ 164.17, 162.95, 157.49, 155.96, 147.69, 141.24, 131.13, 129.85, 129.80, 129.62, 129.52, 120.35, 118.37, 115.14, 115.00, 97.20, 97.00, 55.84, 49.78, 49.48, 45.37, 38.42, 37.54, 36.38, 33.73, 30.42, 29.63, 29.15, 28.05, 20.14, 18.92, 15.49. HRMS (ESI) (M+H) + m / z calculated value C 29 H 34 F2N3O 478.2664, Measured: 478.2665.

[0198] Example 29: 4-Fluoro-N-((3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)benzamide (compound 29) [ka]

[0199] (3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-16-formyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl acetate (127) Compound II-2 (4 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-bromoimidazole (1.5 g, 10.27 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the reaction completion was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 3.4 g of yellow solid compound 127 was obtained, with a yield of 68.19%. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.11 (d, J = 1.5 Hz, 1H), 5.43 (d, J = 5.1 Hz, 1H), 4.63 (dq, J = 15.9, 5.2 Hz, 1H), 2.71 (dd, J = 15.5, 6.3 Hz, 1H), 2.06 (s, 3H), 1.08 (s, 6H).

[0200] (3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (128) Compound 1,3-bis(diphenylphosphino)propane (0.21 g, 0.51 mmol) and carbonylbis(triphenylphosphine)rhodium(I) chloride (0.17 g, 0.24 mmol) were dissolved in dry xylene, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 80°C and stirred for half an hour, and then compound 127 (1 g, 2.06 mmol) was added, the reaction temperature was raised to 135°C, and the reaction was stirred at that temperature and reacted overnight. After the reaction was completed, the reaction system was cooled to room temperature, and then extracted with ethyl acetate and water, the organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 322 mg of compound 128 was obtained as a white solid, with a yield of 34.18%. 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.02 (s, 1H), 5.72 (s, 1H), 5.41 (d, J = 5.0 Hz, 1H), 4.60 (dt, J = 10.9, 5.9 Hz, 1H), 2.04 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H).

[0201] (3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-ol (129) Compound 128 (0.497 g, 1.08 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (183 mg, 3.26 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 2 h and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 278 mg of compound 129 was obtained as a white solid, with a yield of 65.85%. 1 H NMR (400 MHz, DMSO) δ 7.84 (s, 1H), 7.54 (s, 1H), 5.90 (s, 1H), 5.31 (d, J = 4.6 Hz, 1H), 4.64 (d, J = 4.5 Hz, 1H), 3.31 - 3.22 (m, 1H), 1.00 (s, 3H), 0.98 (s, 3H).

[0202] (3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (130) Compound 129 (278 mg, 0.668 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.28 mL, 2.3 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (150 μL, 1.71 mmol) was slowly added, and after the addition was completed, the mixture was stirred at room temperature for 2 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 382 mg of compound 130 was obtained as a yellow oil, which was directly used in the next step.

[0203] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-bromo-1H-imidazole (131) Compound 130 (0.382 g, 0.77 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.3 mL, 2.24 mmol) and boron trifluoride ethyl ether (0.34 mL, 2.42 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, then filtered, concentrated with silica gel, and purified by automated chromatography (15-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 183 mg of compound 131 was obtained as a white solid, with a yield of 53.66%. 1 H NMR (400 MHz, DMSO) δ 7.84 (s, 1H), 7.54 (s, 1H), 5.90 (s, 1H), 5.43 (d, J = 4.1 Hz, 1H), 1.01 (s, 3H), 0.98 (s, 3H).

[0204] (3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (132) Compound 131 (180 mg, 0.408 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water and stirred at room temperature, then weighed triphenylphosphine (160 mg, 0.61 mmol) was added, then the temperature was slowly raised to 60 ° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of ethyl acetate was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid precipitated, and the aqueous phase was extracted three times with a small amount of ethyl acetate, collected and combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 147 mg of white solid compound 132, with a yield of 86.98%. It was directly put into the next step.

[0205] 4-Fluoro-N-((3S,10R,13S)-17-(4-bromo-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)benzamide (compound 29) Compound 132 (50 mg, 0.12 mmol) was added to give 45 mg of compound 29 as a white solid, with a yield of 69.55%. 1 H NMR (600 MHz, DMSO) δ 8.28 (d, J = 8.0 Hz, 1H), 7.91 - 7.87 (m, 2H), 7.81 (d, J = 1.4 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 5.88 (s, 1H), 5.34 (d, J = 4.6 Hz, 1H), 3.68 (ddd, J = 16.3, 12.0, 5.9 Hz, 1H), 1.02 (s, 3H), 0.95 (s, 3H). 13C NMR (151 MHz, DMSO) δ 164.18, 147.23, 141.25, 135.94, 129.86, 129.80, 120.37, 118.99, 117.55, 115.16, 115.02, 114.96, 55.81, 49.78, 49.41, 45.44, 38.41, 37.52, 36.35, 33.67, 30.43, 29.64, 29.16, 28.05, 20.12, 18.95, 15.49; + m / z calculated value C 29 H 34 BrFN3O 538.1864, Found: 538.1852.

[0206] Example 30: N-((3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 30) [ka]

[0207] (3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-16-formyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl acetate (133) Compound II-2 (4 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were added together in a flask, and then dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, 4-chloroimidazole (1 g, 9.75 mmol) was added to the system, and the temperature was slowly raised to 80°C. The system was stirred at this temperature overnight, and the completion of the reaction was monitored by TLC. After the reaction was completed, the system was extracted with ethyl acetate, and the organic phase was collected and washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by silica gel in the system, and purified by automatic chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.53 g of yellow solid compound 133 was obtained, with a yield of 35.58%. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 4.63 (ddd, J = 15.9, 10.7, 5.4 Hz, 1H), 2.71 (dd, J = 15.5, 6.3 Hz, 1H), 2.06 (s, 3H), 1.08 (s, 6H).

[0208] (3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthrenequinon-3-yl acetate (134) Compound 1,3-bis(diphenylphosphino)propane (0.47 g, 1.14 mmol) and carbonylbis(triphenylphosphine)rhodium(I) chloride (0.47 g, 0.66 mmol) were dissolved in dry xylene, and the mixture was replaced with argon gas three times. The temperature of the system was slowly raised to 80°C and stirred for half an hour, and then compound 133 (1 g, 2.26 mmol) was added, the reaction temperature was raised to 135°C, and the reaction was stirred at that temperature and reacted overnight. After the reaction was completed, the reaction system was cooled to room temperature, and then extracted with ethyl acetate and water, the organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate, filtered, and then concentrated by adding silica gel to the system, and purified by automatic chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 569 mg of compound 134 was obtained as a white solid, with a yield of 60.73%. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.2 Hz, 1H), 6.97 (d, J = 1.3 Hz, 1H), 5.73 (dd, J = 3.2, 1.7 Hz, 1H), 5.42 (d, J = 5.2 Hz, 1H), 4.67 - 4.57 (m, 1H), 2.05 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H).

[0209] (3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-ol (135) Compound 134 (0.56 g, 1.35 mmol) was dissolved in anhydrous methanol and stirred at room temperature, then weighed potassium hydroxide (183 mg, 3.26 mmol) was added, and after the addition was completed, the mixture was stirred at room temperature for 2 h, and the reaction completion was monitored by TLC. After the reaction was completed, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water, and the organic phase was collected, washed twice with saturated saline, and further dried over anhydrous sodium sulfate. After filtration, the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 440 mg of compound 135 was obtained as a white solid, with a yield of 87.44%. 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.97 (d, J = 1.0 Hz, 1H), 5.74 (dd, J = 3.1, 1.6 Hz, 1H), 5.42 - 5.38 (m, 1H), 3.61 - 3.50 (m, 1H), 1.08 (s, 3H), 1.01 (s, 3H).

[0210] (3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-3-yl methanesulfonate (136) Compound 135 (440 mg, 1.182 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (0.5 mL, 4.1 mmol) was added and stirred for a certain period of time. Finally, methanesulfonyl chloride (0.2 mL, 2.28 mmol) was slowly added, and after the dropwise addition was completed, the mixture was stirred at room temperature for 2 h and the reaction completion was monitored by TLC. Then, the mixture was quenched with ice water and extracted with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 493 mg of compound 136 was obtained as a white solid, with a yield of 92.67%. 1H NMR (400 MHz, DMSO) δ 7.83 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 5.90 (s, 1H), 5.45 (d, J = 3.9 Hz, 1H), 4.43 (d, J = 7.5 Hz, 1H), 3.19 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H).

[0211] 1-((3S,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinon-17-yl)-4-chloro-1H-imidazole (137) Compound 136 (0.486 g, 1.08 mmol) was dissolved in dry dichloromethane and stirred at room temperature, then azidotrimethylsilane (0.5 mL, 3.73 mmol) and boron trifluoride ethyl ether (0.7 mL, 4.84 mmol) were added in a plastic feed apparatus, and the mixture was stirred at room temperature overnight and monitored for completion by TLC. The mixture was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed twice with saturated saline and dried over anhydrous sodium sulfate, then filtered, the organic phase was concentrated with silica gel, and purified by automated chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 330 mg of compound 137 was obtained as a white solid, with a yield of 76.96%. 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.94 (d, J = 1.4 Hz, 1H), 5.71 (s, 1H), 5.42 (d, J = 4.6 Hz, 1H), 3.21 (d, J = 4.1 Hz, 1H), 1.05 (s, 3H), 0.99 (s, 3H).

[0212] (3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (138) Compound 137 (330 mg, 0.83 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water and stirred at room temperature, then weighed triphenylphosphine (326 mg, 1.24 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of ethyl acetate was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of ethyl acetate, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 295 mg of white solid compound 138, with a yield of 95.65%. 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 1.5 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 5.72 (dd, J = 3.1, 1.7 Hz, 1H), 5.37 (d, J = 5.3 Hz, 1H), 2.72 - 2.61 (m, 1H), 1.06 (s, 3H), 1.01 (s, 3H).

[0213] N-((3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)pyridazine-4-carboxamide (compound 30) Compound 138 (50 mg, 0.136 mmol) was added to give 49 mg of compound 30 as a pale yellow solid, with a yield of 76.23%. 1H NMR (500 MHz, CDCl3) δ 9.53 (dd, J = 2.0, 1.2 Hz, 1H), 9.42 (dd, J = 5.3, 1.0 Hz, 1H), 8.84 (d, J = 7.8 Hz, 1H), 7.99 (dd, J = 5.3, 2.3 Hz, 1H), 7.83 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 5.38 (d, J = 4.8 Hz, 1H), 3.73 (ddd, J = 15.8, 12.0, 6.1 Hz, 1H), 1.05 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 167.45, 157.31, 154.05, 152.42, 146.20, 141.17, 136.99, 129.36, 125.92, 124.30, 122.78, 120.16, 61.01, 55.08, 54.98, 50.66, 43.34, 42.63, 41.58, 38.90, 35.62, 34.84, 34.43, 33.04, 25.32, 24.14, 20.70. HRMS (ESI) (M+H) + m / z calculated value C 27 H 33 ClNO 478.2368, Found: 478.2365.

[0214] Example 31: 4-Fluoro-N-((3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)benzamide (compound 31) [ka]

[0215] Compound 138 (50 mg, 0.136 mmol) was added to give 56 mg of compound 31 as a white solid, with a yield of 84.3%. 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.92 (dd, J = 8.5, 5.6 Hz, 2H), 7.81 (s, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H), 5.89 (s, 1H), 5.35 (d, J = 3.4 Hz, 1H), 3.71 (dd, J = 7.6, 4.0 Hz, 1H), 1.04 (s, 3H), 0.97 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 169.44, 152.41, 146.41, 140.01, 135.00, 133.85, 125.55, 124.18, 120.36, 120.19, 119.56, 61.02, 55.01, 54.72, 50.63, 43.62, 42.76, 41.60, 38.92, 35.63, 34.86, 34.42, 33.26, 25.33, 24.13, 20.68. HRMS (ESI) (M+H) + m / z calculated value C 29 H 34 ClFN3O 494.2369, Found: 494.2366.

[0216] Example 32: N-((3S,10R,13S)-17-(4-chloro-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-cyanobenzamide (compound 32) [ka]

[0217] Compound 138 (50 mg, 0.136 mmol) was added to give 47 mg of compound 32 as a pale yellow solid, with a yield of 69.75%. 1 H NMR (600 MHz, DMSO) δ 8.52 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 0.9 Hz, 1H), 7.46 (d, J = 0.8 Hz, 1H), 5.86 (s, 1H), 5.33 (d, J = 3.7 Hz, 1H), 3.72 - 3.65 (m, 1H), 1.00 (s, 3H), 0.94 (s, 3H). 13 C NMR (151 MHz, DMSO) δ 163.85, 147.28, 141.07, 138.55, 134.79, 132.36, 128.56, 128.09, 120.43, 118.90, 114.34, 113.45, 55.79, 49.75, 49.69, 45.41, 38.26, 37.48, 36.36, 33.67, 30.41, 29.61, 29.20, 27.92, 20.07, 18.92, 15.47; + m / z calculated value C 30 H 34 ClNO 501.2416, Found: 501.2411.

[0218] Example 33: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-fluorobenzamide (compound 33) [ka]

[0219] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of compound 33 as a white solid, with a yield of 74.23%. 1 H NMR (500 MHz, DMSO) δ 8.30 (d, J = 7.9 Hz, 1H), 7.95 - 7.89 (m, 2H), 7.69 (s, 1H), 7.28 (t, J = 8.7 Hz, 2H), 7.05 (s, 1H), 5.74 (s, 1H), 5.37 (s, 1H), 3.72 (d, J = 7.2 Hz, 1H), 2.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 164.31, 147.82, 141.28, 137.25, 134.77, 131.20, 129.82, 129.75, 120.35, 115.24, 114.94, 114.44, 55.79, 49.79, 49.47, 45.36, 38.38, 37.53, 36.36, 34.06, 30.44, 29.65, 29.12, 28.01, 20.15, 18.90, 15.66, 13.41; (M+H) + m / z calculated value C 30 H 37 FN3O 474.2915, measured value: 474.2923.

[0220] Example 34: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-nitrobenzamide (compound 34) [ka]

[0221] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of compound 34 as a pale yellow solid, with a yield of 70.38%. 1H NMR (500 MHz, DMSO) δ 8.64 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.9 Hz, 2H), 7.69 (s, 1H), 7.04 (s, 1H), 5.73 (s, 1H), 5.38 (d, J = 4.6 Hz, 1H), 3.79 - 3.69 (m, 1H), 2.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.69, 148.90, 148.01, 141.09, 140.37, 137.39, 134.73, 128.69, 123.40, 120.57, 116.11, 114.40, 109.50, 55.74, 49.77, 45.35, 38.20, 37.52, 36.40, 34.06, 30.43, 29.64, 29.19, 27.88, 20.14, 18.88, 15.59, 13.42. (ESI) (M+H) + m / z calculated value C 30 H 37 N4O3501.286, Found: 501.2866.

[0222] Example 35: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-(methylsulfonyl)benzamide (compound 35) [ka]

[0223] Compound 67 (25 mg, 0.071 mmol) was added to give 28 mg of compound 35 as a white solid, with a yield of 73.96%. 1H NMR (500 MHz, DMSO) δ 8.57 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.06 (s, 1H), 5.74 (s, 1H), 5.38 (d, J = 4.4 Hz, 1H), 3.80 - 3.69 (m, 1H), 2.11 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 164.07, 147.93, 142.78, 141.21, 139.06, 137.21, 134.76, 128.18, 126.93, 120.43, 116.16, 114.45, 55.79, 49.78, 49.68, 45.36, 43.32, 38.24, 37.48, 36.36, 34.04, 30.44, 29.65, 29.07, 27.92, 20.15, 18.90, 15.60, 13.37. HRMS (ESI) (M+H) + m / z calculated value C 31 H 40 N3OS 534.2785, Actual value: 534.2786.

[0224] Example 36: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-cyanobenzamide (compound 36) [ka]

[0225] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of compound 36 as a white solid, with a yield of 73.31%. 1H NMR (500 MHz, DMSO) δ 8.56 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.05 (s, 1H), 5.74 (s, 1H), 5.37 (d, J = 4.4 Hz, 1H), 3.78 - 3.68 (m, 1H), 2.11 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.93, 147.91, 140.99, 138.72, 137.21, 134.72, 132.31, 128.05, 120.48, 116.16, 114.43, 113.51, 55.78, 49.77, 49.68, 45.36, 38.22, 37.47, 36.35, 34.11, 30.43, 29.69, 29.12, 27.89, 20.21, 18.88, 15.60, 13.39; (M+H) + m / z calculated value C 31 H 37 N4O 481.2962, Found: 481.2959.

[0226] Example 37: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-2,4-difluorobenzamide (compound 37) [ka]

[0227] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of compound 37 as a pale yellow solid, with a yield of 71.67%. 1H NMR (500 MHz, DMSO) δ 8.23 ​​(d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.64 (dt, J = 15.2, 7.8 Hz, 1H), 7.32 (t, J = 9.9 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 5.74 (s, 1H), 5.38 (d, J = 3.8 Hz, 1H), 3.67 (dd, J = 7.8, 3.9 Hz, 1H), 2.11 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 162.59, 148.46, 141.64, 137.69, 135.30, 132.22, 120.85, 116.72, 114.98, 112.19, 112.08, 105.07, 104.85, 104.67, 56.38, 50.22, 50.15, 45.94, 38.69, 37.89, 36.79, 34.61, 30.98, 30.06, 29.68, 28.35, 20.57, 19.47, 16.01, 13.85. HRMS (ESI) (M+H) + m / z calculated value C 30 H 36 F2N3O 492.2821, Measured value: 492.2829.

[0228] Example 38: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-2,4-difluorobenzamide hydrochloride (compound 38) [ka]

[0229] Compound 37 (30 mg, 0.061 mmol) was placed in a flask and stirred at room temperature using dioxane as a solvent. After that, a 2 M solution of hydrogen chloride in dioxane was added and reacted at room temperature for 2 h. The solvent was then removed by rotary evaporation to obtain 28 mg of compound 38 as a white solid, with a yield of 86.96%.

[0230] Example 39: N-((3S,10R,13S)-17-(4-methyl-1H-imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-2,4-difluorobenzamide methanesulfonate (compound 39) [ka]

[0231] Compound 37 (30 mg, 0.061 mmol) was placed in a flask and stirred at room temperature using dichloromethane as the solvent. A small amount of methanesulfonic acid was slowly added dropwise. After stirring at room temperature overnight, a white solid precipitated out. The precipitate was filtered through a Buchner funnel and the cake was washed with ethyl acetate several times. The cake was dried in a vacuum drying apparatus to finally obtain 30 mg of white solid compound 39, with a yield of 83.3%.

[0232] Example 40: N-((3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthren-3-yl)cyclopropylsulfonamide (Compound 40) [ka]

[0233] Compound 47 (60 mg, 0.172 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and the mixture was stirred in an ice bath with dry dichloromethane. Triethylamine (60 μL, 0.42 mmol) was added and stirred for a certain period of time. Finally, cyclopropylsulfonyl chloride (30 μL, 0.21 mmol) was added and stirred at room temperature for 4 h. The reaction was monitored for completion by TLC. After the reaction was completed, the mixture was extracted with dichloromethane and water. The organic phase was collected, washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated chromatography (30-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 51 mg of compound 40 was obtained as a white solid, with a yield of 65.5%. 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J = 1.8 Hz, 1H), 8.44 (dd, J = 4.7, 1.3 Hz, 1H), 7.77 (dd, J = 8.0, 1.8 Hz, 1H), 7.34 (dd, J = 7.9, 4.8 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.12 (s, 1H), 5.37 (d, J = 4.6 Hz, 1H), 3.01 (d, J = 7.0 Hz, 1H), 1.02 (s, 3H), 1.00 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 151.48, 148.27, 147.62, 141.56, 133.76, 132.59, 129.46, 123.83, 121.22, 57.47, 53.88, 50.17, 47.11, 37.95, 36.62, 35.11, 31.75, 31.36, 31.13, 30.36, 30.25, 20.82, 19.36, 16.71, 5.48. HRMS (ESI) (M+H) + m / z calculated value C 27 H 37 N2O2S 453.257, Measured: 453.258.

[0234] Example 41: N-((3S,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-sulfonamide (compound 41) [ka]

[0235] Compound 67 (50 mg, 0.142 mmol) was added to give 46 mg of compound 41 as a white solid, with a yield of 64.7%. 1 H NMR (500 MHz, DMSO) δ 7.68 (s, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 5.73 (s, 1H), 5.36 (d, J = 4.2 Hz, 1H), 3.66 - 3.60 (m, 4H), 2.99 (m, 4H), 2.93 (m, 1H), 2.10 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 148.33, 141.53, 137.80, 135.30, 121.11, 116.73, 114.87, 65.96, 56.27, 54.26, 50.20, 46.36, 45.85, 37.89, 36.66, 34.49, 32.00, 30.88, 30.09, 29.90, 29.80, 29.60, 29.19, 20.62, 19.31, 16.09, 13.92. HRMS (ESI) (M+H) + m / z calculated value C 27 H 41 N4O3S 501.2894, Found: 501.2904.

[0236] Example 42: N-((3R,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-fluorobenzamide (compound 42) [ka]

[0237] 1-((3R,10R,13S)-3-azido-10, 13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-17-yl)-4-methyl-1H-imidazole (134) Compound 65 (1.5 g, 3.48 mmol) and 15-crown-5 (77 mg, 0.35 mmol) were dissolved in anhydrous DMF, and then sodium azide (0.68 g, 10.44 mmol) was added. After the addition was completed, the reaction system was slowly heated to 80° C., and stirred at this temperature for 18 hours, and the reaction completion was monitored by TLC. Then, the reaction system was cooled to room temperature, and a certain amount of ice water was added, and the reaction was extracted with dichloromethane, and the organic phase was washed twice with saturated saline, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated by silica gel and purified by automatic chromatography (15-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 0.63 g of pale yellow solid 134 was obtained, with a yield of 48.09%. 1 H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 6.84 (s, 1H), 5.92 - 5.88 (m, 1H), 5.42 (d, J = 4.9 Hz, 1H), 3.27 - 3.17 (m, 1H), 2.39 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0238] (3R,10R,13S)-10,13-Dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopenta[a]phenanthrenequinone-3-amine (135) Compound 134 (2 g, 5.3 mmol) was dissolved in 16 mL of tetrahydrofuran and 8 mL of water and stirred at room temperature, then weighed triphenylphosphine (2.08 g, 7.95 mmol) was added, then the temperature was slowly raised to 60° C. and stirred at that temperature overnight, and the reaction was monitored by TLC for completion. Then, a part of the solvent was removed by rotary evaporation, 20 mL of dichloromethane was added to dissolve, and 2 M hydrochloric acid was slowly added to adjust the solution to pH 2 or so, and the aqueous phase was collected by separation, and then 2 M sodium hydroxide solution was added to adjust the pH to a weak base, at this time, a large amount of white solid was precipitated, and the aqueous phase was extracted three times with a small amount of dichloromethane, respectively, and the organic phase was collected and combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 664 mg of white solid 135, with a yield of 36.08%. 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.78 (s, 1H), 5.63 (dd, J = 3.0, 1.7 Hz, 1H), 5.37 (d, J = 5.2 Hz, 1H), 2.25 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0239] N-((3R,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-4-fluorobenzamide (compound 42) Compound 135 (100 mg, 0.284 mmol) was added to give 86 mg of compound 42 as a white solid, with a yield of 63.7%. 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 1.7 Hz, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.18 - 8.14 (m, 1H), 7.73 (s, 1H), 7.48 (dd, J = 7.9, 4.9 Hz, 1H), 7.05 (s, 1H), 5.73 (s, 1H), 5.36 (d, J = 4.0 Hz, 1H), 3.77 - 3.65 (m, 1H), 2.09 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 163.90, 151.73, 148.40, 141.15, 137.05, 134.95, 134.73, 123.31, 120.51, 116.43, 114.56, 55.84, 49.81, 49.50, 45.37, 38.36, 37.53, 36.40, 34.09, 30.38, 29.68, 29.17, 28.01, 20.13, 18.95, 15.64, 13.35; + m / z calculated value C 30 H 37 FN3O 474.2915, measured value: 474.2916.

[0240] Example 43: N-((3R,10R,13S)-10,13-dimethyl-17-(4-methyl-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodehydro-1H-cyclopenta[a]phenanthren-3-yl)-2,4-difluorobenzamide (compound 43) [ka]

[0241] Compound 135 (100 mg, 0.028 mmol) was added to give 94 mg of compound 43 as a pale yellow solid, with a yield of 67.14%. 1H NMR (500 MHz, DMSO) δ 8.20 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 1.1 Hz, 1H), 7.63 (td, J = 8.5, 6.8 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.14 (td, J = 8.4, 2.1 Hz, 1H), 7.03 (s, 1H), 5.73 - 5.71 (m, 1H), 5.37 (d, J = 4.8 Hz, 1H), 3.70 - 3.61 (m, 1H), 2.09 (d, J = 0.4 Hz, 3H), 1.01 (s, 3H), 0.96 (s, 3H). 13 C NMR (126 MHz, DMSO) δ 162.42, 148.46, 141.53, 137.82, 135.16, 132.06, 120.97, 116.59, 114.89, 112.20, 111.96, 104.98, 104.93, 104.72, 56.29, 50.27, 50.03, 45.85, 38.74, 37.93, 36.85, 34.61, 30.93, 30.05, 29.51, 28.49, 20.65, 19.39, 16.11, 13.94. HRMS (ESI) (M+H) + m / z calculated value C 30 H 36 F2N3O 492.2821, Measured Value: 492.2837.

[0242] Bioactivity assays A series of in vitro and in vitro activity assays have demonstrated that the steroid compounds of the present invention can be applied to the treatment of diseases mediated by AR signal pathway.The in vitro activity assays include wild-type AR antagonist activity assay, mutant AR antagonist activity assay, AR decomposition activity assay and cytostatic activity assay, and the in vivo activity assays include androgen-dependent organ development (Hershberger) assay and other drug-likeness tests such as metabolism.

[0243] 1. Wild-type AR Antagonism Activity Assay HEK293 cells were cultured in DMEM containing 10% fetal bovine serum (FBS) at 5% CO2 and 37°C. Then, the cells were digested with tryptase and counted. Then, 10 μL / well of transfection solution was prepared with opti-MEM containing 5 ng of androgen receptor clone, 100 ng of pGL4.36 vector and 315 nL of fugene. The cell suspension was diluted with DMEM without phenol red, and 10% dialyzed FBS and 1% GlutaMax were added and mixed with the transfection solution to 444,444 cells / mL. The diluted cell suspension was inoculated into a 96-well plate in a volume of 90 μL (40000 cells / well), and the plate was incubated for 24 hours. Then, 10 μL of drug solution (containing gradient diluted compounds or DMSO) was added, and the plate was further incubated for 30 minutes. 10 nL DHT (final concentration 1.5 nM) was added to each well of the plate, and the plate was then incubated at 37° C., 5% CO2. After 24 hours of incubation, 100 μL of Steady-Glo was added to each well of the plate, the plate was shaken for 20 minutes at room temperature, and the plate was read in the Envision. IC 50 was defined as the drug concentration causing 50% inhibition of luciferase expression and was determined by a dose-response curve.

[0244] The second-generation AR antagonist enzalutamide was used as a positive control, and the AR antagonist activity of representative compounds is shown in Table 1. [Table 1]

[0245] The assay results in Table 1 show that the compounds of the present invention have excellent AR antagonistic activity and can antagonize / block the AR receptor signal pathway, and the representative compounds 34, 33, 37, 13, and 14 have AR antagonistic activity that is 6.2, 3.6, 1.9, 1.8, and 1.8 times improved, respectively, compared to the control enzalutamide.

[0246] 2. In Vitro AR Degradation Activity Assay LNCaP cells (prostate cancer cells) were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) at 5% CO2 and 37°C. The cells were then digested with tryptase and the cell density was counted with an automated cell counter. The cell suspension was diluted to the desired density in growth medium. The cell suspension was then inoculated into a 96-well plate in a volume of 100 μL, and the plate was then incubated at 37°C and 5% CO2 for 24 hours. The compounds were then diluted to 200 times the final concentration in DMSO or 3 times the final concentration in medium, and 50 μL of the compound solution was transferred to the 96-well plate and incubated at 37°C for 24 hours. After 24 hours of incubation, the cell plate was washed three times with DPBS, 100 μL of 1× lysis buffer was added to each well, and the wells were placed on ice for 30 minutes, and the supernatant was collected. Protein in the cell lysate sample was quantified and then diluted to the desired concentration. 100 μL of cell lysate samples were placed into the appropriate wells, sealed with tape and pressed firmly on the top of the wells, and the plate was incubated at 37°C for 2 hours. The plate contents were then discarded and washed 4 times with 1× wash buffer, placing 200 μL in each well each time. 100 μL of reconstituted detection antibody was then placed, sealed with tape, and the plate was placed at 37°C for 1 hour. The aspiration / wash process was then repeated, 100 μL of recombinant HRP-conjugated secondary antibody was added to each well, sealed with tape, and the plate was incubated at 37°C for 30 minutes. The aspiration / wash process was then repeated, 100 μL of substrate solution was added to each well, and incubated at 37°C for 10 minutes, and finally 100 μL of stop solution was placed in each well, the plate was gently tapped to mix thoroughly, and the OD450nm was recorded.

[0247] Degradation rate (%) = (OD450_max-OD450_sample) / (OD450_max-OD450_min) × 100. Graphs were created using GraphPad Prism 5 software, and ICs were calculated using SPSS software. 50 was calculated.

[0248] Enzalutamide only has AR antagonistic activity and does not have AR degrading activity, but galeterone (CAS: 851983-85-2), which has a steroid structure similar to that of the compound of the present invention, has been clinically studied for the treatment of CRPC. Galeterone has a triple mechanism of action of CYP17A1 enzyme inhibitory activity, AR degrading and antagonism (J. Med. Chem. 2015, 58, 2077-2087). Therefore, galeterone was used as a positive control drug to test the AR degrading activity of the representative compounds of the present invention, and the results are shown in Table 2. [Table 2]

[0249] From the assay results in Table 2, it can be seen that the steroid compounds of the present invention exhibit excellent in vitro AR degradation activity, and are obviously better than the control drug galeterone, with significant improvements ranging from 2.4 to 8.1 times. Among them, compounds 33, 36, 35, and 37 were 8.1, 7.6, 6.7, and 6.2 times higher than galeterone, respectively.

[0250] 3. In vitro LNCaP (hormone-sensitive prostate cancer) cell proliferation inhibition assay LNCaP cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) at 37°C with 5% CO2. After that, cells were digested with tryptase and the cell density was counted with an automated cell counter. The cell suspension was diluted to the desired density in growth medium. The cell suspension was then inoculated into a 96-well plate in a volume of 100 μL, and the plate was incubated at 37°C with 5% CO2 for 24 hours. Each well was filled with 10 μL of equally divided sample reagent solution (3-fold gradient diluted compound or DMSO) and incubated at 37°C with 5% CO2 for 6 days. The measurement plate was equilibrated to room temperature before measurement. Each well was filled with 40 μL of CellTiter-GloR reagent. Mixing was performed on an orbital shaker for 2 minutes to induce cell lysis. The luminescence signal was stabilized by incubation at room temperature for 60 minutes. The plate was then read on an Envision. IC 50was defined as the drug concentration causing 50% cell growth inhibition and was determined by dose-response curves.

[0251] Abiraterone and enzalutamide, which are currently used in clinical practice to treat late-stage prostate cancer, were used as positive control drugs to measure the anti-LNCaP prostate cancer cell proliferation activity of representative compounds of the present invention. The results are shown in Table 3. [Table 3]

[0252] From the assay results in Table 3, the compounds of the present invention have excellent antiprostate cancer cell proliferation activity (IC 50 ), and their antitumor activities were obviously better than those of abiraterone, and their antitumor activities were significantly improved by 3.0-15.8 times compared with the latter. Among them, compounds 14, 17, 37, and 18 were improved by 15.8, 8.8, 8.6, and 7.9 times compared with abiraterone, respectively.

[0253] The biggest feature of the compounds of this patent is that their antitumor effect (maximum inhibitory activity) is significantly improved by about 2 times compared to enzalutamide, because the compounds of the present invention have strong AR decomposition / downregulation ability, while enzalutamide does not have AR decomposition activity. Compounds 14, 16-19, and 37 have significantly better antitumor activity and antitumor effect than enzalutamide, while compounds 13, 24, and 33 have antitumor activity equivalent to enzalutamide, but all have significantly better antitumor effect than enzalutamide.

[0254] Thus, it is evident that the steroid compounds of the present invention have antitumor activity that is significantly better than that of existing AR antagonists or male hormone synthesis enzyme inhibitors.

[0255] 4. Mutant AR Antagonism Activity Assay First-generation AR antagonists, such as flutamide, bicalutamide, and second-generation AR antagonists, such as enzalutamide, apalutamide, etc., may cause acquired / successive drug resistance due to mutations in AR ligand binding domain after a certain period of clinical treatment.The compound of the present invention has a unique decomposition / antagonism dual function, so it also has strong antagonistic activity against various mutant AR receptors, and is still effective in tumor patients with resistance to enzalutamide, etc. in clinical practice.

[0256] HEK293 cells were cultured in DMEM supplemented with 10% FBS and 1% GlutaMax at 37°C with 5% CO2. The day before transfection, the medium was replaced with DMEM medium containing 10% dialyzed FBS and 1% GlutaMax. Androgen-responsive reporter gene constructs (pGL 4.36) encoding AR mutants AR(F876L), AR(T877A) or AR(W741L) were transfected in OptiMEM with Lipofectamine2000 for 15 min at room temperature. The cell suspension was diluted to 500000 cells / mL with cell inoculum solution and transfection reagent was added. Then, 96 μL of the cell suspension was inoculated into each well of the detection plate. The following day, compounds were prepared and serially diluted 3-fold in DMSO starting from 8 mM for a total of eight concentrations, and 500 nL was transferred to the compound plate in Echo. Compounds were then diluted to 10x the final concentration in 40 μL of medium, and 10 μL was transferred to the cell plate and placed in a 37°C incubator for 30 minutes. 10 nL of DHT was then transferred to each well of the detection plate using TECAN to a final concentration of 10 nM. After 24 hours of incubation, the plate was measured using 100 μL of Steady-Glo and the plate was read on Envision. Data was finalized and analyzed using GraphPad Prism.

[0257] For the W741L and T877A mutations, the second generation AR antagonist enzalutamide was used as a positive control, while for the F876L mutation, enzalutamide showed agonist activity. The assay results are shown in Table 4. [Table 4]

[0258] From the assay results in Table 4, the compounds of the present invention show excellent antagonistic activity against the main mutant ARs appearing in clinical practice, and compound 35 has 4.0 times higher activity than enzalutamide against W741L mutation, and compound 33 has 1.4 times higher activity than enzalutamide against T877A mutation, and the compounds of the present invention also show excellent antagonistic activity against F876L mutations resistant to enzalutamide and apalutamide, which are second-generation AR antagonists.This shows that the compounds of the present invention can treat prostate cancer resistant to existing first-generation and second-generation AR antagonists.

[0259] 5. Anti-drug resistant cell (22RV1) proliferation activity Another major way that AR acquires / successive drug resistance occurs is the expression of AR-V7 truncated mutants, and about 50% of patients treated with enzalutamide or abiraterone express truncated mutants, and the ligand binding domain of such AR truncated mutants is completely lost, so that all current AR antagonists cannot bind to AR and act, and thus cause successive drug resistance or natural drug resistance and lose activity.The steroid compound of the present invention has excellent AR decomposition activity, and can also decompose AR truncated mutants, so that the problem of drug resistance of truncated mutants can be solved.

[0260] The compounds of the present invention were tested for their anti-AR-V7 truncated mutant-expressing 22RV1 prostate cancer cell proliferation activity against all commercially available second-generation AR antagonists, enzalutamide, apalutamide and darolutamide, and the experimental procedures were similar to those of LNCaP cells. The results are shown in Table 5. [Table 5]

[0261] The assay results in Table 5 show that, as expected, enzalutamide, apalutamide and darolutamide had no activity against tumor cells expressing AR truncated mutants, whereas the steroid compounds of the present invention exhibited excellent anti-22RV1 prostate cancer cell proliferation activity and can be used to treat drug-resistant patients expressing AR truncated mutants.

[0262] The results of the above experiments 1-5 can be summarized that the compounds of the present invention have strong antitumor activity in both the prostate cancer that is sensitive to existing AR antagonists (first and second generation) and abiraterone and the prostate cancer that is drug-resistant, and can be used to treat all stages of prostate cancer, such as early hormone-sensitive prostate cancer, CRPC and drug-resistant CRPC. This provides an unprecedentedly powerful therapy for AR signal pathway-related diseases such as prostate cancer.

[0263] 6. Metabolism of the Compounds of the Invention Male SD rats were randomly divided into 6 groups, 3 rats per group, and fasted for 12-14 h on the day before administration, with free access to water. The test sample was then administered intragastrically at 10 mg / kg in a solvent mixture of 5% DMSO + 30% PEG400 + 65% (0.5% Mc), and fed 4 h after administration. After that, 0.10 mL of blood was collected from the eye margin at 0, 15, 30 min, 1, 2, 4, 6, 8, and 24 h, and anticoagulated with EDTAK2. After blood samples were collected, they were placed on ice and centrifuged within 30 min to separate plasma (centrifugation conditions: 5000 rpm, 10 min, 4°C). 50.0 μL of plasma sample (taken out of the -80 °C refrigerator, allowed to dissolve naturally at room temperature, and then mixed by vortexing for 30 seconds) was placed in a 1.5 mL centrifuge tube, and 500 μL of internal standard solution (methanol (TEDIA, HPLC grade), acetonitrile (TEDIA, HPLC grade), formic acid (FA, ACROS ORGANICS, HPLC grade)) was added. Water was ultrapure water (100.0 ng mL ) made in-house in the laboratory. -1), mixed with a vortex for 60 seconds, and then centrifuged for 3 minutes (centrifugal force 12000 rpm). The supernatant was transferred to a 96-well plate containing an equal volume of 100 μL of water, shaken to mix uniformly, and then loaded into the LC-MS / MS for analysis; the loading volume was 10 μL. The data acquisition and control system software was Analyst 1.5.1 software (Applied Biosystem). The integration mode of the sample peak in the spectrum was automatic integration, and the ratio of the sample peak area to the internal standard peak area was used as an index to perform regression with the sample concentration.

[0264] When the representative compound of the present invention is intragastrically administered at 10mg / kg by the above-mentioned conventional method, the relevant pharmacokinetic parameters in SD male rats are measured, and the pharmacokinetic characteristics of the compound of the present invention in rats are considered. The assay results are shown in Table 6. [Table 6]

[0265] Pharmacokinetic studies in rats show that these compounds exhibit superior pharmacokinetic properties and drug-likeness compared to the steroid compound abiraterone. max The efficacy and safety of abiraterone was improved by 32-133 times, and the drug exposure was improved by more than 138 times. Its metabolic properties are obviously better than those of abiraterone, and it has ideal drug efficacy.

[0266] 7. Antiandrogenic activity in the body The in vivo anti-androgenic signaling activity of the compounds of the present invention was detected by Hershberger experiments. In these assays, the compounds described in the present invention (14, 33 and 37) were administered to male Sprague-Dawley rats prepubertally castrated in the presence of 0.4 mg / kg testosterone propionate (TP) and the weights of androgenic-dependent organs were measured. Ten consecutive days of administration were administered and measurements were made 24 hours after the last administration. The degree of AR antagonism and subsequent organ growth inhibition was evaluated compared to castrated controls. The test compounds were administered orally at 20 mg / kg QD and the endpoint was evaluated by the weight changes of two androgenic-sensitive organs (ASO): seminal vesicles with fluid and coagulation glands (SVCG) and ventral prostate (VP). Enzalutamide (ENZ) was used as a positive control and the assay results are shown in Figure 2.

[0267] In vivo Hershberger experiments showed that compounds 14, 33 and 37 could significantly inhibit the growth of androgen-dependent organs compared with the castrated group, and all of them showed activity equivalent to that of enzalutamide. The compounds of the present invention can also effectively antagonize the androgen receptor signal pathway in vivo and can be used for the treatment of prostate cancer.

[0268] 8. Inhibitory activity of type II transmembrane serine protease (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) expression of the compounds of the present invention To verify whether AR antagonists or AR degraders can effectively downregulate the expression of the two proteins TMPRSS2 and ACE2 and be used to treat COVID-19 pneumonia, A549 lung cancer cells were used. Cells in the logarithmic growth phase were collected, counted, and resuspended in complete medium at a cell concentration of 3 × 10 5The cells were adjusted to 12 cells / well, inoculated into a 12-well plate, and 1 mL of cell culture medium was added to each well. The cells were cultured for 24 hours in an incubator at 37°C, 100% relative humidity, and 5% CO2. The medium in the dish containing A549 cells was then discarded and washed once with PBS. The compound of this patent, the positive drug Proxalutamide (concentration 10 μM), and 1 nM DHT were mixed uniformly with the medium, then placed in a dish, and further incubated at 37°C, 100% relative humidity, and 5% CO2 incubator for 48 h each. After 48 h, the cells were collected and RNA in the A549 cells was extracted by an RNA extraction kit. cDNA was obtained by reverse transcription according to the instructions of the reverse transcription kit. The effects of different candidate compounds on the mRNA expression levels of ACE2 protein and TMPRSS2 protein in A549 cells were detected by qPCR. The results of the assay are shown in Table 7. [Table 7]

[0269] The assay results in Table 7 show that in A549 cells, compounds 21 and 35 can significantly down-regulate the expression of ACE2 and TMPRSS2 proteins, and are better than the control drug proxalutamide. In vitro protein expression experiments have shown that the compounds of the present invention can effectively inhibit the AR-TMPRSS2 / ACE2 signal pathway and can be used to treat patients with COVID-19 pneumonia.

[0270] From all the above assay results, it can be seen that the compound of the present invention has the dual mechanism of action of AR antagonism and degradation at the same time, and is a new generation of anti-prostate cancer drug with stronger antitumor activity, and shows better therapeutic effect than single-function AR antagonist or male hormone synthesis enzyme inhibitor, and has better therapeutic effect on clinical CRPC patients and even on all stages of prostate cancer patients.In the future, it can be more suitable for use in the treatment of diseases related to AR signal pathway.

Claims

1. A compound represented by general formula (I), or an enantiomer, diastereomer, stereoisomer, prodrug, deuterated product, hydrate, solvate, racemate, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, A is 【Chemistry 2】 -SO- or a C1-C3 alkylene group. B is hydrogen, substituted or unsubstituted C １－６ Alkyl group, substituted or unsubstituted C ３－８ Cycloalkyl groups, substituted or unsubstituted 4-8 membered heterocycloalkyl groups, substituted or unsubstituted C ６－１０ An aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group. X is selected from a substituted or unsubstituted 5-12 membered heteroaryl group, and a substituted or unsubstituted 4-8 membered heterocycloalkyl group. Each of the above substitutions is independently a deuterium group, a hydroxyl group, a carboxyl group, an amino group, a mercapto group, C １－６ Alkyl group, C １－６ Alkoxy group, sulfonic group, halogen, cyano group, NO ２ , C １－６ Haloalkyl group, —SO—C １－６ Alkyl group, -SO ２ -C １－６ Alkyl group, -CONH-C １－６ Alkyl group, -NHCO-C １－６ Alkyl group, C ３－６ It is substituted with one or more groups selected from the group consisting of cycloalkyl groups. The heteroatoms of the heterocycloalkyl group and the heteroaryl group are selected from O, N, and S, and the number of heteroatoms is 1, 2, 3, or 4.

2. A is, 【Chemistry 3】 -SO-, -CH ２ --, --CH ２ CH ２ - or -CH ２ CH ２ CH ２ The compound according to claim 1, characterized in that:

3. B is a substituted or unsubstituted C １－４ Alkyl group, substituted or unsubstituted C ３－６ Cycloalkyl groups, substituted or unsubstituted 5-6 membered heterocycloalkyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-7 membered heteroaryl groups, the substitution being deuterium, hydroxyl groups, carboxy groups, amino groups, mercapto groups, C １－４ Alkyl group, C １－４ Alkoxy group, sulfonic group, F, Cl, Br, CN, NO ２ , C １－４ Haloalkyl group, —SO—C １－４ Alkyl group, -SO ２ -C １－４ Alkyl group, -CONH-C １－４ Alkyl group, -NHCO-C １－４ Alkyl group, C ３－６ The compound according to claim 1, characterized in that the heterocycloalkyl group, the heteroaryl group, and the heteroatoms of the heterocycloalkyl group, the heteroaryl group are selected from O, N, and S, and the number of heteroatoms is 1, 2, or 3.

4. X is selected from a substituted or unsubstituted 5- to 9-membered heteroaryl group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, and the substitution is deuterium, a hydroxyl group, a carboxyl group, an amino group, a mercapto group, C １－４ Alkyl group, C １－４ Alkoxy group, sulfonic group, F, Cl, Br, CN, NO ２ , C １－４ Haloalkyl group, —SO—C １－４ Alkyl group, -SO ２ -C １－４ Alkyl group, -CONH-C １－４ Alkyl group, -NHCO-C １－４ Alkyl group, C ３－６ By being substituted with one, two or three groups selected from the group consisting of cycloalkyl groups, The compound according to claim 1, wherein the heteroatoms of the heterocycloalkyl group and the heteroaryl group are selected from O, N and S, and the number of the heteroatoms is 1, 2, 3 or 4.

5. The compound or a pharma- ceutically acceptable salt thereof may be any of the following: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 The compound according to claim 1, characterized in that it is selected from:

6. A method for producing the compound of claim 1, comprising the steps of: 【Chemistry 7】 a) reacting intermediate I-1 with methanesulfonyl chloride to obtain intermediate I-2; b) reacting intermediate I-2 with azidotrimethylsilane and boron trifluoride ethyl etherate to obtain intermediate I-3; c) reacting intermediate I-3 with lithium aluminum hydride to obtain intermediate I-4; d) reacting intermediate I-4 with an acid chloride to give the desired compound I; or e) Condensation reaction of intermediate I-4 with a carboxylic acid to obtain target compound I. The method according to claim 1, further comprising: (In each formula, X, A and B are defined as above.)

7. A method for preparing the compound according to claim 1, comprising: subjecting compound II-1 to a Suzuki coupling reaction with a boronic acid or a boronic ester to obtain intermediate I-1; 【Chemistry 8】 Alternatively, the method for producing the intermediate I-1 comprises the following steps: 【Chemistry 9】 i) subjecting compound II-2 to an addition-elimination reaction to obtain compound II-3; ii) removing the aldehyde group from compound II-3 to obtain compound II-4; iii) Hydrolysis of compound II-4 to obtain intermediate I-1 The method according to claim 1, further comprising: (In each formula, X is defined as above.)

8. A pharmaceutical composition comprising a compound represented by general formula (I) according to claim 1, or an enantiomer, diastereomer, stereoisomer, prodrug, deuterated product, hydrate, solvate, racemate or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

9. Use of the compound represented by general formula (I) as claimed in claim 1, or its enantiomer, diastereomer, stereoisomer, prodrug, deuterated product, hydrate, solvate, racemate or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 8, for the manufacture of a drug for preventing and / or treating a disease associated with the AR signal pathway.

10. The use according to claim 9, wherein the disease associated with the AR signal pathway is selected from the group consisting of prostate cancer, castration-resistant prostate cancer, breast cancer, SARS-CoV-2 infectious disease, osteoporosis, and digestive system diseases.

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