Steroidal compounds, methods of making and uses thereof

Abstract

The application discloses a kind of steroid compounds and preparation method and purposes, and the structure of the steroid compound is as shown in formula I, wherein the definition of each substituent group is described in the specification and claims.The steroid compound of the application is a steroid compound with excellent AR antagonistic and AR degradation activity dual function, with good drug properties, good safety characteristics, and can be used for the treatment of diseases related to AR signal pathway.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceuticals, and relates to the field of drug synthesis and pharmacology. More specifically, it relates to a steroid compound having a dual mechanism of androgen receptor degradation and antagonism, a preparation method and its application in the treatment of diseases related to androgen receptor (AR) signaling pathways, including prostate cancer, castration-resistant prostate cancer, SARS-CoV-2 infectious diseases, and advanced breast cancer patients. TECHNICAL BACKGROUND

[0002] Prostate cancer (PCa) is a common malignant tumor of the male urogenital system, and is an androgen-dependent malignancy. Its occurrence, development, metastasis and malignancy are closely related to androgen and its receptor signaling pathway. Therefore, androgen blockade therapy (ADT) has become the main treatment for early PCa. However, after 18-24 months of ADT treatment, patients will adapt to low levels of androgens in the body and develop into lethal castration-resistant prostate cancer (CRPC). In the past two decades, there has been significant progress in the treatment of CRPC patients. Among them, CYP17A1 enzyme (male hormone synthesis enzyme) inhibitors such as abiraterone acetate and second-generation AR antagonists such as enzalutamide, apalutamide and darolutamide have been approved for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) patients, and have achieved good therapeutic effects.

[0003] However, after 9-15 months of clinical treatment with abiraterone and second-generation AR antagonists, acquired resistance still occurs, which can be divided into AR-related resistance and AR bypass activation resistance. AR-related resistance includes: 1) amplification and overexpression of AR gene. About 80% of CRPC patients exhibit high AR expression levels, enabling the tumor to adapt to low levels of androgens and continue to grow and proliferate; 2) point mutations and expression of splice variants in the AR ligand binding domain. Among CRPC patients who have received enzalutamide and abiraterone treatment, about 12-48% have AR mutations. The F876L mutation causes enzalutamide and apalutamide to change from AR antagonistic activity to AR agonistic activity, which actually promotes tumor growth, and the L701H and T877A mutations cause abiraterone to lose efficacy due to resistance; among patients who have received enzalutamide or abiraterone treatment, about 50% express splice variants. AR-V567 and AR-V7 are the two most common splice variants, which partially or completely lack the ligand binding domain of AR, so that all current AR antagonists cannot bind to AR to function, resulting in resistance and inactivation. AR bypass-driven resistance refers to the increased expression of glucocorticoid receptor (GR) in CRPC patients, which can compete with AR for binding to response elements, allowing the patient to promote the transcription of downstream tumor-related genes independent of the AR signaling pathway, leading to disease progression.

[0004] Since the five-year survival rate of CRPC patients is less than 30%, the current treatment for CRPC patients cannot effectively control the disease, so there is an urgent need to find new treatment strategies for CRPC patients and drug-resistant CRPC.

[0005] SARS-CoV-2 invades (infects) host cells mainly through two proteases, namely transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 adheres to the cell membrane through ACE2, and TMPRSS2 completes the hydrolytic cleavage of the spike protein S1 / S2 site of SARS-CoV-2 to initiate the fusion and entry of SARS-CoV-2 and host cells, and complete the invasion / infection of host cells. TMPRSS2 and ACE2 proteins are positively regulated by the human androgen receptor signaling pathway, so AR antagonists or AR degraders can inhibit the function of AR, down-regulate the expression of TMPRSS2 and ACE2 at the transcriptional level, and thus block the invasion of SARS-CoV-2 into host cells, blocking the infection of the new coronavirus from the source. Figure 1 .

[0006] Clinical studies have also shown that treatment strategies targeting the AR signaling pathway can effectively treat COVID-19 patients and significantly reduce mortality. AR antagonist Pukrutamine developed by Suzhou Kaihua Pharmaceutical has completed a phase II proof-of-concept study of AR antagonists for the treatment of COVID-19 patients, and has achieved surprising clinical anti-COVID-19 effects. It is currently conducting a phase III clinical study in multiple countries. The drug has been granted emergency use authorization in Paraguay in July 2021.

[0007] In summary, the AR signaling pathway plays an important role in various diseases including prostate cancer and COVID-19. The development of AR antagonists or AR degraders is expected to better treat diseases related to the AR signaling pathway. SUMMARY

[0008] The present application aims to provide a class of steroid compounds with excellent AR antagonistic and AR degrading activities, which can more completely block the AR signaling pathway compared to existing antagonists, and can be better used for the treatment of diseases related to the AR signaling pathway.

[0009] In a first aspect of the present application, a compound represented by general formula (I) is provided, or an enantiomer, diastereomer, stereoisomer, prodrug, deuteride, hydrate, solvate, racemate thereof or a pharmaceutically acceptable salt thereof,

[0010]

[0011] In the formula, A is -SO- or C1-C3 alkylene;

[0012] B is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl;

[0013] X is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 4-8 membered heterocycloalkyl;

[0014] Each substitution is independently substituted with one or more groups selected from the group consisting of deuterium, hydroxyl, carboxyl, amino, thiol, C 1-6 alkyl, C 1-6 alkoxy, sulfone, halogen, cyano, NO2, C 1-6 haloalkyl, -SO-C 1-6 alkyl, -SO2-C 1-6 alkyl, -CONH-C 1-6 alkyl, -NHCO-C 1-6 alkyl, C3-6 cycloalkyl;

[0015] the heteroatom of the heterocycloalkyl, heteroaryl is selected from: O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0016] In another preferred embodiment, the compound of Formula I has the following formula:

[0017]

[0018] In another preferred embodiment, A is -SO-, -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0019] In another preferred embodiment, B is hydrogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaryl;

[0020] the substitution means substituted with 1, 2 or 3 groups selected from: deuterium, hydroxy, carboxy, amino, thiol, C 1-4 alkyl, C 1-4 alkoxy, sulfone, F, Cl, Br, CN, NO2, C 1-4 haloalkyl, -SO-C 1-4 alkyl, -SO2-C 1-4 alkyl, -CONH-C 1-4 alkyl, -NHCO-C 1-4 alkyl, C 3-6 cycloalkyl;

[0021] the heteroatom of the heterocycloalkyl, heteroaryl is selected from: O, N or S, and the number of heteroatoms is 1, 2 or 3.

[0022] In another preferred embodiment, B is cyclopropanyl, morpholinyl or phenyl, which are optionally substituted with 1, 2 or 3 groups selected from: deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxy, amino, F, Cl, Br, cyano, NO2, -SOCH3, -SOCH2CH3, -SOCH(CH3)2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2.

[0023] In another preferred embodiment, X is selected from: substituted or unsubstituted 5-9 membered heteroaryl, substituted or unsubstituted 4-6 membered heterocycloalkyl;

[0024] said substituents are 1, 2 or 3 groups selected from the group consisting of deuterium, hydroxy, carboxy, amino, thiol, C 1-4 alkyl, C 1-4 alkoxy, sulfone, F, Cl, Br, CN, NO2, C 1-4 haloalkyl, -SO-C 1-4 alkyl, -SO2-C 1-4 alkyl, -CONH-C 1-4 alkyl, -NHCO-C 1-4 alkyl, C 3-6 cycloalkyl;

[0025] said heterocycloalkyl, heteroaryl have heteroatoms selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0026] In another preferred embodiment, X is a nitrogen-containing heteroaryl selected from the group consisting of pyridyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl; said groups are optionally substituted with 1, 2 or 3 groups selected from the group consisting of deuterium, hydroxy, carboxy, amino, thiol, C 1-4 alkyl, C 1-4 alkoxy, sulfone, F, Cl, Br, CN, NO2, C 1-4 haloalkyl, -SO-C 1-4 alkyl, -SO2-C 1-4 alkyl, -CONH-C 1-4 alkyl, -NHCO-C 1-4 alkyl, C 3-6 cycloalkyl.

[0027] In another preferred embodiment, X is selected from: said groups are optionally substituted with 1 or 2 groups selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, cyano, nitro, carboxy, fluorine, chlorine, bromine, -CONHCH3, -NHCOCH3.

[0028] In another preferred embodiment, the pharmaceutically acceptable salt is formed from a compound of general formula (I) with an organic or inorganic acid, an organic or inorganic base. The pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, propionate, maleate, fumarate, succinate, tartrate, citrate, acid amino acid salts, alkylsulfonate (such as methanesulfonate, ethanesulfonate, and the like), arylsulfonate (such as benzenesulfonate, p-toluenesulfonate, and the like), and the like. The pharmaceutically acceptable salts include, but are not limited to, inorganic base salts, such as sodium salt, potassium salt, magnesium salt, calcium salt; organic base salts, including ethylenediamine salt, meglumine salt, tromethamine salt, and the like.

[0029] The compounds of general formula (I) of the present invention, their optical isomers or pharmaceutically acceptable salts thereof may also exist in the form of solvates, such as hydrates, alcohols, etc., which are also included within the scope of the present invention.

[0030] In another preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is selected from:

[0031]

[0032]

[0033]

[0034] A second aspect of the present invention provides a method for preparing the compound described in the first aspect, comprising the following steps:

[0035]

[0036] a) Intermediate I-1 reacts with methanesulfonyl chloride to give intermediate I-2;

[0037] b) Intermediate I-2 reacts with azide-trimethylsilane and boron trifluoride diethyl ether to give intermediate I-3;

[0038] c) Intermediate I-3 reacts with lithium aluminum hydride to obtain intermediate I-4;

[0039] d) Intermediate I-4 reacts with acyl chloride to give target compound I; or

[0040] e) Intermediate I-4 undergoes a condensation reaction with a carboxylic acid to give the target compound I.

[0041] In each formula, X, A, and B are defined as described above.

[0042] 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 hours under the catalysis of 4-dimethylaminopyridine to obtain intermediate I-2. The organic base may be triethylamine or N,N-diisopropylethylamine; the polar aprotic solvent may be 1,4-dioxane, toluene, tetrahydrofuran, or dichloromethane; dichloromethane is the preferred solvent.

[0043] In another preferred embodiment, in step b, intermediate I-2 is dissolved in an ultra-dry dichloromethane solution, and 3-6 equivalents of azidotrimethylsilane and 4-8 equivalents of boron trifluoride diethyl ether are added sequentially. The mixture is reacted at room temperature for 12-24 hours to obtain intermediate I-3 with its stereoconfiguration preserved. The optimal equivalent ratio of azidotrimethylsilane is 3 equivalents; the optimal equivalent ratio of boron trifluoride diethyl ether is 4 equivalents.

[0044] 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 and reacted at room temperature for 2-6 hours to obtain intermediate I-4. The polar aprotic solvent can be 1,4-dioxane, toluene, tetrahydrofuran, or dichloromethane; tetrahydrofuran is the preferred solvent.

[0045] 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 acyl chlorides (isonicotinyl chloride hydrochloride, nicotinyl chloride hydrochloride, pyridine-3-sulfonyl chloride hydrochloride, etc.) at room temperature for 6-12 h under the catalysis of 4-dimethylaminopyridine to obtain target compound I. The organic base may be triethylamine or N,N-diisopropylethylamine; the polar aprotic solvent may be 1,4-dioxane, toluene, tetrahydrofuran, or dichloromethane; the optimal solvent is dichloromethane.

[0046] In another preferred embodiment, in step e, intermediate I-4 is dissolved in N,N-dimethylformamide and then reacted with various carboxylic acids (4-pyridazinic acid, 4-fluoropyridine-3-carboxylic acid, etc.) at room temperature in the presence of the condensing agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) for 8-12 h to obtain target compound I. The reaction temperature is 0-50℃, with room temperature being the optimal temperature.

[0047] In another preferred embodiment, compound II-1 undergoes a Suzuki coupling reaction with boric acid or a borate ester to obtain intermediate I-1.

[0048]

[0049] In the formula, X is defined as described above.

[0050] In another preferred embodiment, compound II-1 is dissolved in a mixed solution of 1,4-dioxane and water, and then subjected to a Suzuki coupling reaction at 100°C with various boric acids or borate esters (5-pyrimidineboronic acid, 5-methylpyridine-3-boronic acid, 5-methoxy-3-pyrimidinepinacol boronic acid, etc.) under the catalysis of bis(triphenylphosphine)palladium dichloride to obtain the corresponding compound I-1. The volume ratio of 1,4-dioxane to water is 5:1-2:1, with an optimal volume ratio of 3:1; the reaction temperature is 80-110°C, with an optimal reaction temperature of 100°C.

[0051] In another preferred embodiment, the method for preparing intermediate I-1 includes the following steps:

[0052]

[0053] i) Compound II-2 undergoes an addition-elimination reaction to give compound II-3;

[0054] ii) Compound II-3 is de-aldehyded to give compound II-4;

[0055] iii) Hydrolysis of compound II-4 yields intermediate I-1.

[0056] In the formula, X is defined as described above.

[0057] In another preferred embodiment, in step i, compound II-2 is dissolved in a polar solvent, and then, under the action of an inorganic base, undergoes an addition-elimination reaction with various aromatic heterocyclic compounds (1,2,3-triazole, imidazole, 4-methylimidazolium, 4-ethylimidazolium, etc.) at 80°C to obtain the corresponding compound II-3. The polar solvent can be acetonitrile, N,N-dimethylformamide, or N,N-dimethylacetamide; the inorganic base can be sodium carbonate, potassium carbonate, or cesium carbonate, with potassium carbonate being the preferred inorganic base.

[0058] In another preferred embodiment, in step ii, compound II-3 is dissolved in dry N,N-dimethylformamide, and a stoichiometric amount of palladium on carbon is added. The reaction is carried out for 18-72 hours to remove the aldehyde group, yielding compound II-4. The reaction temperature can be 140-170°C, with an optimal reaction temperature of 160°C.

[0059] 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.

[0060] It should be understood that, for the compounds represented by formula (I) of the present invention, those skilled in the art, under the guidance of the above methods, can use a combination of various methods well known to those skilled in the art of organic synthesis or medicinal chemistry to prepare them. The methods described above can be combined with synthetic methods known in the art or variations thereon as understood by those skilled in the art to synthesize the compounds of the present invention, and are not limited to the methods described above.

[0061] A third aspect of the present invention provides a pharmaceutical composition comprising:

[0062] The compound represented by general formula (I) as described in the first aspect, or its enantiomers, diastereomers, stereoisomers, prodrugs, deuterated derivatives, hydrates, solvates, racemates, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

[0063] A fourth aspect of the present invention provides the use of a compound of formula (I) as described in the first aspect or a pharmaceutical composition as described in the third aspect for the preparation of a medicament for the prevention and / or treatment of diseases related to the AR signaling pathway.

[0064] In another preferred embodiment, the diseases associated with the AR signaling pathway are selected from: prostate cancer, castration-resistant prostate cancer, breast cancer, SARS-CoV-2 infectious diseases, osteoporosis, and digestive system diseases.

[0065] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Due to space limitations, these will not be elaborated upon here. Attached Figure Description

[0066] Figure 1 This demonstrates that the AR-ACE2 / TMPRSS2 signaling pathway mediates SARS-CoV-2 virus infection of host cells.

[0067] Figure 2 The effects of the compound on gonadal weight gain in vivo are shown, including (A) the weight of the seminal vesicle and (B) the weight of the prostate. Detailed Implementation

[0068] The inventors of this patent, through extensive and in-depth research, designed and synthesized a series of steroidal compounds with the general structural formula (I). Systematic bioactivity tests, including in vitro AR antagonistic activity, AR degradation activity, mutant AR antagonistic activity, and cell proliferation inhibition activity tests, as well as in vivo tests on gonadal weight gain in rats and xenograft tumors in mice, demonstrated that the compounds of this invention possess excellent antitumor activity and are safer and more effective AR degradation / antagonist agents. Furthermore, in vivo pharmacokinetic experiments in rats showed that these compounds have high plasma exposure, exhibiting excellent pharmacokinetic characteristics and drug-likeness. All these results prove that the compounds of this invention can be used to treat AR signaling pathway-related diseases, including prostate cancer and COVID-19 patients. Based on these findings, this invention was completed.

[0069] the term

[0070] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0071] In this invention, the halogen is F, Cl, Br or I.

[0072] In this invention, the term "C" 1-6"C" refers to having 1, 2, 3, 4, 5, or 6 carbon atoms. 1-4 "" refers to having 1, 2, 3 or 4 carbon atoms, and so on.

[0073] In this invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety consisting only of carbon and hydrogen atoms, such as the term "C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0074] In this invention, the term "alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having a specified number of carbon atoms and being attached to at least two other groups. The two groups attached to the alkylene group can be the same or different atoms attached to the alkylene group. For example, a straight-chain alkylene group can be -(CH2). n - a divalent group, 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.

[0075] In this invention, the term "alkoxy" represents -O-(C 1-6 Alkyl group. For example, the term "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0076] In this invention, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spirocyclic systems, and typically has 3 to 15 carbon atoms. For example, the term "C 3-8 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C"... 3-6 "Cycloalkyl" has a similar meaning.

[0077] In this invention, the term "heterocyclic alkyl" refers to a saturated or unsaturated non-aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) cyclic heteroatoms (e.g., N, O, or S), such as tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, or morpholinyl.

[0078] In this invention, the term "4-8-membered" refers to the number of atoms forming the closed ring skeleton in the defined closed ring group (such as aryl, heteroaryl, heterocycloalkyl, etc.) being 4, 5, 6, 7, or 8. This number can vary depending on the number of rings, saturation, and the properties of the atoms constituting the ring. The meanings of other terms described in a similar manner, such as "3-6-membered" and "4-6-membered," can be inferred from this.

[0079] In this invention, the term "aryl" refers to a hydrocarbon moiety comprising one or more aromatic rings. For example, the term "C 6-10 "Aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0080] In this invention, the term "heteroaryl" refers to a conjugated aromatic cyclic group composed of a carbon atom and a heteroatom selected from nitrogen, oxygen, and sulfur. This group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of heteroaryl groups typically include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, isoindoleyl, indoleyl, benzimidazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzopyridazinyl, quinazolinyl, and quinoxalinyl.

[0081] Unless otherwise stated, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups mentioned herein are substituted or unsubstituted groups. Possible substituents include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, and C1-C20 heterocycloalkenyl. C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, 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, guanidinyl, ureyl, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid ester groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused together.

[0082] In this invention, the substitution can be monosubstituted or polysubstituted, and the polysubstituted can be disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. Disubstituted means having two substituents, and so on.

[0083] compound

[0084] This invention provides a class of steroidal compounds with both AR degradation and antagonistic mechanisms of action. They can antagonize AR while promoting AR degradation, thereby completely blocking the androgen receptor signaling pathway. This results in better efficacy than existing single-function AR antagonists, single-function AR degraders, or single-function androgen synthase inhibitors. This invention can be used to treat CRPC and even prostate cancer patients at all stages, addressing the increasingly serious drug resistance problem in PCa patients. It can also be used to treat diseases such as COVID-19, achieving better treatment for diseases related to the AR signaling pathway.

[0085] The structure of the compound of this invention is as follows:

[0086]

[0087] In the formula, the definitions of each substitution are the same as before.

[0088] Pharmaceutical Composition

[0089] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective range, and a pharmaceutically acceptable carrier.

[0090] The "active ingredient" mentioned in this invention refers to the compound of formula (I) described in this invention.

[0091] The "active ingredient" and pharmaceutical composition described in this invention are used to prepare drugs for treating diseases related to the AR signaling pathway. The "active ingredient" and pharmaceutical composition described in this invention can be used as AR degrading agents or antagonists. The AR signaling pathway-related diseases are selected from: prostate cancer, SARS-CoV-2 infectious diseases, castration-resistant prostate cancer, breast cancer, osteoporosis, and digestive system diseases.

[0092] "Safe and effective dose" means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0093] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0094] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0095] The compounds of this invention can be administered alone or in combination with other therapeutic agents (such as antitumor drugs).

[0096] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) in need of treatment. The dosage at the time of administration is the pharmaceutically considered effective dosage. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0098] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. These improvements to the invention without inventive effort using techniques known to those skilled in the art, such as prodrugs or prodrug formulations (hydroxyl, carboxyl, NH, etc., in the compound structure of this invention can all be prepared into prodrugs by conventional methods), deuteration, salt formation, solvates, etc., are all within the scope of this patent protection.

[0099] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement the present invention. They should not be considered as limiting the scope of the invention, but merely as exemplary illustrations and typical representatives. Those skilled in the art should understand that there are other synthetic routes to form the compounds of the present invention; the examples provided below are non-limiting.

[0100] All reactions were monitored using thin-layer chromatography (TLC) on silica gel F-254 TLC plates. Column chromatography was performed using silica gel (200-300 mesh). The structures of the compounds were determined by nuclear magnetic resonance (NMR). The solvents used for analysis were deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3). 1 H and 13C10 NMR measurements were performed using a Bruker 400, Bruker 500, or Bruker 600 NMR spectrometer. Chemical shifts (δ) are expressed in parts per million (ppm), and coupling constants (J) are expressed in Hertz (Hz). Mass spectrometry measurements were performed using a Finnigan MAT95 mass spectrometer for electron ionization (EI) mass spectrometry, a Krats MS 80 mass spectrometer for electrospray ionization (ESI) mass spectrometry, and a 1290-6545U HPLC-QTOF high-resolution mass spectrometer for small molecule drug structure analysis. All compounds were purified to >95% purity using analytical high-performance liquid chromatography (PLATISIL ODS 250 mm × 4.6 mm, 5 μm particle size) with acetonitrile / water, acetonitrile / buffer (0.1% trifluoroacetic acid / water), or methanol / buffer (0.1% trifluoroacetic acid / water) as the mobile phase.

[0101] Example 1:

[0102] 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-cyclopentan[a]phenanthrene-3-yl)pyridine-3-sulfonamide (Compound 1)

[0103]

[0104] (3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentane[a]phenanthrene-3-yl methanesulfonate (45)

[0105] Abiraterone (44) (1 g, 2.86 mmol) and 4-dimethylaminopyridine (35 mg, 0.286 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (1.19 mL, 8.58 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.5 mL, 5.72 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (20-50% ethyl acetate / petroleum ether) to obtain the desired product. 705 mg of a pale yellow solid (45) was finally obtained, with a yield of 57.6%. 1HNMR (400MHz, CDCl3) δ8.63(s,1H),8.48(d,J=4.7Hz,1H),7.66(d,J=7.7Hz,1H),7.24(dd,J= 7.6, 4.9Hz, 1H), 6.01 (s, 1H), 5.49 (d, J = 4.5Hz, 1H), 4.56 (dq, J = 16.2, 5.3Hz, 1H), 3.04 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H).

[0106] 3-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)pyridine (46)

[0107] Compound 45 (470 mg, 1.1 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.22 mL, 1.65 mmol) and boron trifluoride diethyl ether (0.27 mL, 2.2 mmol) were added dropwise using a plastic pipette. After the addition was complete, the mixture was stirred at room temperature for 16 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 120 mg of white solid compound 46 was obtained, with a yield of 29.1%. 1 H NMR (400MHz, CDCl3) δ8.64(d,J=1.8Hz,1H),8.48(dd,J=4.8,1.4Hz,1H),7.67(dt,J=7.9,1.9Hz,1H),7.24(dd,J=7.9,4.8Hz, 1H), 6.02 (dd, J=3.1, 1.7Hz, 1H), 5.45 (d, J=5.1Hz, 1H), 3.24 (ddd, J=10.5, 9.2, 4.1Hz, 1H), 1.09 (s, 3H), 1.07 (s, 3H).

[0108] (3S,10R,13S)-10,13-dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentane[a]phenanthracene-3-amine (47)

[0109] Compound 46 (253 mg, 0.68 mmol) was dissolved in ultradry tetrahydrofuran and stirred in an ice bath. Then, a 1 M solution of lithium aluminum hydride in tetrahydrofuran (1 mL, 1 mmol) was slowly added dropwise using a plastic pipette. After the addition was complete, the mixture was stirred at room temperature for 1.5 h, and the reaction was monitored by TLC until complete. After the reaction was complete, the system was placed in an ice bath and quenched with ice water. The mixture was then extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column 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 (400MHz, CDCl3) δ8.63(d,J=1.7Hz,1H),8.47(dd,J=4.7,1.4Hz,1H),7.66(d,J=7.9Hz,1H),7.24(dd,J=7.8,4.8Hz,1H),6.01(s,1H),5.39(d,J= 5.1Hz,1H),1.07(s,6H).

[0110] 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-cyclopentan[a]phenanthrene-3-yl)pyridine-3-sulfonamide (Compound 1)

[0111] Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (60 μL, 0.42 mmol) and stirring for a period of time. Finally, pyridine-3-sulfonyl chloride hydrochloride (40 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was then washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (30-40% ethyl acetate / petroleum ether) to obtain the desired product. 45 mg of a white solid, compound 1, was finally obtained, with a yield of 64.1%. 1H NMR (400 MHz, DMSO) δ8.97 (d, J=2.1Hz, 1H), 8.82 (dd, J=4.8, 1.5Hz, 1H), 8.58 (s, 1H), 8.43 (d, J= 3.5Hz,1H),8.23–8.17(m,1H),8.02(d,J=7.4Hz,1H),7.78–7.71(m,1H),7.65(dd,J=8.0, 4.8Hz,1H),7.33(dd,J=7.9,4.8Hz,1H),6.11(s,1H),5.21(d,J=4.8Hz,1H),2.90(dd,J=11.6,4.7Hz,1H),0.99(s,3H),0.95(s,3H). 13 C NMR(126MHz,DMSO)δ153.36,148.26, 147.61,147.27,140.99,138.94,134.70,133.75,132.57,129.44,124.76,123.82,121.51,57.43,53.9 9,50.04,47.07,37.64,36.55,34.97,31.72,31.26,30.27,29.51,20.73,19.27,16.68.HRMS(ESI)(M+H) + Calculated value of m / z C 29 H 36 N3O2S 490.2523, measured value: 490.2513.

[0112] Example 2:

[0113] 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-cyclopentan[a]phenanthrene-3-yl)isonicotinamide (compound 2)

[0114]

[0115] Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (60 μL, 0.42 mmol) and stirring for a period of time. Finally, isonicotinamide hydrochloride (30 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was concentrated directly with silica gel and purified by an automated column chromatography system (1-3% methanol / dichloromethane) to obtain the desired product. 34 mg of a white solid, compound 2, was finally obtained, with a yield of 52.3%. 1 H NMR (600MHz, CDCl3) δ8.69(d,J=5.8Hz,2H),8.59(s,1H),8.43(d,J=4.3Hz,1H),7.65(d,J=7.9Hz,1H),7.59(d,J=5.8 Hz,2H),7.22(dd,J=7.8,4.9Hz,1H),6.28(d,J=7.9Hz,1H),5.99(s,1H),5.43(d,J=5.1Hz,1H),3.94–3.86(m,1H),1.05(s,3H),1.02(s,3H). 13 C NMR (151MHz, CDCl3) δ164.77,151.48, 150.52,147.43,141.95,140.29,134.23,133.07,129.49,123.21,122.05,120.90,57.45,50.44,50.2 9,47.32,39.14,37.75,36.78,35.09,31.81,31.47,30.40,29.01,20.77,19.30,16.58.HRMS(ESI)(MH) - Calculated value of m / z C 30 H 34 N3O 452.2707, measured value: 452.2703.

[0116] Example 3:

[0117] 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-cyclopentan[a]phenanthrene-3-yl)nicotinamide (compound 3)

[0118]

[0119] Compound 47 (50 mg, 0.143 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (60 μL, 0.42 mmol) and stirring for a period of time. Finally, nicotinic acid chloride hydrochloride (30 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was concentrated directly with silica gel and purified by an automated column chromatography system (1-3% methanol / dichloromethane) to obtain the desired product. 44 mg of a white solid, compound 3, was finally obtained, with a yield of 67.7%. 1 H NMR (500MHz, CDCl3) δ8.98(d,J=1.6Hz,1H),8.72(dd,J=4.8,1.6Hz,1H),8.64(d,J=1.7Hz,1H),8.47(dd,J=4.8,1.4Hz, 1H),8.14–8.10(m,1H),7.67(dt,J=7.9,1.8Hz,1H),7.39(dd,J=7.8,4.9Hz,1H),7.24(dd,J =7.9,4.8Hz,1H),6.24(d,J=7.8Hz,1H),6.02(dd,J=3.1,1.7Hz,1H),5.48–5.45(m,1H), 3.95(tdd,J=12.1,8.1,4.3Hz,1H),1.11(s,3H),1.07(s,3H). 13 C NMR(126MHz, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 36 N3O4 54.2853, measured value: 454.2849.

[0120] Example 4:

[0121] 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-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 4)

[0122]

[0123] Compound 47 (50 mg, 0.143 mmol) and 4-pyridazinic acid (20 mg, 0.161 mmol) were placed in a flask. Ultra-dry N,N-dimethylformamide was added as a solvent and the mixture was stirred at room temperature. Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (74 mg, 0.195 mmol) was added and stirred for a period of time. Finally, N,N-diisopropylethylamine (43 μL, 0.29 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (30-60% ethyl acetate / petroleum ether) to obtain the desired product. 29 mg of a pale yellow solid, compound 4, was finally obtained, with a yield of 44.6%. 1 H NMR (600MHz, DMSO) δ9.50(dd,J=2.1,1.3Hz,1H),9.39(dd,J=5.3,1.1Hz,1H),8.82(d,J=7.9Hz,1H),8.77(d, J=1.6Hz,1H),8.63(d,J=4.4Hz,1H),8.24(d,J=8.2Hz,1H),7.96(dd,J=5.3,2.3Hz,1H),7.72(dd,J=8.0,5.3 Hz,1H),6.33(d,J=1.0Hz,1H),5.36(d,J=5.0Hz,1H),3.73–3.65(m,1H),1.03(s,3H),1.01(s,3H). 13 C NMR (151MHz, DMSO) δ162.66,152.40,149.28,142.67,141.30,139.28,132.89, 132.01,125.99,124.67,121.33,117.45,57.47,50.30,50.05,47.07,38.54,37.8 8,36.86,34.55,32.02,31.26,30.26,28.23,20.83,19.46,16.53.HRMS(ESI)(MH) - Calculated value of m / z C 29 H 33 N4O 453.266, measured value: 453.2654.

[0124] Example 5:

[0125] 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-cyclopentan[a]phenanthrene-3-yl)-4-fluoronicotinamide (compound 5)

[0126]

[0127] Compound 47 (50 mg, 0.143 mmol) and 4-fluoropyridine-3-carboxylic acid (22 mg, 0.143 mmol) were placed in a flask, and ultradry N,N-dimethylformamide was added as a solvent and stirred at room temperature. Then, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (74 mg, 0.195 mmol) was added and stirred for a period of time. Finally, N,N-diisopropylethylamine (43 μL, 0.29 mmol) was added and stirred at room temperature for 10 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic phase was collected. The mixture was then washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (1-2% methanol / dichloromethane) to obtain the desired product. 36 mg of white solid compound 5 was finally obtained, with a yield of 53.2%. 1 H NMR (600MHz, CDCl3) δ8.88(s,1H),8.69(d,J=4.8Hz,1H),8.61(d,J=2.0Hz,1H),8.59(d,J=4.8Hz,1H),8.28(d, J=8.1Hz,1H),7.99–7.95(m,1H),7.78(dd,J=7.8,5.6Hz,1H),6.65–6.59(m,1H),6.33(s,1H),5.48(d,J=4.8Hz, 1H), 3.96 (d, J = 5.8Hz, 1H), 1.12 (s, 6H). 13 C NMR (151MHz, CDCl3) δ160.23,148.55,146.44, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 35FN3O 472.2759, measured value: 472.2763.

[0128] Example 6:

[0129] 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-cyclopentan[a]phenanthryl-3-yl)pyridine-3-sulfonamide (compound 6)

[0130]

[0131] (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-cyclopentan[a]phenanthrene-3-yl methanesulfonate (49)

[0132] Galeterone (48) (1.645 g, 4.24 mmol) and 4-dimethylaminopyridine (52 mg, 0.424 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (1.8 mL, 12.72 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.7 mL, 8.4 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 8 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. A final yield of 1.64 g of a pale yellow solid, compound 49, was obtained, with a yield of 83.2%. 1 H NMR(400MHz, CDCl3)δ7.97(s,1H),7.86–7.82(m,1H),7.52–7.49(m,1H),7.35 –7.30(m,2H),6.00(dd,J=3.1,1.7Hz,1H),5.50(d,J=5.2Hz,1H),4.57(tdd,J=11.4,7.1,4.7Hz,1H),3.04(s,3H),1.09(s,3H),1.03(s,3H).

[0133] 3-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-benzo[d]imidazolium (50)

[0134] Compound 49 (979 mg, 2.1 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.41 mL, 3.15 mmol) and boron trifluoride diethyl ether (0.52 mL, 4.2 mmol) were added sequentially using a plastic pipette. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. 266 mg of compound 50 was finally obtained as a white solid, with a yield of 30.7%. 1 H NMR(400MHz, CDCl3)δ8.45(s,1H),8.11(d,J=7.6Hz,1H),7.60–7.52(m,3H),6.24(dd,J=3.0 ,1.6Hz,1H),5.47(d,J=5.0Hz,1H),3.25(dt,J=11.5,6.3Hz,1H),1.08(s,3H),1.05(s,3H).

[0135] (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-cyclopentan[a]phenanthracene-3-amine (51)

[0136] Compound 50 (266 mg, 0.643 mmol) was dissolved in ultradry tetrahydrofuran and stirred in an ice bath. Then, a 1 M solution of lithium aluminum hydride in tetrahydrofuran (1 mL, 1 mmol) was slowly added dropwise using a plastic pipette. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC to ensure complete reaction. After the reaction was complete, the system was placed in an ice bath and quenched with ice water. The mixture was then extracted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (5-10% methanol / dichloromethane) to obtain the desired product. Finally, 107 mg of a white solid, compound 51, was obtained, with a yield of 43.3%. 1 H NMR (400MHz, DMSO) δ8.27(s,1H),7.71(d,J=7.4Hz,1H),7.57(d,J=7.4Hz,1H),7.28(ddd,J=15.0,13.7,6.6Hz,2H),6.06(s,1H),5.32(d,J=4.3Hz, 1H),0.99(s,3H),0.97(s,3H).

[0137] 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-cyclopentan[a]phenanthryl-3-yl)pyridine-3-sulfonamide (compound 6)

[0138] Compound 51 (50 mg, 0.129 mmol) and 4-dimethylaminopyridine (2 mg, 0.013 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (54 μL, 0.39 mmol) and stirring for a period of time. Finally, pyridine-3-sulfonyl chloride (20 μL, 0.155 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 6 h, and the reaction was monitored by TLC until complete. After the reaction was complete, the mixture was directly concentrated with silica gel and purified by an automated column chromatography system (30-60% ethyl acetate / petroleum ether) to obtain the desired product. 35 mg of a white solid, compound 6, was finally obtained, with a yield of 51.3%. 1 HNMR (600MHz, CDCl3) δ9.09 (d, J=1.9Hz, 1H), 8.78 (dd, J=4.8, 1.6Hz, 1H), 8.16 (ddd, J=8.0, 2.2,1.7Hz,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=3.1,1.6Hz,1H),5.31(d,J=7.0Hz,2H),3.16–3.08(m,1H),0.97(s,6H). 13 C NMR (151MHz, CDCl3) δ153.03,147.92,146.97,141.52,140.13,138.18,134.59,134.42,124.42, 123.74,123.63,122.76,121.93,119.94,111.24,55.75,54.21,50.36,47.21,40.2 8,37.65,36.59,34.73,30.96,30.28,30.23,20.50,19.15,15.98.HRMS(ESI)(M+H) + Calculated value of m / z C 31 H 37 N4O2S 529.2632, measured value: 529.2635.

[0139] Example 7:

[0140] (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-cyclopentan[a]phenanthracene-3-amine (Compound 7)

[0141]

[0142] Compound 51 (50 mg, 0.129 mmol) was placed in a flask, and ultradry N,N-dimethylformamide was added as a solvent. The mixture was stirred at room temperature, followed by the addition of potassium carbonate (36 mg, 0.261 mmol) and stirring for a period of time. Finally, 4-(bromomethyl)pyridine hydrochloride (33 mg, 0.130 mmol) was added. After the addition was complete, the system was slowly heated to 50 °C and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (2-5% methanol / dichloromethane) to obtain the desired product. 32 mg of a white solid, compound 7, was finally obtained, with a yield of 51.8%. 1 H NMR (600MHz, CDCl3) δ8.53(dd,J=4.6,1.3Hz,2H),7.94(s,1H),7.81–7.77(m,1H),7.48–7.45(m,1H),7.30(d,J=5. 6Hz,2H),7.29–7.26(m,2H),5.96(dd,J=2.9,1.6Hz,1H),5.38–5.35(m,1H),3.87(s,2H),1.03(s,3H),0.99(s,3H). 13 C NMR (151MHz, CDCl3) δ149.92,147.17,143.22,141.64,134.55,124.11,123 .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) + Calculated value of m / z C 32 H 39 N4 479.3169, measured value: 479.3168.

[0143] Example 8:

[0144] 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-cyclopentan[a]phenanthryl-3-yl)isonicotinamide (compound 8)

[0145]

[0146] Compound 8 was synthesized using the same method as compound 2. Adding compound 51 (50 mg, 0.129 mmol) yielded 24 mg of white solid compound 8, with a yield of 37.8%. 1 H NMR (500MHz, DMSO) δ8.74(d,J=4.4Hz,2H),8.65(s,1H),8.62(d,J=8.0Hz,1H),7.80(d,J=5.9Hz,2H),7.75(d,J=7.6Hz,1H),7.65(d,J =7.7Hz,1H),7.41–7.32(m,2H),6.15(s,1H),5.39(d,J=4.6Hz,1H),3.77–3.67(m,1H), 1.03(s,3H),0.97(s,3H). 13 C NMR (126MHz, DMSO) δ163.98,149.94,146.22,141.55,126.38, 124.68,123.90,121.98,120.98,118.70,112.46,55.72,50.39,50.16,47.17,38.6 5,37.96,36.86,34.17,30.86,30.41,28.34,20.63,19.41,16.07.HRMS(ESI)(M+H) + Calculated value of m / z C 32 H 37 N4O 493.2962, measured value: 493.2969.

[0147] Example 9:

[0148] 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-cyclopentan[a]phenanthryl-3-yl)pyridazine-4-amide (Compound 9)

[0149]

[0150] Compound 9 was synthesized using the same method as compound 4. Adding compound 51 (50 mg, 0.129 mmol) yielded 24 mg of white solid compound 9, with a yield of 37.8%. 1 H NMR (600MHz, CDCl3) δ9.53 (dd, J=2.1, 1.2Hz, 1H), 9.28 (dd, J=5.2, 1.0Hz, 1H) ,7.94(s,1H),7.86(dd,J=5.2,2.3Hz,1H),7.78–7.73(m,1H),7.49–7.44(m,1H ),7.30–7.25(m,2H),7.18(d,J=7.9Hz,1H),5.97(dd,J=2.8,1.5Hz,1H),5.43( d, J=5.0Hz, 1H), 3.94 (tdd, J=12.1, 8.1, 4.2Hz, 1H), 1.01 (s, 3H), 0.99 (s, 3H). 13 C NMR (151MHz, CDCl3) δ162.79,151.81,148.56,142.98,141.55,140.26,134.53,132.28, 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) + Calculated value of m / z C 31 H 36 N5O 494.2914, measured value: 494.2917.

[0151] Example 10:

[0152] N-((3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 10)

[0153]

[0154] (3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecylhydro-1H-cyclopentan[a]phenanthracene-3-ol (52)

[0155] Compound II-1 (7 g, 17.6 mmol), 5-pyrimidineboronic 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 placed in a flask, followed by the addition of 60 mL of dioxane and 20 mL of water. The mixture was stirred at room temperature, then purged three times with argon gas. The temperature was slowly increased to 100 °C and the reaction was allowed to proceed overnight. The reaction was monitored by TLC the next day until complete. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (30-50% ethyl acetate / petroleum ether) to obtain the desired product. A final yield of 2.2 g of yellow solid compound 52 was obtained, with a yield of 35.78%. 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.72 (s, 2H), 6.10 (s, 1H), 5.38 (d, J = 5.1Hz, 1H), 3.58–3.49 (m, 1H), 1.06 (s, 3H), 1.04 (s, 3H).

[0156] (3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthrene-3-yl methanesulfonate (53)

[0157] Compound 52 (2.2 g, 6.28 mmol) and 4-dimethylaminopyridine (80 mg, 0.65 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (2.6 mL, 19.34 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (1 mL, 11.54 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. 534 mg of white solid compound 53 was finally obtained, with a yield of 19.9%. 1 HNMR (400MHz, CDCl3) δ9.09 (s, 1H), 8.74 (s, 2H), 6.13 (dd, J = 3.1, 1.7Hz, 1H), 5.49 (d, J = 5.1Hz, 2H),4.60–4.51(m,1H),3.04(s,3H),1.11(s,3H),1.07(s,3H).

[0158] 5-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)pyrimidine (54)

[0159] Compound 53 (534 mg, 1.24 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.5 mL, 3.77 mmol) and boron trifluoride diethyl ether (0.6 mL, 4.83 mmol) were added dropwise using a plastic pipette. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. 231 mg of compound 54 was finally obtained as a white solid, with a yield of 49.4%.

[0160] (3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentane[a]phenanthracene-3-amine (55)

[0161] Compound 54 (231 mg, 0.615 mmol) was dissolved in ultradry tetrahydrofuran and stirred in an ice bath. Then, a 1 M solution of lithium aluminum hydride in tetrahydrofuran (0.9 mL, 0.9 mmol) was slowly added dropwise using a plastic pipette. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. After the reaction was complete, the system was placed in an ice bath and quenched with ice water. The mixture was then extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column chromatography (5-8% methanol / dichloromethane) to obtain the desired product. Finally, 101 mg of a white solid, compound 55, was obtained, with a yield of 47.02%.

[0162] N-((3S,10R,13S)-10,13-dimethyl-17-(pyrimidin-5-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 10)

[0163] Compound 55 (43 mg, 0.123 mmol) was added to give 42 mg of yellow solid compound 10, with a yield of 75%. 1HNMR(400MHz,DMSO)δ9.52(s,1H),9.41(d,J=5.3Hz,1H),9.04(s,1H),8.81(s,3H),7.97(dd,J =5.2, 2.2Hz, 1H), 6.28 (s, 1H), 5.37 (d, J = 4.1Hz, 1H), 3.71 (dd, J = 11.8, 4.1Hz, 1H), 1.04 (s, 3H), 1.01 (s, 3H). 13 C NMR (126MHz, DMSO) δ162.21,156.70,153.81,152.12,148.82,147.92, 140.88,131.64,131.25,130.07,124.07,120.85,56.89,49.87,49.61,46.67,38.17,3 7.47,36.37,34.30,31.52,30.91,29.88,27.87,20.35,18.97,16.08.HRMS(ESI)(M+H) + Calculated value of m / z C 28 H 34 N5O 456.2758, measured value: 456.2762.

[0164] Example 11:

[0165] 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-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 11)

[0166]

[0167] (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-cyclopentane[a]phenanthracene-3-yl acetate (56)

[0168] Compound II-2 (2 g, 5.3 mmol) and potassium carbonate (2.56 g, 18.6 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. 1.26 g of white solid compound 56 was finally obtained, with a yield of 58%. 1 H NMR(400MHz, CDCl3)δ9.92(s,1H),7.85(d,J=1.1Hz,1H),7.83(d,J=1.1Hz,1H),5.41(d,J=4.9Hz,1H), 4.59(dt,J=10.8,6.1Hz,1H),2.03(s,3H),1.16(s,3H),1.07(s,3H).

[0169] (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-cyclopentane[a]phenanthrene-3-yl acetate (57)

[0170] Compound 56 (2 g, 4.89 mmol) was dissolved in dry N,N-dimethylformamide and stirred at room temperature. Then, 1 g of palladium on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 3 days. TLC monitoring confirmed complete reaction. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (20-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 720 mg of yellow solid compound 57 was obtained, with a yield of 38.6%. 1H NMR(400MHz, CDCl3)δ7.72(d,J=1.0Hz,1H),7.71(d,J=1.0Hz,1H), 5.96(dd,J=3.1,1.7Hz,1H),5.41(d,J=5.0Hz,1H),4.61(dt,J=11.4,4.4Hz,1H),2.03(s,3H),1.13(s,3H),1.08(s,3H).

[0171] (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-cyclopentane[a]phenanthrene-3-ol (58)

[0172] Compound 57 (720 mg, 1.88 mmol) was dissolved in anhydrous methanol and stirred at room temperature. Then, 0.4 g (7.3 mmol) of potassium hydroxide was added. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then directly dried by rotary evaporation to obtain the target compound. 554 mg of a yellow solid, compound 58, was obtained, with a yield of 86.4%. 1 H NMR (400MHz, CDCl3) δ7.72(s,1H),7.71(s,1H),5.97(s,1H),5.38(d,J=4.7Hz,1H),3.54(m,1H),1.13(s,3H),1.07(s,3H).

[0173] (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-cyclopentane[a]phenanthrene-3-yl methanesulfonate (59)

[0174] Compound 58 (550 mg, 1.62 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.7 mL, 5.04 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.25 mL, 3.3 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was directly evaporated by rotary evaporation to obtain the desired product. 500 mg of a white solid 59 was finally obtained, with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ7.75(s,1H),7.73(s,1H),5.98(s,1H),5.47(d, J=5.1Hz,1H),4.60–4.49(m,1H),3.03(s,3H),1.15(s,3H),1.10(s,3H).

[0175] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-1,2,3-triazole(60)

[0176] Compound 59 (100 mg, 0.24 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (47 μL, 0.26 mmol) and boron trifluoride diethyl ether (59 μL, 0.48 mmol) were added sequentially using a plastic pipette. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. 63 mg of a white solid 60 was finally obtained, with a yield of 72.16%. 1 H NMR(400MHz, CDCl3)δ7.75(s,1H),7.74(s,1H), 5.99(dd,J=3.1,1.8Hz,1H),5.45(d,J=5.1Hz,1H),3.24(ddd,J=10.4,8.8,4.1Hz,1H),1.15(s,3H),1.08(s,3H).

[0177] (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-cyclopentane[a]phenanthracene-3-amine (61)

[0178] Compound 60 (63 mg, 0.173 mmol) was dissolved in dry tetrahydrofuran and stirred at room temperature. Then, a 1 M solution of lithium aluminum hydride in tetrahydrofuran (0.3 mL, 0.3 mmol) was added, and the reaction was allowed to proceed for 2 hours. The reaction was monitored by TLC until complete. The reaction mixture was quenched with saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated by rotary evaporation to obtain the desired product. 30 mg of a white solid, compound 61, was finally obtained, with a yield of 51.2%. 1 H NMR (400MHz, DMSO) δ8.41 (s, 1H), 7.81 (d, J = 0.9Hz, 1H), 6.12 (s, 1H), 5.27 (s, 1H), 1.05 (s, 3H), 0.99 (s, 3H).

[0179] 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-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 11)

[0180] Compound 61 (50 mg, 0.148 mmol) was added to give 58 mg of white solid compound 11, with a yield of 88.3%. 1 H NMR (400MHz, DMSO) δ9.55–9.53(m,1H),9.43(dd,J=5.3,1.0Hz,1H),8.85(d,J=7.9Hz, 1H),8.45(d,J=0.8Hz,1H),8.00(dd,J=5.3,2.3Hz,1H),7.83(d,J=0.9Hz,1H),6.15(s, 1H), 5.39 (d, J = 4.5Hz, 1H), 3.79–3.67 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H). 13C NMR(151MHz, DMSO)δ162.12,152.10,148.82,133.25,124.13,123.46,120.75,118.75,67.03,55.84,49.84, 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) + Calculated value of m / z C 26 H 33 N6O 445.271, measured value: 445.2722.

[0181] Example 12:

[0182] 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-cyclopentan[a]phenanthroline-3-yl)nicotinamide (compound 12)

[0183]

[0184] (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-cyclopentan[a]phenanthracene-3-yl acetate (62)

[0185] Compound II-2 (7.90 g, 20.96 mmol) and potassium carbonate (7.24 g, 52.40 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 7.0 g of yellow solid compound 62 was obtained, with a yield of 79%. 1H NMR (400MHz, CDCl3) δ9.77(s,1H),7.54(d,J=1.1Hz,1H),6.84(s,1H),5.43(d,J=5.2Hz,1H),4.62(tt,J= 10.5, 5.4Hz, 1H), 2.29 (d, J = 0.6Hz, 3H), 2.06 (s, 3H), 1.08 (s, 6H).

[0186] (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-cyclopentan[a]phenanthrene-3-yl acetate (63)

[0187] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 18 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 3.0 g of yellow solid compound 63 was obtained, with a yield of 50.6%. 1 H NMR (400MHz, CDCl3) δ7.50 (s, 1H), 6.75 (s, 1H), 5.60 (s, 1H), 5.40 (d, J = 4.8Hz, 1 H),4.60(tt,J=10.8,5.3Hz,1H),2.22(s,3H),2.02(s,3H),1.06(s,3H),0.98(s, 3H).

[0188] (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-cyclopentan[a]phenanthracene-3-ol (64)

[0189] 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. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then directly dried by rotary evaporation to obtain the target compound. 1.6 g of yellow solid compound 64 was obtained, with a yield of 99.5%. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J=0.9Hz, 1H), 6.78 (s, 1H), 5.63 (dd, J=3.0, 1.7Hz, 1H), 5.40 (d, J=5.2Hz, 1H), 3.61–3.50 (m, 1H), 2.25 (s, 3H), 1.07(s,3H),1.01(s,3H).

[0190] (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-cyclopentan[a]phenanthrene-3-yl methanesulfonate (65)

[0191] Compound 64 (1.06 g, 3.01 mmol) and 4-dimethylaminopyridine (37 mg, 0.30 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (1.25 mL, 9.03 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.47 mL, 6.01 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 10 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The mixture was purified by an automated column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. 1.05 g of yellow solid compound 65 was finally obtained, with a yield of 81.4%. 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 6.80 (s, 1H), 5.69 (d, J = 1.3Hz, 1H), 5.47 (d, J=4.8Hz,1H),4.60–4.49(m,1H),3.04(s,3H),2.28(s,3H),1.09(s,3H),1.01(s,3H).

[0192] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-methyl-1H-imidazolium (66)

[0193] Compound 65 (1.95 g, 4.53 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (3.6 mL, 27.18 mmol) and boron trifluoride diethyl ether (5.6 mL, 45.30 mmol) were added dropwise using a plastic pipette. After the addition was complete, the reaction was stirred at room temperature for 5 hours, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column 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(400MHz,DMSO)δ8.06(s,1H), 6.84(s,1H),5.92–5.88(m,1H),5.42(d,J=4.9Hz,1H),3.27–3.17(m,1H),2.39(s,3H),1.05(s,3H),1.01(s,3H).

[0194] (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-cyclopentan[a]phenanthracene-3-amine (67)

[0195] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 350 mg of white solid 67, with a yield of 24.3%. 1H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 6.78 (s, 1H), 5.63 (dd, J = 3.0, 1.7Hz, 1H), 5.37 (d, J = 5.2Hz, 1H), 2.25 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H).

[0196] 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-cyclopentan[a]phenanthroline-3-yl)nicotinamide (compound 12)

[0197] Compound 67 (55 mg, 0.156 mmol) was added to give 55 mg of brown solid compound 12, with a yield of 77%. 1 H NMR (400MHz, DMSO) δ8.98(d,J=1.7Hz,1H),8.67(dd,J=4.8,1.5Hz,1H),8.49(d,J=7.9Hz ,1H),8.18–8.14(m,1H),7.73(s,1H),7.48(dd,J=7.9,4.9Hz,1H),7.05(s,1H),5.73(s, 1H), 5.36 (d, J = 4.0Hz, 1H), 3.77–3.65 (m, 1H), 2.09 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H). 13 C NMR (126MHz, DMSO) δ163.90,151.73,148.40,141.15,137.05,134.95,134.73,123.31,120.51,116.43,114.56,55.84,49 .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.HRMS(ESI)(M+H) + Calculated value of m / z C 29 H 37 N4O4 45.271, measured value: 445.2722.

[0198] Example 13:

[0199] 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-cyclopentan[a]phenanthrene-3-yl)pyridazine-4-amide (compound 13)

[0200]

[0201] Compound 67 (55 mg, 0.156 mmol) was added to give 46 mg of a pale yellow solid, compound 13, with a yield of 64.3%. 1 H NMR (400MHz, DMSO) δ9.52 (s, 1H), 9.41 (d, J = 4.4Hz, 1H), 8.82 (d, J = 7.8Hz, 1H), 7.97(dd,J=5.2,2.2Hz,1H),7.68(s,1H),7.02(s,1H),5.71(s,1H),5.36(d,J=3.3Hz,1H), 3.71(d,J=7.2Hz,1H),2.08(s,3H),1.03(s,3H),0.95(s,3H). 13 C NMR(126MHz,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) + Calculated value of m / z C 28 H 36 N5O 458.2914, measured value: 458.2912.

[0202] Example 14:

[0203] 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-cyclopentan[a]phenanthroline-3-yl)isonicotinamide (compound 14)

[0204]

[0205] Compound 67 (55 mg, 0.156 mmol) was added to give 52 mg of white solid compound 14, with a yield of 72.8%. 1 H NMR(500MHz,DMSO)δ8.72(dd,J=4.4,1.6Hz,2H),8.59(d,J=8.0Hz,1H),7.81(d,J=0.7 Hz,1H),7.75(dd,J=4.5,1.6Hz,2H),7.10(s,1H),5.79–5.76(m,1H),5.39(d,J=4.9Hz, 1H),3.78–3.68(m,1H),2.12(d,J=0.5Hz,3H),1.06(s,3H),0.99(s,3H). 13 C NMR(126MHz, DMSO)δ164.19,150.62,148.26,142.08,137.21,135.12,121.64,121.01,115.15,56.30,50.35, 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) + Calculated value of m / z C 29 H 37 N4O 457.2962, measured value: 457.2959.

[0206] Example 15:

[0207] 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-cyclopentan[a]phenanthroline-3-yl)-3-fluoroisonicotinamide (compound 15)

[0208]

[0209] Compound 67 (100 mg, 0.285 mmol) was added to give 89 mg of brown solid compound 15, with a yield of 65.9%. 1H NMR (600MHz, DMSO) δ8.68 (s, 1H), 8.59 (d, J = 7.9Hz, 1H), 8.53 (d, J = 4.7Hz, 1H), 7.71(s,1H),7.57–7.54(m,1H),7.06(s,1H),5.74(s,1H),5.40(d,J=4.6Hz,1H),3.68(dt,J= 16.9,8.6Hz,1H),2.11(s,3H),1.03(s,3H),0.97(s,3H). 13 C NMR(151MHz,DMSO)δ161.60, 148.38,146.64,141.34,139.13,137.71,135.23,123.72,121.12,116.60,114.86,56.29,50.20,5 0.15,45.85,38.65,37.86,36.79,34.52,30.93,30.11,29.62,28.37,20.65,19.39,16.11,13.93. HRMS(ESI)(M+H) + Calculated value of m / z C 29 H 36 FN4O 457.2868, measured value: 457.2874.

[0210] Example 16:

[0211] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (compound 16)

[0212]

[0213] (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-cyclopentan[a]phenanthracene-3-yl acetate (68)

[0214] Compound II-2 (6 g, 15.92 mmol) and potassium carbonate (4.39 g, 31.83 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.27 g of yellow solid compound 68 was obtained, with a yield of 34.97%. 1 H NMR (400MHz, CDCL3) δ9.72(s,1H),7.61(s,1H),7.20(s,1H),7.09(s,1H),5.40(d,J=4.6Hz,1H),4.58(dt,J=10.8, 5.7Hz,1H),2.01(s,3H),1.05(s,6H).

[0215] (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-cyclopentan[a]phenanthrene-3-yl acetate (69)

[0216] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was carried out for 20 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered with diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The mixture was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 875 mg of yellow solid compound 69 was obtained, with a yield of 41.47%. Directly input into the next reaction (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-cyclopentan[a]phenanthracene-3-ol (70)

[0217] 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. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, part of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then directly dried by rotary evaporation to obtain the target compound. 730 mg of a yellow solid, compound 70, was obtained, with a yield of 95.4%. This was then used in the next step.

[0218] (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-cyclopentan[a]phenanthrene-3-yl methanesulfonate (71)

[0219] Compound 70 (105 mg, 0.31 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (129 μL, 0.93 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (48 μL, 0.62 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The mixture was purified by an automated column chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. 111 mg of a white solid, compound 71, was finally obtained, with a yield of 86.3%. 1 ¹H NMR (400MHz, 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). 1-((3S, 10R, 13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazolium (72)

[0220] Compound 71 (44 mg, 0.106 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.15 mL, 1.13 mmol) and boron trifluoride diethyl ether (0.15 mL, 1.21 mmol) were added dropwise using a plastic pipette. After the addition was complete, the reaction was stirred at room temperature for 5 hours, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column 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 (400MHz, CDCl3) δ8.16(s,1H),7.39(s,1H),7.16(s,1H),6.01(s,1H),5.45(d,J=4.9Hz,1H),3.24(dt,J=16.1,5.8Hz,1H), 1.08(s,3H),1.05(s,3H).

[0221] (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-cyclopentan[a]phenanthracene-3-amine (73)

[0222] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 80 mg of white solid 73, with a yield of 54.9%. 1 H NMR (400MHz, DMSO) δ8.10 (s, 2H), 7.84 (s, 1H), 7.36 (s, 1H), 7.00 (s, 1H), 5.83 (s, 1H), 5.41 (d, J = 4.8Hz, 1H), 1.01 (s, 3H), 0.99 (s, 3H).

[0223] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (compound 16)

[0224] Compound 73 (35 mg, 0.104 mmol) was added to give 28 mg of white solid compound 16, with a yield of 61%. 1 HNMR(500MHz,DMSO)δ9.56(d,J=0.7Hz,1H),9.42(d,J=5.2Hz,1H),9.25(s,1H),8.97(d, J=7.8Hz,1H),8.05(dd,J=5.3,2.3Hz,1H),7.90(s,1H),7.80(s,1H),6.26(d,J=1.3Hz,1H), 5.39(d,J=4.6Hz,1H),3.78–3.69(m,1H),1.06(s,3H),1.02(s,3H). 13 C NMR (126MHz, DMSO) δ162.64,152.53,149.31,146.43,141.41,132.14,124.63,121.57,121.42,121.00,56.29, 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) + Calculated value of m / z C 27 H 34 N5O 444.2758, measured value: 444.2757.

[0225] Example 17:

[0226] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 17)

[0227]

[0228] Compound 73 (35 mg, 0.104 mmol) was added to give 17 mg of white solid compound 17, with a yield of 37%. 1HNMR(500MHz,DMSO)δ9.33(s,1H),8.88(d,J=6.0Hz,2H),8.79(d,J=7.9Hz,1H),8.01(d, J=6.2Hz,2H),7.95(s,1H),7.87(s,1H),6.29(s,1H),5.40(d,J=4.4Hz,1H),3.79–3.69(m,1H),1.07(s,3H),1.03(s,3H). 13 C NMR (126MHz, DMSO) δ163.24,147.80,146.19,141.47,134.57,125.71,123.31,121.65,121.00,56.29,50.33, 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) + Calculated value of m / z C 28 H 35 N4O 443.2805, measured value: 443.2812.

[0229] Example 18:

[0230] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 18)

[0231]

[0232] (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-cyclopentan[a]phenanthracene-3-yl acetate (74)

[0233] Compound II-2 (4 g, 10.61 mmol) and potassium carbonate (2.15 g, 15.59 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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 (400MHz, DMSO) δ9.77(s,1H),7.54(s,1H),6.81(s,1H),5.42(s,1H),4.66–4.55(m,1H),2.63(q,J=7.5Hz, 2H),2.04(s,3H),1.26(t,J=7.5Hz,3H),1.01(s,3H),0.88(s,3H).

[0234] (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-cyclopentan[a]phenanthrene-3-yl acetate (75)

[0235] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 36 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (1-4% methanol / dichloromethane) to obtain the desired product. Finally, 1.264 g of a yellow solid, compound 75, was obtained, with a yield of 39.9%. 1H NMR (400MHz, CDCl3) δ7.54 (d, J = 1.2 Hz, 1H), 6.76 (d, J = 0.9 Hz, 1H),5.41(d,J=3.8Hz,1H),4.67–4.56(m,1H),2.63(q,J=7.5Hz,2H),2.05(s,3H),1.26(t,J=7.5Hz,3H),1.01(s,3H),0.88(s,3H).

[0236] (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-cyclopentan[a]phenanthracene-3-ol (76)

[0237] 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. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, part of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The solution was purified by automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 537 mg of a yellow solid, compound 76, was obtained, with a yield of 47.5%. 1 H NMR (400MHz, CDCl3) δ7.56 (d, J=0.8Hz, 1H), 6.78 (s, 1H), 5.64 (dd, J=3.0, 1.7Hz, 1H) ,5.41(d,J=5.2Hz,1H),3.56(dt,J=15.5,5.4Hz,1H),2.63(q,J=7.5Hz,2H),1.26(t, J=7.5Hz,3H),1.08(s,3H),1.02(s,3H).

[0238] (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-cyclopentan[a]phenanthrene-3-yl methanesulfonate (77)

[0239] Compound 76 (537 mg, 1.47 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.6 mL, 4.41 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.24 mL, 2.94 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The mixture was purified by automated column chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. 489 mg of yellow solid compound 77 was finally obtained, with a yield of 75.1%. 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),6.77(s,1H),5.67–5.64(m,1H),5.48(d,J=5.1Hz,1H),4.59–4 .50(m,1H),3.04(s,3H),2.63(q,J=7.5Hz,2H),1.26(t,J=7.5Hz,3H),1.09(s,3H),1.02(s,3H).

[0240] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-ethyl-1H-imidazolium (78)

[0241] Compound 77 (900 mg, 2.02 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.8 mL, 6.06 mmol) and boron trifluoride diethyl ether (1 mL, 8.08 mmol) were added dropwise using a plastic pipette. After the addition was complete, the reaction was stirred at room temperature for 5 hours, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 156 mg of a white solid, 78, was obtained, with a yield of 19.7%. 1H NMR (400MHz, CDCl3) δ8.09(d,J=1.3Hz,1H),6.84(s,1H),5.94(dd,J=3.1,1.7Hz,1H),5.44(d,J=5.0Hz,1H),3.25(ddd,J=15.9,11.6, 4.1Hz,1H),2.87(q,J=7.5Hz,2H),1.29(t,J=7.5Hz,3H),1.08(s,3H),1.04(s,3H).

[0242] (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-cyclopentan[a]phenanthracene-3-amine (79)

[0243] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the solid. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline. At this point, a large amount of white solid precipitated. The aqueous phase was extracted three times with a small amount of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 75 mg of white solid 79, with a yield of 53.57%. 1 H NMR (400MHz, CDCl3) δ7.51(s,1H),6.73(s,1H),5.58(s,1H),5.31(d,J=5.0Hz,1H),2.57(q,J= 7.4Hz, 2H), 1.21 (t, J = 7.5Hz, 3H), 1.01 (s, 3H), 0.97 (s, 3H).

[0244] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 18)

[0245] Compound 79 (75 mg, 0.205 mmol) was added to give 57 mg of white solid compound 18, with a yield of 59.07%. 1H NMR (600MHz, DMSO) δ8.68 (dd, J=4.5, 1.4Hz, 2H), 8.54 (d, J=8.0Hz, 1H), 7.71 (dd, J=4.5, 1.5Hz,2H),7.67(s,1H),7.00(s,1H),5.71(s,1H),5.35(d,J=4.8Hz,1H),3.73–3.65(m, 1H), 2.44 (dd, J=15.0, 7.5Hz, 3H), 1.12 (t, J=7.5Hz, 2H), 1.02 (s, 3H), 0.95 (s, 3H). 13 C NMR (151MHz, DMSO) δ164.18,150.62,148.49,144.30,142.07,141.59,135.19,121.72,121.04, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 39 N4O 471.3118, measured value: 471.3125.

[0246] Example 19:

[0247] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 19)

[0248]

[0249] Compound 79 (32 mg, 0.08 mmol) was added to give 10 mg of white solid compound 19, with a yield of 24.3%. 1HNMR(500MHz,DMSO)δ9.56(s,1H),9.43(d,J=5.1Hz,1H),8.95(s,1H),8.79(s,1H),8.04(s,1H),7.50(s,1H),6.1 1(s,1H),5.40(s,1H),3.78–3.70(m,1H),2.62(q,J=7.5Hz,2H),1.22(t,J=7.6Hz,3H),1.07(s,3H),1.02(s,3H). 13 C NMR (126MHz, DMSO) δ162.57,152.59,149.25,147.01,141.43,138.76,134.10,132.08,124.62,122.40,121.06,116. 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) + Calculated value of m / z C 29 H 38 N5O 472.3071, measured value: 472.3066.

[0250] Example 20:

[0251] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 20)

[0252]

[0253] (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-cyclopentane[a]phenanthracene-3-yl acetate (80)

[0254] Compound II-2 (7 g, 18.57 mmol) and potassium carbonate (3.8 g, 27.55 mmol) were placed in a flask, and ultra-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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by an automated column 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(400MHz, CDCL3)δ9.76(s,1H),7.54(s,1H),6.78(s,1H).5.42(d,J=5.0Hz,1H),4.60–4.54(m,1H), 2.96–2.80(m,2H),2.04(s,3H),1.26(t,J=6.1Hz,6H),1.08(s,3H),0.96(s,3H).

[0255] (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-cyclopentan[a]phenanthracene-3-yl acetate (81)

[0256] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 24 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.13 g of a yellow solid, compound 81, was obtained, with a yield of 52.8%. 1H NMR (400MHz, CDCl3) δ7.75 (d, J = 0.8Hz, 1H), 6.96 (s, 1H), 5.43 (d, J=5.0Hz,1H),4.65–4.54(m,1H),2.96–2.80(m,2H),2.04(s,3H),1.26(t,J=6.1Hz,6H),1.08(s,3H),0.96(s,3H).

[0257] (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-cyclopentan[a]phenanthracene-3-ol (82)

[0258] Compound 81 (1 g, 2.37 mmol) was dissolved in anhydrous methanol and stirred at room temperature. Then, 0.45 g (8.02 mmol) of potassium hydroxide was added. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, part of the solvent was evaporated by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The solution was purified by automated column chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 426 mg of a white solid, compound 82, was obtained, with a yield of 47.3%. 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=1.2Hz, 1H), 6.75 (s, 1H), 5.64 (dd, J=3.1, 1.7Hz, 1H), 5.42–5.39(m,1H),3.60–3.51(m,1H),2.91(dt,J=13.7,6.9Hz,1H),1.28(d,J=6.9Hz,6H), 1.08(s,3H),1.03(s,3H).

[0259] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (83)

[0260] Compound 82 (426 mg, 1.12 mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.47 mL, 3.45 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.18 mL, 2.21 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The mixture was purified by an automated column chromatography (40-60% ethyl acetate / petroleum ether) to obtain the desired product. 490 mg of white solid compound 83 was finally obtained, with a yield of 95.5%. 1 H NMR(400MHz,DMSO)δ7.56(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=13.7,6.9Hz,1H),1.27(d,J=6.9Hz,6H),1.08(s,3H),1.01(s,3H).

[0261] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-isopropyl-1H-imidazolium (84)

[0262] Compound 83 (490 mg, 1.07 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.45 mL, 3.4 mmol) and boron trifluoride diethyl ether (0.53 mL, 4.28 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 151 mg of a white solid, 84, was obtained, with a yield of 34.87%. 1H NMR (400MHz, CDCl3) δ7.65(s,1H),6.74(s,1H),5.67–5.65(m,1H),5.41(d,J=4.9Hz,1H),3.21(ddd,J =10.2,8.7,4.7Hz,1H),2.88(dq,J=13.8,6.9Hz,1H),1.25(d,J=6.9Hz,6H),1.04(s,3H),1.00(s,3H).

[0263] (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-cyclopentan[a]phenanthracene-3-amine (85)

[0264] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 100 mg of white solid 85, with a yield of 70.77%. 1 H NMR (400MHz, CDCl3) δ7.54(s,1H),6.72(s,1H),5.60(s,1H),5.34(d,J=5.0Hz,1H),2.86(dq,J= 13.6, 6.8Hz, 1H), 1.24 (d, J = 6.9Hz, 6H), 1.03 (s, 3H), 0.99 (s, 3H).

[0265] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 20)

[0266] Compound 85 (100 mg, 0.264 mmol) was added to give 63 mg of white solid compound 20, with a yield of 49.2%. 1H NMR (500MHz, DMSO) δ9.28(d,J=1.5Hz,1H),8.89(d,J=8.0Hz,1H),8.84(d,J=5.7Hz,2H),8.00(d,J=6.2Hz,2H),7.68(s,1H),6.30– 6.27(m,1H),5.39(d,J=5.0Hz,1H),3.75(qd,J=12.4,5.0Hz,1H),3.03(dq,J=14.0,7.0Hz,1H),1.29(d,J=6.9Hz,6H),1.07(s,3H), 1.04(s,3H).13C NMR (126MHz, 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, measured value: 485.3279.

[0267] Example 21:

[0268] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 21)

[0269]

[0270] (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-cyclopentane[a]phenanthracene-3-yl acetate (86)

[0271] Compound II-2 (10 g, 26.53 mmol) and potassium carbonate (5.49 g, 39.8 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column chromatography (30-50% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 7 g of grayish-green solid compound 86 was obtained, with a yield of 58.3%. 1 H NMR (400MHz, CDCl3) δ9.77(s,1H),7.93(d,J=1.5Hz,1H),7.59(d,J=1.5Hz,1H),5.44(d,J=5.1Hz,1H) ,4.63(ddd,J=16.0,11.1,5.1Hz,1H),2.77(dd,J=15.7,6.0Hz,1H),2.06(s,3H),1.13(s,3H),1.10(s, 3H).

[0272] (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-cyclopentan[a]phenanthracene-3-yl acetate (87)

[0273] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 39 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (20-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 1.07 g of yellow solid compound 87 was obtained, with a yield of 16.3%. 1H NMR (400MHz, CDCl3) δ7.87 (d, J = 1.4Hz, 1H), 7.56 (d, J = 1.3Hz, 1H),5.96–5.92(m,1H),5.43(d,J=5.1Hz,1H),4.68–4.57(m,1H),2.06(s,3H),1.09(s,3H),1.05(s,3H).

[0274] (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-cyclopentan[a]phenanthracene-3-ol (88)

[0275] Compound 87 (1.07 g, 2.52 mmol) was dissolved in anhydrous methanol and stirred at room temperature. Then, 0.45 g (8.02 mmol) of potassium hydroxide was added. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The solution was purified by automated column chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 910 mg of a white solid, compound 88, was obtained, with a yield of 94.3%. 1 H NMR (400MHz, CDCl3) δ7.87(d,J=1.5Hz,1H),7.56(d,J=1.4Hz,1H),5.95(dd, J=3.0,1.6Hz,1H),5.40(d,J=5.1Hz,1H),3.61–3.51(m,1H),1.08(s,3H),1.05(s,3H).

[0276] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (89)

[0277] Compound 88 (910 mg, 2.375 mmol) and 4-dimethylaminopyridine (30 mg, 0.245 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (1 mL, 7.34 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.4 mL, 4.91 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. A final yield of 1.02 g of yellow-green solid compound 89 was obtained, with a yield of 93.1%. 1 H NMR (400MHz, CDCl3) δ7.87 (d, J = 1.5Hz, 1H), 7.56 (d, J=1.5Hz,1H),5.95(dd,J=3.1,1.7Hz,1H),5.48(d,J=4.8Hz,1H),4.60–4.51(m,1H),3.04(s,3H),1.10(s,3H),1.05(s,3H).

[0278] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-nitro-1H-imidazolium (90)

[0279] Compound 89 (1.02 g, 2.21 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.88 mL, 6.65 mmol) and boron trifluoride diethyl ether (1.1 mL, 8.88 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. 714 mg of a yellow solid 90 was finally obtained, with a yield of 78.63%. 1 H NMR (400MHz, CDCl3) δ7.87(d,J=1.5Hz,1H),7.56(d,J=1.4Hz,1H),5.95(dd,J=3. 2,1.7Hz,1H),5.45(d,J=5.1Hz,1H),3.30–3.20(m,1H),1.08(s,3H),1.05(s,3H).

[0280] (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-cyclopentan[a]phenanthracene-3-amine (91)

[0281] 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 overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The aqueous phase was separated and collected. Immediately afterwards, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 75 mg of white solid 91, with a yield of 11.2%, which was directly added to the next step. 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 21)

[0282] Compound 91 (75 mg, 0.196 mmol) was added to give 68 mg of white solid compound 21, with a yield of 70.8%. 1 H NMR (500MHz, DMSO) δ9.54(dd,J=2.1,1.3Hz,1H),9.43(dd,J=5.3,1.1Hz,1H),8.82(d,J=7.9Hz,1H),8.50(d,J=1.4Hz,1H),8.06(d ,J=1.4Hz,1H),7.99(dd,J=5.3,2.3Hz,1H),6.17(d,J=1.2Hz,1H),5.39(d,J=4.8Hz,1H),3.79–3.68(m,1H),1.06(s,3H),1.01(s, 3H). 13C NMR (126MHz, DMSO) δ162.69,159.92,152.51,149.26,148.07,146.98,141.37,136.23,132.03,124.59,123.21,121.03,120.0 0,56.22,50.32,50.15,46.07,38.59,37.87,36.83,33.78,30.84,30.08,29.91,28.37,20.49,19.38,15.78.HRMS(ESI)(M+H) + Calculated value of m / z C 27 H 33 N6O3 489.2609, measured value: 489.2603.

[0283] Example 22:

[0284] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 22)

[0285]

[0286] (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-cyclopentane[a]phenanthracene-3-yl acetate (92)

[0287] Compound II-2 (3.6 g, 9.55 mmol) and potassium carbonate (3.96 g, 28.7 mmol) were placed in a flask, and ultra-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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (20-40% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2.2 g of yellow solid compound 92 was obtained, with a yield of 48.4%. 1H NMR (400MHz, CDCl3) δ9.75(s,1H),7.67(s,1H),7.45(s,1H),5.43(d,J=5.1Hz,1H),4.63(dq,J=15.9,5.2 Hz,1H),2.73(dd,J=15.5,6.1Hz,1H),2.06(s,3H),1.10(s,3H),1.09(s,3H).

[0288] (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-cyclopentan[a]phenanthracene-3-yl acetate (93)

[0289] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 38 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (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 (400MHz, CDCl3) δ7.64(s,1H),7.36(s,1H),5.80(s,1H),5.41(d,J=4.8Hz,1H),4.66–4.56(m,1H),2.04(s,3H),1.07(s,3H),1.00(s,3H).

[0290] (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-cyclopentan[a]phenanthracene-3-ol (94)

[0291] Compound 93 (720 mg, 1.61 mmol) was dissolved in anhydrous methanol and stirred at room temperature. Then, 0.36 g (6.02 mmol) of potassium hydroxide was added. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. 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 a pale yellow solid, compound 94, was obtained, with a yield of 99.5%. 1 H NMR (400MHz, CDCl3) δ7.62(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).

[0292] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (95)

[0293] Compound 4 (650 mg, 1.60 mmol) and 4-dimethylaminopyridine (20 mg, 0.164 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.66 mL, 4.84 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.25 mL, 3.06 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 0.747 g of a pale yellow solid, compound 95, was finally obtained, with a yield of 96.4%. 1 H NMR (400MHz, CDCl3) δ7.71(s,1H),7.39(s,1H),5.84(d,J=1.3Hz,1H),5.48(d,J=5.0Hz,1H),4.56(tdd,J=11.3,7.0,4.7Hz,1H),3.04(s, 3H),1.09(s,3H),1.03(s,3H).

[0294] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-trifluoromethyl-1H-imidazolium (96)

[0295] Compound 95 (650 mg, 1.34 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (1.06 mL, 8.01 mmol) and boron trifluoride diethyl ether (1.66 mL, 13.4 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 570 mg of a yellow solid, 96, was obtained, with a yield of 98.4%. 1 H NMR (400MHz, CDCl3) δ7.65(s,1H),7.38(s,1H),5.82(dd,J=3.0,1.6Hz,1H),5.45(d,J=5.0Hz,1H),3.24(ddd,J=11.4,8.8,4.0Hz,1H), 1.07(s,3H),1.03(s,3H).

[0296] (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-cyclopentan[a]phenanthracene-3-amine (97)

[0297] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 355 mg of white solid 97, with a yield of 58.1%. 1H NMR (400 MHz, CDCl3) δ8.46 (s, 2H), 7.72 (s, 1H), 7.38 (s, 1H), 5.84 (s, 1H), 5.49 (d, J = 3.6Hz, 1H), 3.13 (s, 1H), 1.10 (s, 3H), 1.03 (s, 3H).

[0298] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 22)

[0299] Compound 97 (100 mg, 0.247 mmol) was added to give 96 mg of white solid compound 22, with a yield of 76.2%. 1 H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 9.36 (d, J = 5.0Hz, 1H), 7.92 (dd, J = 5.1, 1.9Hz, 1H), 7.64(s,1H),7.38(s,1H),6.98(d,J=7.9Hz,1H),5.83(d,J=1.1Hz,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 (151MHz, DMSO) δ162.60,152.55,149.22,147.44,141.36,137.99,131.95,124.58,121.15,56.25,50.30,50.23,45. 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) + Calculated value of m / z C 28 H 31 F3N5O 510.2486, measured value: 510.2489.

[0300] Example 23:

[0301] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 23)

[0302]

[0303] (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-cyclopentane[a]phenanthracene-3-yl acetate (98)

[0304] Compound II-2 (4.2 g, 11.14 mmol) and potassium carbonate (4.6 g, 33.35 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight at this temperature. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column chromatography (10-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 2 g of yellow solid compound 98 was obtained, with a yield of 41.08%. 1 H NMR(400MHz, CDCl3)δ9.80(s,1H),7.31(d,J=1.5Hz,1H),6.44(d,J=1.6Hz,1H),5.44(d,J=5.0Hz,1H), 4.63(ddd,J=15.9,10.7,5.3Hz,1H),3.88(s,3H),2.06(s,3H),1.09(d,J=1.9Hz,6H).

[0305] (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-cyclopentanane-3-ylacetate (99)

[0306] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was carried out for 30 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered with diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The mixture was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 0.45 g of yellow solid compound 99 was obtained, with a yield of 18.75%. 1 H NMR (400MHz, DMSO) δ7.28 (s, 1H), 6.34 (s, 1H), 5.61 (s, 1H), 5.40 (d, J = 4.2Hz, 1H) ,4.66–4.55(m,1H),3.81(d,J=0.5Hz,3H),2.03(s,3H),1.06(s,3H),1.00(s,3H).

[0307] (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-cyclopentan[a]phenanthracene-3-ol (100)

[0308] 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. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated with silica gel. The solution was purified by automated column chromatography (1-2% methanol / dichloromethane) to obtain the desired product. Finally, 330 mg of a yellow solid, compound 100, was obtained, with a yield of 81.88%. 1 H NMR (400MHz, CDCl3) δ7.30(d,J=1.3Hz,1H),6.37(d,J=1.5Hz,1H),5.63(d, J=1.2Hz,1H),5.40(d,J=5.1Hz,1H),3.84(s,3H),3.55(ddd,J=15.7,11.0,4.5Hz,1H),1.07(s,3H),1.02(s,3H).

[0309] (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-cyclopentan[a]phenanthracene-3-ylmethanesulfonate (101)

[0310] Compound 100 (330 mg, 0.896 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.4 mL, 2.936 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.14 mL, 1.72 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 0.38 g of orange-yellow solid compound 101 was finally obtained, with a yield of 95.2%. 1 H NMR (400MHz, CDCl3) δ7.30(d,J=1.4Hz,1H),6.37(d,J=1.5Hz,1H),5.64(dd,J=3.0,1.6Hz,1H) ,5.48(d,J=5.0Hz,1H),4.60–4.50(m,1H),3.84(s,3H),3.04(s,3H),1.09(s,3H),1.02(s,3H).

[0311] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-methoxy-1H-imidazolium(102)

[0312] Compound 101 (0.4 g, 0.896 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.54 mL, 4.08 mmol) and boron trifluoride diethyl ether (1.74 mL, 14 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. Finally, 300 mg of a yellow solid, 102, was obtained, with a yield of 84.98%. 1H NMR (400MHz, CDCl3) δ7.33 (s, 1H), 6.37 (s, 1H), 5.65 (s, 1H), 5.44 (d, J = 4.8Hz, 1H), 3.84 (s, 3H), 3.23 (dt, J = 10.2, 4.7Hz, 1H), 1.07 (s, 3H),1.03(s,3H).

[0313] (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-cyclopentan[a]phenanthracene-3-amine (103)

[0314] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the solid. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterwards, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, 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 (400MHz, CDCl3) δ7.30 (s, 1H), 6.37 (s, 1H), 5.63 (s, 1H), 5.36 (d, J = 4.8Hz, 1H), 3.83 (s, 3H), 2.63(td,J=11.3,5.6Hz,1H),1.05(s,3H),1.02(s,3H).

[0315] 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-cyclopentan[a]phenanthracene-3-yl)isonicotinamide (compound 23)

[0316] Compound 103 (61 mg, 0.166 mmol) was added to give 52 mg of white solid compound 23, with a yield of 66.67%. 1H NMR (500MHz, DMSO) δ8.81(d,J=4.9Hz,1H),8.71(d,J=7.9Hz,1H),7.90(d,J=3.5 Hz,1H),7.64–7.61(m,1H),7.56(d,J=2.6Hz,1H),6.89(d,J=1.5Hz,1H),5 .89(s,1H),5.39(d,J=4.7Hz,1H),3.76(s,3H),1.06(s,3H),1.02(s,3H). 13 C NMR(126MHz,DMSO)δ163.68, 155.36,149.08,143.72,141.49,132.66,132.04,130.36,129.17,122.53,121.04,96.85,57.74,5 6.39,50.23,45.86,38.62,37.97,36.76,34.30,30.82,30.02,29.58,28.31,20.55,19.30,15.97. HRMS(ESI)(M+H) + Calculated value of m / z C 29 H 37 N4O2 473.2911, measured value: 473.2917.

[0317] Example 24:

[0318] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (compound 24)

[0319]

[0320] Compound 103 (70 mg, 0.191 mmol) was added to give 58 mg of white solid compound 24, with a yield of 64.4%. 1 H NMR(400MHz, CDCl3)δ9.57(s,1H),9.31(d,J=5.0Hz,1H),7.93–7.90(m,1H),7.49(d,J= 7.8Hz,1H),7.29(s,1H),6.36(s,1H),5.64(s,1H),5.43(d,J=4.3Hz,1H),4.01–3.89(m, 1H),3.80(s,3H),1.05(s,3H),1.01(s,3H). 13C NMR (126MHz, CDCl3) δ162.84,157.25,151.79,148.64,148.55,140.32,132.36,130.58,124.22,121.70,118.09,95.87,56.8 7,56.16,50.86,50.32,46.09,38.77,37.72,36.77,34.83,30.89,30.12,29.66,28.62,20.56,19.13,15.93.HRMS(ESI)(M+H) + Calculated value of m / z C 28 H 36 N5O2 474.2864, measured value: 474.2875.

[0321] Example 25:

[0322] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 25)

[0323]

[0324] (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-cyclopentane[a]phenanthracene-3-yl acetate (104)

[0325] Compound II-2 (3.8 g, 10.08 mmol) and potassium carbonate (4.07 g, 29.5 mmol) were placed in a flask, and ultra-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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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%. 1H NMR (400MHz, CDCl3) δ9.72(s,1H),7.66(s,2H),5.43(d,J=5.0Hz,1H),4.66–4.57(m,1H),2.74(dd,J=15.6,6.1Hz,1H),2.05(s,3H),1.09(s,6H).

[0326] (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-cyclopentan[a]phenanthracene-3-yl acetate (105)

[0327] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was carried out for 30 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the reaction system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered with diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The mixture was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column 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 (400MHz, CDCl3) δ7.64(d,J=1.1Hz,1H),7.59(d,J=1.2Hz,1H),5.86(dd,J=3.2,1.7Hz,1H),5.43(d,J=5.1Hz,1H),4.63(ddd,J=15.9,11.1,5.1Hz,1H), 2.06(s,3H),1.09(s,3H),1.01(s,3H).

[0328] (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-cyclopentan[a]phenanthracene-3-ol (106)

[0329] 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. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. After the reaction was complete, part of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to obtain the desired product. Finally, 175 mg of a white solid, compound 106, was obtained, with a yield of 62.05%. 1 H NMR (400MHz, DMSO) δ8.37(d,J=0.9Hz,1H),8.11(d,J=0.8Hz,1H),6.04(s,1H),5.31(d,J=4.4Hz,1H),4.65(d,J=4.5Hz,1H), 3.27(td,J=10.8,5.5Hz,1H),0.99(s,3H),0.97(s,3H).

[0330] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (107)

[0331] Compound 106 (175 mg, 0.482 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.2 mL, 1.64 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (75 μL, 0.856 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 0.21 g of a pale yellow solid, compound 107, was finally obtained, with a yield of 99%. 1 H NMR (400MHz, CDCl3) δ7.65 (s, 1H), 7.59 (d, J = 1.0Hz, 1H), 5.87 (dd, J = 3.1, 1.7Hz, 1H), 5.48 (d, J = 4.9Hz, 1H), 4.55 (tdd, J = 11.5, 7.2, 4.7Hz, 1H), 3.04(s,3H),1.09(s,3H),1.02(s,3H).

[0332] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-cyano-1H-imidazolium (108

[0333] Compound 107 (0.21 g, 0.48 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.19 mL, 1.42 mmol) and boron trifluoride diethyl ether (0.3 mL, 2.42 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. 110 mg of a yellow solid, 108, was finally obtained, with a yield of 59.45%. 1 H NMR (400MHz, CDCl3) δ7.64(s,1H), 7.59(d,J=1.0Hz,1H), 5.86(dd,J=3.1,1.7Hz,1H), 5.45(d,J=5.1Hz,1H), 3.24(td,J=12.4, 5.9Hz,1H),1.08(s,3H),1.02(s,3H).

[0334] (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-cyclopentan[a]phenanthracene-3-amine (109)

[0335] Compound 108 (110 mg, 0.283 mmol) was dissolved in 6 mL of tetrahydrofuran and 3 mL of water under stirring at room temperature. Then, weighed triphenylphosphine (90 mg, 0.343 mmol) was added, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the solid. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 60 mg of white solid 109, with a yield of 58.2%. This was directly used in the next step.

[0336] 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-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 25)

[0337] Compound 109 (60 mg, 0.166 mmol) was added to give 25 mg of yellow solid compound 25, with a yield of 32.5%. 1 H NMR(400MHz,DMSO)δ9.57(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=4.6Hz,1H),3.96(s,1H),1.07(s,3H),0.99(s,3H). 13 CNMR (126MHz, CDCl3) δ162.68,152.00,148.45,147.18,140.19,137.62,132.40,126.60,124.25,122.79,121.64,114.77,114. 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.HRMS(ESI)(M+H) + Calculated value of m / z C 28 H 33 N6O 469.271, measured value: 469.2706.

[0338] Example 26:

[0339] N-((3S,10R,13S)-10,13-dimethyl-17-(4-(methylcarbamoyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11, 12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 26)

[0340]

[0341] 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-cyclopentan[a]phenanthracene-17-yl)-1H-imidazolium-4-carboxylic acid ethyl ester (110)

[0342] Compound II-2 (2 g, 5.3 mmol) and potassium carbonate (1.1 g, 7.97 mmol) were placed in a flask, and ultra-dry N,N-dimethylformamide was added as a solvent. After stirring at room temperature for half an hour, ethyl imidazole-4-carboxylate (0.75 g, 5.35 mmol) was added to the system, and the temperature was slowly raised to 80 °C and stirred at this temperature for 1 hour. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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(400MHz, CDCl3)δ 9.75(s,1H),7.77(s,1H),7.65(s,1H),5.43(d,J=4.8Hz,1H),4.67–4.56(m,1H),4.42(q,J= 7.1Hz,2H),2.73(dd,J=15.5,6.2Hz,1H),2.06(s,3H),1.43(t,J=7.1Hz,3H),1.10(s,3H), 1.09(s,3H).

[0343] 1-((3S,10R,13S)-3-acetoxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid ethyl ester (111)

[0344] 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 on carbon was added, followed by purging with argon three times. The system temperature was slowly raised to 160 °C, and the reaction was allowed to proceed for 18 hours. The reaction was monitored by TLC until complete. After the reaction was complete, the system was cooled to room temperature, and a certain amount of ethyl acetate was added. After stirring for a period of time, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was then extracted with ethyl acetate and water, and the organic phase was collected. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered. The system was then concentrated with silica gel and purified using an automated column chromatography system (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%. 1H NMR (400MHz, CDCl3) δ7.73(d,J=1.1Hz,1H),7.65(d,J=1.0Hz,1H),5.83(d,J=1.3Hz,1H),5.43(d,J=5.0Hz,1H),4.63(ddd,J=16.0,10.8,5.3Hz, 1H), 4.40 (q, J = 7.1Hz, 2H), 2.06 (s, 3H), 1.42 (t, J = 7.1Hz, 3H), 1.09 (s, 3H), 1.02 (s, 3H).

[0345] 1-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-N-methyl-1H-imidazol-4-carboxamide (112)

[0346] Compound 111 (0.75 g, 1.66 mmol) was loaded into a sealed tube, and then 10 mL of an alcoholic solution of methylamine was added. The tube was sealed and the reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until completion. After the reaction was complete, the system was cooled to room temperature, and then extracted with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (1-3% methanol / dichloromethane) to obtain the desired product. 408 mg of white solid compound 112 was finally obtained, with a yield of 62.29%. 1 ¹H NMR (400MHz, 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). (3S, 10R, 13S)-10,13-dimethyl-17-(4-(methylcarbamoyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11,12, 13,14,15-Dodecyl-1H-cyclopentane[a]phenanthrene-3-ylmethanesulfonate (113)

[0347] Compound 112 (408 mg, 1.03 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.43 mL, 3.28 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (160 μL, 2.06 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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 a pale yellow solid, compound 113, was obtained, with a yield of 94.26%. 1 H NMR (400MHz, CDCl3) δ7.71(s,1H),7.71(s,1H),7.39(s,1H),5.86(dd,J=3.0,1.6Hz,1H),5.48(d,J=4.7Hz,1H),4.56(ddd,J=14.2,11.4,4.8 Hz, 1H), 3.04 (s, 3H), 3.00 (d, J = 5.0Hz, 3H), 1.09 (s, 3H), 1.03 (s, 3H).

[0348] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-N-methyl-1H-imidazol-4-carboxamide (114)

[0349] Compound 113 (0.46 g, 0.97 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.5 mL, 3.55 mmol) and boron trifluoride diethyl ether (0.6 mL, 4.84 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (30-60% ethyl acetate / petroleum ether) to obtain the desired product. 219 mg of a white solid, 114, was finally obtained, with a yield of 53.68%. 1H NMR (400MHz, CDCl3) δ7.70(d,J=1.3Hz,1H),7.58(d,J=1.2Hz,1H),7.22(d,J=4.4Hz,1H),5.81(dd,J=3.1,1.7Hz,1H),5.44(d, J=5.1Hz, 1H), 3.24 (ddd, J=9.9, 8.7, 3.9Hz, 1H), 2.99 (d, J=5.0Hz, 3H), 1.07 (s, 3H), 1.02 (s, 3H).

[0350] 1-((3S,10R,13S)-3-amino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-N-methyl-1H-imidazol-4-carboxamide (115)

[0351] 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 overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the solid. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 58 mg of white solid 115, with a yield of 28.3%. This was directly used in the next step.

[0352] N-((3S,10R,13S)-10,13-dimethyl-17-(4-(methylcarbamoyl)-1H-imidazol-1-yl)-2,3,4,7,8,9,10,11, 12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-3-yl)pyridazine-4-carboxamide (Compound 26)

[0353] Compound 115 (58 mg, 0.147 mmol) was added to give 53 mg of white solid compound 26, with a yield of 72.1%. 1H NMR (500MHz, DMSO) δ9.52–9.50(m,1H),9.41(dd,J=5.3,1.0Hz,1H),8.79(d,J=7.9Hz,1H),7.98–7.94(m,2H),7.88(d,J=1.1Hz,1 H),7.72(d,J=1.1Hz,1H),5.96(s,1H),5.37(d,J=4.6Hz,1H),3.76–3.65(m,1H),2.72(d,J=4.8Hz,3H),1.03(s,3H),0.97(s,3H). 13 C NMR (126MHz, DMSO) δ162.69,162.63,152.55,149.27,147.76,141.36,137.68,136.34, 132.12,124.59,121.17,120.30,119.79,56.20,50.32,50.22,46.06,38.61,37.88,3 6.84,34.28,30.89,30.12,29.73,28.30,25.92,20.58,19.39,15.98.HRMS(ESI)(M+H) + Calculated value of m / z C 28 H 41 N2O6 501.2959, measured value: 501.2954.

[0354] Example 27:

[0355] 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazin-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid (Compound 27)

[0356]

[0357] 1-((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid methyl ester (116)

[0358] Compound 111 (2.14 g, 4.73 mmol) was placed in a flask, and then 20 mL of a sodium methoxide methanol solution was added. The mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. After the reaction was complete, the solution was neutralized with 4 M hydrochloric acid methanol solution. After the solution changed from yellow to colorless, it was extracted with dichloromethane and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and then the solution was directly evaporated by rotary evaporation to obtain the desired product. Finally, 1.85 g of a yellow solid, compound 116, was obtained, with a yield of 98.9%. 1 H NMR(400MHz,DMSO)δ7.96(d,J=1.2Hz,1H),7.94(s,1H),6.00(s,1H),5.28(d,J =4.4Hz,1H),4.65(s,1H),3.74(s,3H),3.25(s,1H),0.97(s,3H),0.95(s,3H).

[0359] 1-((3S,10R,13S)-10,13-dimethyl-3-((methanesulfonyl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazolium-4-carboxylic acid methyl ester (117)

[0360] Compound 116 (105 mg, 0.25 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.1 mL, 0.75 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (39 μL, 0.5 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 117 mg of a white solid, compound 117, was finally obtained, with a yield of 97.8%. 1 H NMR (400MHz, CDCl3) δ7.72(s,2H),5.83(s,1H),5.45(d, J=4.9Hz,1H),4.54(d,J=5.0Hz,1H),3.91(s,3H),3.02(s,3H),1.07(s,3H),1.00(s,3H).

[0361] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid methyl ester (118)

[0362] Compound 117 (0.11 g, 0.23 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (92 μL, 0.69 mmol) and boron trifluoride diethyl ether (143 μL, 1.15 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column 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 (400MHz, CDCl3) δ7.74(s,1H),7.68(s,1H),5.84(s,1H),5.44(d,J=5.0Hz,1H),3.93(s,3H),3.28–3.19(m,1H),1.07(s,3H),1.02(s,3H).

[0363] 1-((3S,10R,13S)-3-amino-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid methyl ester (119)

[0364] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the solid. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, 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) δ7.74 (s, 1H), 7.63 (s, 1H), 5.82 (s, 1H), 5.38 (s, 1H), 3.92 (d, J = 2.1Hz, 3H), 1.06 (s, 3H), 1.01 (s, 3H).

[0365] 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazin-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid methyl ester (120)

[0366] Compound 119 (24 mg, 0.06 mmol) was added to give 22 mg of white solid compound 120, with a yield of 73.3%. 1 H NMR (500MHz, CDCl3) δ9.58 (s, 1H), 9.31 (d, J = 5.2Hz, 1H), 7.93 (dd, J = 5.0, 1.8Hz, 1H), 7.72(s,1H),7.63(s,1H),7.29(s,1H),5.83(s,1H),5.44(d,J=4.6Hz,1H),3.95(qd,J= 12.3,6.4Hz,1H),3.89(s,3H),1.05(s,3H),1.01(s,3H).

[0367] 1-((3S,10R,13S)-10,13-dimethyl-3-(pyridazin-4-carboxamido)-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-1H-imidazol-4-carboxylic acid (Compound 27)

[0368] Compound 120 (50 mg, 0.1 mmol) was dissolved in 5 mL of methanol and 5 mL of tetrahydrofuran, stirred at room temperature, and then 1 mL of 2 M sodium hydroxide solution was added. The reaction was allowed to proceed for 2 h at room temperature, and TLC was used to monitor the reaction until complete. A portion of the solution was then removed by rotary evaporation. The pH was adjusted to acidic with dilute hydrochloric acid, and the solution was extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated by direct rotary evaporation to obtain the desired product. 33 mg of a white solid 27 was finally obtained, with a yield of 67.8%. 1 H NMR (500MHz, DMSO) δ9.54 (s, 1H), 9.43 (d, J = 4.7Hz, 1H), 8.82(d,J=7.4Hz,1H),8.00(d,J=2.9Hz,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(126MHz,DMSO)δ163.85,162.63, 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) + Calculated value of m / z C 28 H 34 N5O3 488.2656, measured value: 488.2657.

[0369] Example 28:

[0370] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)benzamide (Compound 28)

[0371]

[0372] (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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl acetate (121)

[0373] Compound II-2 (4.38 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were placed in a flask, and ultra-dry 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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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%. 1H NMR (400MHz, CDCl3) δ9.78(s,1H),7.25(s,1H),6.69(dd,J=8.1,1.6Hz,1H),5.43(d,J=5.2Hz,1H),4.67–4.58(m, 1H),2.06(s,3H),1.09(s,6H).

[0374] (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-dodecylhydro-1H-cyclopentan[a]phenanthracene-3-yl acetate (122)

[0375] Compound 1,3-bis(diphenylphosphine)propane (0.48 g, 1.16 mmol) and rhodium(I) carbonylbis(triphenylphosphine)chloride (0.48 g, 0.69 mmol) were dissolved in dry xylene. After purging with argon three times, the system temperature was slowly raised to 80 °C and stirred for half an hour. Then, compound 121 (1 g, 2.35 mmol) was added, and the reaction temperature was raised to 135 °C. The reaction was stirred at this temperature overnight. After the reaction was complete, 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 brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 230 mg of white solid compound 122 was obtained, with a yield of 24.62%. 1 H NMR (400MHz, CDCl3) δ7.24 (s, 1H), 6.59 (d, J = 8.1Hz, 1H), 5.72 (s, 1H), 5.43 (d, J = 5.1Hz, 1H), 4.63 (tt, J = 10.7, 5.1Hz, 1H), 2.06 (s, 3H), 1.09 (s, 3H),1.02(s,3H).

[0376] (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-cyclopentan[a]phenanthracene-3-ol (123)

[0377] Compound 122 (0.22 g, 0.55 mmol) was dissolved in anhydrous methanol and stirred at room temperature. Then, 50 mg (0.9 mmol) of potassium hydroxide was added. After the addition was complete, the mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to obtain the desired product. Finally, 167 mg of a white solid, compound 123, was obtained, with a yield of 84.77%. 1 H NMR (600MHz, CDCl3) δ7.14(s,1H),6.50(dd,J=8.1,1.4Hz,1H),5.62(dd,J=3.0,1.7Hz,1H),5.33–5.29(m,1H),3.50–3.44(m,1H),0.99(s, 3H),0.93(s,3H).

[0378] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (124)

[0379] Compound 123 (160 mg, 0.449 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.2 mL, 1.64 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (150 μL, 1.71 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solution was concentrated by rotary evaporation to obtain the desired product. Finally, 0.29 g of a yellow solid, compound 124, was obtained and directly added to the next step.

[0380] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-fluoro-1H-imidazolium (125)

[0381] Compound 124 (0.29 g, 0.68 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.3 mL, 2.24 mmol) and boron trifluoride diethyl ether (0.34 mL, 2.42 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (5-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 146 mg of white solid compound 125 was obtained, with a yield of 56.59%. 1 H NMR (600MHz, CDCl3) δ7.16 (s, 1H), 6.50 (dd, J=8.1, 1.1Hz, 1H), 5.63 (dd, J=3.0, 1.6Hz, 1H), 5.36 (d, J=5.3Hz, 1H), 3.18– 3.12(m,1H),0.98(s,3H),0.93(s,3H).

[0382] (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-cyclopentan[a]phenanthracene-3-amine (126)

[0383] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of ethyl acetate was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of ethyl acetate, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 72 mg of white solid compound 126, with a yield of 55.38%. This was then directly introduced into the next step.

[0384] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)benzamide (Compound 28)

[0385] Compound 126 (47 mg, 0.132 mmol) was added to give 47 mg of white solid compound 28, with a yield of 74.6%. 1 H NMR(600MHz,DMSO)δ8.28(d,J=8.0Hz,1H),7.89(dd,J=8.7,5.6Hz,2H),7.54(s,1H),7 .25(t,J=8.8Hz,2H),7.09(dd,J=8.2,1.6Hz,1H),5.83(s,1H),5.33(d,J=4.7Hz,1H), 3.72–3.64(m,1H),1.01(s,3H),0.95(s,3H). 13 C NMR (151MHz, DMSO) δ164.17,162.95,157.49,155.96,147.69,141.24,131.13,129.85,129.80,129.62,129.52,120.35 ,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) + Calculated value of m / z C 29 H 34 F2N3O4 78.2664, measured value: 478.2665.

[0386] Example 29:

[0387] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)benzamide (Compound 29)

[0388]

[0389] (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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl acetate (127)

[0390] Compound II-2 (4 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were placed in a flask, and ultra-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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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 (400MHz, CDCl3) δ9.76 (s, 1H), 7.52 (d, J = 1.4Hz, 1H), 7.11 (d, J = 1.5Hz, 1H), 5.43 (d, J = 5.1Hz, 1H), 4.63 (dq, J=15.9,5.2Hz,1H),2.71(dd,J=15.5,6.3Hz,1H),2.06(s,3H),1.08(s,6H).

[0391] (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-dodecylhydro-1H-cyclopentan[a]phenanthracene-3-yl acetate (128)

[0392] Compound 1,3-bis(diphenylphosphine)propane (0.21 g, 0.51 mmol) and carbonylbis(triphenylphosphine)rhodium chloride (I) (0.17 g, 0.24 mmol) were dissolved in dry xylene. After purging with argon three times, the system temperature was slowly raised to 80 °C and stirred for half an hour. Then, compound 127 (1 g, 2.06 mmol) was added, and the reaction temperature was raised to 135 °C. The reaction was stirred at this temperature overnight. After the reaction was complete, 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 brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (10-30% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 322 mg of white solid compound 128 was obtained, with a yield of 34.18%. 1H NMR (400MHz, CDCl3) δ7.50(s,1H),7.02(s,1H),5.72(s,1H),5.41(d,J=5.0Hz,1H),4.60(dt,J=10.9,5.9Hz,1H),2.04(s,3H),1.07(s,3H),0.99(s, 3H).

[0393] (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-cyclopentan[a]phenanthracene-3-ol (129)

[0394] 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. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. After the reaction was complete, some of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to obtain the desired product. Finally, 278 mg of a white solid, compound 129, was obtained, with a yield of 65.85%. 1 H NMR (400MHz, DMSO) δ7.84(s,1H),7.54(s,1H),5.90(s,1H),5.31(d,J=4.6H z,1H),4.64(d,J=4.5Hz,1H),3.31–3.22(m,1H),1.00(s,3H),0.98(s,3H).

[0395] (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-cyclopentan[a]phenanthrene-3-yl methanesulfonate (130)

[0396] Compound 129 (278 mg, 0.668 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were placed in a flask, and ultra-dry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.28 mL, 2.3 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (150 μL, 1.71 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 382 mg of a yellow oily compound 130 was finally obtained and directly added to the next step.

[0397] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-bromo-1H-imidazolium(131)

[0398] Compound 130 (0.382 g, 0.77 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.3 mL, 2.24 mmol) and boron trifluoride diethyl ether (0.34 mL, 2.42 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (15-25% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 183 mg of white solid compound 131 was obtained, with a yield of 53.66%. 1 H NMR (400MHz, DMSO) δ7.84 (s, 1H), 7.54 (s, 1H), 5.90 (s, 1H), 5.43 (d, J = 4.1Hz, 1H), 1.01 (s, 3H), 0.98 (s, 3H).

[0399] (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-cyclopentan[a]phenanthracene-3-amine (132)

[0400] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of ethyl acetate was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of ethyl acetate, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 147 mg of white solid compound 132, with a yield of 86.98%. This was directly used in the next step.

[0401] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)benzamide (Compound 29)

[0402] Compound 132 (50 mg, 0.12 mmol) was added to give 45 mg of white solid compound 29, with a yield of 69.55%. 1 H NMR (600MHz, DMSO) δ8.28(d,J=8.0Hz,1H),7.91–7.87(m,2H),7.81(d,J=1.4Hz,1H),7.52(d,J=1.4Hz,1H),7.26(t ,J=8.8Hz,2H),5.88(s,1H),5.34(d,J=4.6Hz,1H),3.68(ddd,J=16.3,12.0,5.9Hz,1H),1.02(s,3H),0.95(s,3H). 13 C NMR (151MHz, DMSO) δ164.18,147.23,141.25,135.94,129.86,129.80,120.37,118.99,117.55,115.16,115.02,114.96, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 29 H 34 BrFN3O 538.1864, measured value: 538.1852.

[0403] Example 30:

[0404] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)pyridazine-4-carboxamide (compound 30)

[0405]

[0406] (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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl acetate (133)

[0407] Compound II-2 (4 g, 11.62 mmol) and potassium carbonate (2.4 g, 17.5 mmol) were placed in a flask, and ultra-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 and stirred overnight. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automatic column 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 (400MHz, CDCl3) δ9.76 (s, 1H), 7.50 (d, J = 1.6Hz, 1H), 7.04 (d, J = 1.6Hz, 1H), 5.43 (d, J = 5.2Hz, 1H), 4.63 (ddd, J=15.9, 10.7, 5.4Hz, 1H), 2.71 (dd, J=15.5, 6.3Hz, 1H), 2.06 (s, 3H), 1.08 (s, 6H).

[0408] (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-dodecylhydro-1H-cyclopentan[a]phenanthracene-3-yl acetate (134)

[0409] Compound 1,3-bis(diphenylphosphine)propane (0.47 g, 1.14 mmol) and rhodium(I) carbonylbis(triphenylphosphine)chloride (0.47 g, 0.66 mmol) were dissolved in dry xylene. After purging with argon three times, the system temperature was slowly raised to 80 °C and stirred for half an hour. Then, compound 133 (1 g, 2.26 mmol) was added, and the reaction temperature was raised to 135 °C. The reaction was stirred at this temperature overnight. After the reaction was complete, 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 brine, dried with anhydrous sodium sulfate, filtered, and then concentrated with silica gel and purified by an automated column chromatography (10-20% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 569 mg of white solid compound 134 was obtained, with a yield of 60.73%. 1 H NMR (400MHz, CDCl3) δ7.49 (d, J=1.2Hz, 1H), 6.97 (d, J=1.3Hz,1H),5.73(dd,J=3.2,1.7Hz,1H),5.42(d,J=5.2Hz,1H),4.67–4.57(m,1H),2.05(s,3H),1.08(s,3H),1.00(s,3H).

[0410] (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-cyclopentan[a]phenanthracene-3-ol (135)

[0411] 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. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. After the reaction was complete, part of the solvent was removed by rotary evaporation, followed by extraction with ethyl acetate and water. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to obtain the desired product. Finally, 440 mg of a white solid, compound 135, was obtained, with a yield of 87.44%. 1 H NMR (400MHz, CDCl3) δ7.50(s,1H),6.97(d,J=1.0Hz,1H),5.74(dd,J=3.1,1.6Hz,1H),5.42–5.38(m,1H),3.61–3.50(m,1H),1.08(s,3H),1.01(s,3H).

[0412] (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-cyclopentan[a]phenanthracene-3-yl methanesulfonate (136)

[0413] Compound 135 (440 mg, 1.182 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (0.5 mL, 4.1 mmol) and stirring for a period of time. Finally, methanesulfonyl chloride (0.2 mL, 2.28 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The reaction was then quenched with ice water, followed by extraction 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. 493 mg of a white solid, compound 136, was finally obtained, with a yield of 92.67%. 1 H NMR (400MHz, DMSO) δ7.83 (d, J = 1.3Hz, 1H), 7.50(d,J=1.3Hz,1H),5.90(s,1H),5.45(d,J=3.9Hz,1H),4.43(d,J=7.5Hz,1H),3.19(s,3H),1.03(s,3H),0.98(s,3H).

[0414] 1-((3S,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-chloro-1H-imidazolium(137)

[0415] Compound 136 (0.486 g, 1.08 mmol) was dissolved in ultradry dichloromethane and stirred at room temperature. Then, azidotrimethylsilane (0.5 mL, 3.73 mmol) and boron trifluoride diethyl ether (0.7 mL, 4.84 mmol) were added sequentially using a plastic pipette. After the addition was complete, the reaction was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (5-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 330 mg of white solid compound 137 was obtained, with a yield of 76.96%. 1H NMR (400MHz, CDCl3) δ7.47(s,1H),6.94(d,J=1.4Hz,1H),5.71(s,1H),5.42(d,J=4.6Hz,1H),3.21(d,J=4.1Hz,1H),1.05(s,3H),0.99(s,3H).

[0416] (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-cyclopentan[a]phenanthracene-3-amine (138)

[0417] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of ethyl acetate was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH of the solution to approximately 2. The solution was separated and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of ethyl acetate, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, 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 (400MHz, CDCl3) δ7.48 (d, J=1.5Hz, 1H), 6.96 (d, J=1.5Hz, 1H), 5.72 (dd, J=3.1, 1.7Hz,1H),5.37(d,J=5.3Hz,1H),2.72–2.61(m,1H),1.06(s,3H),1.01(s,3H).

[0418] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)pyridazine-4-carboxamide (compound 30)

[0419] Compound 138 (50 mg, 0.136 mmol) was added to give 49 mg of pale yellow solid compound 30, with a yield of 76.23%. 1H NMR (500MHz, CDCl3) δ9.53 (dd, J=2.0, 1.2Hz, 1H), 9.42 (dd, J=5.3, 1.0Hz, 1H), 8.84 ( d,J=7.8Hz,1H),7.99(dd,J=5.3,2.3Hz,1H),7.83(d,J=1.4Hz,1H),7.53(d,J=1.4Hz, 1H),5.90(d,J=1.2Hz,1H),5.38(d,J=4.8Hz,1H),3.73(ddd,J=15.8,12.0,6.1Hz,1H),1.05(s,3H),0.98(s,3H). 13 C NMR (126MHz, CDCl3) δ167.45,157.31,154.05,152.42,146.20, 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) + Calculated value of m / z C 27 H 33 ClN5O 478.2368, measured value: 478.2365.

[0420] Example 31:

[0421] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)benzamide (Compound 31)

[0422]

[0423] Compound 138 (50 mg, 0.136 mmol) was added to give 56 mg of white solid compound 31, with a yield of 84.3%. 1H NMR (500MHz, CDCl3) δ8.29 (d, J=7.9Hz, 1H), 7.92 (dd, J=8.5, 5.6Hz, 2H), 7.81 (s, 1H), 7. 47(d,J=1.1Hz,1H),7.28(t,J=8.8Hz,2H),5.89(s,1H),5.35(d,J=3.4Hz,1H),3.71(dd,J =7.6,4.0Hz,1H),1.04(s,3H),0.97(s,3H). 13 C NMR (126MHz, CDCl3) δ169.44,152.41, 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) + Calculated value of m / z C 29 H 34 ClFN3O 494.2369, measured value: 494.2366.

[0424] Example 32:

[0425] 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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl)-4-cyanobenzamide (compound 32)

[0426]

[0427] Compound 138 (50 mg, 0.136 mmol) was added to give 47 mg of pale yellow solid compound 32, with a yield of 69.75%. 1 H NMR (600MHz, DMSO) δ8.52(d,J=7.9Hz,1H),7.97(d,J=8.3Hz,2H),7.92(d,J=8.3 Hz,2H),7.79(d,J=0.9Hz,1H),7.46(d,J=0.8Hz,1H),5.86(s,1H),5.33(d,J=3.7Hz,1H), 3.72–3.65(m,1H),1.00(s,3H),0.94(s,3H). 13C NMR(151MHz,DMSO)δ163.85,147.28, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 34 ClN4O 501.2416, measured value: 501.2411.

[0428] Example 33:

[0429] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)-4-fluorobenzamide (compound 33)

[0430]

[0431] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of white solid compound 33, with a yield of 74.23%. 1 H NMR (500MHz, DMSO) δ8.30 (d, J=7.9Hz, 1H), 7.95–7.89 (m, 2H), 7.69 (s, 1H), 7.28 (t, J=8.7Hz,2H),7.05(s,1H),5.74(s,1H),5.37(s,1H),3.72(d,J=7.2Hz,1H),2.11(s,3H),1.05(s,3H),0.98(s,3H). 13 C NMR (126MHz, DMSO) δ164.31,147.82,141.28,137.25,134.77,131.20,129.82,129.75,120.35,115.24,114.94,114.44,55.7 9,49.79,49.47,45.36,38.38,37.53,36.36,34.06,30.44,29.65,29.12,28.01,20.15,18.90,15.66,13.41.HRMS(ESI)(M+H) + Calculated value of m / z C30 H 37 FN3O 474.2915, measured value: 474.2923.

[0432] Example 34:

[0433] 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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl)-4-nitrobenzamide (compound 34)

[0434]

[0435] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of pale yellow solid compound 34, with a yield of 70.38%. 1 H NMR (500MHz, DMSO) δ8.64(d,J=8.0Hz,1H),8.31(d,J=8.8Hz,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=4.6Hz,1H),3.79–3.69(m,1H), 2.11(s,3H),1.05(s,3H),0.98(s,3H). 13 C NMR(126MHz,DMSO)δ163.69,148.90,148.01, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 37 N4O3 501.286, measured value: 501.2866.

[0436] Example 35:

[0437] 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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl)-4-(methylsulfonyl)benzamide (compound 35)

[0438]

[0439] Compound 67 (25 mg, 0.071 mmol) was added to give 28 mg of white solid compound 35, with a yield of 73.96%. 1 H NMR (500MHz, DMSO) δ8.57(d,J=8.0Hz,1H),8.08(d,J=8.5Hz,2H),8.02(d,J=8.4Hz,2H),7.71(s,1H),7. 06(s,1H),5.74(s,1H),5.38(d,J=4.4Hz,1H),3.80–3.69(m,1H),2.11(s,3H),1.06(s,3H),0.98(s,3H). 13 C NMR (126MHz, DMSO) δ164.07,147.93,142.78,141.21,139.06,137.21,134.76,128.18,126.93,120.43,116.16,114.45,55.79,4 9.78,49.68,45.36,43.32,38.24,37.48,36.36,34.04,30.44,29.65,29.07,27.92,20.15,18.90,15.60,13.37.HRMS(ESI)(M+H) + Calculated value of m / z C 31 H 40 N3OS 534.2785, measured value: 534.2786.

[0440] Example 36:

[0441] 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-dodecylhydro-1H-cyclopentadien[a]phenanthrene-3-yl)-4-cyanobenzamide (compound 36)

[0442]

[0443] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of white solid compound 36, with a yield of 73.31%. 1 H NMR (500MHz, DMSO) δ8.56(d,J=7.9Hz,1H),8.01(d,J=8.4Hz,2H),7.95(d,J=8.4Hz,2H),7.71(s,1H),7. 05(s,1H),5.74(s,1H),5.37(d,J=4.4Hz,1H),3.78–3.68(m,1H),2.11(s,3H),1.05(s,3H),0.98(s,3H). 13 C NMR (126MHz, DMSO) δ163.93,147.91,140.99,138.72,137.21,134.72,132.31,128.05,120.48,116.16,114.43,113.51,55.7 8,49.77,49.68,45.36,38.22,37.47,36.35,34.11,30.43,29.69,29.12,27.89,20.21,18.88,15.60,13.39.HRMS(ESI)(M+H) + Calculated value of m / z C 31 H 37 N4O 481.2962, measured value: 481.2959.

[0444] Example 37:

[0445] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)-2,4-difluorobenzamide (compound 37)

[0446]

[0447] Compound 67 (25 mg, 0.071 mmol) was added to give 25 mg of pale yellow solid compound 37, with a yield of 71.67%. 1H NMR(500MHz,DMSO)δ8.23(d,J=7.7Hz,1H),7.69(s,1H),7.64(dt,J=15.2,7.8Hz, 1H),7.32(t,J=9.9Hz,1H),7.15(t,J=7.6Hz,1H),5.74(s,1H),5.38(d,J=3. 8Hz,1H),3.67(dd,J=7.8,3.9Hz,1H),2.11(s,3H),1.03(s,3H),0.98(s,3H). 13 C NMR(126MHz,DMSO)δ 162.59,148.46,141.64,137.69,135.30,132.22,120.85,116.72,114.98,112.19,112.08,105.07,1 04.85,104.67,56.38,50.22,50.15,45.94,38.69,37.89,36.79,34.61,30.98,30.06,29.68,28.35, 20.57,19.47,16.01,13.85.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 36 F2N3O 492.2821, measured value: 492.2829.

[0448] Example 38:

[0449] 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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl)-2,4-difluorobenzamide hydrochloride (compound 38)

[0450]

[0451] Compound 37 (30 mg, 0.061 mmol) was placed in a flask, and dioxane was used as a solvent. The mixture was stirred at room temperature, and then 2 M dioxane solution of hydrogen chloride was added. After reacting at room temperature for 2 h, the solvent was directly evaporated by rotary evaporation to obtain 28 mg of white solid compound 38, with a yield of 86.96%.

[0452] Example 39:

[0453] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)-2,4-difluorobenzamide methanesulfonate (compound 39)

[0454]

[0455] Compound 37 (30 mg, 0.061 mmol) was placed in a flask and stirred at room temperature with dichloromethane as solvent. Then, a small amount of methanesulfonic acid was slowly added dropwise. After stirring overnight at room temperature, a white solid was observed to precipitate. The mixture was filtered through a Buchner funnel and the filter cake was washed several times with ethyl acetate. The filter cake was then dried in a vacuum drying oven to finally obtain 30 mg of white solid compound 39, with a yield of 83.3%.

[0456] Example 40:

[0457] 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-cyclopentan[a]phenanthrene-3-yl)cyclopropanesulfonamide (compound 40)

[0458]

[0459] Compound 47 (60 mg, 0.172 mmol) and 4-dimethylaminopyridine (2 mg, 0.015 mmol) were placed in a flask, and ultradry dichloromethane was added as a solvent. The mixture was stirred in an ice bath, followed by the addition of triethylamine (60 μL, 0.42 mmol) and stirring for a period of time. Finally, cyclopropylsulfonyl chloride (30 μL, 0.21 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was extracted with dichloromethane and water, and the organic phase was collected. The organic phase was then washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (30-40% ethyl acetate / petroleum ether) to obtain the desired product. 51 mg of a white solid, compound 40, was finally obtained, with a yield of 65.5%. 1H NMR (400MHz, DMSO) δ8.59(d,J=1.8Hz,1H),8.44(dd,J=4.7,1.3Hz,1H),7.77(dd,J=8.0,1.8Hz,1H),7.34(dd,J =7.9,4.8Hz,1H),7.10(d,J=8.0Hz,1H),6.12(s,1H),5.37(d,J=4.6Hz,1H),3.01(d,J=7.0Hz,1H),1.02(s,3H),1.00(s,3H). 13 C NMR (126MHz, DMSO) δ151.48,148.27,147.62,141.56, 133.76,132.59,129.46,123.83,121.22,57.47,53.88,50.17,47.11,37.95,36.62,3 5.11,31.75,31.36,31.13,30.36,30.25,20.82,19.36,16.71,5.48.HRMS(ESI)(M+H) + Calculated value of m / z C 27 H 37 N2O2S 453.257, measured value: 453.258.

[0460] Example 41:

[0461] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)morpholine-4-sulfonamide (compound 41)

[0462]

[0463] Compound 67 (50 mg, 0.142 mmol) was added to give 46 mg of white solid compound 41, with a yield of 64.7%. 1 H NMR (500MHz, DMSO) δ7.68(s,1H),7.34(d,J=7.3Hz,1H),7.04(s,1H),5.73(s,1H),5.36(d,J=4 .2Hz,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). 13C NMR (126MHz, DMSO) δ148.33,141.53,137.80,135.30,121.11,116.73,114.87,65.96,56.27,54.26,50.20,46.36,45.8 5,37.89,36.66,34.49,32.00,30.88,30.09,29.90,29.80,29.60,29.19,20.62,19.31,16.09,13.92.HRMS(ESI)(M+H) + Calculated value of m / z C 27 H 41 N4O3S 501.2894, measured value: 501.2904.

[0464] Example 42:

[0465] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)-4-fluorobenzamide (compound 42)

[0466]

[0467] 1-((3R,10R,13S)-3-azido-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecyl-1H-cyclopentan[a]phenanthracene-17-yl)-4-methyl-1H-imidazolium(134)

[0468] Compound 65 (1.5 g, 3.48 mmol) and 15-crown-5 (77 mg, 0.35 mmol) were dissolved in anhydrous DMF, followed by the addition of sodium azide (0.68 g, 10.44 mmol). After the addition was complete, the reaction mixture was slowly heated to 80 °C and stirred at this temperature for 18 hours. The reaction was monitored by TLC until complete. The reaction mixture was then cooled to room temperature, and a certain amount of ice water was added. Extraction was performed with dichloromethane, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and purified by automated column chromatography (15-30% ethyl acetate / petroleum ether) to obtain the desired product. The final product was 0.63 g of a pale yellow solid 134, with a yield of 48.09%. 1H NMR(400MHz,DMSO)δ8.06(s,1H),6.84(s,1H),5.92 –5.88(m,1H),5.42(d,J=4.9Hz,1H),3.27–3.17(m,1H),2.39(s,3H),1.05(s,3H),1.01(s,3H).

[0469] (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-cyclopentan[a]phenanthracene-3-amine (135)

[0470] 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, and the temperature was slowly raised to 60 °C and stirred overnight. The reaction was monitored by TLC until complete. Part of the solvent was then evaporated by rotary evaporation, and 20 mL of dichloromethane was added to dissolve the compound. 2 M hydrochloric acid was slowly added to adjust the pH to approximately 2. The solution was separated, and the aqueous phase was collected. Immediately afterward, 2 M sodium hydroxide solution was added to adjust the pH to weakly alkaline, at which point a large amount of white solid precipitated. The aqueous phase was extracted three times with small amounts of dichloromethane, and the organic phases were collected and combined. After drying with anhydrous sodium sulfate, 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) δ7.53(s,1H),6.78(s,1H),5.63(dd,J=3.0,1.7Hz,1H),5.37(d,J=5.2Hz,1H), 2.25(s,3H),1.05(s,3H),1.01(s,3H).

[0471] 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-dodecano-1H-cyclopentadieno[a]phenanthrene-3-yl)-4-fluorobenzamide (compound 42)

[0472] Compound 135 (100 mg, 0.284 mmol) was added to give 86 mg of white solid compound 42, with a yield of 63.7%. 1H NMR (400MHz, DMSO) δ8.98 (d, J=1.7Hz, 1H), 8.67 (dd, J=4.8, 1.5Hz, 1H), 8.49 (d, J= 7.9Hz,1H),8.18–8.14(m,1H),7.73(s,1H),7.48(dd,J=7.9,4.9Hz,1H),7.05(s,1H),5.73(s, 1H), 5.36 (d, J = 4.0Hz, 1H), 3.77–3.65 (m, 1H), 2.09 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H). 13 C NMR (126MHz, DMSO) δ163.90,151.73,148.40,141.15,137.05,134.95,134.73,123.31, 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.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 37 FN3O 474.2915, measured value: 474.2916.

[0473] Example 43:

[0474] 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-dodecano-1H-cyclopentadien[a]phenanthrene-3-yl)-2,4-difluorobenzamide (compound 43)

[0475]

[0476] Compound 135 (100 mg, 0.028 mmol) was added to give 94 mg of pale yellow solid compound 43, with a yield of 67.14%. 1H NMR(500MHz,DMSO)δ8.20(d,J=7.9Hz,1H),7.67(d,J=1.1Hz,1H),7.63(td,J=8.5, 6.8Hz,1H),7.34–7.28(m,1H),7.14(td,J=8.4,2.1Hz,1H),7.03(s,1H),5.73–5.71(m,1H), 5.37(d,J=4.8Hz,1H),3.70–3.61(m,1H),2.09(d,J=0.4Hz,3H),1.01(s,3H),0.96(s,3H). 13 C NMR (126MHz, DMSO) δ162.42,148.46,141.53,137.82,135.16,132.06,120.97,116.59, 114.89,112.20,111.96,104.98,104.93,104.72,56.29,50.27,50.03,45.85,38.74,37.9 3,36.85,34.61,30.93,30.05,29.51,28.49,20.65,19.39,16.11,13.94.HRMS(ESI)(M+H) + Calculated value of m / z C 30 H 36 F2N3O 492.2821, measured value: 492.2837.

[0477] Bioactivity test

[0478] The steroidal compounds of this invention are demonstrated to be suitable for treating diseases mediated by the AR signaling pathway through a series of in vivo and in vitro activity tests. In vitro activity tests include: wild-type AR antagonistic activity test, mutant AR antagonistic activity test, AR degradation activity test, and cell proliferation inhibition activity test; in vivo activity tests include the androgen-dependent organ development (Hershberger) test and other drug-likeness tests such as metabolism.

[0479] 1. Wild-type AR antagonistic activity test

[0480] HEK293 cells were cultured in DMEM containing 10% fetal bovine serum (FBS) at 37°C with 5% CO2. Cells were then digested with trypsin and counted. A 10 μL / well transfection solution was prepared using opti-MEM containing 5 ng of the androgen receptor clone, 100 ng of the pGL4.36 vector, and 315 nL of fugene. The cell suspension was diluted with phenol red-free DMEM, and 10% dialyzed FBS and 1% GlutaMax were added, mixing with the transfection solution to achieve a cell density of 444,444 cells / mL. This diluted cell suspension was seeded at a volume of 90 μL (40,000 cells / well) into 96-well plates and incubated for 24 h. 10 μL of drug solution (including serially diluted compounds or DMSO) was then added, and the plates were incubated for 30 min. 10 nL of DHT (final concentration 1.5 nM) was added to each well of the plate, and the plates were incubated at 37°C with 5% CO2. After 24 hours of incubation, 100 μL of Steady-Glo was added to each well of the plate, the plate was shaken at room temperature for 20 minutes, and the plate was read on Envision. IC 50 Defined as the drug concentration that causes 50% inhibition of luciferase expression, determined by dose-response curves.

[0481] Using enzalutamide, a second-generation AR antagonist, as a positive control, the AR antagonistic activities of representative compounds are shown in Table 1:

[0482] Table 1. AR antagonistic activity of representative compounds

[0483]

[0484] Table 1 shows that the compounds of this invention have excellent AR antagonistic activity and can antagonize / block the AR receptor signaling pathway. The AR antagonistic activities of the representative compounds 34, 33, 37, 13, and 14 were 6.2, 3.6, 1.9, 1.8, and 1.8 times higher than those of the control enzalutamide, respectively.

[0485] 2. In vitro AR degradation activity test

[0486] LNCaP cells (prostate cancer cells) were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) at 5% CO2 and 37°C. Cells were then digested with trypsin and cell density was counted using an automated cell counter. The cell suspension was diluted to the desired density in growth medium. The cell suspension was then seeded at 100 μL into 96-well plates and incubated at 37°C and 5% CO2 for 24 hours. The compound was then diluted 200-fold with DMSO or 3-fold with culture medium, and 50 μL of the compound solution was transferred to each well and incubated at 37°C for 24 hours. After 24 hours of incubation, the cell lysate was washed three times with DPBS, and 100 μL of 1x lysis buffer was added to each well. The plates were incubated on ice for 30 minutes, and the supernatant was collected. Proteins in the cell lysate samples were quantified and then diluted to the desired concentration. Add 100 μL of cell lysate sample to the appropriate wells, seal with tape and press firmly onto the top of the microplate, and incubate at 37°C for 2 hours. Discard the plate contents and wash four times with 1x wash buffer, 200 μL per well each time. Next, add 100 μL of reconstituted detection antibody, seal with tape, and incubate at 37°C for 1 hour. Repeat the aspiration / washing steps, adding 100 μL of recombinant HRP-Linked secondary antibody to each well, sealing with tape, and incubating at 37°C for 30 minutes. Repeat the aspiration / washing steps again, adding 100 μL of substrate solution to each well, incubating at 37°C for 10 minutes, and finally adding 100 μL of stop solution to each well. Gently tap the plate to ensure thorough mixing and record OD at 450 nm.

[0487] Degradation rate (%) = (OD450_max - OD450_sample) / (OD450_max - OD450_min) × 100. Plot the value using GraphPad Prism 5 software and calculate the IC using SPSS software. 50 .

[0488] Since enzalutamide only possesses AR antagonistic activity and not AR degradation activity, while Galeterone (CAS: 851983-85-2), which has the same steroidal structure as the compound of this invention, has been used in clinical trials for the treatment of CRPC. Galeterone has a triple mechanism of action: CYP17A1 enzyme inhibition, AR degradation, and antagonism (J.Med.Chem. 2015, 58, 2077-2087). Therefore, using Galeterone as a positive control, the AR degradation activity of the representative compound of this invention was tested, and the results are shown in Table 2:

[0489] Table 2. AR degradation activity of representative compounds

[0490]

[0491] Table 2 shows that the steroidal compounds of this invention exhibit excellent in vitro AR degradation activity, significantly superior to the control drug Galeterone, with varying degrees of improvement ranging from 2.4 to 8.1 times. Among them, compounds 33, 36, 35, and 37 showed improvements of 8.1, 7.6, 6.7, and 6.2 times compared to Galeterone, respectively.

[0492] 3. In vitro LNCaP (hormone-sensitive prostate cancer) cell proliferation inhibition test

[0493] LNCaP cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS) at 37°C and 5% CO2. Cells were then digested with trypsin and cell density was counted using an automated cell counter. The cell suspension was diluted to the desired density in growth medium. The cell suspension was then seeded into 96-well plates at 100 μL each, and the plates were incubated at 37°C and 5% CO2 for 24 hours. 10 μL of aliquots of the drug solution (including 3-fold serially diluted compounds or DMSO) were added to each well, and the plates were incubated at 37°C and 5% CO2 for 6 days. The assay plates were equilibrated to room temperature before measurement. 40 μL of the drug solution was added to each well. Reagents. Mix on an orbital oscillator for 2 minutes to induce cell lysis. Incubate at room temperature for 60 minutes to stabilize the luminescence signal. Read the plate on the Envision plate. IC 50 Defined as the drug concentration that causes 50% inhibition of cell growth, determined by dose-response curves.

[0494] Using abiraterone and enzalutamide, currently used clinically to treat advanced prostate cancer, as positive control drugs, the anti-LNCaP prostate cancer cell proliferation activity of the representative compound of this invention was determined, and the results are shown in Table 3:

[0495] Table 3. Anti-LNCaP cell proliferation activity of representative compounds

[0496]

[0497] Table 3 shows that the test results indicate that the compounds of this invention exhibit excellent anti-prostate cancer cell proliferation activity (IC50). 50 Its antitumor activity is significantly better than that of abiraterone, with a substantial increase of 3.0-15.8 times compared to the latter; among them, compounds 14, 17, 37, and 18 have increased by 15.8, 8.8, 8.6, and 7.9 times compared to abiraterone, respectively.

[0498] The most significant characteristic of this patented compound compared to enzalutamide is its antitumor efficacy (maximum inhibitory activity) is approximately twice as high. This is attributed to the compound's strong AR degradation / downregulation ability, while enzalutamide lacks AR degradation activity. Compounds 14, 16-19, and 37 exhibit significantly better antitumor activity and efficacy than enzalutamide, while compounds 13, 24, and 33 have comparable antitumor activity to enzalutamide but significantly superior antitumor efficacy.

[0499] Therefore, the steroidal compounds of the present invention have significantly superior antitumor activity compared to existing AR antagonists or androgen synthase inhibitors.

[0500] 4. Mutant AR antagonistic activity test

[0501] First-generation AR antagonists such as flutamide and bicalutamide, and second-generation AR antagonists such as enzalutamide and apatamide, all develop acquired / secondary resistance after a period of clinical treatment due to mutations in the AR ligand-binding domain. The compounds of this invention, possessing unique dual degradation / antagonistic functions, still exhibit strong antagonistic activity against various mutated AR receptors, and will remain effective for clinically resistant tumor patients to drugs such as enzalutamide.

[0502] 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 containing 10% dialyzed FBS and 1% GlutaMax. The androgen-responsive reporter gene construct (pGL 4.36) encoding AR mutants AR (F876L), AR (T877A), or AR (W741L) was incubated in OptiMEM using Lipofectamine 2000 at room temperature for 15 minutes. The cell suspension was diluted with seeding medium, and the transfection reagent was transferred to a concentration of 500,000 cells / mL. 90 μL of the cell suspension was then seeded into each well of the assay plate. The compound was prepared the next day: starting at 8 mM, 3-fold serial dilutions were performed with DMSO for a total of 8 spots, and then 500 nmol was transferred to the compound plate using an Echo assay. The compound was then diluted 10-fold to a final concentration using 40 μL of culture medium, and 10 μL was transferred to a cell plate and incubated at 37°C for 30 minutes. Next, 10 nL of DHT, with a final concentration of 10 nM, was transferred to each well of the assay plate using TECAN. After 24 hours of incubation, 100 μL of Steady-Glo assay plates were used, and readings were taken on an Envision. Data were identified and analyzed using a GraphPad Prism.

[0503] For the W741L and T877A mutations, the second-generation AR antagonist enzalutamide was used as a positive control. For the F876L mutation, enzalutamide showed agonistic activity. The test results are shown in Table 4.

[0504] Table 4. Antagonistic activity of representative compounds against mutant AR

[0505]

[0506] Table 4 shows that the compounds of this invention exhibit excellent antagonistic activity against the major mutant AR types observed clinically: for the W741L mutation, compound 35 showed a 4.0-fold increase in activity compared to enzalutamide; for the T877A mutation, compound 33 showed a 1.4-fold increase compared to enzalutamide; and for the F876L mutation, which is resistant to the second-generation AR antagonists enzalutamide and apatamide, the compounds of this invention all showed excellent antagonistic activity. This indicates that the compounds of this invention can treat prostate cancer resistant to existing first- and second-generation AR antagonists.

[0507] 5. Proliferative activity of drug-resistant cells (22RV1)

[0508] Another major form of acquired / secondary resistance to AR is the expression of the AR-V7 scission variant. Approximately 50% of patients treated with enzalutamide or abiraterone express this variant. The ligand-binding domain of this AR scission variant is completely lost, preventing all current AR antagonists from binding to AR and exerting their effects, leading to secondary resistance or natural resistance inactivation. Since the steroidal compounds of this invention possess excellent AR-degrading activity, they can also degrade AR scission variants, thus addressing the problem of resistance to scission variants.

[0509] Using enzalutamide, apatamide, and dalotamide—all commercially available second-generation AR antagonists—as controls, the antiproliferative activity of the compounds of this invention against 22RV1 prostate cancer cells expressing the AR-V7 splicing variant was tested. The experimental procedure was basically the same as that for LNCaP cells, and the results are shown in Table 5.

[0510] Table 5. Antiproliferative activity of representative compounds against 22RV1 cells

[0511]

[0512] Table 5 shows that, as expected, enzalutamide, apatamide, and darotamide had no activity against tumor cells expressing AR splice variants, while the steroidal compounds of the present invention exhibited excellent anti-proliferative activity against 22RV1 prostate cancer cells and can be used for the treatment of patients resistant to AR splice variants.

[0513] The results of experiments 1-5 above demonstrate that the compounds of this invention exhibit strong antitumor activity against both existing AR antagonists (first and second generation) and abiraterone, regardless of whether the cancer is sensitive or resistant. This allows for the treatment of prostate cancer at all stages, including early-stage hormone-sensitive prostate cancer, CRPC, and drug-resistant CRPC. This will provide an unprecedentedly powerful therapeutic approach for prostate cancer and other diseases related to the AR signaling pathway.

[0514] 6. In vivo metabolism of the compounds of this invention

[0515] Male SD rats were randomly assigned to 6 groups of 3 rats each. One day prior to drug administration, the rats were fasted for 12–14 hours but allowed free access to water. The test sample was then administered via gavage at a concentration of 10 mg / kg in a solvent of 5% DMSO + 30% PEG400 + 65% (0.5% MC). Four hours after administration, the rats were fed. Blood samples (0.10 mL) were collected via the orbital cavity at 0, 15, 30 min, 1, 2, 4, 6, 8, and 24 h, and were anticoagulated with EDTAK2. After collection, the blood samples were placed on ice and centrifuged within 30 minutes to separate the plasma (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). Take 50.0 μL of plasma sample (taken from -80℃ and allowed to thaw naturally at room temperature, then vortex for 30 seconds) into a 1.5 mL centrifuge tube, add 500 μL of internal standard solution (methanol (TEDIA, HPLC grade), acetonitrile (TEDIA, HPLC grade), formic acid (FA, ACROSORGANICS, HPLC grade), and laboratory-prepared ultrapure water (100.0 ng / mL). -1 The sample was vortexed for 60 seconds and then centrifuged for 3 minutes (12000 rpm). 100 μL of the supernatant was transferred to a 96-well plate containing an equal volume of water, vortexed to mix, and then injected for LC-MS / MS analysis at a volume of 10 μL. The data acquisition and control system software was Analyst 1.5.1 (Applied Biosystem). The peak integration method was automatic integration; the ratio of the sample peak area to the internal standard peak area was used as an indicator and regressed against the sample concentration.

[0516] The pharmacokinetic parameters of the representative compound of this invention were tested in male SD rats after oral administration of 10 mg / kg using the conventional methods described above, and the pharmacokinetic characteristics of the compound in rats were investigated. The test results are shown in Table 6.

[0517] Table 6. Results of pharmacokinetic activity assays in rats (PO: 10 mg / kg)

[0518]

[0519] In vivo pharmacokinetic studies in rats showed that, compared to the steroidal compound abiraterone, this class of compounds exhibited superior pharmacokinetic properties and drug-likeness. Compared to abiraterone (ABT)C... max It increased by 32-133 times, and drug exposure increased by more than 138 times. Its metabolic properties are significantly better than abiraterone, and it has very rational drug-like properties.

[0520] 7. In vivo anti-androgen activity

[0521] The Hershberger assay was used to detect the in vivo anti-androgen signaling activity of the compounds of the present invention. In this assay, pre-pubescent castrated male Sprague-Dawley rats were administered the compounds (14, 33, and 37) of the present invention in the presence of 0.4 mg / kg testosterone propionate (TP), and the weight of androgen-dependent organs was measured. Administration continued for 10 days, with measurements taken 24 hours after the last administration. The degree of antagonism of AR and subsequent organ growth inhibition were assessed by comparison with castration controls. The test compounds were administered orally at 20 mg / kg QD, and endpoint assessment was performed by changes in weight of two androgen-sensitive organs (ASOs): the seminal vesicle with fluid and coagulated glands (SVCG) and the ventral prostate (VP). Enzalutamide (ENZ) was used as a positive control. The results are as follows. Figure 2 As shown.

[0522] In vivo Hershberger assays showed that compounds 14, 33, and 37 significantly inhibited the growth of androgen-dependent organs compared to the castration group, and all exhibited activity comparable to enzalutamide. This demonstrates that the compounds of this invention can effectively antagonize the androgen receptor signaling pathway in vivo, making them suitable for the treatment of prostate cancer.

[0523] 8. The compounds of this invention inhibit the expression activity of membrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2).

[0524] To verify whether AR antagonists or AR degraders can effectively downregulate the expression of TMPRSS2 and ACE2 proteins for the treatment of COVID-19, A549 lung cancer cells were used. Logarithmic growth phase cells were collected, counted, and resuspended in complete culture medium to adjust the cell concentration to 3 × 10⁻⁶. 5Cells were seeded at 1 mL / well in 12-well plates, with 1 mL of cell culture medium added to each well. Cells were cultured at 37°C, 100% relative humidity, and 5% CO2 for 24 hours. The culture medium in the plates containing A549 cells was then discarded, and the cells were washed once with PBS. The patented compound, the positive control drug proxalutamide (10 μM), and 1 nM DHT were mixed with the culture medium and added to the plates. The plates were then incubated at 37°C, 100% relative humidity, and 5% CO2 for 48 hours. After 48 hours, cells were collected, and RNA was extracted from A549 cells using an RNA extraction kit. cDNA was obtained by reverse transcription according to the reverse transcription kit instructions. The effects of different candidate compounds on the mRNA expression levels of ACE2 and TMPRSS2 proteins in A549 cells were detected by qPCR. The results are shown in Table 7.

[0525] Table 7. mRNA expression levels of the compounds in A549 cells for ACE2 and TMPRSS2 proteins.

[0526]

[0527] Table 7 shows that in A549 cells, compounds 21 and 35 significantly downregulated the expression of ACE2 and TMPRSS2 proteins, and were superior to the control drug proxalutamide. In vitro protein expression experiments confirmed that the compounds of this invention can effectively inhibit the AR-TMPRSS2 / ACE2 signaling pathway and can be used for the treatment of COVID-19 patients.

[0528] All the above test results indicate that the compounds of this invention will be a new generation of anti-prostate cancer drugs with both AR antagonism and degradation mechanisms of action, exhibiting stronger anti-tumor activity. Compared with single-function AR antagonists or androgen synthase inhibitors, they show better efficacy and will have better effects on clinical CRPC patients and even prostate cancer patients at all stages. In the future, they can be better used for the treatment of diseases related to the AR signaling pathway.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, In the formula, A is B is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; among which, The substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, hydroxyl, carboxyl, amino, mercapto, C. 1-6 Alkyl, C 1-6 Alkyl groups, halogens, cyano groups, NO2, C 1-6 Halogenated alkyl groups, -SO-C 1-6 Alkyl group, -SO2-C 1-6 Alkyl, -CONH-C 1-6 Alkyl, -NHCO-C 1-6 Alkyl group; the heteroatom of the heteroaryl group is O or N, and the number of heteroatoms is 1, 2, 3 or 4; X is pyridyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, or pyridazinyl; the above group is optionally substituted by one, two, or three groups selected from the group consisting of: deuterium, hydroxyl, carboxyl, amino, mercapto, C. 1-4 Alkyl, C 1-4 Alkoxy, F, Cl, Br, CN, NO2, C 1-4 Halogenated alkyl groups, -SO-C 1-4 Alkyl group, -SO2-C 1-4 Alkyl, -CONH-C 1-4 Alkyl, -NHCO-C 1-4 alkyl.

2. The compound according to claim 1, characterized in that, The compound of formula I has the following formula:

3. The compound according to claim 1, characterized in that, B is selected from: substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-7 membered heteroaryl groups; The substitution refers to substitution by one, two, or three groups selected from the group consisting of: deuterium, hydroxyl, carboxyl, amino, mercapto, C. 1-4 Alkyl, C 1-4 Alkoxy, F, Cl, Br, CN, NO2, C 1-4 Halogenated alkyl groups, -SO-C 1-4 Alkyl group, -SO2-C 1-4 Alkyl, -CONH-C 1-4 Alkyl, -NHCO-C 1-4 alkyl; The heteroatom of the heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3.

4. The compound according to claim 1, characterized in that, B is Or phenyl, wherein the above groups are optionally substituted by one, two or three groups selected from the group consisting of: deuterium, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, F, Cl, Br, cyano, NO2, -SOCH3, -SOCH2CH3, -SOCH(CH3)2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2.

5. The compound according to claim 1, characterized in that, X is selected from: The above groups are optionally substituted by one or two groups selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, cyano, nitro, carboxyl, fluorine, chlorine, bromine, -CONHCH3, -NHCOCH3.

6. The compound according to claim 1, characterized in that, The compound or a pharmaceutically acceptable salt thereof is selected from:

7. The method for preparing the compound according to claim 1, characterized in that, The preparation method includes the following steps: a) Intermediate I-1 reacts with methanesulfonyl chloride to give intermediate I-2; b) Intermediate I-2 reacts with azide-trimethylsilane and boron trifluoride diethyl ether to give intermediate I-3; c) Intermediate I-3 reacts with lithium aluminum hydride to obtain intermediate I-4; d) Intermediate I-4 reacts with acyl chloride to give target compound I; or e) Intermediate I-4 undergoes a condensation reaction with a carboxylic acid to give the target compound I. In each formula, X, A, and B are defined as described in claim 1.

8. The preparation method according to claim 7, characterized in that, 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 hours under the catalysis of 4-dimethylaminopyridine to obtain intermediate I-2; the organic base is selected from triethylamine and N,N-diisopropylethylamine; the polar aprotic solvent is selected from 1,4-dioxane, toluene, tetrahydrofuran, and dichloromethane.

9. The preparation method according to claim 7, characterized in that, In step b, intermediate I-2 is dissolved in dichloromethane solution, and 3-6 equivalents of azide-trimethylsilane and 4-8 equivalents of boron trifluoride diethyl ether are added sequentially. The mixture is reacted at room temperature for 12-24 hours to obtain intermediate I-3 with preserved stereoconfiguration.

10. The preparation method according to claim 7, characterized in that, In step c, intermediate I-3 is dissolved in a polar aprotic solvent, and 1.5 equivalents of lithium aluminum hydride are added and reacted at room temperature for 2-6 hours to obtain intermediate I-4; the polar aprotic solvent is selected from: 1,4-dioxane, toluene, tetrahydrofuran, and dichloromethane.

11. The preparation method according to claim 7, characterized in that, In step d, intermediate I-4 is dissolved in a polar aprotic solvent in the presence of an organic base, and then reacted with an acyl chloride at room temperature for 6-12 h under the catalysis of 4-dimethylaminopyridine to obtain target compound I; the organic base is selected from: triethylamine, N,N-diisopropylethylamine; the polar aprotic solvent is selected from: 1,4-dioxane, toluene, tetrahydrofuran, dichloromethane; the acyl chloride is selected from: isonicotinic chloride hydrochloride, nicotinic chloride hydrochloride.

12. The preparation method according to claim 7, characterized in that, In step e, intermediate I-4 is dissolved in N,N-dimethylformamide and reacted with a carboxylic acid in the presence of the condensing agent 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate for 8-12 h to obtain target compound I; the reaction temperature is 0-50℃; the carboxylic acid is selected from: 4-pyridazine carboxylic acid, 4-fluoropyridine-3-carboxylic acid.

13. The method for preparing the compound according to claim 1, characterized in that, Compound II-1 undergoes a Suzuki coupling reaction with boric acid or borate ester to yield intermediate I-1. Alternatively, the preparation method of intermediate I-1 includes the following steps: i) Compound II-2 reacts to give compound II-3; ii) Compound II-3 is de-aldehyded to give compound II-4; iii) Hydrolysis of compound II-4 yields intermediate I-1. In each formula, X is defined as described in claim 1.

14. The preparation method according to claim 13, characterized in that, Compound II-1 was dissolved in a mixed solution of 1,4-dioxane and water, and then subjected to a Suzuki coupling reaction at 100°C with 5-pyrimidineboronic acid, 5-methylpyridine-3-boronic acid or 5-methoxy-3-pyrimidinepinacolborate to obtain the corresponding compound I-1. The volume ratio of 1,4-dioxane to water is 5:1-2:1, and the reaction temperature is 80-110℃.

15. The preparation method according to claim 13, characterized in that, In step i, compound II-2 is dissolved in a polar solvent, and then reacted with 1,2,3-triazole, imidazole, 4-methylimidazolium, or 4-ethylimidazolium at 80°C under the action of an inorganic base to obtain the corresponding compound II-3; the polar solvent is selected from acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the inorganic base is selected from sodium carbonate, potassium carbonate, and cesium carbonate.

16. The preparation method according to claim 13, characterized in that, In step ii, compound II-3 is dissolved in dry N,N-dimethylformamide, and stoichiometric amounts of palladium on carbon are added. The reaction is carried out for 18-72 h to remove the aldehyde group and obtain compound II-4. The reaction temperature is 140-170 °C.

17. The preparation method according to claim 13, characterized in that, 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 is selected from methanol and ethanol.

18. A pharmaceutical composition, characterized in that, It comprises: a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

19. Use of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, characterized in that, Drugs for the preparation of drugs to prevent and / or treat diseases related to the AR signaling pathway.

20. The use as described in claim 19, characterized in that, The diseases associated with the AR signaling pathway are selected from: prostate cancer, breast cancer, SARS-CoV-2 infectious diseases, osteoporosis, and digestive system diseases.

21. The use as described in claim 19, characterized in that, The disease associated with the AR signaling pathway is castration-resistant prostate cancer.

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