A rosin acid derivative and its preparation method and application

Abstract

The present invention discloses a rosin acid derivative, a preparation method, and an application thereof. The rosin acid derivative has significant anti-proliferative activity against glioma cells, can achieve a significant anti-glioma proliferation effect at relatively low concentrations, and has good tumor treatment effects. The compound with outstanding activity has low hepatotoxicity and exerts an anti-proliferative effect on glioma cells in a time- and concentration-dependent manner. In addition, the representative rosin acid derivative has a pKa value within the range of 6.2 to 7.2, has good blood-brain barrier permeability, and is conducive to entering the brain to exert its medicinal effect.

Description

Technical Field

[0001] The present invention relates to the fields of natural products and medicinal chemistry, and in particular to a rosin acid derivative and a preparation method and application thereof. Background Art

[0002] Gliomas are malignant brain tumors that typically require a combination of surgical resection, radiotherapy, and chemotherapy. However, current drug treatments still have limitations due to their complex etiology and pathogenesis, the underlying barrier (BBB), BBTB, and increasing drug resistance. In recent years, no new drugs have been marketed for the treatment of gliomas, and most remain in clinical trials. EGFR gene alterations (including mutations, rearrangements, alternative splicing, and focal amplification) are common in 57% of patients with GBM (a common high-grade malignancy among gliomas). While some EGFR inhibitors currently on the market or in clinical trials have shown some efficacy in GBM patients, their therapeutic potential is significantly limited by the low concentrations of drugs that can reach the lesions through the BBB. Chemotherapeutic agents such as temozolomide (TMZ), cisplatin, and carmustine are important adjuvant therapies in clinical practice. Even with standard treatment, almost all GBM patients will experience recurrence. This is because surgeons find it difficult to completely remove highly invasive glioma cells without affecting normal brain function. These cells also have characteristics such as rapid proliferation, resistance to apoptosis, and rapid metastasis. Therefore, postoperative recurrence is one of the biggest challenges in treating GBM. Most GBM patients are insensitive to radiotherapy after recurrence and easily develop resistance to chemotherapy. Due to the drug resistance caused by chemotherapy, the median survival rate of GBM patients is approximately 15 months, and the treatment effect is not ideal. Therefore, it is crucial to design and develop drugs that can penetrate the BBB to reach the tumor site to exert their efficacy and have low toxic side effects on normal cells. How to effectively improve the blood-brain barrier penetration rate of drugs and reduce drug toxicity and side effects have been driving the research and development of new anti-glioma drugs.

[0003] Natural products, with their extensive structural diversity and pleiotropic pharmacological properties, are an important source for the discovery of lead compounds, profoundly impacting drug development. Natural products and their molecular skeletons serve as valuable starting points for drug discovery and can provide innovative insights into new drug development. Numerous studies have shown that rosin acid derivatives possess broad biological activity and exhibit potent antiproliferative activity against various tumor cell types. Furthermore, rosin acid derivatives exhibit good lipid solubility, making them promising candidates for further investigation as lead compounds for the development of anti-glioma drugs. Currently, there is a lack of effective drugs for the treatment of gliomas, and therefore, there remains a need to develop more effective drugs to inhibit gliomas. Summary of the Invention

[0004] To overcome the drawbacks and deficiencies of existing glioma treatment drugs, embodiments of the present invention provide abietic acid derivatives. The natural products abietic acid (AA) and dehydroabietic acid (DHAA) are tricyclic diterpenoid oxygen-containing compounds obtained from rosin or disproportionated rosin and are relatively safe. Based on the structures of abietic acid and dehydroabietic acid, a series of compounds with anti-glioma efficacy have been developed.

[0005] A rosin acid derivative having a structure of Formula I or Formula II:

[0006]

[0007] in,

[0008] R is

[0009] R1 is selected from hydrogen, halogen, methoxy or methyl;

[0010] R2 is selected from hydrogen, halogen, methoxy or methyl;

[0011] R3 is selected from hydrogen, methyl, methoxy or difluoromethoxy.

[0012] Preferably, R is one of the following:

[0013]

[0014]

[0015] For example, the rosin acid derivative has any of the following structures:

[0016]

[0017]

[0018] Preferably, pharmaceutically acceptable salts obtained by reacting the rosin acid derivatives with acids are also within the scope of protection of the present invention, wherein the acid is hydrochloric acid, nitric acid, sulfuric acid, trifluoroacetic acid, phosphoric acid, acetic acid, or carbonic acid.

[0019] Another embodiment of the present invention provides a method for preparing abietic acid derivatives, comprising the following steps:

[0020]

[0021] S1. Using AA as a starting material, an acylation reaction occurs in the presence of an acylating agent and a polar organic solvent to obtain compound 1, which is then reacted with one of the anilinopyrimidine compounds 2a-2h in the presence of an acid-binding agent and a polar organic solvent to produce compounds A1-A8;

[0022]

[0023] S2. Using DHAA as a starting material, an acylation reaction occurs in the presence of an acylating agent and a polar organic solvent to obtain compound 3, which is then reacted with one of the anilinopyrimidine compounds 2a-2h in the presence of an acid-binding agent and a polar organic solvent to produce compounds B1-B8;

[0024]

[0025] S3. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an N-alkylation reaction with an alkaline reagent, a polar organic reagent, and one of aniline compounds 5a-5h to obtain compounds A9-A16;

[0026]

[0027] S4. Using DHAA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 6, which is then subjected to an N-alkylation reaction with an alkaline reagent, a polar organic reagent, and one of aniline compounds 5a-5h to obtain compounds B9-B16;

[0028]

[0029] S5. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and a pyridine compound 7 to obtain compound A17;

[0030]

[0031] S6, using DHAA as a starting material, an alkylation reaction occurs in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 6, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and a pyridine compound 7 to obtain compound B17;

[0032]

[0033] S7. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and benzimidazole compounds 8a-8d to obtain compounds A18-A21;

[0034]

[0035] S8. Using DHAA as the starting material, an alkylation reaction occurs in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and benzimidazole compounds 8a-8d to obtain compounds B18-B21.

[0036] Furthermore, the acylating agent is selected from one or more of oxalyl chloride, thionyl chloride and diphenylcarbamoyl chloride.

[0037] Furthermore, the acid binding agent is selected from one or more of triethylamine, pyridine and N,N-diisopropylethylamine.

[0038] Furthermore, the polar organic solvent is selected from one or more of N,N-dimethylformamide and dichloromethane.

[0039] Furthermore, the alkaline agent is selected from one or more of potassium carbonate, triethylamine and N,N-diisopropylethylamine.

[0040] Preferably, the equivalent ratio of AA or DHAA to the acylating agent is 1:1.5-1.8; and the acylation reaction occurs at a reaction temperature of 0°C to room temperature to produce Compound 1 or Compound 3.

[0041] Preferably, the compound 1 or compound 3 and the compound One of the compounds undergoes an amide condensation reaction, the reaction temperature is room temperature, and the reaction time is 16-18 hours.

[0042] Preferably, the equivalent ratio of AA or DHAA to 1,2-dibromoethane is 1:2-2.5; and the alkylation reaction occurs at room temperature to produce compound 4 or compound 6.

[0043] Another aspect of the embodiments of the present invention further provides the use of the rosin acid derivatives or pharmaceutically acceptable salts thereof in the preparation of anti-glioma drugs.

[0044] Preferably, the cancer includes glioma caused by abnormal expression of epidermal growth factor receptor and / or its mutants.

[0045] In addition, the present invention also claims protection for a pharmaceutical composition comprising one or more of the rosin acid derivatives, their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers and stereoisomers, or their prodrugs.

[0046] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients and / or carriers.

[0047] Preferably, the excipients include at least one of the following substances: solvents, propellants, solubilizers, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-chelating agents, integrators, penetration enhancers, pH regulators, buffers, plasticizers, solubilizers, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, release agents, flocculants and deflocculating agents, filter aids, and release retardants.

[0048] The pharmaceutical composition of the present invention can be prepared into various dosage forms: classified by the dispersion system of the dosage form, specifically, it can be prepared into the following preparations: solution type, colloidal solution type, emulsion type, suspension type, gas dispersion type, microparticle dispersion type, solid dispersion type; classified by the morphology, specifically, it can be prepared into the following dosage forms: liquid dosage forms (such as aromatic water preparations, solutions, injections, mixtures, lotions, liniments, etc.), solid dosage forms (such as powders, pills, tablets, films, etc.), and semi-solid dosage forms (such as ointments, suppositories, pastes, etc.).

[0049] The present invention has the following beneficial effects:

[0050] The present invention provides a rosin acid derivative. Experiments have shown that the rosin acid derivative has significant anti-proliferation effects on glioma cells, can achieve significant anti-glioma proliferation effects at relatively low concentrations, and has good anti-glioma therapeutic effects. In addition, the pKa of the representative rosin acid derivative is within the range of 6.2 to 7.2, has good blood-brain barrier permeability, and is conducive to entering the brain to exert its medicinal effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0052] Figure 1 The cell viability of U87MG cells after being treated with the compound of Example 44 of the present invention at different concentrations and for different time periods.

[0053] Figure 2 This is a pH-VKOH (μL) curve of the compound of Example 45 of the present invention. DETAILED DESCRIPTION

[0054] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0055] Unless otherwise specified, all reagents and materials used in the following examples were commercially available.

[0056] Example 1

[0057] Synthesis of (1R, 4aR, 4bR, 10aR)-7-isopropyl-1, 4a-dimethyl-N-(4-phenylamino)pyrimidin-2-yl)-1, 2, 3, 4, 4a, 4b, 5, 6, 10, 10a-decahydrophenanthrene-1-carboxamide (A1)

[0058] 1. N4-phenylpyrimidine-2,4-diamine (2a)

[0059]

[0060] 4-Amino-6-chloropyrimidine (1 g, 7.72 mmol) and aniline (1.08 g, 11.58 mmol) were weighed and added to isopropanol (10 mL). Two drops of concentrated HCl were then added at room temperature and refluxed at 80°C for 2 h. After completion of the reaction as monitored by thin-layer plate, the reaction was quenched with saturated NaHCO₃, extracted with EAC, and the organic phase was washed with saturated NaCl and dried over anhydrous Na₂SO₄. The concentrated organic mixture was purified by silica gel column chromatography to afford 2a as a white solid in 85% yield.

[0061] 1H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 7.79 (d, J = 5.7Hz, 1H), 7.70 (d, J = 7.4Hz, 2H ),7.31–7.21(m,2H),6.94(t,J=7.3Hz,1H),6.17(s,2H),5.99(d,J=5.7Hz,1H).

[0062] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-N-(4-phenylamino)pyrimidin-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A1)

[0063]

[0064] To a mixed solution of abietic acid (2 g, 6.61 mmol) in dichloromethane (25 mL) was slowly added dropwise oxalyl chloride (1.26 g, 9.92 mmol) in an ice bath, followed by 1-2 drops of N,N-dimethylformamide. The mixture was allowed to react at room temperature in an anhydrous state for 5 h. After 5 h, the solvent was evaporated under reduced pressure to obtain a yellowish-brown oil, which was then added with anhydrous dichloromethane (10 mL) to obtain a yellowish-brown abietic acid chloride for later use. Subsequently, triethylamine (0.57 g, 5.61 mmol) was added to DCM containing the synthesized intermediate 2a (0.615 g, 3.30 mmol). The mixture was reacted at room temperature for 15 min, and then the prepared abietic acid chloride was slowly added dropwise in an ice bath. The mixture was allowed to react at room temperature in an anhydrous state for 16 h. After completion of the reaction as monitored by thin-layer chromatography, the reaction mixture was concentrated, extracted with H2O and EAC, and the organic phase was washed with saturated NaCl and dried over anhydrous Na2SO4. The concentrated organic mixture was then purified by silica gel column chromatography to obtain the final product A1 in a 28% yield, mp: 90.0-91.4°C.

[0065] 1H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.12 (d, J = 5.8Hz, 1H), 7.89 (d, J = 5.0Hz, 2H ),7.28(t,J=7.9Hz,2H),6.98(t,J=7.4Hz,1H),6.50(d,J=5.8Hz,1H),5.72(s,1 H),5.32(d,J=4.5Hz,1H),2.25–2.01(m,4H),1.84(d,J=58.5Hz,6H),1.58(d,J= 12.8Hz, 5H), 1.26 (s, 3H), 0.96 (dd, J=6.8, 1.7Hz, 6H), 0.79 (s, 3H); ESI-MS: m / z calcdfor C30H38N4O[M+H]+:471.30,found 471.5.

[0066] Example 2

[0067] Synthesis of (1R, 4aR, 4bR, 10aR)-N-(4-fluorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A2)

[0068] 1. Synthesis of N4-(4-fluorophenyl)pyrimidine-2,4-diamine (2b)

[0069]

[0070] Compound 2b was prepared by referring to the method for compound 2a to obtain a light yellow solid 2b with a yield of 81%.

[0071] 1H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 7.79 (d, J = 5.7Hz, 1H), 7.72 (dd, J = 9.0, 4.9Hz, 2H), 7.09 (t, J = 8.9Hz, 2H), 6.21 (s, 2H), 5.95 (d, J = 5.7Hz, 1H).

[0072] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-N-(4-fluorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A2)

[0073]

[0074] The synthesis of compound A2 was carried out by referring to the synthesis method of compound A1 to obtain yellow solid compound A2 with a yield of 35% and mp: 114.6-115.5°C.

[0075] 1H NMR (400MHz, DMSO-d6) δ9.62(s,1H),9.57(s,1H),8.12(d,J=5.8Hz,1H),7.93(dd,J=9.1,4.9Hz,2H),7.10(t,J=8.9Hz,2H),6.46(d,J=5.9Hz,1H) ,5.72(s,1H),5.33(d,J=4.9Hz,1H),2.19(td,J=12.7,12.0,5.6Hz,2H), 2.09–1.93(m,4H),1.90–1.68(m,5H),1.59(d,J=26.1Hz,4H),1.26(s,3H ),0.97(dd,J=6.8,1.7Hz,6H),0.79(s,3H);13CNMR(101MHz,DMSO-d6)δ176.55,160.70,157.88,156.17,144.79,136.83,135.49,122.92,121.50 ,121.11,115.70,115.48,102.90,50.64,47.52,44.44,37.44,36.25,34 .74,34.65,27.41,25.33,22.40,21.79,21.53,21.20,17.32,14.41; 19F NMR (376MHz, DMSO-d6) δ-121.10; ESI-MS: m / z calcd for C30H37FN4O[M+H]+: 489.65, found 489.5.

[0076] Example 3

[0077] Synthesis of (1R,4aR,4bR,10aR)-N-(4-chlorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A3)

[0078] 1. Synthesis of N4-(4-chlorophenyl)pyrimidine-2,4-diamine (2c)

[0079]

[0080] Compound 2c was prepared by referring to the method of compound 2a to obtain white solid compound 2c with a yield of 83%.

[0081] 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 7.83 (d, J = 5.7Hz, 1H), 7.78 (d, J = 8.9Hz, 2H), 7.29 (d, J = 8.9Hz, 2H), 6.29 (s, 2H), 5.99 (d, J = 5.7Hz, 1H).

[0082] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-N-(4-chlorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A3)

[0083]

[0084] Compound A3 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A3 with a yield of 31% and mp: 133.8-134.8°C.

[0085] 1H NMR (400MHz, DMSO-d6) δ9.75(s,1H),9.66(s,1H),8.15(d,J=5.8Hz,1H),7.98(d,J =8.9Hz,2H),7.30(d,J=8.8Hz,2H),6.49(d,J=5.8Hz,1H),5.72(s,1H),5.32(d,J= 5.0Hz,1H),2.37–2.11(m,3H),2.05(d,J=18.0Hz,2H),1.96–1.69(m,6H),1.57(d, J=12.7Hz, 4H), 1.26 (s, 3H), 0.97 (dd, J=6.8, 1.8Hz, 6H), 0.79 (s, 3H); ESI-MS: m / z calcdfor C30H37ClN4O[M+H]+:505.27, found 505.4.

[0086] Example 4

[0087] Synthesis of (1R,4aR,4bR,10aR)-N-(4-bromophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A4)

[0088] 1. Synthesis of N4-(4-bromophenyl)pyrimidine-2,4-diamine (2d)

[0089]

[0090] Compound 2d was prepared by referring to the method of compound 2a to obtain yellow solid compound 2d with a yield of 72%.

[0091] 1H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 7.83 (d, J = 5.7Hz, 1H), 7.73 (d, J = 8.9Hz, 2H), 7.41 (d, J = 8.8Hz, 2H), 6.24 (s, 2H), 6.01 (d, J = 5.7Hz, 1H).

[0092] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-N-(4-bromophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A4)

[0093]

[0094] Compound A4 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A4 with a yield of 30% and mp: 120.4-122.6°C.

[0095] 1H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 9.67 (s, 1H), 8.16 (d, J = 5.7Hz, 1H), 7.93 (d ,J=8.9Hz,2H),7.43(d,J=8.7Hz,2H),6.50(d,J=5.8Hz,1H),5.72(s,1H),5.32( d,J=5.0Hz,1H),2.41–2.11(m,3H),2.04(d,J=14.3Hz,2H),1.95–1.72(m,5H),1 .57(d,J=12.4Hz,5H),1.26(s,3H),0.97(dd,J=6.9,1.7Hz,6H),0.79(s,3H); 13C NMR(101MHz,Chloroform-d)δ176.34,161.28,157.25,156.75,145.35,137.29,135.52,132.44,123.54,122.37,120.34,11 7.44,50.97,48.03,45.77,38.16,37.50,34.90,34.75,27.42,25.47,22.50,21.42,20.85,18.35,17.14,14.16; ESI-MS:m / z calcd for C30H37BrN4O[M+H]+:549.22, found 549.3.

[0096] Example 5

[0097] Synthesis of (1R,4aR,4bR,10aR)-N-(4-(4-iodophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A5)

[0098] 1. Synthesis of N4-(4-iodophenyl)pyrimidine-2,4-diamine (2e)

[0099]

[0100] Compound 2e was prepared by referring to the method of compound 2a to obtain yellow solid compound 2e with a yield of 52%.

[0101] 1H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 7.83 (d, J = 5.7Hz, 1H), 7.66–7.46 (m, 4H), 6.25 (s, 2H), 6.01 (d, J = 5.7Hz, 1H).

[0102] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-N-(4-(4-iodophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A5)

[0103]

[0104] Compound A5 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A5 with a yield of 22% and mp: 96.4-98.1°C.

[0105] 1H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 9.67 (s, 1H), 8.16 (d, J = 5.7Hz, 1H), 7.93 (d ,J=8.9Hz,2H),7.43(d,J=8.7Hz,2H),6.50(d,J=5.8Hz,1H),5.72(s,1H),5.32( d,J=5.0Hz,1H),2.41–2.11(m,3H),2.04(d,J=14.3Hz,2H),1.95–1.72(m,5H),1 .57(d,J=12.4Hz,5H),1.26(s,3H),0.97(dd,J=6.9,1.7Hz,6H),0.79(s,3H); 13C NMR(101MHz,Chloroform-d)δ176.34,161.28,157.25,156.75,145.35,137.29,135.52,132.44,123.54,122.37,120.34,11 7.44,50.97,48.03,45.77,38.16,37.50,34.90,34.75,27.42,25.47,22.50,21.42,20.85,18.35,17.14,14.16; ESI-MS:m / z calcd for C30H37BrN4O[M+H]+:549.22, found 549.3.

[0106] Example 6

[0107] Synthesis of (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-N-(4-p-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A6)

[0108] 1. Synthesis of N4-(p-tolyl)pyrimidine-2,4-diamine (2f)

[0109]

[0110] Compound 2f was prepared by referring to the method of compound 2a to obtain white solid compound 2f with a yield of 68%.

[0111] 1H NMR (400MHz, DMSO-d6) δ8.97 (s, 1H), 7.76 (d, J = 5.7Hz, 1H), 7.56 (d, J = 8.2Hz ,2H),7.07(d,J=8.1Hz,2H),6.15(s,2H),5.95(d,J=5.7Hz,1H),2.24(s,3H).

[0112] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-N-(4-p-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A6)

[0113]

[0114] Compound A6 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A6 with a yield of 31% and mp: 107.3-108.9°C.

[0115] 1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.09(d,J=5.8Hz,1H),7.75(d,J=7.8Hz,2H), 7.09(d,J=8.1Hz,2H),6.45(d,J=5.8Hz,1H),5.72(s,1H),5.33(d,J=4.4Hz,1H),2 .25(s,3H),2.17(dt,J=12.5,6.0Hz,2H),2.10–1.90(m,5H),1.87–1.74(m,4H),1. 57(d,J=12.6Hz,4H),1.25(s,3H),0.96(d,J=6.8Hz,6H),0.78(s,3H); ESI-MS:m / z calcdfor C31H40N4O[M+H]+:485.32, found 485.5.

[0116] Example 7

[0117] Synthesis of (1R,4aR,4bR,10aR)-7-isopropyl-N-(4-methoxyphenylamino)pyrimidin-2-yl)-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A7)

[0118] 1. Synthesis of N4-(p-methoxyphenyl)pyrimidine-2,4-diamine (2g)

[0119]

[0120] Compound 2g was synthesized by referring to the synthesis method of compound 2a to obtain 5g of yellow solid compound with a yield of 88%.

[0121] 1H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H), 7.74 (d, J = 5.7Hz, 1H), 7.54 (d, J = 9.0Hz, 2H), 6.92–6.80 (m, 2H), 6.04 (s, 2H), 5.91 (d, J = 5.7Hz, 1H), 3.73 (s, 3H).

[0122] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-7-isopropyl-N-(4-methoxyphenylamino)pyrimidin-2-yl)-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A7)

[0123]

[0124] Compound A7 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A7 with a yield of 15% and mp: 105.4-107.5°C.

[0125] 1H NMR (400MHz, DMSO-d6) δ9.52(s,1H),9.44(s,1H),8.06(d,J=5.9Hz,1H),7.77(d,J=8.0Hz,2H),6.86(d,J=8.9Hz,2H),6.40(d,J=5.9Hz,1H),5.72(s ,1H),5.34(s,1H),3.73(s,3H),2.28–2.01(m,4H),1.99–1.73(m,6H),1.7 2–1.34(m,5H),1.26(s,3H),0.97(dd,J=6.8,1.7Hz,6H),0.79(s,3H); 13C NMR(101MHz,Chloroform-d)δ162.69,157.70,145.21,130.36,125.63,122.43,120.47,114.79,99.05,55.55,50. 91,48.06,45.62,38.07,37.33,34.90,34.74,27.42,25.45,22.50,21.41,20.85,18.38,17.09,14.16; ESI-MS:m / z calcd for C31H40N4O2[M+H]+:501.32, found 501.4.

[0126] Example 8

[0127] Synthesis of (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-N-(m-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A8)

[0128] 1. Synthesis of N4-(m-tolyl)pyrimidine-2,4-diamine (2h)

[0129]

[0130] Compound 2h was synthesized by referring to the synthesis method of compound 2a to obtain yellow solid compound 2h with a yield of 53%.

[0131] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),7.79(d,J=5.7Hz,1H),7.55(d,J=8.2Hz,1H),7.48(s,1H) ,7.14(t,J=7.8Hz,1H),6.76(d,J=7.5Hz,1H),6.21(s,2H),5.99(d,J=5.7Hz,1H),2.29(s,3H).

[0132] 2. Synthesis of (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-N-(m-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxamide (A8)

[0133]

[0134] Compound A8 was synthesized by referring to the synthesis method of Compound A1 to obtain yellow solid Compound A8 with a yield of 33% and mp: 116.-113.0°C.

[0135] 1H NMR (400MHz, DMSO-d6) δ9.64(s,1H),9.53(s,1H),8.11(d,J=5.8Hz,1H),7.93(s,1H),7.54(d ,J=7.9Hz,1H),7.15(t,J=7.9Hz,1H),6.79(d,J=7.5Hz,1H),6.48(d,J=5.9Hz,1H),5.71(s,1 H),5.32(d,J=5.1Hz,1H),2.29(s,3H),2.19(dt,J=12.9,6.3Hz,2H),1.99(s,5H),1.90–1.74 (m,4H),1.58(d,J=13.4Hz,4H),1.26(s,3H),0.96(d,J=6.8Hz,6H),0.79(s,3H); ESI-MS:m / z calcd for C31H40N4O[M+H]+:485.32, found 485.4.

[0136] Example 9

[0137] Synthesis of 2-(phenylamino)ethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A9)

[0138] Synthesis of 2-bromoethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (4)

[0139]

[0140] Abietic acid (2 g, 6.61 mmol) and potassium carbonate (2.74 g, 19.8 mmol) were weighed, and DMF (6 mL) was added, followed by 1,2-dibromoethane (2.48 g, 13.22 mmol). The reaction was allowed to react at room temperature for 13 h. After completion, as monitored by thin-layer chromatography, the reaction was quenched with H₂O, extracted with EAC, and the organic phase was washed with saturated NaCl and dried over anhydrous Na₂SO₄. The concentrated organic mixture was purified by silica gel column chromatography to obtain intermediate 4 as a clear oil in a 35% yield.

[0141] 1H NMR(400MHz,Chloroform-d)δ5.77(s,1H),5.40–5.32(m,1H),4.40–4.28(m,2H),3.49(t,J=6.1Hz,2H),2.22(p,J=6.8Hz,1H),2.1 3–2.04(m,4H),1.98–1.74(m,6H),1.64–1.55(m,4H),1.28(d,J=3.7Hz,3H),1.01(dd,J=6.9,3.4Hz,6H),0.83(s,3H); ESI-MS:m / z calcd for C22H33BrO2[M+H]+:409.17, found 409.2.

[0142] Synthesis of 2-(phenylamino)ethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A9)

[0143]

[0144] Intermediate 4 (1 g, 2.44 mmol) was weighed, along with potassium iodide (0.081 g, 0.488 mmol), potassium carbonate (1.01 g, 7.33 mmol), and aniline (0.27 g, 2.93 mmol). DMF (5 mL) was added and the mixture was allowed to react at 45°C for 13 h. After completion of the reaction as monitored by thin-layer chromatography, the mixture was quenched with H₂O, extracted with EAC, and the organic phase was washed with saturated NaCl and dried over anhydrous Na₂SO₄. The concentrated organic mixture was purified by silica gel column chromatography to afford A9, a pale yellow oil, in a 40% yield.

[0145] 1H NMR (400MHz, DMSO-d6) δ7.10–7.02(m,2H),6.58(d,J=7.9Hz,2H),6.52(t,J=7.2Hz,1H),5.70(s,1H),5 .27(s,1H),4.09(q,J=5.9Hz,2H),3.26(t,J=5.9Hz,2H),2.19(p,J=6.9Hz,1H),2.09–1.98(m,2H),1.9 2(s,1H),1.78(dd,J=19.1,10.7Hz,3H),1.65(dq,J=12.1,5.7,4.6Hz,2H),1.49(d,J=9.1Hz,2H),1.32 13C NMR(101MHz,DMSO-d6)δ178.08,148.95,144.81,135.29,129.35,122.84,120.80,116.32,112.54,63.62,50.73,46 .37,45.14,41.92,38.12,37.01,34.73,34.49,27.31,25.53,22.40,21.79,21.18,18.06,17.20,14.23; ESI-MS:m / z calcd for C28H39NO2[M+H]+:422.30, found 422.4.

[0146] Example 10

[0147] Synthesis of 2-((4-fluorophenyl)amino)ethyl(1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A10)

[0148]

[0149] Compound A10 was synthesized by referring to the synthesis method of compound A9 to obtain yellow oil A10 with a yield of 63%.

[0150] 1H NMR(400MHz,Chloroform-d)δ6.88(t,J=8.7Hz,2H),6.61–6.51(m,2H),5.77(s,1H),5.32(d,J=6.1Hz,1H),4.23(t,J=5.5Hz,2H),3.34(t,J=5.5H z,2H),2.23(p,J=6.9Hz,1H),2.12–2.02(m,4H),1.95–1.69(m,6H),1.66 –1.51(m,4H),1.25(s,3H),1.02(dd,J=6.8,3.5Hz,6H),0.82(s,3H); 13C NMR(101MHz,Chloroform-d)δ145.51,122.33,120.36,115.84,115.62,113.93,113.85,63.13,51.00,46. 75,45.27,43.68,38.31,37.14,34.91,34.56,27.48,25.69,22.49,21.44,20.88,18.11,17.04,14.05; 19F NMR(376MHz,Chloroform-d)δ-25.20,-127.60(tt,J=8.6,4.5Hz); ESI-MS:m / z calcd for C28H38FNO2[M+H]+:440.29,found 440.01.

[0151] Example 11

[0152] Synthesis of 2-(4-chlorophenyl)amino)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A11)

[0153]

[0154] Compound A11 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid compound A11 with a yield of 47% and mp: 77.1-78.6°C.

[0155] 1H NMR(400MHz,Chloroform-d)δ7.12(d,J=8.8Hz,2H),6.55(d,J=8.7Hz,2H),5.77(s,1H),5.32(d,J=2.8Hz,1H),4.23(t,J=5.5Hz,2H),3.36(t,J=5.5Hz, 2H),2.23(p,J=6.6Hz,1H),2.11–2.02(m,4H),1.96–1.70(m,6H),1.62–1.5 4(m,4H),1.25(s,3H),1.02(dd,J=6.8,3.6Hz,6H),0.81(s,3H); ESI-MS:m / z calcd for C28H38ClNO2[M+H]+:456.26,found456.03.

[0156] Example 12

[0157] Synthesis of 2-(4-bromophenyl)amino)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A12)

[0158]

[0159] Compound A12 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid compound A12 with a yield of 50% and mp: 80.4-82.3°C.

[0160] 1H NMR(400MHz,Chloroform-d)δ7.27(d,J=8.7Hz,2H),6.51(d,J=8.6Hz,2H),5.79(s,1H),5.33(s,1H),4.26(t,J=5.6Hz,2H),3.37(t,J=5.6Hz,2H),2 .26(p,J=6.7Hz,1H),2.14–2.02(m,4H),1.97–1.71(m,6H),1.60(d,J=4.2 Hz, 4H), 1.28 (s, 3H), 1.05 (dd, J=6.9, 3.3Hz, 6H), 0.84 (s, 3H); ESI-MS: m / z calcd for C28H38BrNO2[M+H]+:500.21, found 499.93.

[0161] Example 13

[0162] Synthesis of 2-((4-iodophenyl)amino)ethyl(1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A13)

[0163]

[0164] Compound A13 was synthesized by referring to the synthesis method of compound A9 to obtain reddish-brown solid compound A13 with a yield of 23% and mp: 76.7-77.8°C.

[0165] 1H NMR(400MHz,Chloroform-d)δ7.43(d,J=8.5Hz,2H),6.42(d,J=8.5Hz,2H),5.80(s,1H),5.39–5.29(m,1H),4.25(t,J=5.5Hz,2H),3.37(t,J=5.5Hz,2 H),2.26(p,J=6.8Hz,1H),2.15–2.04(m,4H),1.98–1.71(m,6H),1.66–1.54 (m,4H),1.28(s,3H),1.05(dd,J=6.9,3.4Hz,6H),0.84(s,3H); ESI-MS:m / z calcd for C28H38INO2[M+H]+:548.19, found 547.94.

[0166] Example 14

[0167] Synthesis of 2-(p-Tolylamino)ethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A14)

[0168]

[0169] Compound A14 was synthesized by referring to the synthesis method of compound A9 to obtain brown solid compound A14 with a yield of 65% and mp: 60.6-61.9°C.

[0170] 1H NMR (400MHz, Chloroform-d) δ6.99(d,J=8.0Hz,2H),6.55(d,J=8.3Hz,2H),5.78(s,1H),5.34(d,J=6.2Hz,1H),4.23(t,J=5.5Hz,2H),3.36(t,J=5. 6Hz,2H),2.24(s,4H),2.11–2.02(m,4H),1.96–1.72(m,6H),1.66–1.52( m,4H),1.26(s,3H),1.02(dd,J=6.9,3.6Hz,6H),0.82(s,3H); ESI-MS:m / z calcd for C29H41NO2[M+H]+:436.31,found436.03.

[0171] Example 15

[0172] Synthesis of 2-((4-methoxyphenyl)amino)ethyl(1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A15)

[0173]

[0174] Compound A15 was synthesized by referring to the synthesis method of compound A9 to obtain yellow oil A15 with a yield of 46%.

[0175] 1H NMR (400MHz, Chloroform-d) δ6.78(d,J=8.9Hz,2H),6.60(d,J=8.9Hz,2H),5.78(s,1H),5.34(d,J=6.0Hz,1H),4.23(t,J=5.5Hz,2H),3.75(s,3H),3.34(t ,J=5.5Hz,2H),2.23(p,J=6.7Hz,1H),2.12–2.04(m,4H),1.99–1.69(m,6H), 1.68–1.50(m,4H),1.26(s,3H),1.02(dd,J=6.9,3.6Hz,6H),0.83(s,3H); 13C NMR(101MHz,Chloroform-d)δ145.43,141.83,135.64,122.37,120.45,114.96,114.53,63.26,55.82,50.99,46.7 4,45.29,44.01,38.31,37.16,34.91,34.57,27.48,25.70,22.50,21.44,20.88,18.13,17.05,14.06; ESI-MS:m / z calcd for C29H41NO3[M+H]+:452.31, found 452.04.

[0176] Example 16

[0177] Synthesis of 2-(m-tolylamino)ethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A16)

[0178]

[0179] Compound A16 was synthesized by referring to the synthesis method of compound A9 to obtain a transparent oily substance A16 with a yield of 23%.

[0180] 1H NMR(400MHz,Chloroform-d)δ7.08(d,J=7.4Hz,1H),6.55(d,J=7.5Hz,1H),6.44(d,J=2.7Hz,2H) ,5.78(s,1H),5.38–5.30(m,1H),4.24(t,J=5.5Hz,2H),3.37(t,J=5.5Hz,2H),2.27(d,J=4.8Hz,4 H),2.25–2.19(m,1H),2.16–1.99(m,4H),1.91(dd,J=25.3,14.0Hz,2H),1.76(ddd,J=17.2,8.9, 4.4Hz, 3H), 1.64–1.53 (m, 4H), 1.26 (s, 3H), 1.01 (dd, J=6.8, 3.5Hz, 6H), 0.82 (s, 3H); ESI-MS: m / z calcd for C29H41NO2[M+H]+:436.31, found 436.02.

[0181] Example 17

[0182] Synthesis of 2-(pyridine-4-thio)ethyl (1R, 4aR, 4bR, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A17)

[0183]

[0184] Intermediate 4 (1 g, 2.44 mmol), potassium carbonate (1.01 g, 7.33 mmol), and mercaptopyridine (2.71 g, 2.44 mmol) were weighed and added to DMF (5 mL). The reaction was allowed to react at room temperature for 13 h. After completion, as monitored by thin-layer chromatography, the reaction was quenched with H₂O, extracted with EAC, and the organic phase was washed with saturated NaCl and dried over anhydrous Na₂SO₄. The concentrated organic mixture was purified by silica gel column chromatography to obtain the final product A17 as a clear oil in a 55% yield.

[0185] 1H NMR(400MHz,Chloroform-d)δ8.41(d,J=6.3Hz,2H),7.21–7.18(m,2H),5.77(s,1H),5.37–5.32(m,1H),4.31–4.21(m,2H),3.21(t,J=7.0Hz,2H 13C NMR(101MHz,Chloroform-d)δ178.39,149.31,145.52,135.63,122.33,120.77,120.37,62.23,50.91,46.71,4 5.07,38.26,37.09,34.91,34.54,28.99,27.47,25.73,22.47,21.43,20.87,18.08,17.00,14.04; ESI-MS:m / z calcdfor C27H37NO2S[M+H]+:440.25, found 440.01.

[0186] Example 18

[0187] Synthesis of 2-(1H-benzimidazol-2-yl)thio)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A18)

[0188]

[0189] Compound A18 was synthesized by referring to the synthesis method of compound A17 to obtain white solid A18 with a yield of 75% and mp: 66.0-67.9°C.

[0190] 1H NMR (400MHz, Chloroform-d) δ7.52(dd,J=6.0,3.1Hz,2H),7.22–7.17(m,2H),5.77(s,1H),5.38–5.31(m,1H),4.37(tt,J=6.5,3.7Hz,2H),3.47(t,J=6. 6Hz,2H),2.23(hept,J=7.4Hz,1H),2.12–1.99(m,4H),1.99–1.65(m,6H),1 .64–1.44(m,4H),1.24(s,3H),1.01(dd,J=6.9,3.2Hz,6H),0.81(s,3H); 13C NMR(101MHz,Chloroform-d)δ179.10,145.57,122.43,122.36,120.49,62.85,50.88,46.79,45.04,38 .19,37.16,34.92,34.54,30.98,27.45,25.76,22.47,21.43,20.85,18.08,17.00,14.06; ESI-MS:m / z calcd forC29H38N2O2S[M+H]+:479.27, found 479.00.

[0191] Example 19

[0192] Synthesis of 2-(5-methyl-1H-benzimidazol-2-yl)thio)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A19)

[0193]

[0194] Compound A19 was synthesized by referring to the synthesis method of compound A17 to obtain white solid A19 with a yield of 77% and mp: 51.0-52.4°C.

[0195] 1H NMR (400MHz, Chloroform-d) δ7.42 (d, J = 7.7Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8. 1Hz,1H),5.78(s,1H),5.36(s,1H),4.35(t,J=6.5Hz,2H),3.44(t,J=6.5Hz,2H ),2.45(s,3H),2.27–2.20(m,1H),2.07(t,J=9.0Hz,3H),1.95–1.71(m,6H),1. 58(d,J=14.1Hz,4H),1.25(d,J=9.0Hz,4H),1.05–1.00(m,6H),0.82(s,3H); 13C NMR(101MHz,Chloroform-d)δ148.17,145.59,135.72,132.33,123.86,122.35,120.53,62.81,50.88,46.78,45.0 2,38.18,37.16,34.92,34.54,31.14,27.46,25.76,22.48,21.64,21.44,20.87,18.09,17.01,14.08; ESI-MS:m / z calcd for C30H40N2O2S[M+H]+:493.28, found 493.01.

[0196] Example 20

[0197] Synthesis of 2-(5-methoxy-1H-benzimidazol-2-yl)thio)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A20)

[0198]

[0199] Compound A20 was synthesized by referring to the synthesis method of compound A17 to obtain a transparent oily substance A20 with a yield of 80%.

[0200] 1H NMR(400MHz,Chloroform-d)δ7.40(s,1H),7.02(s,1H),6.85(d,J=8.8Hz,1H),5.78(s,1H),5.36(s,1H),4.36(td,J=6.4,2.4Hz,2H),3.8 4(s,3H),3.43(t,J=6.5Hz,2H),2.23(dt,J=13.3,6.7Hz,1H),2.08(d,J=10.2Hz,3H),1.98–1.69(m,6H),1.66–1.50(m,4H),1.25(d,J=9. 7Hz, 4H), 1.02 (dd, J = 6.8, 3.0Hz, 6H), 0.82 (s, 3H); 13CNMR (101MHz, Chloroform-d) δ 179.10, 156.31, 145.57, 135.68, 122.33, 120.52, 62 .82,55.85,50.89,46.78,45.03,38.19,37.18,34.91,34.54,31.33,27.46,25.75,22.47,21.43,20.86,18.09,17.01,14.07; ESI-MS: m / z calcd for C30H40N2O3S[M+H]+:509.28, found 508.97.

[0201] Example 21

[0202] 2-(5-(Difluoromethoxy)-1H-benzimidazol-2-yl)thio)ethyl (1R,4aR,4bR,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxylate (A21)

[0203]

[0204] Compound A21 was synthesized by referring to the synthesis method of compound A17 to obtain A21 as a transparent oil with a yield of 69%.

[0205] 1H NMR(400MHz,Chloroform-d)δ7.47(d,J=8.2Hz,1H),7.31(s,1H),7.02(dd,J=8.6,2.0 Hz,1H),6.50(t,J=74.3Hz,1H),5.78(s,1H),5.36(s,1H),4.37(t,J=6.1Hz,2H),3.45( t,J=6.6Hz,2H),2.23(dt,J=13.2,6.3Hz,1H),2.10–2.04(m,3H),1.98–1.68(m,6H),1 .66–1.51(m,4H),1.25(d,J=11.2Hz,4H),1.02(dd,J=6.8,3.0Hz,6H),0.82(s,3H); 13C NMR(101MHz,Chloroform-d)δ179.34,145.71,135.75,122.29,120.41,116.47,115.42,62.76,50.90,46. 83,45.06,38.18,37.18,34.91,34.55,30.78,27.46,25.77,22.46,21.43,20.86,18.07,17.00,14.06; 19F NMR(376MHz,Chloroform-d)δ-80.12(d,J=3.8Hz),-80.32(d,J=3.8Hz); ESI-MS:m / zcalcd for C30H38F2N2O3S[M+Na]+:567.26, found 567.03.

[0206] Example 22

[0207] Synthesis of (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-N-(4-(phenylamino)pyrimidin-2-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B1)

[0208]

[0209] The synthesis of compound B1 was carried out by referring to the synthesis method of compound A1 to obtain light yellow solid B1 with a yield of 27% and mp: 105.6-106.9°C.

[0210] 1H NMR (400MHz, DMSO-d6) δ9.80(s,1H),9.59(s,1H),8.12(d,J=5.8Hz,1H),7.91(d,J= 7.9Hz,2H),7.28(t,J=7.9Hz,2H),7.19(d,J=8.1Hz,1H),6.98(t,J=7.8Hz,2H),6.86 (s,1H),6.49(d,J=5.8Hz,1H),2.80(dp,J=20.8,6.8Hz,3H),2.28(dd,J=33.6,12.4H z,2H),1.95–1.55(m,7H),1.25(d,J=10.9Hz,6H),1.15(d,J=6.8Hz,6H); ESI-MS:m / z calcd for C30H36N4O[M+H]+:469.29, found 469.05.

[0211] Example 23

[0212] Synthesis of (1R,4aS,10aR)-N-(4-fluorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B2)

[0213]

[0214] The synthesis of compound B2 was carried out by referring to the synthesis method of compound A1 to obtain light yellow solid B2 with a yield of 36% and mp: 100.3-102.7°C.

[0215] 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 9.64 (s, 1H), 8.12 (d, J = 5.7Hz, 1H), 7.96 (dd ,J=9.0,5.0Hz,2H),7.19(d,J=8.1Hz,1H),7.11(t,J=8.8Hz,2H),6.99(d,J=8.0Hz ,1H),6.86(s,1H),6.46(d,J=5.8Hz,1H),2.80(ddt,J=20.5,13.5,6.8Hz,3H),2.2 8(dd,J=33.8,12.4Hz,2H),2.03–1.51(m,7H),1.26(s,3H),1.20–1.12(m,9H); 13C NMR(101MHz,Chloroform-d)δ176.43,157.38,156.79,146.80,145.84,134.67,126.94,125.00,124.92,124.09,123 19F NMR(376MHz,Chloroform-d)δ-116.52; ESI-MS:m / zcalcd for C31H38N4O[M+H]+:483.30, found 487.4.

[0216] Example 24

[0217] Synthesis of (1R,4aS,10aR)-N-(4-chlorophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B3)

[0218]

[0219] The synthesis of compound B3 was carried out by referring to the synthesis method of compound A1 to obtain white solid B3 with a yield of 35% and mp: 107.2-108.7°C.

[0220] 1H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 9.72 (s, 1H), 8.15 (d, J = 5.7Hz, 1H), 7.99 (d ,J=9.0Hz,2H),7.30(d,J=8.9Hz,2H),7.19(d,J=8.2Hz,1H),6.98(d,J=8.2Hz,1H ),6.86(s,1H),6.49(d,J=5.8Hz,1H),2.79(qt,J=13.4,6.8Hz,3H),2.28(dd,J=3 2.7,12.4Hz,2H),1.90–1.41(m,7H),1.26(s,3H),1.19–1.11(m,9H); ESI-MS:m / z calcd forC30H35ClN4O[M+H]+:503.25, found 503.4.

[0221] Example 25

[0222] Synthesis of (1R,4aS,10aR)-N-(4-bromophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B4)

[0223]

[0224] Compound B4 was synthesized by referring to the synthesis method of compound A1 to obtain light yellow solid B4 with a yield of 36% and mp: 115.6-116°C.

[0225] 1H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 9.75 (s, 1H), 8.15 (d, J = 5.7Hz, 1H), 7.94 (d ,J=8.6Hz,2H),7.43(d,J=8.8Hz,2H),7.19(d,J=8.2Hz,1H),6.98(d,J=8.1Hz,1H ),6.86(s,1H),6.49(d,J=5.8Hz,1H),2.77(dq,J=21.1,7.2,6.7Hz,2H),2.36–2 .20(m,2H),1.85–1.44(m,8H),1.33–1.20(m,6H),1.17–1.14(m,6H); ESI-MS:m / z calcd forC30H35BrN4O[M+H]+:547.20, found 547.4.

[0226] Example 26

[0227] Synthesis of (1R,4aS,10aR)-N-(4-(4-iodophenylamino)pyrimidin-2-yl)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B5)

[0228]

[0229] Compound B5 was synthesized by referring to the synthesis method of compound A1 to obtain light yellow solid B5 with a yield of 18% and mp: 115.4-117.2°C.

[0230] 1H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 9.70 (s, 1H), 8.15 (d, J = 5.8Hz, 1H), 7.80 (d, J = 8.9Hz ,2H),7.58(d,J=8.8Hz,2H),7.19(d,J=8.2Hz,1H),6.99(d,J=8.1Hz,1H),6.86(s,1H),6.4 9(d,J=5.8Hz,1H),2.80(ddt,J=20.5,13.8,6.8Hz,3H),2.28(dd,J=29.6,12.3Hz,2H),1. 94–1.71(m,3H),1.68–1.42(m,4H),1.25(d,J=11.2Hz,6H),1.17–1.15(m,6H); ESI-MS:m / z calcd for C30H35IN4O[M+H]+:595.19, found 594.79.

[0231] Example 27

[0232] Synthesis of (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-N-(4-p-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B6)

[0233]

[0234] Compound B6 was synthesized by referring to the synthesis method of compound A1 to obtain light yellow solid B6 with a yield of 25% and mp: 99.3-100.7°C.

[0235] 1H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 9.49 (s, 1H), 8.09 (d, J = 5.8Hz, 1H), 7.77 (d, J=7.5Hz,2H),7.19(d,J=8.2Hz,1H),7.10(d,J=8.0Hz,2H),6.99(d,J=8.0Hz,1H), 6.86(s,1H),6.45(d,J=5.8Hz,1H),2.86–2.74(m,3H),2.28(d,J=15.0Hz,5H),2.0 7–1.96(m,1H),1.80–1.58(m,6H),1.26(s,3H),1.16(d,J=6.8Hz,9H); ESI-MS:m / z calcd forC31H38N4O[M+H]+:483.30, found 483.4.

[0236] Example 28

[0237] Synthesis of (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-N-(4-p-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B7)

[0238]

[0239] The synthesis of compound B7 was carried out by referring to the synthesis method of compound A1 to obtain yellow solid B7 with a yield of 15% and mp: 112.4-114.7°C.

[0240] 1H NMR (400MHz, DMSO-d6) δ9.72(s,1H),9.43(s,1H),8.06(d,J=5.8Hz,1H),7.78(d,J= 8.5Hz,2H),7.19(d,J=8.2Hz,1H),6.98(d,J=10.0Hz,1H),6.86(d,J=9.0Hz,3H),6. 40(d,J=5.9Hz,1H),3.73(s,3H),2.80(tq,J=13.9,6.7Hz,3H),2.27(dd,J=28.7,11 .4Hz,2H),1.89–1.65(m,4H),1.60–1.44(m,3H),1.26(s,3H),1.18–1.13(m,9H).13C NMR(101MHz,Chloroform-d)δ176.43,157.38,156.79,146.80,145.84,134.67,126.94,125.00,124.92,124.09,123.97, 116.45,116.22,99.53,48.90,45.30,37.82,37.19,37.15,33.48,29.93,25.27,24.00,21.39,18.77,16.68; ESI-MS:m / z calcd forC31H38N4O2[M+H]+:499.30, found 499.03.

[0241] Example 29

[0242] Synthesis of (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-N-(4-m-tolylamino)pyrimidin-2-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide (B8)

[0243]

[0244] The synthesis of compound B8 was carried out by referring to the synthesis method of compound A1 to obtain white solid B8 with a yield of 33% and mp: 106.9-109.3°C.

[0245] 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 9.52 (s, 1H), 8.11 (d, J = 5.8Hz, 1H), 7.9 9(s,1H),7.55(d,J=10.1Hz,1H),7.17(dd,J=17.2,8.0Hz,2H),6.99(d,J=8.1 Hz,1H),6.86(s,1H),6.80(d,J=7.5Hz,1H),6.48(d,J=5.8Hz,1H),2.88–2.7 0(m,3H),2.31(s,5H),1.91–1.49(m,7H),1.27(s,3H),1.19–1.13(m,9H); 13C NMR(101MHz,Chloroform-d)δ161.85,157.01,145.82,139.59,134.71,129.31,126.95,126.03,124.09,123.95,123.33 ,119.68,99.68,48.85,45.34,37.86,37.28,37.16,33.48,29.95,25.30,24.00,21.45,21.40,18.78,16.72; ESI-MS: m / z calcd for C31H38N4O[M+H]+:483.30, found 483.4.

[0246] Example 30

[0247] Synthesis of 2-(phenylamino)ethyl (1R, 4aS, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B9)

[0248] Synthesis of 2-bromoethyl (1R, 4aS, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (6)

[0249]

[0250] The synthesis of compound 6 was carried out by referring to the synthesis method of compound 4 to obtain a transparent oily substance 6 with a yield of 26%.

[0251] 1H NMR(400MHz,Chloroform-d)δ7.19(d,J=8.1Hz,1H),7.03(d,J=8.1Hz,1H),6.91(s,1H),4.40(ddt,J=41.9,11.9,5.9Hz,2H),3.52(t,J=5 .8Hz,2H),3.03–2.78(m,3H),2.37–2.25(m,2H),1.93–1.62(m,6H),1.49–1.42(m,1H),1.31(s,3H),1.25(s,3H),1.23(s,6H); ESI-MS: m / z calcd for C22H31BrO2[M+H]+:407.15, found 406.87.

[0252] Synthesis of 2-(phenylamino)ethyl (1R, 4aS, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B9)

[0253]

[0254] Compound B9 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid B9 with a yield of 45% and mp: 102.7-104.6°C.

[0255] 1H NMR(400MHz,Chloroform-d)δ7.21–7.11(m,3H),7.00(dd,J=8.2,2.1Hz,1H),6.87(s,1H),6.71(t ,J=7.3Hz,1H),6.61(dd,J=8.7,1.1Hz,2H),4.39–4.18(m,2H),3.39(t,J=5.5Hz,2H),2.91–2.73( m,3H),2.30(dd,J=13.6,2.5Hz,1H),2.24(dd,J=12.5,2.2Hz,1H),1.88–1.68(m,4H),1.63(dd,J= 6.7, 2.3Hz, 1H), 1.51 (dd, J=12.6, 4.0Hz, 1H), 1.43–1.36 (m, 1H), 1.29–1.19 (m, 12H); ESI-MS: m / z calcd for C28H37NO2[M+H]+:420.28, found 419.99.

[0256] Example 31

[0257] Synthesis of 2-(4-fluorophenyl)amino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B10)

[0258]

[0259] Compound B10 was synthesized by referring to the synthesis method of compound A9 to obtain yellow solid B10 with a yield of 47% and mp: 88.6-90.9°C.

[0260] 1H NMR (400MHz, DMSO-d6) δ7.15(d,J=8.0Hz,1H),6.97(d,J=8.2Hz,1H),6.82(d,J =6.9Hz,3H),6.57(dd,J=6.1,3.4Hz,2H),4.12(dp,J=22.7,5.9Hz,2H),3.26(d, J=6.1Hz,2H),2.83–2.67(m,3H),2.28(d,J=12.9Hz,1H),2.06(d,J=12.2Hz,1H) ,1.88–1.43(m,7H),1.28(d,J=14.0Hz,3H),1.19–1.15(m,6H),1.12(s,3H); 13C NMR(101MHz,Chloroform-d)δ178.70,146.82,134.54,126.93,124.18,124.02,115.87,115.65,113.87,113 19F NMR (376MHz, Chloroform-d) δ-127.49; ESI-MS: m / z calcd forC28H36FNO2[M+H]+: 438.27, found438.08.

[0261] Example 32

[0262] Synthesis of 2-((4-chlorophenyl)amino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B11)

[0263]

[0264] The synthesis of compound B11 was carried out by referring to the synthesis method of compound A9 to obtain yellow solid B11 with a yield of 55% and mp: 86.3-88.6°C.

[0265] 1H NMR(400MHz,Chloroform-d)δ7.16(d,J=8.2Hz,1H),7.12–7.07(m,2H),7.01(dd,J=8.2,2.1Hz,1H),6.86(d ,J=2.0Hz,1H),6.57–6.49(m,2H),4.27(ddt,J=36.3,11.2,5.5Hz,2H),3.35(t,J=5.5Hz,2H),2.82(q,J=9.0 ,7.9Hz,3H),2.30(dt,J=10.8,2.3Hz,1H),2.22(dd,J=12.5,2.2Hz,1H),1.88–1.79(m,1H),1.78–1.72(m,2H ),1.71–1.60(m,2H),1.52–1.44(m,1H),1.37(ddt,J=13.0,5.6,2.5Hz,1H),1.28–1.19(m,12H); ESI-MS:m / z calcd for C28H36ClNO2[M+H]+:454.24, found 453.97.

[0266] Example 33

[0267] Synthesis of 2-((4-bromophenyl)amino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B12)

[0268]

[0269] Compound B12 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid B12 with a yield of 33% and mp: 78.6-80.2°C.

[0270] 1H NMR(400MHz,Chloroform-d)δ7.23(d,J=8.7Hz,2H),7.17(d,J=8.1Hz,1H),7.01( d,J=10.1Hz,1H),6.87(s,1H),6.48(d,J=8.7Hz,2H),4.27(ddt,J=37.5,11.2,5.4 Hz,2H),3.35(t,J=5.5Hz,2H),2.89–2.76(m,3H),2.26(dd,J=30.7,12.4Hz,2H), 1.88–1.65(m,5H),1.55–1.39(m,2H),1.27(s,3H),1.24–1.19(m,9H); ESI-MS:m / z calcdfor C28H36BrNO2[M+H]+:498.19, found 499.93.

[0271] Example 34

[0272] Synthesis of 2-((4-iodophenyl)amino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B13)

[0273]

[0274] Compound B13 was synthesized by referring to the synthesis method of compound A9 to obtain yellow oil B13 with a yield of 35%.

[0275] 1H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.7Hz,2H),7.16(d,J=8.2Hz,1H),7.01(dd,J=8.1,2. 1Hz,1H),6.87(s,1H),6.42–6.35(m,2H),4.26(ddt,J=36.2,11.2,5.5Hz,2H),3.34(t,J=5.5H z,2H),2.90–2.72(m,3H),2.34–2.16(m,2H),1.87–1.78(m,1H),1.77–1.66(m,3H),1.65–1.60 (m,1H),1.48(td,J=13.0,12.1,3.8Hz,1H),1.39–1.33(m,1H),1.27–1.19(m,12H); ESI-MS:m / z calcd for C28H36INO2[M+H]+:546.18,found545.88.

[0276] Example 35

[0277] Synthesis of 2-(p-Tolylamino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B14)

[0278]

[0279] Compound B14 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid B14 with a yield of 50% and mp: 60.5-62.8°C.

[0280] 1H NMR(400MHz,Chloroform-d)δ7.16(d,J=8.1Hz,1H),7.03–6.94(m,3H),6.87(d, J=2.0Hz,1H),6.60–6.50(m,2H),4.37–4.16(m,2H),3.36(t,J=5.5Hz,2H),2.89 –2.76(m,3H),2.36–2.18(m,5H),1.88–1.79(m,1H),1.78–1.67(m,3H),1.66–1. 61(m,1H),1.53–1.45(m,1H),1.43–1.37(m,1H),1.28–1.19(m,12H); ESI-MS:m / z calcd for C29H39NO2[M+H]+:434.30, found 434.08.

[0281] Example 36

[0282] Synthesis of 2-((4-methoxyphenyl)amino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B15)

[0283]

[0284] Compound 152 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid B15 with a yield of 52% and mp: 56.7-58.8°C.

[0285] 1H NMR(400MHz,Chloroform-d)δ7.17(d,J=8.1Hz,1H),7.00(d,J=8.1Hz,1H),6.87(s ,1H),6.77(d,J=8.8Hz,2H),6.59(d,J=6.6Hz,2H),4.26(ddt,J=33.8,11.2,5.5Hz ,2H),3.74(s,3H),3.34(t,J=5.5Hz,2H),2.88–2.76(m,3H),2.27(dd,J=25.8,12. 3Hz,2H),1.90–1.67(m,5H),1.52–1.38(m,2H),1.27(s,3H),1.24–1.19(m,9H); 13C NMR(101MHz,Chloroform-d)δ178.65,145.80,141.65,134.59,126.95,124.19,123.99,114.97,114.48,63.30, 55.82,47.78,44.93,44.12,37.97,36.96,36.65,33.48,30.09,25.17,24.01,21.77,18.59,16.56; ESI-MS:m / z calcd for C29H39NO3[M+H]+:450.29, found 450.05.

[0286] Example 37

[0287] Synthesis of 2-(m-Tolylamino)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B16)

[0288]

[0289] Compound B12 was synthesized by referring to the synthesis method of compound A9 to obtain light yellow solid B16 with a yield of 55% and mp: 86.5-88.5°C.

[0290] 1H NMR (400MHz, Chloroform-d) δ7.17(d,J=8.2Hz,1H),7.05(t,J=8.0Hz,1H),7.00(dd,J=8.2,2. 0Hz,1H),6.87(s,1H),6.54(d,J=8.9Hz,1H),6.43(d,J=7.8Hz,2H),3.37(t,J=5.5Hz,2H),2.87 –2.78(m,3H),2.32–2.22(m,5H),1.82(ddd,J=12.5,9.4,4.0Hz,1H),1.78–1.68(m,3H),1.66– 1.61(m,1H),1.53–1.45(m,1H),1.43–1.36(m,1H),1.28(s,3H),1.24–1.20(m,9H); ESI-MS:m / z calcd for C29H39NO2[M+H]+:434.30,found436.08.

[0291] Example 38

[0292] Synthesis of 2-(pyridine-4-thio)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B17)

[0293]

[0294] Compound B17 was synthesized by referring to the synthesis method of compound A17 to obtain white solid B17 with a yield of 59% and mp: 80.5-82.3°C.

[0295] 1H NMR(400MHz,Chloroform-d)δ8.36(d,J=5.6Hz,2H),7.20–7.13(m,3H),7.01(d, J=8.1Hz,1H),6.89(s,1H),4.39–4.22(m,2H),3.21(td,J=6.9,3.7Hz,2H),2.93 –2.79(m,3H),2.29(d,J=12.1Hz,1H),2.20(d,J=12.5Hz,1H),1.82(ddd,J=30.5 ,14.8,7.0Hz,2H),1.74–1.61(m,3H),1.47–1.38(m,2H),1.28–1.20(m,12H); 13C NMR(101MHz,Chloroform-d)δ178.42,149.38,147.98,146.79,145.84,134.55,126.91,124.23,124.04,120.72 ,62.28,47.78,44.71,37.88,36.91,36.49,33.49,30.04,29.06,25.16,24.03,21.80,18.54,16.49; ESI-MS:m / z calcd for C27H35NO2S[M+H]+:438.24, found 437.95.

[0296] Example 39

[0297] Synthesis of 2-(1H-benzimidazol-2-yl)thio)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B18)

[0298]

[0299] Compound B18 was synthesized by referring to the synthesis method of compound A18 to obtain white solid B18 with a yield of 69% and mp: 73.2-74.2°C.

[0300] 1H NMR(400MHz,Chloroform-d)δ7.49(s,2H),7.23–7.14(m,3H),7.02(d,J=8.1Hz,1H ),6.88(s,1H),4.41(tt,J=11.6,5.9Hz,2H),3.48(td,J=6.4,2.2Hz,2H),2.88(ddt ,J=28.1,13.7,6.5Hz,3H),2.33–2.19(m,2H),1.80(ddd,J=31.5,15.3,7.8Hz,3H), 1.65(dd,J=16.1,5.5Hz,2H),1.44(dd,J=13.0,6.9Hz,2H),1.28–1.20(m,12H); 13C NMR(101MHz,Chloroform-d)δ179.16,148.91,146.83,145.86,134.63,126.93,124.28,124.03,122.47,63. 03,47.85,44.80,37.85,36.94,36.59,33.50,31.08,30.08,25.19,24.03,21.82,18.53,16.49; ESI-MS:m / z calcd for C29H36N2O2S[M+H]+:477.25,found476.98.

[0301] Example 40

[0302] Synthesis of 2-(5-methyl-1H-benzimidazol-2-yl)thio)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B19)

[0303]

[0304] Compound B19 was synthesized by referring to the synthesis method of compound A18 to obtain white solid B19 with a yield of 65% and mp: 71.7-72.6°C.

[0305] 1H NMR(400MHz,Chloroform-d)δ7.48–7.34(m,1H),7.29(s,1H),7.16(d,J=8.2Hz,1 H),7.02(d,J=8.1Hz,2H),6.88(s,1H),4.48–4.33(m,2H),3.45(td,J=6.4,2.3Hz, 2H),2.85(dh,J=20.5,6.9Hz,3H),2.44(s,3H),2.25(t,J=13.8Hz,2H),1.90–1.7 3(m,3H),1.69–1.61(m,2H),1.44(dd,J=13.1,6.7Hz,2H),1.28–1.20(m,12H); 13C NMR(101MHz,Chloroform-d)δ179.15,146.84,145.84,134.64,132.34,126.94,124.26,124.02,123.88,63.03, 47.85,44.79,37.85,36.94,36.59,33.50,31.24,30.08,25.19,24.02,21.81,21.64,18.54,16.49; ESI-MS:m / z calcd for C30H38N2O2S[M+H]+:491.27, found 490.96.

[0306] Example 41

[0307] Synthesis of 2-((5-methoxy-1H-benzimidazol-2-yl)thio)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B20)

[0308]

[0309] Compound B20 was synthesized by referring to the synthesis method of compound A18 to obtain white solid B20 with a yield of 66% and mp: 63.2-65.2°C.

[0310] 1H NMR(400MHz,Chloroform-d)δ7.38(d,J=7.4Hz,1H),7.17(d,J=8.1Hz,1H),7.06–6.92(m,2H),6.89(s,1H),6.84(d,J=8.8Hz,1H),4.39(tq,J=11 .8,6.4Hz,2H),3.83(s,3H),3.43(h,J=7.7,6.1Hz,2H),2.88(dqt,J=20 .6,13.7,7.1Hz,3H),2.26(t,J=13.8Hz,2H),1.90–1.73(m,3H),1.69–1. 62(m,2H),1.45(dd,J=12.3,7.3Hz,2H),1.28–1.20(m,12H);13CNMR(101MHz,Chloroform-d)δ179.17,156.34,146.84,145.86,134.64,126.93, 124.27,124.02,111.78,62.98,55.85,47.86,44.80,37.86,36.94,36. 60,33.49,31.48,30.07,25.18,24.02,21.81,18.54,16.49; ESI-MS:m / z calcd for C30H38N2O3S[M+H]+:507.26, found 506.98.

[0311] Example 42

[0312] Synthesis of 2-((5-(difluoromethoxy)-1H-benzimidazol-2-yl)thio)ethyl (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (B21)

[0313]

[0314] Compound B21 was synthesized by referring to the synthesis method of compound A18 to obtain white solid B21 with a yield of 68% and mp: 59.3-62.9°C.

[0315] 1H NMR(400MHz,Chloroform-d)δ7.42(s,1H),7.27(s,1H),7.16(d,J=8.2Hz,1H),7.02(td,J=8.5,7.9,2.1Hz,2H),6.89(d,J=2.0Hz,1H),6.49(t,J=74.3Hz, 1H),4.40(hept,J=6.3,5.7Hz,2H),3.56–3.38(m,2H),2.99–2.78(m,3H),2. 31–2.18(m,2H),1.91–1.73(m,3H),1.69–1.62(m,2H),1.47–1.36(m,2H); 13C NMR(101MHz,Chloroform-d)δ179.32,146.81,145.91,134.57,126.91,124.30,124.07,115.46,62.97,47.89,44.81,37.83,36. 92,36.57,33.50,30.93,30.06,25.15,24.02,21.82,18.51,16.47; 19FNMR (376MHz, Chloroform-d)δ-80.13,-80.33; ESI-MS: m / z calcd for C30H36F2N2O3S[M+H]+:543.24, found 542.95.

[0316] Example 43

[0317] Determination of the antiproliferative activity of compounds on glioma cells

[0318] Experimental methods:

[0319] The CCK-8 assay was used to investigate the antiproliferative activity of rosin acid derivatives A1-A21 and B1-B21 against human astrocytic glioblastoma U87MG cells, as well as the toxicity of the more active derivatives against the normal hepatocyte L-02 cell line. The CCK-8 assay (Cell Counting Kit-8) is currently one of the most common standard methods for assessing cell proliferation and toxicity in vitro. Temozolomide (TMZ) was used as a positive control, and the half-maximal inhibitory concentrations (IC50) of the various compounds on human glioma cells were determined. The results are shown in Table 1.

[0320] Table 1 Antiproliferative activity of target compounds against U87MG cells (IC50, μM)

[0321]

[0322]

[0323] As shown in the table, among the 28 diterpene derivatives of rosin with detected activity, 27 compounds had better in vitro anti-proliferative activity (32 μM < IC50 < 808 μM) against U87MG cells than the positive control TMZ (IC50 = 937.2 μM). Generally, the anti-proliferative activity of the B series of dehydroabietic acid derivatives was higher than that of the A series of abietic acid derivatives. The final products obtained by condensing the primary amine of the N4-phenylpyrimidine-2,4-diamine intermediate with the carboxyl amide at the C18 position of the parent nucleus had a significant inhibitory effect on the proliferation of U87MG cells (50 μM < IC50 < 181 μM). The alkyl side chain derivatives obtained by esterification and N-alkylation of the abietic acid parent nucleus with the benzene ring had poor anti-proliferative activity (IC50 values were all greater than 170 μM), while the alkyl side chain derivatives obtained by esterification and S-alkylation of the abietic acid parent nucleus with pyridine and benzimidazole had better anti-proliferative activity (32 μM < IC50 < 268 μM). The intermediate rosin alkyl bromides 4 and 6 also showed certain anti-proliferative activity against U87MG.

[0324] Among these detected compounds, the activities of B3, B8, B17, B19, and B21 were relatively prominent, with IC50 values between 32 μM and 72 μM. Among them, the compound B21 with an IC50 value of 32.87 μM had the best activity. In order to screen out anti-glioma drugs with high efficiency and low toxicity, this study continued to further study the representative compounds with prominent activities and detected their cytotoxicity to human normal liver cells L-02. The experimental results are shown in Table 2.

[0325] Table 2 Toxicity of B3, B8, B17, B19, B21 to normal liver cells (IC50, μM)

[0326]

[0327]

[0328] According to Table 2, it was significantly found that B19 and B21 showed higher safety, while B3, B8, and B17 might damage normal liver cells while exerting anti-glioma efficacy.

[0329] Example 44

[0330] Time-dependent and concentration-dependent study of the representative compound B21 on U87MG

[0331] Experimental method: U87MG cells were treated with different concentrations of compound B21 for 24 h, 48 h, and 72 h respectively, and then the cell viability was detected by the CCK-8 method. The time-dependent and concentration-dependent effects on U87MG are as Figure 1 shown.

[0332] According to Figure 1 , it is shown that the inhibitory effect of compound B21 on the proliferation of U87MG cells shows a certain concentration-dependence and time-dependence.

[0333] Example 45

[0334] Determination of pKa values of representative compounds

[0335] Experimental method: Prepare stock solutions of representative compounds (acetonitrile, 1 mM, 5 mL), acetonitrile aqueous solution (Vacetonitrile: Vwater = 3:7, 50 mL), KCl solution (water, 0.15 M, 10 mL), KOH solution (Vacetonitrile: Vwater = 3:7, 60 mM, 10 mL), and HCl solution (Vacetonitrile: Vwater = 3:7, 100 mM, 10 mL) for standby; Add 10 mL of the prepared acetonitrile aqueous solution to a 15 mL beaker, measure its pH using a pH meter, and record the value after the reading stabilizes; Add 1 mL of the stock solution to this solution, measure and record the pH, and soak the probe in absolute ethanol for 30 min; Take another 10 mL of acetonitrile aqueous solution into a 25 mL beaker, measure its pH value, add 1 mL of KCl solution, stir well, and then measure the pH; Adjust the pH to 2.0 using 100 mM HCl solution, add 1 mL of the stock solution, wait until the solution is stirred well, and then slowly titrate the above solution with 60 mM KOH solution, recording the change in pH value; The experimental data is processed and the pH-VKOH is plotted using Origin2022 software. Representative compounds B3, B8, B17, B19, and B21 are used for testing, and the results of the other compounds are similar.

[0336] The results are shown in Table 3 and Figure 2 , it can be seen that the pKa values of representative compounds B3, B8, B17, B19, and B21 are 6.24 - 7.06, all within the ideal parameter range. According to Lipinski's five rules, the pKa of small molecule compounds that can improve BBB permeability needs to be within the range of 6 < pKa < 10.5, and the possibility of compounds with pKa < 8 becoming substrates of P-glycoprotein (P-gp) is extremely small, indicating that these target compounds may have good blood-brain barrier permeability to enter the brain and exert their pharmacological effects.

[0337] Table 3 pKa of representative compounds

[0338]

[0339] The specific embodiments described above further elaborate on the purpose, technical solutions, and beneficial effects of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A rosin acid derivative, characterized in that: The rosin acid derivatives have a structure of Formula I or Formula II: in, R is R1 is selected from hydrogen, halogen, methoxy or methyl; R2 is selected from hydrogen, halogen, methoxy or methyl; R3 is selected from hydrogen, methyl, methoxy or difluoromethoxy.

2. The rosin acid derivative according to claim 1, characterized in that R is one of the following:

3. The method for preparing abietic acid derivatives according to claims 1 to 2, characterized in that: The steps include: S1. Using AA as a starting material, an acylation reaction occurs in the presence of an acylating agent and a polar organic solvent to obtain compound 1, which is then reacted with one of the anilinopyrimidine compounds 2a-2h in the presence of an acid-binding agent and a polar organic solvent to produce compounds A1-A8; S2. Using DHAA as a starting material, an acylation reaction occurs in the presence of an acylating agent and a polar organic solvent to obtain compound 3, which is then reacted with one of the anilinopyrimidine compounds 2a-2h in the presence of an acid-binding agent and a polar organic solvent to produce compounds B1-B8; S3. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an N-alkylation reaction with an alkaline reagent, a polar organic reagent, and one of aniline compounds 5a-5h to obtain compounds A9-A16; S4. Using DHAA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 6, which is then subjected to an N-alkylation reaction with an alkaline reagent, a polar organic reagent, and one of aniline compounds 5a-5h to obtain compounds B9-B16; S5. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and a pyridine compound 7 to obtain compound A17; S6, using DHAA as a starting material, an alkylation reaction occurs in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 6, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and a pyridine compound 7 to obtain compound B17; S7. Using AA as a starting material, an alkylation reaction is carried out in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and benzimidazole compounds 8a-8d to obtain compounds A18-A21; S8. Using DHAA as the starting material, an alkylation reaction occurs in the presence of 1,2-dibromoethane, an alkaline reagent, and a polar organic solvent to obtain compound 4, which is then subjected to an S-alkylation reaction with an alkaline reagent, a polar organic reagent, and benzimidazole compounds 8a-8d to obtain compounds B18-B21.

4. The preparation method according to claim 3, characterized in that The acylating agent is selected from one or more of oxalyl chloride, thionyl chloride and diphenylcarbamoyl chloride.

5. The preparation method according to claim 3, characterized in that: The acid binding agent is selected from one or more of triethylamine, pyridine and N,N-diisopropylethylamine.

6. The preparation method according to claim 3, characterized in that The alkaline agent is selected from one or more of potassium carbonate, triethylamine and N,N-diisopropylethylamine.

7. The preparation method according to claim 3, characterized in that The equivalent ratio of AA or DHAA to the acylating agent is 1:1.5-1.8; the acylation reaction occurs at a reaction temperature of 0°C to room temperature to produce compound 1 or compound 3.

8. The preparation method according to claim 7, characterized in that The compound 1 or compound 3 and the compound One of the compounds undergoes an amide condensation reaction, the reaction temperature is room temperature, and the reaction time is 16-18 hours.

9. The preparation method according to claim 3, characterized in that The equivalent ratio of AA or DHAA to 1,2-dibromoethane is 1:2-2.5; and an alkylation reaction occurs at room temperature to produce compound 4 or compound 6.

10. Use of the rosin acid derivatives or pharmaceutically acceptable salts thereof according to claim 1 or 2 in the preparation of anti-glioma drugs.

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