Phenanthroquinolizidine alkaloid derivatives, processes for their preparation, pharmaceutical compositions and uses thereof

Abstract

The present application relates to compounds as shown in general formula I-a, I-b or I-c, and their respective corresponding stereoisomers II-a, II-b or II-c, a preparation method thereof, a pharmaceutical composition and a use in the preparation of a medicament for treating human glioma, particularly glioblastoma. The preferred compounds in the present application can inhibit the proliferation of glioblastoma cells, have a significant therapeutic effect on various drug-resistant glioblastoma, have lower toxicity, show potential to overcome drug resistance in vivo, and have a broad clinical application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical development technology, specifically relating to phenanthrenequinolizidine alkaloid derivatives of general formulas Ia, Ib or Ic and their respective corresponding stereoisomers II-a, II-b or II-c, methods for their preparation, pharmaceutical compositions containing them, and their use in the preparation of medicaments for the treatment and / or prevention of human glioma-related diseases. Background Technology

[0002] Glioblastoma (GBM) is one of the most common and aggressive malignant tumors of the central nervous system, characterized by high incidence, high malignancy, poor prognosis, and extremely low cure rate. Because GBM often occurs in critical areas of the brain and is highly invasive, complete surgical resection of the lesions is difficult, leading to significant treatment challenges and short patient survival. Currently, temozolomide (TMZ), as a first-line chemotherapy drug, has some efficacy in newly diagnosed GBM patients, but drug resistance is a prominent issue, with some patients even exhibiting natural resistance to TMZ. Although targeted therapy and immunotherapy have made some progress in recent years, they have not significantly prolonged the overall survival of patients. Therefore, the development of novel therapeutic drugs for relapsed and drug-resistant GBM is urgently needed to meet the pressing clinical needs.

[0003] (S)-3-neovaleroxy-6,7-dimethoxyphenanthreneindolizidine (CAT3) is a novel active molecule derived from the parent compound PF403 through bioactivity studies and structural optimization of phenanthreneindolizidine alkaloids. This compound possesses the ability to cross the blood-brain barrier and exhibits significant antitumor activity in the treatment of gliomas (Cancer Lett. 2016, 381, 391-403). The applicant has successfully achieved large-scale preparation of CAT3 and its specific crystal forms through optimized synthetic processes (CN110294752A, CN110117279A, CN110117280A). However, animal experiments have shown that CAT3 exhibits high gastrointestinal toxicity, limiting its clinical application potential. Therefore, it is necessary to further optimize its pharmacological properties through structural modification to improve activity, reduce toxicity, and thus enhance its drug-likeness, providing a safer and more effective candidate drug for the treatment of gliomas.

[0004]

[0005] Phenylaminoid quinolizidine is a homologue of phenylaminoid indolizidine. This type of alkaloid also has a variety of excellent biological activities, such as antitumor activity. Based on the principles of homologues and molecular assembly, this patent expands the phenylaminoid indolizidine core of PF403 into a phenylaminoid quinolizidine core and links it with a triazole group that has high biocompatibility and rich pharmacological activity to obtain a novel compound with excellent anti-GBM activity and safety. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide compounds having the general formula Ia, Ib or Ic and their respective corresponding stereoisomers II-a, II-b or II-c, their racemates or pharmaceutically acceptable salts thereof.

[0007] Another technical problem to be solved by the present invention is to provide a method for preparing compounds having the general formula Ia, Ib or Ic and their respective corresponding stereoisomers II-a, II-b or II-c, their racemates or pharmaceutically acceptable salts thereof.

[0008] Another technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising at least one compound of general formula Ia, Ib or Ic and its respective stereoisomers II-a, II-b or II-c, its racemate or a pharmaceutically acceptable salt thereof.

[0009] Another technical problem to be solved by the present invention is to provide the use of compounds of general formula Ia, Ib or Ic and their respective stereoisomers II-a, II-b or II-c, their racemates or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of tumor-related diseases.

[0010] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0011] This invention relates to compounds having the general formula Ia, Ib or Ic and their respective stereoisomers II-a, II-b or II-c:

[0012]

[0013] Wherein, R1 is selected from unsubstituted or arbitrarily substituted by one, two or more R1s. 1a Substituted benzyl group; R2 and R3 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, unsubstituted or optionally surrounded by one, two or more R groups. 2a The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy groups; each R 1a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-6 Alkyl, Halogenated C1-6 Alkyl, C 1-6 Alkoxy groups; each R 2a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl group.

[0014] According to the present invention, preferred compounds include:

[0015]

[0016]

[0017] According to embodiments of the present invention, the compound further comprises a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include inorganic and organic salts. The inorganic acids include hydrochloric acid, sulfuric acid, methanesulfonic acid, and phosphoric acid. The organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, aspartic acid, and tartaric acid.

[0018] The present invention also provides a method for preparing the compounds of the present invention. The present invention also relates to a pharmaceutical composition comprising a pharmaceutically effective dose of a compound of general formula Ia, Ib, or Ic and its respective stereoisomers II-a, II-b, or II-c, and a pharmaceutically acceptable carrier. The content of the compound in the pharmaceutical composition of the present invention is generally 0.1-95% by weight. A pharmaceutically acceptable carrier is selected from the following combinations: binders, fillers, diluents, disintegrants, suspending agents, suspending agents, sustained-release (controlled-release) agents, lyophilization protectants, coating agents, enteric materials, lubricants, flow aids, anti-adhesives, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, osmotic pressure regulators, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, lipid-soluble matrices, oil-soluble matrices, pore-forming agents, gelling agents, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.

[0019] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0020] Another aspect of this invention relates to combining the compounds of this invention with one or more pharmaceutically acceptable carriers to formulate a dosage form suitable for human or animal use, which may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. Liquid dosage forms may include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms may include tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms may include ointments, gels, pastes, etc.

[0021] The compounds of this invention can be formulated into conventional formulations, as well as sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0022] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0023] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0024] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs.

[0025] This invention also relates to the use of the compounds of this invention in the preparation of drugs for treating cancer, particularly in cancers such as glioblastoma, primary drug-resistant glioblastoma, and acquired drug-resistant glioblastoma.

[0026] Terminology Definitions and Explanations

[0027] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0028] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0029] "More than" means three or more, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0030] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0031] The term “C1-10 alkyl” should be understood to mean straight-chain and branched alkyl with 1 to 10 carbon atoms, “C1-8 alkyl” to mean straight-chain and branched alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and “C1-6 alkyl” to mean straight-chain and branched alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof.

[0032] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0033] In this invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of H, C, N, O, S, F, and Cl, respectively such as 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H or D substitutions can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and are therefore preferred in some cases. The presence of hydrogen in the substituents of this invention, without the separate mention of the terms deuterium or tritium, does not imply the exclusion of deuterium or tritium, but rather may also include deuterium or tritium.

[0034] Based on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, and racemates. Detailed Implementation

[0035] The starting compounds used in the embodiments of the present invention can be prepared according to conventional methods in the art and / or methods well known to those skilled in the art, and can be prepared as exemplified below.

[0036] Compound synthesis methods:

[0037]

[0038]

[0039] I. Preparation of PF6O3S:

[0040] 1a: Compound 1 (10.75 g, 27 mmol), ultra-dry acetonitrile (200 mL), and ultra-dry 1,4-dioxane (150 mL) were added to a 2000 mL three-necked reaction flask and stirred at room temperature until completely dissolved. Sodium iodide (8.1 g, 0.054 mol) was added and stirred until homogeneous. Trimethylchlorosilane (5.1 mL, 40 mmol) was added dropwise under ice-water bath cooling. After the addition was complete, stirring was continued at room temperature for 1 h. Potassium carbonate (7.5 g, 50 mmol) and dimethyl L-2-aminohexanoate hydrochloride (9.1 g, 4 mmol) were added to the reaction flask in sequence and stirred at room temperature. TLC monitoring (PE / EA = 5 / 1) was performed until the intermediate reacted completely. Filter the mixture, wash the filter cake with methanol (about 120 mL), transfer the filtrate to a 1000 mL single-necked reaction flask, and slowly add acetic acid (5% V / V) to the reaction flask while stirring. Continue stirring at 70 °C for about 12 h, and concentrate the organic solvent under reduced pressure to obtain a brownish-black oily substance.

[0041] Then, a mixed solution of 100 mL methanol and 15 mL dichloromethane was added to the reaction flask. After complete dissolution, sodium hydroxide aqueous solution (4 M) was added dropwise with stirring until the pH reached 11-12. Stirring was continued at room temperature, and TLC monitoring was performed (PE / EA = 1 / 1). After the reaction was complete, the organic solvent was concentrated under reduced pressure, diluted with water (100 mL), and extracted with dichloromethane (500 mL × 3) and ethyl acetate (500 mL × 3), respectively. The aqueous phase was retained, and the residual organic solvent in the aqueous layer was removed under reduced pressure. The solution was then placed in a 500 mL three-necked reaction flask and cooled in an ice bath. The pH of the solution was adjusted to 2-3 with hydrochloric acid (3 M), and a large amount of white solid precipitated. The solution was filtered, the filter cake was washed with distilled water, and dried to obtain 4.2 g of off-white solid 2-I, with a yield of 38.03%.

[0042] 2: Compound 2-I (4.1 g, 10 mmol) and trifluoroacetic acid (45 mL) were added to a 500 mL three-necked reaction flask and stirred until suspended. The mixture was heated and stirred at 45 °C for 30 min. Boron trifluoride diethyl ether complex (30 mL) was added. The reaction was monitored by TLC (DCM / MeOH = 10 / 1). After the reaction was complete, the mixture was filtered. The solid was purified by slurrying with dichloromethane to give 1.87 g of dark green solid 3-I, with a yield of 47.71%.

[0043] 3. Add compound 3-I (1.87 g, 4 mmol), dichloromethane (15 mL), and methanol (15 mL) sequentially to a 250 mL round-bottom flask. Stir until homogeneous, cool in an ice bath, and then slowly add sodium borohydride (0.46 g, 12 mmol) in portions, controlling the reaction temperature below 10 °C. After the addition is complete, allow the mixture to stand at room temperature and continue the reaction. Monitor the reaction by TLC (DCM / MeOH = 10 / 1) until the starting material has completely reacted. Then, slowly add hydrochloric acid (1 M) dropwise under ice bath until the pH is adjusted. 7-8. After stirring for another hour, allow the mixture to stand and separate into layers. Extract the aqueous layer with dichloromethane (50 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, and concentrate the organic solvent under reduced pressure to obtain a yellow foamy solid. Transfer the solid directly to a 100 mL round-bottom flask and dissolve it in ultra-dry dichloromethane (15 mL). Add triethylsilane (5 mL) and boron trifluoride ether (5 mL) sequentially while stirring. Stir overnight at room temperature. A solid precipitates out. Concentrate about 2 / 3 of the organic solvent under reduced pressure, filter, and slurry the filter cake with dichloromethane and a small amount of methanol to obtain a pink product 4-I, 0.92 g, yield 65.91%.

[0044] 4: Compound 4-I (0.71 g, 1.88 mmol) and THF (20 mL) were added sequentially to a 100 mL round-bottom flask and stirred thoroughly under ice bath conditions. Lithium aluminum hydride (0.356 g, 9.37 mmol) and 5 mL of dichloromethane were slowly added and stirred overnight. The mixture was then cooled in an ice bath, and the solution of sodium potassium tartrate was slowly added dropwise to quench the reaction. After stirring at room temperature for 12 h, the mixture was extracted with dichloromethane (containing 5%–10% methanol) (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The solid was slurryed with ethyl acetate and methanol to give 0.57 g of a pale pink solid PF6O3S, with a yield of 83.81%.

[0045] II. Preparation of PF603R:

[0046] 1b: Compound 1 (7.2 g, 18 mmol), ultra-dry acetonitrile (50 mL), and ultra-dry 1,4-dioxane (30 mL) were added to a 250 mL three-necked reaction flask and stirred at room temperature until completely dissolved. Sodium iodide (5.4 g, 36 mmol) was added, and stirring was continued until homogeneous. Trimethylchlorosilane (3.5 mL, 27 mmol) was added dropwise under ice-water bath cooling. After the addition was complete, stirring was continued at room temperature for 1 h. Potassium carbonate (5 g, 36 mmol) and dimethyl D-2-aminoadipic acid hydrochloride (5.2 g, 23 mmol) were added to the reaction flask in sequence. The mixture was stirred at room temperature and monitored by TLC (PE / EA = 5 / 1) until the intermediate reacted completely. Filter the mixture, wash the filter cake with methanol (about 100 mL), transfer the filtrate to a 500 mL single-necked reaction flask, and slowly add acetic acid (20 mL, 5% V / V) to the reaction flask while stirring. Continue stirring at 70 °C for about 12 h, and concentrate the organic solvent under reduced pressure to obtain a dark brown oily substance.

[0047] 200 mL of a mixed solution of methanol and dichloromethane (3:1) was added to a reaction flask. After complete dissolution, sodium hydroxide aqueous solution (4M) was added dropwise with stirring until the pH reached 11-12. After the addition was complete, stirring was continued at room temperature. The reaction was monitored by TLC (PE / EA = 1 / 1). After the reaction was complete, the solution was concentrated under reduced pressure, and water (500 mL) was added. The solution was extracted with dichloromethane and ethyl acetate, respectively. The aqueous phase was retained and concentrated under reduced pressure to remove residual organic solvents in the aqueous layer. The solution was then placed in a 1000 mL three-necked reaction flask and cooled in an ice bath. The pH of the reaction solution was adjusted to 2-3 with hydrochloric acid (3M). A large amount of white solid precipitated out. The solid was filtered, and the filter cake was washed with distilled water and dried to obtain 5.16 g of 2-II, with a yield of 69.77%.

[0048] 2: Add 25 mL of trifluoroacetic acid to a 500 mL three-necked reaction flask, and add 2-II (2.0 g, 4.9 mmol) while stirring. Heat and stir at 45 °C for 30 min, then add 35 mL of boron trifluoride diethyl ether complex, and stir for about 6 h. Monitor the reaction by TLC (DCM / MeOH = 10 / 1). The reaction is complete. Pour the reaction solution into ice water and continue stirring for 1 h. Filter the solution, wash the filter cake with distilled water, and dry it to obtain 1.6 g of 3-II, with a yield of 83.68%.

[0049] 3: Compound 3-II (1.6 g, 4.09 mmol), dichloromethane (40 mL), and methanol (20 mL) were added sequentially to a 250 mL three-necked reaction flask. The mixture was stirred until homogeneous and cooled in an ice bath. Sodium borohydride (0.46 g, 12.27 mmol) was added slowly in portions, keeping the reaction temperature below 10 °C. After the addition was complete, the mixture was stirred at room temperature and monitored by TLC (DCM / MeOH = 50 / 1). After the reaction was complete, the mixture was cooled in an ice bath, and hydrochloric acid (3 M) was slowly added dropwise to adjust the pH to 7-8. After stirring for 1 h, a solid precipitated. The solid was filtered, and the filtrate was concentrated under reduced pressure and extracted with DCM (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the solid. The solids were combined and transferred to a 250 mL three-necked reaction flask, dissolved in ultra-dry dichloromethane (60 mL), and triethylsilane (20 mL) and boron trifluoride diethyl ether (20 mL) were added separately under stirring at room temperature. The mixture was stirred at room temperature and monitored by TLC (DCM / MeOH = 100 / 5). After the reaction was complete, the mixture was transferred to an ice-water bath and stirred for 1 h. The mixture was then filtered, and the filter cake was dried to give 1.32 g of 4-II, with a yield of 85.56%.

[0050] 4: Compound 4-II (0.94 g, 2.5 mmol) and THF (50 mL) were added sequentially to a 250 mL three-necked reaction flask. The mixture was stirred thoroughly in an ice bath, and a toluene solution of red aluminum (9.5 mL) was added dropwise under an inert gas atmosphere. After the addition was complete, the mixture was stirred at room temperature for about 24 h, and TLC was used to confirm the complete reaction of the starting material. After cooling again in an ice bath, an aqueous solution of sodium potassium tartrate was added, and the mixture was stirred at room temperature for 12 h. The mixture was then concentrated under reduced pressure to remove a large amount of tetrahydrofuran. Dichloromethane (50 mL) was added, and the mixture was stirred in an ice bath for 10 min. A solid precipitated out, which was filtered, and the solid was retained. The two solid fractions were combined, dried, and 0.84 g of PF603R was obtained, with a yield of 92.45%.

[0051] III. Preparation of intermediates A, B, and C:

[0052] Methyl 1,2,3-triazole-4-carboxylate (40 mmol, 1 eq) and K₂CO₃ (80 mmol, 2 eq) were added sequentially to a 250 mL single-necked reaction flask. DMF (50 mL) was added with stirring at room temperature. After stirring until homogeneous, RX (72 mmol, 1.8 eq) was added, and the mixture was stirred at room temperature for 4 h. TLC monitoring (DCM / MeOH = 100 / 5) indicated complete reaction. The K₂CO₃ solid was removed by filtration, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (200-300 mesh, pH 6.0-7.0, dichloromethane / petroleum ether = 1 / 1 to 3 / 1) to obtain three target products A, B, and C.

[0053] IV. Preparation of the target compound:

[0054] Add any one of compounds A, B, or C (8.0 mmol) to a 250 mL single-necked reaction flask, dissolve in methanol (30 mL) and dichloromethane (40 mL), add NaOH aqueous solution (4 M, 20 mL), stir at room temperature until hydrolysis is complete, concentrate the organic solvent under reduced pressure, add appropriate amount of water, wash with dichloromethane (3 × 10 mL) and ethyl acetate (3 × 10 mL), combine the aqueous phases, remove residual organic solvent by rotary evaporation, cool in an ice bath, add HCl (3 M, 28 mL) dropwise under magnetic stirring, precipitate solid, filter, wash filter cake with water (3 × 5 mL), dry at 45 °C, correspondingly obtain solids a, b, or c. Then, a suitable amount (0.4 mmol) of solid was transferred to a 25 mL round-bottom flask, and HATU (0.8 mmol), DMAP (0.04 mmol), and Et3N (0.6 mmol) were added. 5–10 mL of ultra-dry dichloromethane was added, and the mixture was stirred for 30 min. PF4O3 (0.4 mmol) was added, and the mixture was stirred in the dark. TLC was used for detection. After the reaction was complete, a suitable amount of water was added to quench the reaction. An equal volume of saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred for about 10 min. The mixture was extracted three times with dichloromethane. The organic phases were combined, and the organic layer was washed successively with saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20 / 1–10 / 1) to obtain the final product.

[0055] Example 1: Synthesis of (14aS)-3-(4-trifluoromethyl)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a1)

[0056] According to the synthetic method, the corresponding intermediate A1 was obtained, and compound I-a1 was synthesized through subsequent steps: 34 mg, 13.90%; 1HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.65(s,1H),8.10(s,1H),8.03(d,J=9.0Hz,1H),7.81(d,J=7.9Hz, 2H),7.60(d,J=7.8Hz,2H),7.49(d,J=9.5Hz,1H),7.24(s,1H),5.99(s,2H),4.39(d,J=16.1Hz,1H),3.98 (s,3H),3.95(s,3H),3.48(d,J=15.9Hz,1H),3.25–3.16(m,2H),2.81(t,J=13.8Hz,1H),2.32(s,1H),2.1 9(t,J=13.5Hz,1H),1.98(d,J=10.3Hz,1H),1.84–1.70(m,2H),1.62(d,J=9.6Hz,1H),1.46–1.34(m,2H).

[0057] Example 2: Synthesis of (14aS)-3-(4-trifluoromethyl)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b1) [1] According to the synthetic method, the corresponding intermediate B1 was obtained, and compound I-b1 was synthesized by subsequent steps: 22 mg, 9.00%; 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.68(s,1H),8.08(s,1H),8.05(d,J=9.2Hz,1H),7.77(d,J=8.0H z,1H),7.52(d,J=8.8Hz,2H),7.48(s,1H),7.26(s,1H),6.13(s,2H),4.41(d,J=16.2Hz,1H),4.00(s, 3H),3.97(s,3H),3.50(d,J=16.2Hz,1H),3.27–3.16(m,2H),2.87–2.78(m,1H),2.37–2.30(m,1H),2. 27–2.20(m,1H),2.02–1.97(m,1H),1.85–1.72(m,2H),1.64(d,J=12.1Hz,1H),1.41(d,J=9.6Hz,2H).

[0058] Example 3: Synthesis of (14aS)-3-(4-trifluoromethyl)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c1)

[0059] According to the synthetic method, the corresponding intermediate C1 was obtained, and compound I-c1 was synthesized through subsequent steps: 24 mg, 9.64%; 1 HNMR(400MHz,DMSO-d6)δ9.26(s,1H),8.67(d,J=2.3Hz,1H),8.10(s,1H),8.03(d,J=9.0Hz,1H),7.81(d,J=8 .0Hz,2H),7.62(d,J=7.9Hz,2H),7.48(dd,J=8.8,2.2Hz,1H),7.24(s,1H),5.89(s,2H),4.39(d,J=16.1Hz,1H ),3.98(s,3H),3.95(s,3H),3.47(d,J=16.1Hz,1H),3.25–3.16(m,2H),2.87–2.76(m,1H),2.35–2.26(m,1H), 2.20(t,J=11.6Hz,1H),1.98(d,J=10.3Hz,1H),1.83–1.70(m,1H),1.62(d,J=12.1Hz,1H),1.45–1.33(m,1H).

[0060] Example 4: Synthesis of (14aS)-3-(4-fluoro)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a2)

[0061] According to the synthetic method, the corresponding intermediate A2 was obtained, and compound I-a2 was synthesized through subsequent steps: 25 mg, 10.94%; 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.61(s,1H),8.11(s,1H),8.04(d,J=8.9Hz,1H),7.49(d,J =7.9Hz,2H),7.46(s,1H),7.28(s,1H),7.25(d,J=6.9Hz,2H),5.85(s,2H),4.40(d,J=16.1Hz,1 H),3.97(s,3H),3.95(s,3H),3.49(d,J=16.3Hz,1H),3.25–3.17(m,2H),2.85–2.77(m,1H),2.3 2(s,1H),2.26–2.16(m,1H),1.97(d,1H),1.84–1.70(m,2H),1.60(s,1H),1.40(d,J=8.3Hz,2H).

[0062] Example 5: Synthesis of (14aS)-3-(4-fluoro)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b2)

[0063] According to the synthetic method, the corresponding intermediate B2 was obtained, and compound I-b2 was synthesized through subsequent steps: 40 mg, 17.73%; 1 H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.21(s,1H),8.04(d,J=8.9Hz,1H),7.84(s,1H), 7.42(s,2H),7.33(d,J=9.1Hz,1H),7.16(s,1H),7.02(t,J=8.5Hz,2H),5.95(s,2H),4.41(d, J=14.2Hz,1H),4.08(s,3H),4.06(s,3H),3.65(d,J=12.7Hz,1H),3.32(s,1H),3.23(d,J=16 .6Hz,1H),3.00(s,1H),2.36(d,2H),2.06(d,1H),1.95–1.78(m,3H),1.53(d,J=33.8Hz,2H).

[0064] Example 6: Synthesis of (14aS)-3-(4-fluoro)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c2)

[0065] According to the synthetic method, the corresponding intermediate C2 was obtained, and compound I-c2 was synthesized through subsequent steps: 28 mg, 12.37%; 1H NMR (800MHz, DMSO-d6) δ9.21(s,1H),8.67(d,1H),8.11(s,1H),8.04(d,J=8.8Hz,1H),7.51(dd,J=8.5,5.6Hz,2H),7.4 8(dd,J=8.8,2.2Hz,1H),7.27(t,J=8.8Hz,2H),7.24(s,1H),5.75(s,2H),4.40(d,J=15.8Hz,1H),3.98(s,3H),3.95(s ,3H),3.49(d,J=15.8Hz,1H),3.21(t,J=12.6Hz,2H),2.81(dd,J=16.3,10.5Hz,1H),2.32(s,1H),2.22(t,J=12.2Hz,1 H),1.98(d,J=11.8Hz,1H),1.80(d,J=11.6Hz,1H),1.74(d,J=12.7Hz,1H),1.62(d,J=12.5Hz,1H),1.45–1.36(m,2H).

[0066] Example 7: Synthesis of (14aS)-3-benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a3)

[0067] According to the synthetic method, the corresponding intermediate A3 was obtained, and compound I-a3 was synthesized through subsequent steps: 19 mg, 8.83%; 1 HNMR(400MHz,Chloroform-d)δ8.33(d,J=2.3Hz,1H),8.29(s,1H),8.02(d,J=9.0Hz,1H),7.87(s,1 H),7.46–7.37(m,6H),7.14(s,1H),5.73(s,2H),4.42(d,J=15.5Hz,1H),4.08(s,3H),4.05(s,3H),3 .75–3.59(m,1H),3.34(d,J=11.0Hz,1H),3.23(d,J=18.8Hz,1H),3.08–2.97(m,1H),2.42(d,J=32. 4Hz,2H),2.06(d,J=12.6Hz,1H),1.96–1.79(m,3H),1.60(d,J=12.2Hz,1H),1.47(d,J=10.5Hz,1H).

[0068] Example 8: Synthesis of (14aS)-3-benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b3)

[0069] According to the synthetic method, the corresponding intermediate B3 was obtained, and compound I-b3 was synthesized through subsequent steps: 49 mg, 22.54%; 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),8.20(d,J=2.4Hz,1H),8.03(d,J=9.0Hz,1H),7.83(s,1H), 7.43–7.39(m,2H),7.35–7.30(m,4H),7.15(s,1H),6.00(s,2H),4.42(d,J=15.4Hz,1H),4.08(s,3H), 4.06(s,3H),3.74–3.63(m,1H),3.34(d,J=10.6Hz,1H),3.27–3.18(m,1H),3.03(t,J=14.3Hz,1H),2. 43(d,J=33.5Hz,2H),2.07(d,J=12.0Hz,1H),1.96–1.78(m,3H),1.65–1.55(m,1H),1.54–1.45(m,1H).

[0070] Example 9: Synthesis of (14aS)-3-benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c3)

[0071] According to the synthetic method, the corresponding intermediate C3 was obtained, and compound I-c3 was synthesized through subsequent steps: 38 mg, 17.38%; 1H NMR (800MHz, DMSO-d6) δ9.20(s,1H),8.67(d,J=2.3Hz,1H),8.10(s,1H),8.03(d,J=8.9Hz,1H),7.48(dd,J=8.8,2 .3Hz,1H),7.43(s,2H),7.42(s,2H),7.38(q,J=4.5Hz,1H),7.24(s,1H),5.76(s,2H),4.38(d,J=15.8Hz,1H),3.9 8(s,3H),3.95(s,3H),3.47(d,J=15.7Hz,1H),3.23–3.17(m,2H),2.84–2.79(m,1H),2.30(s,1H),2.20(t,J=11.4 Hz,1H),1.99–1.96(m,1H),1.80(d,J=11.8Hz,1H),1.75–1.72(m,1H),1.62(d,J=12.6Hz,1H),1.44–1.36(m,2H).

[0072] Example 10: Synthesis of (14aS)-3-(4-methoxy)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a4)

[0073] According to the synthetic method, the corresponding intermediate A4 was obtained, and compound I-a4 was synthesized through subsequent steps: 32 mg, 13.87%; 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=2.4Hz,1H),8.58(s,1H),8.11(s,1H),8.03(d,J=9.0Hz,1H),7.49(d, J=8.5Hz,1H),7.37(d,J=8.4Hz,2H),7.24(s,1H),6.97(d,J=8.4Hz,2H),5.76(s,2H),4.40(d,J=15.8Hz, 1H),3.97(s,3H),3.95(s,3H),3.76(s,3H),3.50(d,J=15.2Hz,1H),3.25–3.16(m,2H),2.86–2.77(m,1H ),2.33(s,1H),2.23(s,1H),2.01–1.94(m,1H),1.85–1.71(m,2H),1.65–1.58(m,1H),1.46–1.33(m,2H).

[0074] Example 11: Synthesis of (14aS)-3-(4-methoxy)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b4)

[0075] According to the synthetic method, the corresponding intermediate B4 was obtained, and compound I-b4 was synthesized through subsequent steps: 32 mg, 13.94%; 1 H NMR (800MHz, DMSO-d6) δ8.68(s,1H),8.66(d,J=2.4Hz,1H),8.07(s,1H),8.03(d,J=8.9Hz,1H),7.48(dd,J=8.8,2.3Hz,1H), 7.28(d,J=8.5Hz,2H),7.23(s,1H),6.91(d,J=8.6Hz,2H),5.91(s,2H),4.38(d,J=15.8Hz,1H),3.98(s,3H),3.95(s,3H),3. 72(s,3H),3.46(d,J=15.7Hz,1H),3.21(d,J=9.7Hz,1H),3.17(d,J=16.6Hz,1H),2.80(dd,J=16.4,10.4Hz,1H),2.29(s,1H) ,2.20(s,1H),1.97(d,J=11.8Hz,1H),1.80(d,J=11.8Hz,1H),1.73(d,J=12.8Hz,1H),1.64–1.59(m,1H),1.44–1.35(m,2H).

[0076] Example 12: Synthesis of (14aS)-3-(4-methoxy)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c4)

[0077] According to the synthetic method, the corresponding intermediate C4 was obtained, and compound I-c4 was synthesized through subsequent steps: 54 mg, 23.55%; 1H NMR (800MHz, DMSO-d6) δ9.15(s,1H),8.66(s,1H),8.10(s,1H),8.02(d,J=9.0Hz,1H),7.47(d,J=8.9Hz,1H),7.41(d,J= 8.7Hz,2H),7.24(s,1H),6.98(d,J=8.7Hz,2H),5.67(s,2H),4.38(d,J=15.8Hz,1H),3.98(s,3H),3.95(s,3H),3.76(s,3 H),3.47(d,J=15.8Hz,1H),3.20(dd,J=19.7,14.4Hz,2H),2.80(dd,J=16.4,10.7Hz,1H),2.30(s,1H),2.19(d,J=12.1H z,1H),1.97(d,J=8.9Hz,1H),1.80(d,J=10.9Hz,1H),1.73(d,J=12.8Hz,1H),1.62(d,J=12.6Hz,1H),1.46–1.35(m,2H).

[0078] Example 13: Synthesis of (14aS)-3-(4-cyano)benzyl-2H-1,2,3-triazole-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a5)

[0079] According to the synthetic method, the corresponding intermediate A5 was obtained, and compound I-a5 was synthesized through subsequent steps: 48 mg, 21.12%; 1 HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.66(s,1H),8.10(s,1H),8.03(d,J=8.9Hz,1H),7.91(d,J=7.9Hz ,2H),7.55(d,J=7.9Hz,2H),7.49(d,J=9.6Hz,1H),7.23(s,1H),5.99(s,2H),4.39(d,J=16.1Hz,1H),3.9 8(s,3H),3.95(s,3H),3.47(d,J=16.1Hz,1H),3.24–3.16(m,2H),2.85–2.76(m,1H),2.34–2.27(m,1H), 2.24–2.15(m,1H),1.97(d,J=10.3Hz,1H),1.82–1.71(m,2H),1.61(d,J=13.7Hz,1H),1.45–1.31(m,2H).

[0080] Example 14: Synthesis of (14aS)-3-(4-cyano)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b5)

[0081] According to the synthetic method, the corresponding intermediate B5 was obtained, and compound I-b5 was synthesized through subsequent steps: 26 mg, 11.35%; 1 H NMR (800MHz, DMSO-d6) δ8.75(s,1H),8.64(s,1H),8.06(s,1H),8.04(d,J=8.9Hz,1H),7.85(d,J=8.1Hz,2 H),7.46(d,J=6.6Hz,1H),7.44(d,J=8.0Hz,2H),7.25(s,1H),6.10(s,2H),4.38(d,J=20.9Hz,1H),3.99(s ,3H),3.95(s,3H),3.48(s,1H),3.24–3.18(m,2H),2.84–2.79(m,1H),2.31(s,1H),2.21(s,1H),1.98(d, J=11.2Hz,1H),1.80(d,J=11.8Hz,1H),1.74(d,J=12.8Hz,1H),1.62(d,J=13.0Hz,1H),1.45–1.36(m,2H).

[0082] Example 15: Synthesis of (14aS)-3-(4-cyano)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c5)

[0083] According to the synthetic method, the corresponding intermediate C5 was obtained, and compound I-c5 was synthesized through subsequent steps: 41 mg, 17.77%; 1H NMR (800MHz, DMSO-d6) δ9.25(s,1H),8.67(s,1H),8.11(s,1H),8.04(d,J=8.8Hz,1H),7.91(d,J=8.3Hz,2H) ,7.57(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,1H),7.25(s,1H),5.88(s,2H),4.40(d,J=15.7Hz,1H),3.98(s,3H) ,3.95(s,3H),3.49(d,J=15.8Hz,1H),3.20(d,J=17.4Hz,2H),2.84–2.79(m,1H),2.32(s,1H),2.21(s,1H),1 .98(d,J=10.1Hz,1H),1.80(d,J=12.1Hz,1H),1.74(d,J=11.9Hz,1H),1.67–1.60(m,1H),1.45–1.36(m,2H).

[0084] Example 16: Synthesis of (14aS)-3-(2,6-dimethyl)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a6)

[0085] According to the synthetic method, the corresponding intermediate A6 was obtained, and compound I-a6 was synthesized through subsequent steps: 57 mg, 24.77%; 1 H NMR (800MHz, DMSO-d6) δ8.68(s,1H),8.56(d,J=2.2Hz,1H),8.11(d,J=2.3Hz,1H),8.02(d,J=9.0Hz,1H),7.48(d,J=8. 9Hz,1H),7.24(s,1H),7.20(t,J=7.7Hz,1H),7.13(s,1H),7.12(s,1H),5.85(s,2H),4.39(d,J=17.2Hz,1H),3.98(s,3 H),3.95(s,3H),3.48(d,J=15.8Hz,1H),3.25–3.17(m,2H),2.81(t,J=13.8Hz,1H),2.45(s,6H),2.31(s,1H),2.21(s, 1H), 1.98 (d, J = 11.6Hz, 1H), 1.81 (d, J = 11.8Hz, 1H), 1.74 (d, J = 12.8Hz, 1H), 1.62 (d, J = 12.7Hz, 1H), 1.46–1.35 (m, 2H).

[0086] Example 17: Synthesis of (14aS)-3-(2,6-dimethyl)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b6)

[0087] According to the synthetic method, the corresponding intermediate B6 was obtained, and compound I-b6 was synthesized through subsequent steps: 50 mg, 21.53%; 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.30(s,1H),8.06(d,J=9.0Hz,1H),7.89(s,1H),7.42(d,J=9.2Hz,0H),7.20 (t,J=7.5Hz,1H),7.16(s,1H),7.10(d,J=7.5Hz,2H),5.96(s,2H),4.43(d,J=15.4Hz,1H),4.11(s,3H),4.07(s,3H),3.6 8(d,J=11.9Hz,1H),3.34(d,J=11.2Hz,1H),3.25(d,J=14.1Hz,1H),3.08–2.99(m,1H),2.50(d,J=13.3Hz,1H),2.42(s,0 H),2.36(s,7H),2.08(d,J=12.5Hz,1H),1.91(d,J=12.7Hz,1H),1.85(s,2H),1.60(d,J=11.6Hz,1H),1.54–1.44(m,1H).

[0088] Example 18: Synthesis of (14aS)-3-(2,6-dimethyl)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c6)

[0089] According to the synthetic method, the corresponding intermediate C6 was obtained, and compound I-c6 was synthesized through subsequent steps: 62 mg, 26.78%; 1H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.66(s,1H),8.10(s,1H),8.02(d,J=9.0Hz,1H),7.47(d,J=8.8Hz,1H ),7.24(s,1H),7.21(d,J=7.4Hz,1H),7.14(s,1H),7.12(s,1H),5.76(s,2H),4.39(d,J=16.1Hz,1H),3.97( s,3H),3.95(s,3H),3.47(d,J=16.0Hz,1H),3.25–3.15(m,2H),2.87–2.75(m,1H),2.40(s,6H),2.35–2.27 (m,1H),2.25–2.16(m,1H),2.01–1.93(m,1H),1.84–1.69(m,2H),1.62(d,J=9.2Hz,1H),1.47–1.32(m,2H).

[0090] Example 19: Synthesis of (14aS)-3-(3-fluoro)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a7)

[0091] According to the synthetic method, the corresponding intermediate A7 was obtained, and compound I-a7 was synthesized through subsequent steps: 51 mg, 22.43%; 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.63(s,1H),8.11(s,1H),8.03(d,J=9.0Hz,1H),7.53– 7.44(m,2H),7.27–7.21(m,4H),5.89(s,2H),4.39(d,J=16.1Hz,1H),3.98(s,3H),3.95(s,3 H),3.47(d,J=16.0Hz,1H),3.24–3.15(m,2H),2.85–2.75(m,1H),2.37–2.26(m,1H),2.25–2 .16(m,1H),1.97(d,J=9.0Hz,1H),1.83–1.69(m,2H),1.67–1.56(m,1H),1.49–1.33(m,2H).

[0092] Example 20: Synthesis of (14aS)-3-(3-fluoro)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b7)

[0093] According to the synthetic method, the corresponding intermediate B7 was obtained, and compound I-b7 was synthesized through subsequent steps: 21 mg, 9.35%; 1 HNMR(800MHz,Chloroform-d)δ8.39(s,1H),8.15(s,1H),7.92(d,J=8.0Hz,1H),7.75(s,1H),7.26(d,J=4.3Hz,1H),7.25–7.21(m,1H),7. 09(d,J=7.7Hz,1H),7.02(s,1H),7.01(d,J=8.0Hz,1H),6.94(t,J=8.3Hz,1H),5.89(s,2H),4.29(d,J=15.1Hz,1H),3.99(s,3H),3.96(s,3 H),3.52(d,J=16.8Hz,1H),3.23(d,J=11.0Hz,1H),3.09(d,J=16.5Hz,1H),2.89(dd,J=16.3,10.7Hz,1H),2.34(s,1H),2.26(t,J=12.0Hz ,1H),1.95(d,J=12.8Hz,1H),1.82(d,J=12.9Hz,1H),1.76(d,J=12.7Hz,1H),1.72–1.65(m,1H),1.47(q,J=9.9Hz,1H),1.41–1.34(m,1H).

[0094] Example 21: Synthesis of (14aS)-3-(3-fluoro)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c7)

[0095] According to the synthetic method, the corresponding intermediate C7 was obtained, and compound I-c7 was synthesized through subsequent steps: 27 mg, 12.11%; 1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.66(d,J=2.4Hz,1H),8.09(s,1H),8.02(d,J=9.0Hz,1 H),7.48(d,J=7.3Hz,2H),7.33–7.19(m,4H),5.78(s,2H),4.36(d,J=15.3Hz,1H),3.97(s,3H ),3.94(s,3H),3.51–3.42(m,1H),3.23–3.13(m,2H),2.84–2.74(m,1H),2.27(s,1H),2.22– 2.14(m,1H),2.02–1.92(m,1H),1.81–1.69(m,2H),1.61(d,J=8.7Hz,1H),1.45–1.31(m,2H).

[0096] Example 22: Synthesis of (14aS)-3-(2-fluoro-4-cyano)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a8)

[0097] According to the synthetic method, the corresponding intermediate A8 was obtained, and compound I-a8 was synthesized through subsequent steps: 44 mg, 18.51%; 1 HNMR(800MHz,DMSO-d6)δ8.75(s,1H),8.63(s,1H),8.06(s,1H),8.03(s,1H),7.92(d,J=7.2Hz,1H),7.71( s,1H),7.46(d,J=9.0Hz,1H),7.33(s,1H),7.24(s,1H),6.14(s,2H),4.38(d,J=16.0Hz,1H),3.99(s,3H),3 .95(s,3H),3.46(d,J=16.5Hz,1H),3.24–3.16(m,2H),2.83–2.78(m,1H),2.29(s,1H),2.20(s,1H),1.97(d ,J=11.4Hz,1H),1.80(d,J=13.8Hz,1H),1.73(d,J=12.9Hz,1H),1.61(d,J=13.1Hz,1H),1.45–1.35(m,2H).

[0098] Example 23: Synthesis of (14aS)-3-(2-fluoro-4-cyano)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b8)

[0099] According to the synthetic method, the corresponding intermediate B8 was obtained, and compound I-b8 was synthesized through subsequent steps: 22 mg, 9.13%; 1 HNMR(800MHz,DMSO-d6)δ8.75(s,1H),8.63(s,1H),8.06(s,1H),8.03(s,1H),7.92(d,J=7.2Hz,1H),7.71( s,1H),7.46(d,J=9.0Hz,1H),7.33(s,1H),7.24(s,1H),6.14(s,2H),4.38(d,J=16.0Hz,1H),3.99(s,3H),3 .95(s,3H),3.46(d,J=16.5Hz,1H),3.24–3.16(m,2H),2.83–2.78(m,1H),2.29(s,1H),2.20(s,1H),1.97(d ,J=11.4Hz,1H),1.80(d,J=13.8Hz,1H),1.73(d,J=12.9Hz,1H),1.61(d,J=13.1Hz,1H),1.45–1.35(m,2H).

[0100] Example 24: Synthesis of (14aS)-3-(2-fluoro-4-cyano)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c8)

[0101] According to the synthetic method, the corresponding intermediate C8 was obtained, and compound I-c8 was synthesized through subsequent steps: 28 mg, 11.69%; 1 H NMR (800MHz, DMSO-d6) δ9.21(s,1H),8.68(s,1H),8.12(s,1H),8.04(d,J=8.9Hz,1H),7.98(d,J=9.6Hz,1H),7. 80(d,J=6.8Hz,1H),7.61(d,J=12.3Hz,1H),7.49(d,J=8.2Hz,1H),7.24(s,1H),5.93(s,2H),4.43–4.38(m,1H), 3.98(s,3H),3.95(s,3H),3.52–3.44(m,1H),3.26–3.18(m,2H),2.86–2.79(m,1H),2.32(s,1H),2.24(s,1H),1. 98(d,J=11.9Hz,1H),1.80(d,J=11.6Hz,1H),1.74(d,J=12.8Hz,1H),1.62(d,J=11.7Hz,1H),1.47–1.34(m,2H).

[0102] Example 25: Synthesis of (14aS)-3-(3,4-dimethoxy)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-a9)

[0103] According to the synthetic method, the corresponding intermediate A9 was obtained, and compound I-a9 was synthesized through subsequent steps: 46 mg, 18.82%; 1 HNMR (400MHz, DMSO-d6) δ8.67(s,1H),8.59(s,1H),8.10(s,1H),8.02(d,J=9.0Hz,1H),7.48(dd,J=9.0,2.2H z,1H),7.23(s,1H),7.07(s,1H),7.02–6.93(m,2H),5.74(s,2H),4.38(d,J=16.1Hz,1H),3.97(s,3H),3.94( s,3H),3.76(s,3H),3.75(s,3H),3.46(d,J=15.9Hz,1H),3.24–3.14(m,2H),2.85–2.75(m,1H),2.34–2.26(m ,1H),2.24–2.16(m,1H),1.97(d,J=9.0Hz,1H),1.83–1.69(m,2H),1.62(d,J=9.1Hz,1H),1.48–1.33(m,2H).

[0104] Example 26: Synthesis of (14aS)-3-(3,4-dimethoxy)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-b9)

[0105] According to the synthetic method, the corresponding intermediate B9 was obtained, and compound I-b9 was synthesized through subsequent steps: 62 mg, 25.29%; 1HNMR(400MHz,DMSO-d6)δ8.69(s,1H),8.67(s,1H),8.07(s,1H),8.04(d,J=9.1Hz,1H),7.48(d,J=8.8Hz,1H),7 .23(s,1H),6.99(s,1H),6.92(d,J=8.3Hz,1H),6.83(d,J=8.3Hz,1H),5.90(s,2H),4.39(d,J=16.6Hz,1H),3.98 (s,3H),3.95(s,3H),3.72(s,3H),3.67(s,3H),3.48(d,J=15.8Hz,1H),3.25–3.15(m,2H),2.86–2.76(m,1H),2 .32(s,1H),2.26–2.17(m,1H),2.00–1.94(m,1H),1.83–1.70(m,2H),1.62(d,J=12.3Hz,1H),1.46–1.34(m,2H).

[0106] Example 27: Synthesis of (14aS)-3-(3,4-dimethoxy)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (I-c9)

[0107] According to the synthetic method, the corresponding intermediate C9 was obtained, and compound I-c9 was synthesized through subsequent steps: 74 mg, 30.27%; 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.66(s,1H),8.10(s,1H),8.02(d,J=9.0Hz,1H),7.47(d,J=8.5Hz, 1H),7.23(s,1H),7.14(s,1H),6.98(s,2H),5.64(s,2H),4.38(d,J=16.1Hz,1H),3.97(s,3H),3.94(s,3H ),3.78(s,3H),3.75(s,3H),3.46(d,J=16.0Hz,1H),3.24–3.15(m,2H),2.85–2.75(m,1H),2.34–2.25(m ,1H),2.24–2.14(m,1H),1.97(d,J=9.9Hz,1H),1.83–1.70(m,2H),1.67–1.56(m,1H),1.48–1.31(m,2H).

[0108] Example 28: Synthesis of (14aR)-3-(4-trifluoromethyl)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a1)

[0109] According to the synthetic method, the corresponding intermediate A1 was obtained, and compound II-a1 was synthesized through subsequent steps: 69 mg, 28.10%; 1 HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.65(s,1H),8.10(s,1H),8.03(d,J=9.0Hz,1H),7.81(d,J=7. 9Hz,2H),7.60(d,J=7.9Hz,2H),7.49(d,J=8.9Hz,1H),7.24(s,1H),5.99(s,2H),4.39(d,J=16.1Hz, 1H),3.98(s,3H),3.95(s,3H),3.47(d,J=16.2Hz,1H),3.24–3.15(m,2H),2.86–2.76(m,1H),2.30(s ,1H),2.24–2.17(m,1H),2.02–1.93(m,1H),1.84–1.71(m,2H),1.67–1.59(m,1H),1.46–1.35(m,2H).

[0110] Example 29: Synthesis of (14aR)-3-(4-trifluoromethyl)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b1)

[0111] According to the synthetic method, the corresponding intermediate B1 was obtained, and compound II-b1 was synthesized through subsequent steps: 57 mg, 23.19%; 1HNMR (400MHz, DMSO-d6) δ8.75(s,1H),8.66(s,1H),8.06(s,1H),8.03(d,J=8.9Hz,1H),7.74(d,J= 8.0Hz,2H),7.49(d,J=8.7Hz,2H),7.45(s,1H),7.24(s,1H),6.11(s,2H),4.39(d,J=16.1Hz,1H), 3.97(s,3H),3.95(s,3H),3.47(d,J=15.2Hz,1H),3.23–3.15(m,2H),2.86–2.76(m,1H),2.30(s,1 H),2.25–2.16(m,1H),2.01–1.95(m,1H),1.84–1.70(m,2H),1.65–1.57(m,1H),1.45–1.35(m,2H).

[0112] Example 30: Synthesis of (14aR)-3-(4-trifluoromethyl)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c1)

[0113] According to the synthetic method, the corresponding intermediate C1 was obtained, and compound II-c1 was synthesized through subsequent steps: 73 mg, 29.66%; 1 H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.67(s,1H),8.11(s,1H),8.04(d,J=8.9Hz,1H),7.81(d,J=7.9H z,2H),7.62(d,J=7.9Hz,2H),7.48(d,J=8.6Hz,1H),7.24(s,1H),5.89(s,2H),4.39(d,J=16.1Hz,1H) ,3.98(s,3H),3.95(s,3H),3.47(d,J=15.9Hz,1H),3.26–3.16(m,2H),2.87–2.76(m,1H),2.31(s,1H) ,2.20(t,J=11.7Hz,1H),2.01–1.94(m,1H),1.84–1.69(m,2H),1.67–1.57(m,1H),1.46–1.36(m,2H).

[0114] Example 31: Synthesis of (14aR)-3-(4-fluoro)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a2)

[0115] According to the synthetic method, the corresponding intermediate A2 was obtained, and compound II-a2 was synthesized through subsequent steps: 43 mg, 19.17%; 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.61(s,1H),8.11(s,1H),8.03(d,J=9.0Hz,1H),7.49(d,J=7. 9Hz,2H),7.46(s,1H),7.28(s,1H),7.25(d,J=5.9Hz,2H),5.85(s,2H),4.39(d,J=16.3Hz,1H),3.9 7(s,3H),3.95(s,3H),3.48(d,J=16.1Hz,1H),3.24–3.17(m,2H),2.86–2.76(m,1H),2.31(s,1H),2 .21(t,J=11.6Hz,1H),2.01–1.95(m,1H),1.83–1.70(m,2H),1.66–1.59(m,1H),1.47–1.32(m,2H).

[0116] Example 32: Synthesis of (14aR)-3-(4-fluoro)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b2)

[0117] According to the synthetic method, the corresponding intermediate B2 was obtained, and compound II-b2 was synthesized through subsequent steps: 24 mg, 10.38%; 1 HNMR (400MHz, DMSO-d6) δ8.71(s,1H),8.66(s,1H),8.07(s,1H),8.04(d,J=9.3Hz,1H),7.48(d,J=8 .9Hz,1H),7.38(t,J=6.9Hz,2H),7.24(s,1H),7.20(t,J=8.6Hz,2H),5.98(s,2H),4.40(d,J=16.3H z,1H),3.98(s,3H),3.95(s,3H),3.48(d,J=16.9Hz,1H),3.26–3.15(m,2H),2.87–2.76(m,1H),2.3 2(s,1H),2.22(s,1H),2.03–1.95(m,1H),1.84–1.70(m,2H),1.67–1.55(m,1H),1.50–1.32(m,2H).

[0118] Example 33: Synthesis of (14aR)-3-(4-fluoro)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c2)

[0119] According to the synthetic method, the corresponding intermediate C2 was obtained, and compound II-c2 was synthesized through subsequent steps: 28 mg, 12.19%; 1 HNMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 9.0Hz, 1H), 7. 56–7.46(m,3H),7.31–7.21(m,3H),5.75(s,2H),4.39(d,J=16.3Hz,1H),3.97(s,3H),3.9 4(s,3H),3.47(d,J=16.0Hz,1H),3.25–3.15(m,2H),2.86–2.76(m,1H),2.30(s,1H),2.25 –2.15(m,1H),2.01–1.95(m,1H),1.84–1.70(m,2H),1.67–1.55(m,1H),1.46–1.33(m,2H).

[0120] Example 34: Synthesis of (14aR)-3-benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a3)

[0121] According to the synthetic method, the corresponding intermediate A3 was obtained, and compound II-a3 was synthesized through subsequent steps: 76 mg, 34.78%; 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.61(s,1H),8.11(s,1H),8.03(d,J=9.0Hz,1H),7.49(d, J=8.9Hz,1H),7.41(s,5H),7.24(s,1H),5.85(s,2H),4.39(d,J=16.3Hz,1H),3.97(s,3H),3.95 (s,3H),3.47(d,J=16.1Hz,1H),3.26–3.15(m,2H),2.81(t,J=13.8Hz,1H),2.34–2.26(m,1H), 2.24–2.16(m,1H),2.02–1.94(m,1H),1.84–1.70(m,2H),1.66–1.58(m,1H),1.48–1.33(m,2H).

[0122] Example 35: Synthesis of (14aR)-3-benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b3)

[0123] According to the synthetic method, the corresponding intermediate B3 was obtained, and compound II-b3 was synthesized through subsequent steps: 40 mg, 18.26%; 1 HNMR(400MHz,DMSO-d6)δ8.71(s,1H),8.65(s,1H),8.07(s,1H),8.04(d,J=9.4Hz,1H),7.46( d,J=8.8Hz,1H),7.39–7.28(m,5H),7.24(s,1H),6.00(s,2H),4.39(d,J=16.5Hz,1H),3.98(s, 3H),3.95(s,3H),3.47(d,J=16.6Hz,1H),3.24–3.16(m,2H),2.85–2.76(m,1H),2.31(s,1H),2 .25–2.17(m,1H),2.01–1.95(m,1H),1.83–1.70(m,2H),1.66–1.58(m,1H),1.47–1.35(m,2H).

[0124] Example 36: Synthesis of (14aR)-3-benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c3)

[0125] According to the synthetic method, the corresponding intermediate C3 was obtained, and compound II-c3 was synthesized through subsequent steps: 70 mg, 32.14%; 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.67 (s, 1H), 8.11 (s, 1H), 8.03 (d, J = 9.0Hz, 1H), 7.48 (d, J=9.1Hz,1H),7.45–7.37(m,5H),7.24(s,1H),5.76(s,2H),4.39(d,J=16.4Hz,1H),3.97(s,3H) ,3.95(s,3H),3.48(d,J=16.5Hz,1H),3.25–3.16(m,2H),2.87–2.76(m,1H),2.31(s,1H),2.25 –2.17(m,1H),2.02–1.94(m,1H),1.85–1.70(m,2H),1.62(d,J=12.0Hz,1H),1.48–1.33(m,2H).

[0126] Example 37: Synthesis of (14aR)-3-(4-methoxy)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a4)

[0127] According to the synthetic method, the corresponding intermediate A4 was obtained, and compound II-a4 was synthesized through subsequent steps: 61 mg, 26.45%; 1 HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.58(s,1H),8.10(s,1H),8.02(d,J=9.0Hz,1H),7.48(d,J=9.1Hz,1 H),7.37(d,J=8.2Hz,2H),7.23(s,1H),6.97(d,J=8.2Hz,2H),5.76(s,2H),4.38(d,J=16.3Hz,1H),3.97(s ,3H),3.95(s,3H),3.75(s,3H),3.46(d,J=16.1Hz,1H),3.24–3.15(m,2H),2.86–2.76(m,1H),2.29(s,1H) ,2.20(t,J=11.7Hz,1H),2.00–1.93(m,1H),1.83–1.69(m,2H),1.61(d,J=12.0Hz,1H),1.48–1.33(m,2H).

[0128] Example 38: Synthesis of (14aR)-3-(4-methoxy)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b4)

[0129] According to the synthetic method, the corresponding intermediate B4 was obtained, and compound II-b4 was synthesized through subsequent steps: 35 mg, 15.14%; 1HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.67(s,1H),8.08(s,1H),8.05(d,J=9.0Hz,2H),7.49(d,J=8.9Hz, 1H),7.28(d,J=7.4Hz,2H),7.25(s,1H),6.92(d,J=6.8Hz,2H),5.91(s,2H),4.39(d,J=16.1Hz,1H),3.98 (s,3H),3.95(s,3H),3.72(s,3H),3.47(d,J=16.1Hz,1H),3.26–3.16(m,2H),2.87–2.77(m,1H),2.35–2. 26(m,1H),2.24–2.16(m,1H),2.02–1.95(m,1H),1.84–1.69(m,2H),1.67–1.56(m,1H),1.47–1.35(m,2H).

[0130] Example 39: Synthesis of (14aR)-3-(4-methoxy)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c4)

[0131] According to the synthetic method, the corresponding intermediate C4 was obtained, and compound II-c4 was synthesized through subsequent steps: 72 mg, 32.33%; 1 HNMR(400MHz,DMSO-d6)δ9.15(s,1H),8.67(s,1H),8.10(s,1H),8.03(d,J=9.0Hz,1H),7.48(d,J=9.5Hz,1 H),7.41(d,J=8.2Hz,2H),7.24(s,1H),6.98(d,J=8.2Hz,2H),5.67(s,2H),4.39(d,J=16.2Hz,1H),3.97(s ,3H),3.95(s,3H),3.76(s,3H),3.47(d,J=16.4Hz,1H),3.24–3.15(m,2H),2.86–2.75(m,1H),2.30(s,1H) ,2.20(t,J=11.6Hz,1H),2.01–1.94(m,1H),1.83–1.70(m,2H),1.62(d,J=11.9Hz,1H),1.49–1.34(m,2H).

[0132] Example 40: Synthesis of (14aR)-3-(4-cyano)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a5)

[0133] According to the synthetic method, the corresponding intermediate A5 was obtained, and compound II-a5 was synthesized through subsequent steps: 62 mg, 27.21%; 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.66(s,1H),8.11(s,1H),8.04(d,J=9.0Hz,1H),7.91(d,J=7.8Hz ,2H),7.55(d,J=7.9Hz,2H),7.50(d,J=8.9Hz,1H),7.25(s,1H),5.99(s,2H),4.40(d,J=16.2Hz,1H),3 .98(s,3H),3.95(s,3H),3.48(d,J=16.5Hz,1H),3.25–3.16(m,2H),2.87–2.77(m,1H),2.32(s,1H),2. 21(t,J=11.5Hz,1H),2.01–1.95(m,1H),1.84–1.69(m,2H),1.62(d,J=12.4Hz,1H),1.47–1.35(m,2H).

[0134] Example 41: Synthesis of (14aR)-3-(4-cyano)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b5)

[0135] According to the synthetic method, the corresponding intermediate B5 was obtained, and compound II-b5 was synthesized through subsequent steps: 40 mg, 17.29%; 1 HNMR(400MHz,DMSO-d6)δ8.75(s,1H),8.64(s,1H),8.05(s,1H),8.03(s,1H),7.85(d,J=7.0Hz,2H) ,7.47(s,1H),7.44(d,J=7.7Hz,2H),7.25(s,1H),6.10(s,2H),4.39(d,J=16.3Hz,1H),3.98(s,3H), 3.95(s,3H),3.47(d,J=16.3Hz,1H),3.24–3.14(m,2H),2.86–2.75(m,1H),2.34–2.28(m,1H),2.20 (t,J=11.8Hz,1H),2.01–1.94(m,1H),1.85–1.70(m,2H),1.62(d,J=12.4Hz,1H),1.49–1.34(m,2H).

[0136] Example 42: Synthesis of (14aR)-3-(4-cyano)benzyl-1H-1,2,3-triazole-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c5)

[0137] According to the synthetic method, the corresponding intermediate C5 was obtained, and compound II-c5 was synthesized through subsequent steps: 54 mg, 23.60%; 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.68(s,1H),8.11(s,1H),8.04(d,J=8.8Hz,1H),7.91(d,J=8.3 Hz,2H),7.57(d,J=7.4Hz,2H),7.49(d,J=8.7Hz,1H),7.25(s,1H),5.88(s,2H),4.40(d,J=15.9Hz,1 H),3.98(s,3H),3.95(s,3H),3.49(d,J=16.3Hz,1H),3.26–3.18(m,2H),2.88–2.78(m,1H),2.33(s, 1H),2.27–2.19(m,1H),2.02–1.94(m,1H),1.85–1.70(m,2H),1.69–1.57(m,1H),1.47–1.35(m,2H).

[0138] Example 43: Synthesis of (14aR)-3-(2,6-dimethyl)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a6)

[0139] According to the synthetic method, the corresponding intermediate A6 was obtained, and compound II-a6 was synthesized through subsequent steps: 94 mg, 40.87%; 1HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.56(s,1H),8.10(s,1H),8.02(d,J=8.8Hz,1H),7.48(d,J=8.8Hz, 1H),7.23(s,1H),7.22–7.17(m,1H),7.13(s,1H),7.11(s,1H),5.85(s,2H),4.39(d,J=16.2Hz,1H),3.98 (s,3H),3.95(s,3H),3.47(d,J=16.1Hz,1H),3.26–3.15(m,2H),2.86–2.75(m,1H),2.45(s,6H),2.30(s, 1H),2.25–2.17(m,1H),2.01–1.94(m,1H),1.85–1.70(m,2H),1.62(d,J=11.2Hz,1H),1.48–1.33(m,2H).

[0140] Example 44: Synthesis of (14aR)-3-(2,6-dimethyl)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b6)

[0141] According to the synthetic method, the corresponding intermediate B6 was obtained, and compound II-b6 was synthesized through subsequent steps: 49 mg, 21.33%; 1 HNMR(400MHz,DMSO-d6)δ8.73(s,1H),8.70(s,1H),8.12(s,1H),8.08(d,J=8.9Hz,1H),7.55(d,J=8.9Hz,1 H),7.26(s,1H),7.20(t,J=7.5Hz,1H),7.12(s,1H),7.10(s,1H),5.93(s,2H),4.41(d,J=16.0Hz,1H),4.00 (s,3H),3.96(s,3H),3.50(d,J=15.8Hz,1H),3.22(d,J=12.0Hz,2H),2.88–2.78(m,1H),2.33(s,1H),2.28( s,6H),2.24–2.18(m,1H),2.03–1.95(m,1H),1.85–1.70(m,2H),1.62(d,J=12.1Hz,1H),1.47–1.35(m,2H).

[0142] Example 45: Synthesis of (14aR)-3-(2,6-dimethyl)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c6)

[0143] According to the synthetic method, the corresponding intermediate C6 was obtained, and compound II-c6 was synthesized through subsequent steps: 60 mg, 25.93%; 1 HNMR(400MHz,DMSO-d6)δ8.90(s,1H),8.66(s,1H),8.10(s,1H),8.03(d,J=8.7Hz,1H),7.47(d,J=8.8Hz,1H) ,7.24(s,1H),7.21(d,J=7.4Hz,1H),7.14(s,1H),7.12(s,1H),5.76(s,2H),4.39(d,J=16.2Hz,2H),3.97(s, 3H),3.95(s,3H),3.48(d,J=17.8Hz,1H),3.27–3.15(m,2H),2.87–2.77(m,1H),2.40(s,6H),2.34–2.27(m,1 H),2.21(t,J=11.5Hz,1H),2.03–1.94(m,1H),1.85–1.69(m,2H),1.62(d,J=10.2Hz,1H),1.48–1.33(m,2H).

[0144] Example 46: Synthesis of (14aR)-3-(3-fluoro)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a7)

[0145] According to the synthetic method, the corresponding intermediate A7 was obtained, and compound II-a7 was synthesized through subsequent steps: 86 mg, 38.10%; 1HNMR(400MHz,DMSO-d6)δ8.68(s,1H),8.63(s,1H),8.10(s,1H),8.01(d,J=8.9Hz,1H),7.53–7 .45(m,2H),7.26–7.19(m,4H),5.89(s,2H),4.36(d,J=15.9Hz,1H),3.98(s,3H),3.94(s,3H), 3.44(d,J=15.6Hz,1H),3.18(t,J=14.5Hz,2H),2.85–2.73(m,1H),2.26(s,1H),2.18(t,J=11. 8Hz,1H),1.95(d,J=10.4Hz,1H),1.83–1.69(m,2H),1.61(d,J=12.0Hz,1H),1.45–1.32(m,2H).

[0146] Example 47: Synthesis of (14aR)-3-(3-fluoro)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b7)

[0147] According to the synthetic method, the corresponding intermediate B7 was obtained, and compound II-b7 (80 mg, 35.40%) was synthesized through subsequent steps. 1 HNMR(400MHz,DMSO-d6)δ8.73(s,1H),8.66(s,1H),8.07(s,1H),8.06(s,1H),7.48(d,J=9.0Hz,1H),7 .45–7.39(m,1H),7.25(s,1H),7.18(d,J=8.7Hz,1H),7.15–7.10(m,2H),6.02(s,2H),4.41(d,J=16.0H z,1H),3.98(s,3H),3.95(s,3H),3.50(d,J=16.5Hz,1H),3.26–3.18(m,2H),2.87–2.76(m,1H),2.33( s,1H),2.27–2.18(m,1H),2.04–1.95(m,1H),1.83–1.70(m,2H),1.68–1.58(m,1H),1.47–1.35(m,2H).

[0148] Example 48: Synthesis of (14aR)-3-(3-fluoro)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c7)

[0149] According to the synthetic method, the corresponding intermediate C7 was obtained, and compound II-c7 was synthesized through subsequent steps: 75 mg, 33.22%; 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.67(s,1H),8.11(s,1H),8.03(d,J=8.9Hz,1H),7.54– 7.43(m,2H),7.33–7.19(m,4H),5.79(s,2H),4.39(d,J=17.1Hz,1H),3.98(s,3H),3.95(s,3 H),3.49(d,J=11.1Hz,1H),3.25–3.16(m,2H),2.87–2.77(m,1H),2.31(s,1H),2.26–2.16(m ,1H),1.98(d,J=10.4Hz,1H),1.84–1.70(m,2H),1.62(d,J=11.8Hz,1H),1.48–1.33(m,2H).

[0150] Example 49: Synthesis of (14aR)-3-(2-fluoro-4-cyano)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a8)

[0151] According to the synthetic method, the corresponding intermediate A8 was obtained, and compound II-a8 was synthesized through subsequent steps: 85 mg, 35.81%; 1 HNMR (400MHz, DMSO-d6) δ8.68(s,1H),8.64(s,1H),8.10(s,1H),8.02(d,J=8.9Hz,1H),7.98(d,J=9.8Hz,1H), 7.80(d,J=7.9Hz,1H),7.66(t,J=7.7Hz,1H),7.49(d,J=8.8Hz,1H),7.23(s,1H),6.02(s,2H),4.38(d,J=16.3 Hz,1H),3.98(s,3H),3.95(s,3H),3.46(d,J=16.7Hz,1H),3.18(d,J=14.9Hz,2H),2.85–2.75(m,1H),2.33–2. 27(m,1H),2.20(t,J=11.5Hz,1H),1.99–1.94(m,1H),1.83–1.70(m,2H),1.68–1.56(m,1H),1.47–1.31(m,2H).

[0152] Example 50: Synthesis of (14aR)-3-(2-fluoro-4-cyano)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b8)

[0153] According to the synthetic method, the corresponding intermediate B8 was obtained, and compound II-b8 was synthesized through subsequent steps: 45 mg, 18.84%; 1 HNMR(400MHz,DMSO-d6)δ8.76(s,1H),8.63(s,1H),8.05(s,1H),8.03(d,J=8.8Hz,1H),7.92(d,J=9.8Hz,1H),7 .71(d,J=8.0Hz,1H),7.46(d,J=8.9Hz,1H),7.33(t,J=7.7Hz,1H),7.23(s,1H),6.14(s,2H),4.37(d,J=16.4Hz ,1H),3.99(s,3H),3.95(s,3H),3.44(d,J=14.9Hz,1H),3.18(t,J=13.3Hz,2H),2.84–2.73(m,1H),2.31–2.24( m,1H),2.18(t,J=11.3Hz,1H),1.98–1.93(m,1H),1.83–1.68(m,2H),1.61(d,J=11.7Hz,1H),1.45–1.32(m,2H).

[0154] Example 51: Synthesis of (14aR)-3-(2-fluoro-4-cyano)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c8)

[0155] According to the synthetic method, the corresponding intermediate C8 was obtained, and compound II-c8 was synthesized through subsequent steps: 39 mg, 16.51%; 1H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.68(s,1H),8.11(s,1H),8.04(d,J=8.9Hz,1H),7.98(d,J=9.9Hz,1H),7 .79(d,J=7.9Hz,1H),7.61(t,J=7.7Hz,1H),7.49(d,J=9.1Hz,1H),7.24(s,1H),5.93(s,2H),4.39(d,J=16.4H z,1H),3.98(s,3H),3.95(s,3H),3.47(d,J=16.3Hz,1H),3.20(d,J=17.2Hz,2H),2.87–2.76(m,1H),2.35–2.2 6(m,1H),2.20(t,J=11.7Hz,1H),2.02–1.95(m,1H),1.84–1.70(m,2H),1.66–1.57(m,1H),1.46–1.32(m,2H).

[0156] Example 52: Synthesis of (14aR)-3-(3,4-dimethoxy)benzyl-2H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-a9)

[0157] According to the synthetic method, the corresponding intermediate A9 was obtained, and compound II-a9 was synthesized through subsequent steps: 65 mg, 26.54%; 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.59(s,1H),8.11(s,1H),8.04(d,J=8.9Hz,1H),7.49(d,J=9.2Hz, 1H),7.24(s,1H),7.07(s,1H),7.01–6.91(m,2H),5.74(s,2H),4.40(d,J=15.8Hz,1H),3.97(s,3H),3.95 (s,3H),3.76(s,3H),3.75(s,3H),3.48(d,J=15.8Hz,1H),3.25–3.17(m,2H),2.87–2.76(m,1H),2.32(s, 1H),2.24–2.16(m,1H),2.03–1.94(m,1H),1.84–1.70(m,2H),1.62(d,J=10.6Hz,1H),1.49–1.33(m,2H).

[0158] Example 53: Synthesis of (14aR)-3-(3,4-dimethoxy)benzyl-1H-1,2,3-triazol-5-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-b9)

[0159] According to the synthetic method, the corresponding intermediate B9 was obtained, and compound II-b9 was synthesized through subsequent steps: 75 mg, 31.01%; 1 HNMR (400MHz, DMSO-d6) δ8.69(s,1H),8.68(s,1H),8.08(s,1H),8.04(d,J=9.0Hz,1H),7.49(d,J=9.1Hz,1H),7. 24(s,1H),6.99(s,1H),6.92(d,J=8.3Hz,1H),6.83(d,J=10.4Hz,1H),5.90(s,2H),4.40(d,J=16.1Hz,1H),3.98( s,3H),3.95(s,3H),3.72(s,3H),3.67(s,3H),3.49(d,J=15.0Hz,1H),3.26–3.15(m,2H),2.86–2.76(m,1H),2.33 (s,1H),2.23(t,J=13.2Hz,1H),2.01–1.94(m,1H),1.84–1.71(m,2H),1.62(d,J=12.2Hz,1H),1.48–1.34(m,2H).

[0160] Example 54: Synthesis of (14aR)-3-(3,4-dimethoxy)benzyl-1H-1,2,3-triazol-4-formyl-6,7-dimethoxy-phenanthrene-[9,10-b]-quinolizidine (II-c9)

[0161] According to the synthetic method, the corresponding intermediate C9 was obtained, and compound II-c9 was synthesized through subsequent steps: 96 mg, 39.64%; 1HNMR(400MHz,DMSO-d6)δ9.15(s,1H),8.66(d,J=2.3Hz,1H),8.10(s,1H),8.03(d,J=9.0Hz,1H),7.48(d,J=8 .1Hz,1H),7.24(s,1H),7.14(s,1H),6.98(s,2H),5.64(s,2H),4.38(d,J=16.1Hz,1H),3.97(s,3H),3.95(s, 3H),3.78(s,3H),3.75(s,3H),3.47(d,J=16.1Hz,1H),3.26–3.14(m,2H),2.87–2.75(m,1H),2.35–2.26(m,1 H),2.25–2.16(m,1H),1.97(d,J=10.5Hz,1H),1.85–1.69(m,2H),1.62(d,J=11.4Hz,1H),1.48–1.33(m,2H).

[0162] Pharmacological activity evaluation

[0163] Test Example 1: Evaluation of the inhibitory activity of the compound on the proliferation of glioblastoma U87MG cells (MTT assay)

[0164] To determine the in vitro antitumor activity of the compounds of the present invention, the compounds prepared in the embodiments of the present invention were tested, and the experimental steps were as follows:

[0165] 1. After digesting U87MG cells in the logarithmic growth phase with trypsin, add them to complete culture medium (DMEM + 10% FBS) to prepare a single-cell suspension. After counting, dilute with culture medium to a cell concentration of 40,000 cells / mL, and then seed them into 96-well plates, adding 100 μL of cell suspension to each well, i.e., 4,000 cells per well.

[0166] 2. After culturing for 12 hours, add the corresponding concentration of drug solution to each well, and add culture medium to a total volume of 200 μL. Incubate at 37°C for 72 hours, then add 20 μL of LTT solution (5 mg / mL) and react in the dark for 4 hours.

[0167] 3. Discard the culture medium, add 100 μL LDMSO to each well, shake well on a shaker, and measure the absorbance (OD value) at 570 nm using a microplate reader. Calculate the inhibition rate using the following formula:

[0168]

[0169] 4. Half-maximal inhibitory concentration (IC50) 50Nonlinear regression in Graphpadprism 9.0 was used for fitting, and each experiment was repeated three times. The results are expressed as Mean ± SD.

[0170] Table 1 - Inhibitory activity of compounds on U87MG cell proliferation

[0171]

[0172] The results show that the compounds have strong in vitro antitumor activity, with 12 compounds exhibiting high IC50 values. 50 At concentrations below 10 nM, it exhibits significant antitumor activity.

[0173] Test Example 2: Evaluation of the inhibitory activity of compounds on the proliferation of drug-resistant glioma-blastoma cells (MTT assay)

[0174] To determine the drug resistance of the 12 compounds with high inhibitory activity against U87MG in Test Example 1, the relevant compounds prepared in the embodiments of the present invention were tested, and the experimental steps were as follows:

[0175] The experimental procedure was the same as in Test Example 1, except that the cell lines were replaced with the primary drug-resistant T98G and the acquired drug-resistant U343 / TMZ and U251 / 251.

[0176] Table 2 - Inhibitory activity of compounds against the proliferation of drug-resistant glioblastoma cells.

[0177]

[0178] The results show that the tested compounds have strong inhibitory activity against the proliferation of all three drug-resistant glioblastoma cell lines.

[0179] Test Example 3: Toxicity of the compound to human gastric mucosal cells GES-1

[0180] To determine the toxicity of the 12 compounds with high inhibitory activity against U87MG in Test Example 1, the relevant compounds prepared in the embodiments of the present invention were tested. The experimental steps were as follows:

[0181] The experimental procedure was the same as in Test Example 1, except that the cell line was changed to GES-1.

[0182] Table 3 - Inhibitory activity (toxicity) of compounds on GES-1 cell proliferation.

[0183]

[0184]

[0185] The results show that the tested compound is far less toxic to the GES-1 cell line than CAT3, and has a higher safety profile.

[0186] In summary, the compounds protected by this invention can effectively inhibit the proliferation of glioblastoma, especially drug-resistant glioblastoma. Compared with CAT3, the compounds protected by this invention have lower toxicity and can be potentially used in clinical treatment.

[0187] In addition to the above-described embodiments, the present invention may have other implementations. All technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope claimed by the present invention.

Claims

1. Compounds having the general formula Ia, Ib or Ic and their respective stereoisomers II-a, II-b or II-c, their racemates or pharmaceutically acceptable salts thereof: in, R1 is selected from unsubstituted or arbitrarily selected by one, two or more R1s. 1a Substituted benzyl; each R 1a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl groups; R2 and R3 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, unsubstituted, or optionally surrounded by one, two, or more R groups. 2a The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy groups; each R 2a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl group.

2. The compound according to claim 1, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R2 and R3 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, unsubstituted, or optionally surrounded by one, two, or more R groups. 2a The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkyl group.

3. The compound according to claim 2, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R2 and R3 may be the same or different, and are independently selected from hydrogen, halogen, hydroxyl, unsubstituted, or optionally surrounded by one, two, or more R groups. 2a The following groups are substituted: C 1-3 Alkyl or C 1-3 Alkyl group.

4. The compound according to any one of claims 1 or 2, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Each R 1a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups; each R 2a They may be the same or different, and are independently selected from CN, hydroxyl, amino, halogen, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 1-3 Alkyl group.

5. The compound according to claim 4, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Each R 1a They are either the same or different, and are independently selected from CN, F, Cl, methyl, methoxy, trifluoromethyl, and trifluoromethoxy. Each R 2a They may be the same or different, and are independently selected from CN, hydroxyl, halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy.

6. The compound according to any one of claims 1-3, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from 4-methoxybenzyl, 4-trifluoromethylbenzyl, 2-fluoro-4-cyanobenzyl, 4-cyanobenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 3,4-dimethoxybenzyl, 2,6-dimethylbenzyl, or benzyl.

7. The compound according to any one of claims 1-3, its racemate, or a pharmaceutically acceptable salt thereof, characterized in that: R2 and R3 may be the same or different, and are independently selected from C. 1-3 Alkyl or C 1-3 Alkyl groups; Preferably, R2 and R3 are the same or different, and are independently selected from methyl or methoxy.

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

9. A pharmaceutical composition, characterized in that, It comprises a therapeutic and / or preventive effective dose of the compound as described in any one of claims 1 to 8, its racemate or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, characterized in that, The dosage form of the pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations, or various microparticle delivery systems.

11. Use of the compound, its racemate, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, or the pharmaceutical composition according to claims 9-10, in the preparation of a medicament for treating and / or preventing tumor diseases.

12. The use according to claim 11, characterized in that, The tumor was selected from glioma; Preferably, the glioma is selected from glioblastoma. Preferably, the glioblastoma is selected from primary drug-resistant glioblastoma and / or acquired drug-resistant glioblastoma.

Images