A bazedoxifene derivative, its preparation method and use

Abstract

The present application relates to the field of medicinal chemistry and pharmacotherapy, and in particular to a class of bazedoxifene and its preparation method and application. The bazedoxifene derivative is used for gp130 small molecule inhibitor, the compound is a compound shown in formula (I), or a pharmaceutically acceptable salt or ester thereof, and relates to the application of tumor-related activity and the like, in particular the application in preparing drugs for preventing and / or treating diseases related to tumors, especially colorectal cancer.

Description

Technical Field

[0001] This invention relates to a novel class of GP130 small molecule inhibitors, specifically to a bardoxifene derivative and its preparation method and uses, particularly its application in tumor-related activities, and belongs to the field of pharmaceutical technology. Background Technology

[0002] The regulation of cellular signaling is closely related to tumorigenesis and development. Numerous studies have shown that glycoprotein 130 (GP130, also known as IL-6ST or CD130) is a highly conserved transmembrane glycoprotein closely associated with cancer development in vertebrates and serves as a receptor for various cytokines, including interleukin-6 (IL-6). GP130 protein is involved in multiple aspects of cell apoptosis, proliferation, angiogenesis, invasion, and metastasis. The tumor microenvironment (TME) plays a crucial role in tumor pathogenesis. Cancer-associated fibroblasts (CAFs) are an important component of the TME. Therefore, inhibiting the IL-6 / GP130 signaling pathway may provide important insights for cancer treatment.

[0003] The IL-6 / GP130 / STAT3 pathway is involved in a variety of tumor processes. IL-6 mainly functions through classical and trans signaling by binding to receptors IL-6Rα and gp130[5]. First, IL-6 binds to IL-6Rα or soluble sIL-6Rα on the cell membrane to form a binary complex. The IL-6 / IL-6Rα binary complex then forms an IL-6 / IL-6Rα / GP130 trimer complex with the D2 and D3 domains of GP130 on the cell membrane.

[0004] IL-6 / IL-6Rα / GP130 trimers are homodimers. IL-6 in one trimer binds to the D1 domain of GP130 in another trimer, forming a hexameric receptor complex. This mediates the activation of downstream MAKP, PI3K, and JAK / STAT pathways, resulting in a cascade effect. Studies have shown that aberrant expression of STAT3 plays a crucial role in tumor transformation. Overexpression or lack of negative regulators of upstream IL-6, IL-6Rα, and GP130 signaling can lead to aberrant STAT3 activation. Therefore, regulation of the upstream target of STAT3, IL-6 / IL-6Rα / GP130, may be important for anti-tumor activity. While STAT3 has been extensively reported, research on IL-6 / GP130 signaling is relatively limited. Inhibiting upstream IL-6 / GP130 signaling may provide a novel anti-tumor strategy, making the design of new inhibitors targeting this target significant.

[0005] Badoxifene is an FDA-approved selective estrogen receptor modulator (SERM) used to prevent and treat postmenopausal osteoporosis. Using multiple ligand simultaneous docking (MLSD) and drug repositioning methods, it was discovered that it can serve as a novel small molecule inhibitor of GP130. Summary of the Invention

[0006] Purpose of the invention: The first purpose of this invention is to provide a bardoxifene derivative that enhances the efficacy against colorectal tumors; the second purpose is to provide a method for preparing the bardoxifene derivative.

[0007] Technical solution: The chemical structural formula of the bardoxifene derivative described in this invention is as follows:

[0008]

[0009] Wherein, group A is a substituted or unsubstituted five-, six-, or seven-membered saturated or unsaturated heterocycle, or a substituted or unsubstituted aromatic ring; when group A is a heterocycle, there are one or two heteroatoms in the ring, and the heteroatoms are selected from: N, O, and S.

[0010] The B group is a ternary or quaternary fused-ring aromatic group.

[0011] Preferably, group A is selected from furanyl, thiophene, pyrrole, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, phenyl, substituted phenyl, and pyridinyl.

[0012] Preferably, the B group is selected from fused-ring saturated or unsaturated compounds, specifically...

[0013]

[0014] Where a, b, and c are selected from C or N, and R3 is selected from fused aromatic rings and substituted aromatic heterocycles.

[0015] Preferably, group A is selected from:

[0016]

[0017] Preferably, the aforementioned It has any of the following structures:

[0018]

[0019] Preferably, the B group contains a unique structure as follows:

[0020] Preferably, the badoxifen derivative has any of the following compound structures:

[0021]

[0022] On the other hand, the present invention provides a method for preparing a bardoxifene derivative, wherein when A is... When processing aliphatic heterocyclic compounds, the following steps are included:

[0023]

[0024] p-Hydroxybenzyl alcohol reacts with the hydrochloride salt of the corresponding halide in the presence of a phase transfer catalyst to give compound II.

[0025] (1) Compound II was reacted overnight in the presence of thionyl chloride to give compound III.

[0026] (2) Compound III and fragment B were reacted with sodium hydride to obtain compound I.

[0027] Preferably, in step (1), the reaction solvent is selected from one or more of acetone, water, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or dioxane; the base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, or triethylamine; the phase transfer catalyst is tetrabutylammonium bromide; and the reaction temperature is... The reaction process was monitored by TLC, with ethyl acetate as the developing solvent.

[0028] Preferably, in step (2), the reaction solvent is selected from one or more of acetonitrile, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; the reaction temperature... The reaction time is The reaction process was monitored by TLC, with dichloromethane:methanol = 30:1 as the developing solvent.

[0029] Preferably, in step (3), the reaction solvent is selected from one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, N,N-dimethylformamide, tert-butanol, dimethyl sulfoxide, or dioxane, and the base is selected from sodium hydride or sodium tert-butoxide. The reaction is carried out at room temperature or under reflux. The reaction process is monitored by TLC, and the developing solvent is dichloromethane:methanol = 15:1.

[0030] Specifically, when A is Includes the following steps:

[0031] 1) 4-(hydroxymethyl)-phenol reacts with 1-(2-chloroethyl)pyrrolidine hydrochloride, 1-(2-chloroethyl)piperidine hydrochloride, and 1-(2-chloroethyl)azacyclohexane hydrochloride, respectively, under the action of a phase transfer catalyst, to produce (4-(2-(pyrrolidine-1-yl)ethoxy)phenyl)methanol, (4-(2-(piperidin-1-yl)ethoxy)phenyl)methanol, and (4-(2-(aza-1-yl)ethoxy)phenyl)methanol, respectively.

[0032] 2)(4-(2-(pyrrolidone-1-yl)ethoxy)phenyl)methanol, (4-(2-(piperidin-1-yl)ethoxy)phenyl)methanol, and (4-(2-(aza-1-yl)ethoxy)phenyl)methanol react with sulfoxide in tetrahydrofuran to give 1-(2-(4-(chloromethyl)phenoxy)ethyl)pyrrolidine hydrochloride, 1-(2-(4-(chloromethyl)phenoxy)ethyl)piperidine hydrochloride, and 1-(2-(4-(chloromethyl)phenoxy)ethyl)azacyclohexane hydrochloride, respectively.

[0033] 3) 1-(2-(4-(chloromethyl)phenoxy)ethyl)pyrrolidine hydrochloride, 1-(2-(4-(chloromethyl)phenoxy)ethyl)piperidine hydrochloride, and 1-(2-(4-(chloromethyl)phenoxy)ethyl)azacyclohexane hydrochloride are linked to fragment B under the action of NaH to obtain bardoxifene derivatives.

[0034] When A is When aromatic rings or aromatic heterocycles are present, the following steps are included:

[0035]

[0036] p-hydroxybenzaldehyde was reacted with 2-phenylethane-1-ol, 2-(3-(trifluoromethyl)phenyl)ethane-1-ol, and 2-(pyridin-2-yl)ethane-1-ol under the conditions of diisopropyl azodicarbonate and triphenylphosphine to give compound IV.

[0037] a. Compound IV is reduced to compound V by sodium borohydride.

[0038] b. Compound V is chlorinated to compound VI under the action of thionyl chloride.

[0039] c. Compound VI and fragment B react with sodium hydride to yield compound I.

[0040] Preferably, in step a, the reaction solvent is selected from one or more of acetone, tetrahydrofuran, N,N-dimethylformamide, ethylene glycol dimethyl ether, dimethyl sulfoxide, or dioxane; the reaction temperature... The reaction process was monitored by TLC, with petroleum ether:ethyl acetate = 2:1 as the developing solvent.

[0041] Preferably, in step b, the solvent for the reduction reaction is selected from one or more of acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; the reaction temperature... The reaction time was 2 hours, and the reaction progress was monitored by TLC. The developing solvent was ethyl acetate.

[0042] Preferably, in step c, the reaction solvent is selected from one or more of acetonitrile, ethylene glycol dimethyl ether, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; the reaction temperature... The reaction time is The reaction process was monitored by TLC, with dichloromethane:methanol = 30:1 as the developing solvent.

[0043] Preferably, in step d, the reaction solvent is selected from one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, N,N-dimethylformamide, tert-butanol, dimethyl sulfoxide, or dioxane, and the base is selected from sodium hydride or sodium tert-butoxide. The reaction is carried out at room temperature or under reflux. The reaction process is monitored by TLC, with dichloromethane:methanol = 15:1 as the developing solvent.

[0044] Specifically, when A is Includes the following steps:

[0045] (1) 4-hydroxybenzaldehyde was reacted with 2-phenylethane-1-ol, 2-(3-(trifluoromethyl)phenyl)ethane-1-ol, and 2-(pyridin-2-yl)ethane-1-ol, respectively, to give 4-phenylethoxybenzaldehyde, 4-(3-(trifluoromethyl)phenylethoxy)benzaldehyde, and 4-(2-(pyridin-2-yl)ethoxy)benzaldehyde, respectively.

[0046] (2) 4-Phenylacetoxybenzaldehyde, 4-(3-(trifluoromethyl)phenylacetoxy)benzaldehyde, and 4-(2-(pyridin-2-yl)ethoxy)benzaldehyde were reduced by sodium borohydride to obtain (4-phenylacetoxyphenyl)methanol, (4-(3-(trifluoromethyl)phenylacetoxy)phenyl)methanol, and (4-(2-(pyridin-2-yl)ethoxy)phenyl)methanol.

[0047] (3) (4-phenylethoxyphenyl)methanol, (4-(3-(trifluoromethyl)phenylethoxy)phenyl)methanol, and (4-(2-(pyridin-2-yl)ethoxy)phenyl)methanol are reacted with sulfoxide to generate 1-(chloromethyl)-4-phenylethoxybenzene, 1-(2-(4-(chloromethyl)phenoxy)ethyl)-3-(trifluoromethyl)benzene, and 2-(2-(4-(chloromethyl)phenoxy)ethyl)pyridine.

[0048] (4) Further, 1-(chloromethyl)-4-phenylethoxybenzene, 1-(2-(4-(chloromethyl)phenoxy)ethyl)-3-(trifluoromethyl)benzene, and 2-(2-(4-(chloromethyl)phenoxy)ethyl)pyridine are linked to fragment B under the action of NaH to obtain the bardoxifen derivative (Ⅰ).

[0049] On the other hand, the present invention provides the use of a badoxifene derivative in the preparation of a tumor-treating drug. Preferably, the tumor is a colorectal tumor.

[0050] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0051] (1) By modifying the derivatives, specifically parts A and B, a series of new compounds were synthesized, and a more potent GP130 inhibitor was discovered. This inhibitor exhibited significant inhibitory effects on colorectal tumor cells, and its IC50 value against the colorectal cancer cell line HT-29 was [missing value]. 50 The minimum is 2.048 μM; (2) Preparation method: A new bardoxifene derivative was designed and synthesized. The inhibitory effect on cancer cells was tested by the CCK-8 method and it was found that it can significantly inhibit the occurrence and development of various cancer cells such as colorectal cancer. Attached Figure Description

[0052] Figure 1 The results of the Wounding Healing Assay test on HT29 cells using compound I6 are shown in (a) and (b) are histograms showing the number of colonies formed. Detailed Implementation

[0053] This invention provides a bardoxifene derivative having the structure shown in formula (I):

[0054]

[0055] Wherein, group A is a substituted or unsubstituted five-, six-, or seven-membered saturated or unsaturated heterocycle, or a substituted or unsubstituted aromatic ring; when group A is a heterocycle, there are one or two heteroatoms in the ring, and the heteroatoms are selected from: N, O, and S;

[0056] The B group is a ternary or quaternary fused-ring aromatic group;

[0057] n is 1, 2, or 3.

[0058] This invention provides a method for preparing a bardoxifen derivative, wherein when group A is an aliphatic heterocycle, the method includes the following steps:

[0059]

[0060] (1) p-hydroxybenzyl alcohol reacts with the hydrochloride salt of the corresponding halide under the action of a phase transfer catalyst to give compound II;

[0061] (2) Compound II was reacted overnight in the presence of thionyl chloride to give compound III;

[0062] (3) Compound III and fragment B reacted with sodium hydride to give compound I.

[0063] When group A is an aromatic ring or an aromatic heterocycle, the following steps are included:

[0064]

[0065] p-hydroxybenzaldehyde was reacted with 2-phenylethane-1-ol, 2-(3-(trifluoromethyl)phenyl)ethane-1-ol, and 2-(pyridin-2-yl)ethane-1-ol under the conditions of diisopropyl azodicarbonate and triphenylphosphine to give compound IV;

[0066] a. Compound IV is reduced to compound V by sodium borohydride;

[0067] b. Compound V is chlorinated to compound VI under the action of thionyl chloride;

[0068] c. Compound VI and fragment B react with sodium hydride to yield compound I.

[0069] The technical solution of the present invention will be further described below with reference to the embodiments.

[0070] Example 1

[0071] The bardoxifen derivative of this invention, chemically named 9-(4-(2-(pyrrolidone-1-yl)ethoxy)benzyl)-9H-carbazole, has the following synthetic route:

[0072]

[0073] (1) Synthesis of intermediate II1

[0074] 40.28 mmol of p-hydroxybenzyl alcohol was added to 45 mL of an aqueous solution of sodium hydroxide (88.61 mmol) and stirred for 20 minutes. Toluene (30 mL), 1-(2-chloroethyl)pyrrolidine hydrochloride (48.33 mmol), and tetrabutylammonium bromide (2.42 mmol) were added sequentially. The solution was then heated to reflux (85–90 °C) and stirred vigorously for 2 hours. The organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate and combined with the organic layer. The mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give a white solid, II1, in 75% yield. 1 H NMR(300MHz,Chloroform-d)δ7.27–7.15(m,2H),6.92–6.72(m,2H),4.55(s,2H),3.99(t,J=6.0Hz ,2H),3.90(s,1H),2.84(t,J=6.0Hz,2H),2.59(ddt,J=6.8,4.4,2.4Hz,4H),1.78(p,J=3.1Hz,4H).

[0075] (1) Synthesis of intermediate III1

[0076] A tetrahydrofuran solution of intermediate II1 (27.11 mmol) was cooled to 0 °C, and thionyl chloride (30.35 mmol) was slowly added dropwise while stirring overnight at room temperature. When TLC showed the reaction was complete, the precipitated product was filtered, and the filter cake was washed with cyclohexane:tetrahydrofuran = 1:1. After drying in an oven at 80 °C, a white solid III1 was obtained. The yield was 67%. 1 H NMR(300MHz,DMSO-d6)δ11.05(s,1H),7.44–7.36(m,2H),7.06–6.97(m,2H),4.74(s,2H) ,4.37(t,J=5.1Hz,2H),3.56(q,J=5.0Hz,4H),3.10(d,J=9.0Hz,2H),2.04–1.82(m,4H).

[0077] (2) Synthesis of target product I1

[0078] A solution of carbazole (1.2 mmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (3.55 mmol) was added. After stirring at 0 °C for 1 h, compound III1 (1.32 mmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, a white solid I1. The yield was 78%. 1 H NMR (300MHz, DMSO-d6) δ8.17(d,J=7.7Hz,2H),7.65(d,J=8.2Hz,2H),7.49–7.37(m,2H),7.24–7.16(m,2H),7.12(d,J=8.6Hz,2 H), 6.81 (d, J = 8.7Hz, 2H), 5.57 (s, 2H), 3.95 (t, J = 5.9Hz, 2H), 2.70 (t, J = 5.9Hz, 2H), 2.48–2.38 (m, 4H), 1.64 (h, J = 3.1Hz, 4H). 13 C NMR (75MHz, DMSO-d6) δ158.18,140.52,130.16,128.62,126.24,122.66,120.78,119.39,114.90,110.04,67.05,54.72,54.40,45.46,23.56.

[0079] Example 2

[0080] The bardoxifen derivative of this invention, chemically named 9-(4-(2-(piperidin-1-yl)ethoxy)benzyl)-9H-carbazole, has the following synthetic route:

[0081]

[0082] (1) Synthesis of intermediate II2

[0083] Add 24.17 mmol of p-hydroxybenzyl alcohol to 45 mL of an aqueous solution of sodium hydroxide (53.17 mmol) and stir for 20 minutes. Then add toluene (30 mL), 1-(2-chloroethyl)piperidine hydrochloride (29 mmol), and tetrabutylammonium bromide (14.5 mmol) sequentially. The solution is then heated to reflux (85-90 °C) and stirred vigorously for 2 h. The organic layer is separated, and the aqueous phase is extracted twice with ethyl acetate and combined with the organic layer. The mixture is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography to give a white solid, II2. Yield: 70%. 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J=6.6Hz,2H),6.91–6.85(m,2H),4.61(s,2H),4.09(t,J=6.1 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), 2.51 (t, J = 5.5 Hz, 4H), 1.62 (p, J = 5.6 Hz, 4H), 1.45 (q, J = 6.2 Hz, 2H).

[0084] (2) Synthesis of intermediate III2

[0085] A tetrahydrofuran solution of intermediate II2 (23.16 mmol) was cooled to 0 °C, and thionyl chloride (46.32 mmol) was slowly added dropwise while stirring overnight at room temperature. When TLC showed the reaction was complete, the precipitated product was filtered, and the filter cake was washed with cyclohexane:tetrahydrofuran = 1:1. After drying in an oven at 80 °C, a white solid III2 was obtained. Yield: 67%. 1 H NMR(300MHz,Chloroform-d)δ12.49(s,1H),7.33(d,J=8.0Hz,2H),6.88(d,J=8.1Hz,2H),4.57(d,J=8.2Hz,4H),3 .64(d,J=12.0Hz,2H),3.48–3.33(m,2H),2.83(q,J=11.4Hz,2H),2.28(q,J=13.9Hz,2H),1.88(d,J=13.8Hz,2H).

[0086] (3) Synthesis of target product I2

[0087] A solution of carbazole (598.05 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection, and sodium hydride (1.79 mmol) was added. After stirring the solution at 0 °C for 1 h, compound III1 (777.46 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, white solid I2, in 85% yield. 1 H NMR (300MHz, DMSO-d6) δ8.17(dt,J=7.8,0.9Hz,2H),7.68–7.58(m,2H),7.43(ddd,J=8.3,7.1,1.2Hz,2H),7.20(td,J=7.5,0.9Hz,2H),7.16–7.05(m ,2H),6.86–6.76(m,2H),5.57(s,2H),3.95(t,J=5.9Hz,2H),2.57(t,J=5. 9Hz, 2H), 2.36 (t, J = 5.2Hz, 4H), 1.45 (p, J = 5.4Hz, 4H), 1.39–1.28 (m, 2H). 13 C NMR(75MHz,DMSO-d6)δ158.19,140.52,130.15,128.60,126.24,122.66,1 20.78,119.38,114.94,110.03,65.91,57.80,54.84,45.46,26.01,24.38.

[0088] Example 3

[0089] The bardoxifen derivative of this invention has the chemical name 9-(4-(2-(azacycloheptane-1-yl)ethoxy)benzyl)-9H-carbazole, and its synthetic route is shown below:

[0090]

[0091] (1) Synthesis of intermediate II3

[0092] Add 24.17 mmol of p-hydroxybenzyl alcohol to 45 mL of an aqueous solution of sodium hydroxide (53.17 mmol) and stir for 20 minutes. Then add toluene (30 mL), 1-(2-chloroethyl)azacyclohexane hydrochloride (29 mmol), and tetrabutylammonium bromide (14.5 mmol) sequentially. Heat the solution to reflux (85–90 °C) and stir vigorously for 2 h. Separate the organic layer, extract the aqueous phase twice with ethyl acetate and combine the extracts with the organic layer. Wash with water and brine, dry to anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography to give a white solid, II3. Yield: 67%. 1 H NMR(400MHz,Chloroform-d)δ7.27(d,J=8.6Hz,2H),6.91–6.83(m,2H),4.60(s,2H),4.05( t,J=6.2Hz,2H),2.94(t,J=6.2Hz,2H),2.81–2.74(m,4H),2.32(s,1H),1.71–1.56(m,8H).

[0093] (2) Synthesis of intermediate III3

[0094] A tetrahydrofuran solution of intermediate II2 (18.16 mmol) was cooled to 0 °C, and thionyl chloride (36.32 mmol) was slowly added dropwise while stirring overnight at room temperature. When TLC showed the reaction was complete, the precipitated product was filtered, and the filter cake was washed with cyclohexane:tetrahydrofuran = 1:1. After drying in an oven at 80 °C, a white solid III3 was obtained. Yield: 61%. 1 H NMR(300MHz,Chloroform-d)δ12.52(s,1H),7.39–7.29(m,2H),6.96–6.81(m,2H),4.56(s,4H),3.63(q,J=9.5,8.6H z,2H),3.48(s,2H),3.23–3.04(m,2H),2.19(q,J=9.7Hz,2H),1.95–1.82(m,4H),1.66(dq,J=16.5,8.8,7.2Hz,2H).

[0095] (3) Synthesis of target product I3

[0096] A solution of carbazole (299.02 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection, and sodium hydride (1.35 mmol) was added. After stirring the solution at 0 °C for 1 h, compound III3 (328.993 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, white solid I3, in 83% yield. 1 H NMR (300MHz, DMSO-d6) δ8.17(d,J=7.7Hz,2H),7.65(d,J=8.2Hz,2H),7.48–7.37(m,2H),7.20(t,J=7.4Hz,2H),7.12(d,J=8.5H z,2H),6.85–6.76(m,2H),5.57(s,2H),3.92(t,J=6.1Hz,2H),2.76(t,J=6.0Hz,2H),2.62(t,J=5.1Hz,4H),1.54–1.46(m,8H). 13 C NMR(75MHz,DMSO-d6)δ158.26,140.52,130.14,128.61,126.24,122.67,1 20.77,119.38,114.96,110.03,66.60,56.44,55.57,45.47,28.31,27.00.

[0097] Example 4

[0098] The bardoxifen derivative of this invention, chemically named 5-(4-(2-(pyrrolidone-1-yl)ethoxy)benzyl)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0099]

[0100] (1) Synthesis of target product I4

[0101] A solution of compound 5H-pyrido[4,3-b]indole (297.27 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (1.34 mmol) was added. After stirring the solution at 0 °C for 1 h, compound III1 (356.72 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, white solid I4. Yield: 68%. 1H NMR(300MHz,Chloroform-d)δ9.34(s,1H),8.53(d,J=5.8Hz,1H),8.18(dt,J=7.7,1.0Hz,1H),7.50(ddd,J=8.2,7.0,1.2Hz,1H),7.42(dt,J=8.3,1.1Hz,1H ),7.37–7.27(m,2H),7.10–7.02(m,2H),6.86–6.74(m,2H),5.44(s,2H),4.13 (t,J=5.7Hz,2H),2.99(t,J=5.7Hz,2H),2.85–2.67(m,4H),1.93–1.78(m,4H). 13 CNMR(75MHz,Chloroform-d)δ158.09,145.15,144.74,140.48,128.49,127.82,126.95 ,121.58,120.81,120.81,114.97,109.59,104.43,66.14,54.71,54.61,46.19,23.39.

[0102] Example 5

[0103] The bardoxifen derivative of this invention, chemically named 5-(4-(2-(piperidin-1-yl)ethoxy)benzyl)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0104]

[0105] (1) Synthesis of target product I5

[0106] A solution of compound 5H-pyrido[4,3-b]indole (297.27 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (1.34 mmol) was added. After stirring the solution at 0 °C for 1 h, compound III2 (356.72 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, white solid I5, in 61% yield. 1H NMR(400MHz,Chloroform-d)δ9.35(d,J=0.9Hz,1H),8.52(s,1H),8.19(dt,J=7.8,1. 0Hz,1H),7.51(ddd,J=8.3,7.1,1.2Hz,1H),7.43(dt,J=8.3,1.0Hz,1H),7.39–7.29(m ,2H),7.11–7.01(m,2H),6.84–6.74(m,2H),5.45(s,2H),4.18(t,J=5.4Hz,2H),2.99 (t, J = 5.5 Hz, 2H), 2.75 (t, J = 5.6 Hz, 4H), 1.72 (p, J = 5.7 Hz, 4H), 1.50 (t, J = 6.0 Hz, 2H). 13 C NMR(101MHz,Chloroform-d)δ158.15,144.77,142.53,140.55,128.35,127.81,127.02,121.5 7,120.89,120.84,119.89,114.99,109.61,104.44,65.22,57.22,54.54,46.23,25.06,23.61.

[0107] Example 6

[0108] The bardoxifen derivative of this invention, chemically named 5-(4-(2-(azacyclohept-1-yl)ethoxy)benzyl)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0109]

[0110] (1) Synthesis of target product I6

[0111] A solution of compound 5H-pyrido[4,3-b]indole (297.27 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (1.34 mmol) was added. After stirring the solution at 0 °C for 1 h, compound III3 (356.72 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, white solid I5. Yield: 63%. 1H NMR (400MHz, Chloroform-d) δ9.36 (s, 1H), 8.55 (d, J = 5.8Hz, 1H), 8.20 (d, J = 7. 8Hz,1H),7.56–7.46(m,1H),7.43(d,J=8.1Hz,1H),7.35(t,J=7.5Hz,1H),7.30 (d,J=11.0Hz,1H),7.08(d,J=8.4Hz,2H),6.90–6.75(m,2H),5.45(s,2H),4.07 (t,J=6.0Hz,2H),2.98(t,J=6.0Hz,2H),2.90–2.74(m,4H),1.77–1.54(m,8H). 13 C NMR(101MHz,Chloroform-d)δ158.32,145.01,144.78,142.75,140.53,128.28,127.79,126.95,12 1.60,120.82,120.81,119.88,114.99,109.59,104.42,65.95,56.13,55.66,46.23,27.08,27.03.

[0112] Example 7

[0113] The bardoxifen derivative of this invention, chemically named 7-(6-fluoropyridin-3-yl)-5-(4-(2-(pyrrolidone-1-yl)ethoxy)ethoxy)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0114]

[0115] (1) Synthesis of target product I7

[0116] A solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (189.92 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (854.62 μmol) was added. After stirring the solution at 0 °C for 1 h, compound III1 (189.92 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, a yellow solid I7. The yield was 53%. 1H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.56(d,J=5.7Hz,1H),8.46(s,1H), 8.25(d,J=8.0Hz,1H),8.02(t,J=8.1Hz,1H),7.50(d,J=9.8Hz,2H),7.33(d,J= 5.9Hz,1H),7.12–6.98(m,3H),6.84(d,J=7.6Hz,2H),5.49(s,2H),4.08(t,J=5 .9Hz, 2H), 2.91 (t, J = 5.8Hz, 2H), 2.66 (d, J = 5.9Hz, 4H), 1.81 (t, J = 4.5Hz, 4H). 13 C NMR(75MHz,Chloroform-d)δ158.50,146.25,146.06,145.58,145.37,143.13,141.06,140.20,140.09,135.68,127 .86,127.71,121.50,120.18,119.43,115.08,109.80,109.30,108.04,104.56,66.80,54.91,54.68,46.32,23.44.

[0117] Example 8

[0118] The bardoxifen derivative of this invention has the following chemical name and its synthetic route is as follows:

[0119]

[0120] (1) Synthesis of target product I8

[0121] A solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (189.92 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (854.62 μmol) was added. After stirring the solution at 0 °C for 1 h, compound III2 (227.90 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, a yellow solid I8. The yield was 48%. 1H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.57(d,J=5.8Hz,1H),8.46(s,1H),8.26 (d,J=8.0Hz,1H),8.02(t,J=7.9Hz,1H),7.50(d,J=9.9Hz,2H),7.33(d,J=5.8Hz,1H) ,7.12–6.99(m,3H),6.82(d,J=7.4Hz,2H),5.49(s,2H),4.07(t,J=6.0Hz,2H),2.77( t, J=6.1Hz, 2H), 2.51 (t, J=5.1Hz, 4H), 1.61 (t, J=5.8Hz, 4H), 1.44 (q, J=5.9Hz, 2H). 13 C NMR(75MHz,Chloroform-d)δ158.50,146.26,146.06,145.60,143.14,141.06,140.19,140.09,135.67,127.82,12 7.71,121.50,120.18,119.43,115.08,109.80,109.30,108.03,104.55,65.81,57.75,54.99,46.32,25.70,24.01.

[0122] Example 9

[0123] The bardoxifen derivative of this invention, chemically named 5-(2-(azacyclohepta-1-yl)ethoxy)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0124]

[0125] (1) Synthesis of target product I9

[0126] A solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (189.92 μmol) was obtained by stirring in anhydrous dimethylformamide under argon protection. Sodium hydride (854.62 μmol) was added. After stirring the solution at 0 °C for 1 h, compound III3 (227.90 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound, a yellow solid I9. The yield was 51%. 1H NMR(300MHz,Chloroform-d)δ9.37(d,J=1.0Hz,1H),8.57(d,J=5.8Hz,1H),8.46(q,J= 1.1Hz, 1H), 8.26 (dd, J=7.8, 0.9Hz, 1H), 8.02 (ddd, J=8.4, 7.6, 2.6Hz, 1H), 7.50 (dd, J= 9.1,1.2Hz,2H),7.33(dd,J=5.9,1.0Hz,1H),7.13–7.00(m,3H),6.87–6.78(m,2H),5.5 0(s,2H),4.08(t,J=6.0Hz,2H),2.99(t,J=6.0Hz,2H),2.83(s,4H),1.72–1.59(m,8H). 13 C NMR(75MHz,Chloroform-d)δ158.52,146.26,146.06,145.56,145.38,143.11,141.07,140.09,135.68,128.63,12 7.83,127.72,121.50,120.19,119.44,115.08,109.31,108.04,104.57,66.16,56.16,55.76,46.33,27.38,27.02.

[0127] Example 10

[0128] The bardoxifen derivative of this invention, chemically named 5-(2-(azacyclohepta-1-yl)ethoxy)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole, has the following synthetic route:

[0129]

[0130] (1) Target Product I 10 Synthesis

[0131] A solution of compound 6H-indolo[2,3-b]quinoxaline (228.05 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (912.21 μmol) was then added. After stirring the solution at 0 °C for 1 h, compound III3 (273.66 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a yellow solid I. 10 The yield was 64%. 1H NMR(300MHz,Chloroform-d)δ8.48(dt,J=7.7,1.1Hz,1H),8.35–8.28(m,1H),8.20–8.11( m,1H),7.77(ddd,J=8.4,6.9,1.7Hz,1H),7.70(ddd,J=8.3,6.9,1.6Hz,1H),7.62(ddd,J=8 .3,7.2,1.3Hz,1H),7.43–7.32(m,2H),7.32–7.26(m,2H),6.87–6.77(m,2H),5.65(s,2H), 4.10(t,J=5.8Hz,2H), 2.93(t,J=5.8Hz,2H), 2.68(d,J=6.3Hz,4H), 1.83(p,J=3.3Hz,4H). 13 C NMR(75MHz,Chloroform-d)δ158.23,144.25,140.67,139.50,131.00,129.36,128.82,128.78,128 .65,127.90,126.10,122.69,121.10,119.65,114.82,110.20,66.64,54.91,54.68,44.50,23.42.

[0132] Example 11

[0133] The bardoxifen derivative of this invention, chemically named 6-(4-(2-(piperidin-1-yl)ethoxy)-6H-indolo[2,3-b]quinoxaline, has the following synthetic route:

[0134]

[0135] (1) Target Product I 11 Synthesis

[0136] A solution of compound 6H-indolo[2,3-b]quinoxaline (228.05 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (912.21 μmol) was then added. After stirring the solution at 0 °C for 1 h, compound III3 (273.66 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a yellow solid I. 11 The yield was 60%. 1H NMR(400MHz,Chloroform-d)δ8.48(d,J=7.7Hz,1H),8.32(dd,J=8.4,1.5Hz,1H),8.16(dd,J=8.4 ,1.5Hz,1H),7.78(ddd,J=8.4,6.9,1.6Hz,1H),7.70(ddd,J=8.3,6.8,1.5Hz,1H),7.62(ddd,J=8 .4,7.3,1.3Hz,1H),7.43–7.33(m,2H),7.33–7.26(m,2H),6.86–6.73(m,2H),5.65(s,2H),4.07( t,J=6.0Hz,2H),2.77(t,J=6.0Hz,2H),2.51(s,4H),1.61(p,J=5.5Hz,4H),1.43(d,J=3.4Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ158.29,145.76,144.26,140.68,139.50,130.97,129.35,128.80,128.71,12 8.64,127.90,126.08,122.69,121.08,119.67,114.83,110.18,65.75,57.77,54.95,44.51,25.72,24.03.

[0137] Example 12

[0138] The bardoxifen derivative of this invention, chemically named 6-(4-(2-(azacyclohepta-1-yl)ethoxy)-6H-indo[2,3-b]quinoxaline, has the following synthetic route:

[0139]

[0140] (1) Target Product I 12 Synthesis

[0141] A solution of compound 6H-indolo[2,3-b]quinoxaline (228.05 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (912.21 μmol) was then added. After stirring the solution at 0 °C for 1 h, compound III3 (273.66 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a yellow solid I. 11 The yield was 58%. 1H NMR(300MHz,Chloroform-d)δ8.48(dt,J=7.6,1.0Hz,1H),8.32(dd,J=8.1,1.6Hz,1H),8.21–8 .08(m,1H),7.77(ddd,J=8.4,6.8,1.6Hz,1H),7.70(ddd,J=8.3,6.9,1.6Hz,1H),7.62(ddd,J=8 .3,7.2,1.3Hz,1H),7.44–7.33(m,2H),7.32–7.26(m,2H),6.88–6.74(m,2H),5.65(s,2H),4.06 (t,J=6.1Hz,2H),2.96(t,J=6.0Hz,2H),2.81(s,4H),1.67(s,4H),1.59(dd,J=6.1,3.2Hz,4H). 13 C NMR(75MHz,Chloroform-d)δ158.36,145.77,144.26,140.68,140.09,139.50,130.99,129.36,128.82 ,128.64,127.90,126.09,122.69,121.09,114.82,110.20,66.21,56.24,55.78,44.52,27.60,27.03.

[0142] Example 13

[0143] The bardoxifen derivative of this invention, chemically named 8-chloro-11-(1-(4-(2-(pyrrolidone-1-yl)ethoxy)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cycloheptane[1,2-b]pyridine, is synthesized via the following route:

[0144]

[0145] (1) Target Product I 13 Synthesis

[0146] Compound 6H-indolo[2,3-b]quinoxaline (160.86 μmol), anhydrous potassium carbonate (402.16 μmol), and III1 (209.12 μmol) were added to N,N-dimethylformamide and heated with stirring at 70 °C. After 4 hours of reaction, the reaction was monitored by TLC. When the reaction was complete, ethyl acetate was added for extraction. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound as a yellow solid I. 13 The yield was 82%. 1HNMR(300MHz,Chloroform-d)δ8.38(dd,J=4.8,1.7Hz,1H),7.42(dd,J=7.7,1.7Hz,1H),7.24– 7.16(m,2H),7.16–7.09(m,3H),7.07(dd,J=7.7,4.8Hz,1H),6.89–6.80(m,2H),4.13(t,J=5.8 Hz,2H),3.52–3.28(m,4H),2.94(t,J=5.9Hz,2H),2.89–2.76(m,2H),2.76–2.64(m,6H),2.51( ddd,J=13.8,9.7,4.1Hz,1H),2.44–2.24(m,3H),2.13(d,J=9.4Hz,2H),1.84(h,J=3.2Hz,4H). 13 C NMR(75MHz,Chloroform-d)δ157.89,146.66,139.52,139.20,137.20,132.59,132.50,130.92,130.36,130.30, 128.95,125.98,122.05,114.22,66.85,62.27,55.07,54.72,54.67,54.62,31.87,31.45,30.98,30.74,23.48.

[0147] Example 14

[0148] The bardoxifen derivative of this invention, chemically named 8-chloro-11-(1-(4-(2-(piperidin-1-yl)ethoxy)benzyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cycloheptane[1,2-b]pyridine, is synthesized via the following route:

[0149]

[0150] (1) Target Product I 14 Synthesis

[0151] Compound 6H-indolo[2,3-b]quinoxaline (160.86 μmol), anhydrous potassium carbonate (402.16 μmol), and III1 (209.12 μmol) were added to N,N-dimethylformamide and heated with stirring at 70 °C. After 4 hours of reaction, the reaction was monitored by TLC. When the reaction was complete, ethyl acetate was added for extraction. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound as a yellow solid I. 13 The yield was 85%. 1HNMR(300MHz,Chloroform-d)δ8.38(dd,J=4.8,1.7Hz,1H),7.42(dd,J=7.6,1.7Hz,1 H),7.23–7.16(m,2H),7.15–7.02(m,4H),6.88–6.79(m,2H),4.10(t,J=6.1Hz,2H),3. 52–3.29(m,4H),2.88–2.69(m,6H),2.51(tt,J=9.9,4.0Hz,5H),2.35(tdd,J=14.1,9. 6,4.0Hz,3H),2.12(td,J=10.8,5.4Hz,2H),1.71–1.54(m,4H),1.45(d,J=5.8Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ157.80,146.66,139.53,137.84,137.24,133.41,132.63,130.87,130.46,130.46,128 .97,126.00,122.08,114.26,65.51,62.18,57.76,54.93,54.61,54.55,31.85,31.45,30.85,30.61,25.54,23.90.

[0152] Example 15

[0153] The bardoxifen derivative of this invention, chemically named 11-(1-(4-(2-(azacycloheptane-1-yl)ethoxy)benzyl)piperidin-4-ylidene)-8-chloro-6,11-dihydro-5H-benzo[5,6]cycloheptane[1,2-b]pyridine, is synthesized via the following route:

[0154]

[0155] (1) Target Product I 15 Synthesis

[0156] Compound 6H-indolo[2,3-b]quinoxaline (160.86 μmol), anhydrous potassium carbonate (402.16 μmol), and III3 (209.12 μmol) were added to N,N-dimethylformamide and heated with stirring at 70 °C. After 4 hours of reaction, the reaction was monitored by TLC. When the reaction was complete, ethyl acetate was added for extraction. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound as a yellow solid I. 15 The yield was 82%. 1HNMR(400MHz,Chloroform-d)δ8.38(dd,J=4.9,1.6Hz,1H),7.42(dd,J=7.7,1.7H z,1H),7.21(d,J=8.2Hz,2H),7.16–7.10(m,3H),7.07(dd,J=7.7,4.8Hz,1H),6.8 7–6.81(m,2H),4.13(s,2H),3.49–3.31(m,4H),3.03(s,2H),2.97–2.66(m,8H),2 .52(t,J=11.9Hz,1H),2.46–2.28(m,3H),2.13(s,2H),1.72(s,4H),1.63(s,4H). 13 C NMR(75MHz,Chloroform-d)δ157.93,146.64,139.51,139.21,137.21,133.41,132.59,132.48,130.92,130.36,130.27 ,128.96,125.98,122.06,114.22,66.23,62.28,56.36,55.83,54.68,54.63,31.87,31.44,30.98,30.75,27.68,27.05.

[0157] Example 16

[0158] The bardoxifen derivative of this invention, chemically named 9-(4-phenethoxybenzyl)-9H-pyrido[2,3-b]indole, has the following synthetic route:

[0159]

[0160] (1) Synthesis of intermediate IV1

[0161] Phenylacetyl alcohol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol), and PPh3 (2.22 mmol) were stirred in 20 mL of dry THF at 0 °C under a nitrogen atmosphere. DIAD (2.22 mmol) was added dropwise to this mixture over 5 min, and the reaction was monitored by thin-layer chromatography. After the starting material had completely disappeared (1 h), the solvent was evaporated under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane / AcOEt, 8 / 2). After precipitation, 4-phenylethoxybenzaldehyde was obtained as a white powder, with a yield of 76%. 1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.90–7.80(m,2H),7.38–7.28(m,4H),7.2 6–7.19(m,1H),7.16–7.07(m,2H),4.31(t,J=6.9Hz,2H),3.07(t,J=6.8Hz,2H).

[0162] (2) Synthesis of intermediate V1

[0163] Intermediate IV1 (3.97 mmol) was added to a methanol solution, followed by sodium borohydride (11.91 mmol). The mixture was stirred at room temperature for 2 hours. When the reaction was complete as indicated by TLC, 1 mol / L hydrochloric acid was added to quench the reaction until no more gas was released. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution. The methanol in the system was then evaporated, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a white solid V1 with a yield of 100%. 1 H NMR(300MHz,DMSO-d6)δ7.35–7.26(m,4H),7.26–7.15(m,3H),6.93–

[0164] 6.83 (m, 2H), 5.04 (t, J = 5.7Hz, 1H), 4.40 (d, J = 5.7Hz, 2H), 4.16 (t, J = 6.9Hz, 2H), 3.02 (t, J = 6.9Hz, 2H).

[0165] (3) Synthesis of intermediate VI1

[0166] A tetrahydrofuran solution of intermediate V1 (27.11 mmol) was cooled to 0 °C, and thionyl chloride (30.35 mmol) was slowly added dropwise, followed by stirring overnight at room temperature. Once TLC showed the reaction was complete, the solution was directly evaporated to dryness without further purification to obtain intermediate III1.

[0167] (4) Target Product I 16 Synthesis

[0168] A solution of 9H-pyrido[2,3-b]indole (416.17 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (1.87 mmol) was added. After stirring the solution at 0 °C for 1 h, compound IV3 (457.79 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a white solid I. 16 The yield was 82%. 1H NMR (300MHz, DMSO-d6) δ8.61–8.47(m,2H),8.21(dd,J=7.7,1.2Hz,1H),7.64(d,J=8.2Hz,1H),7.48(ddd,J=8.3, 7.2,1.2Hz,1H),7.31–7.18(m,9H),6.87–6.77(m,2H),5.63(s,2H),4.09(t,J=6.9Hz,2H),2.96(t,J=6.8Hz,2H).

[0169] 13 C NMR(75MHz,Chloroform-d)δ158.13,145.94,139.54,138.19,129.46,129.00,128.49,128. 38,126.82,126.50,121.03,120.60,120.03,115.26,114.68,109.97,68.64,44.54,35.75.

[0170] Example 17

[0171] The bardoxifen derivative of this invention, chemically named 9-(4-(3-trifluoromethyl)phenethoxy)benzyl-9H-pyrido[2,3-b]indole, has the following synthetic route:

[0172]

[0173] (1) Synthesis of intermediate IV2

[0174] 2-(3-(trifluoromethyl)phenyl)ethane-1-ol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol), and PPh3 (2.22 mmol) were stirred in 20 mL of dry THF at 0 °C under a nitrogen atmosphere. DIAD (2.22 mmol) was added dropwise to this mixture over 5 min, and the reaction was monitored by thin-layer chromatography. After the starting material had completely disappeared (1 h), the solvent was evaporated under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane / AcOEt, 8 / 2). After precipitation, 4-phenylethoxybenzaldehyde was obtained as a white powder, with a yield of 76%. 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.89–7.81(m,2H),7.73(s,1H),7.70–7.64(m,1H) ),7.62–7.52(m,2H),7.18–7.09(m,2H),4.37(t,J=6.7Hz,2H),3.19(t,J=6.7Hz,2H).

[0175] (2) Synthesis of intermediate V2

[0176] Intermediate IV1 (3.97 mmol) was added to solution A, followed by sodium borohydride (11.91 mmol). The mixture was stirred at room temperature for 2 hours. When the reaction was complete as indicated by TLC, 1 mol / L hydrochloric acid was added to quench the reaction until no more gas was released. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution. The methanol in the system was then removed by rotary evaporation, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain white solid V2, with a yield of 100%. 1 H NMR (400MHz, DMSO-d6) δ7.70 (d, J = 1.8Hz, 1H), 7.67–7.63 (m, 1H), 7.61–7.51 (m, 2H), 7.25–7.16 (m, 2H), 6. 91–6.83(m,2H),5.03(t,J=5.7Hz,1H),4.40(d,J=5.7Hz,2H),4.21(t,J=6.7Hz,2H),3.13(t,J=6.7Hz,2H).

[0177] (3) Synthesis of intermediate VI3

[0178] A tetrahydrofuran solution of intermediate V1 (27.11 mmol) was cooled to 0 °C, and thionyl chloride (30.35 mmol) was slowly added dropwise, followed by stirring overnight at room temperature. Once TLC showed the reaction was complete, the solution was directly evaporated to dryness without further purification to obtain intermediate VI1.

[0179] (4) Target compound I 17 Synthesis

[0180] A solution of 9H-pyrido[2,3-b]indole (416.17 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection. Sodium hydride (1.87 mmol) was added. After stirring the solution at 0 °C for 1 h, compound IV3 (457.79 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed that the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a white solid I. 17 The yield was 83%. 1H NMR (300MHz, DMSO-d6) δ8.56(dd,J=7.6,1.6Hz,1H),8.50(dd,J=4.9,1.6Hz,1H),8.21(dt,J=7.8,1.0Hz,1H),7. 65–7.44(m,6H),7.30–7.19(m,4H),6.86–6.78(m,2H),5.62(s,2H),4.13(t,J=6.6Hz,2H),3.07(t,J=6.6Hz,2H). 13 C NMR(75MHz,Chloroform-d)δ157.92,139.52,139.31,132.41,132.40,129.70,128.86,128.41,128.36, 126.82,125.81,125.76,123.36,121.04,120.05,116.02,115.27,114.67,109.94,68.05,44.51,35.51.

[0181] Example 18

[0182] The bardoxifen derivative of this invention, chemically named 9-(4-(2-(pyridin-2-yl)ethoxy)benzyl)-9H-pyrido[2,3-b]indole, has the following synthetic route:

[0183]

[0184] (1) Synthesis of intermediate IV3

[0185] 2-(pyridin-2-yl)ethane-1-ol (1.85 mmol), 4-hydroxybenzaldehyde (1.85 mmol), and PPh3 (2.22 mmol) were stirred in 20 mL of dry THF at 0 °C under a nitrogen atmosphere. DIAD (2.22 mmol) was added dropwise to this mixture over 5 min, and the reaction was monitored by thin-layer chromatography. After the starting material had completely disappeared (1 h), the solvent was evaporated under reduced pressure, and the resulting oil was purified by silica gel column chromatography (hexane / AcOEt, 8 / 2). Precipitation yielded 4-phenylethoxybenzaldehyde as a white powder, with a yield of 76%. 1H NMR(400MHz, DMSO-d6)δ9.86(s,1H),8.51(ddd,J=4.9,1.9,1.0Hz,1H),7.91–7.80(m,2H),7.73(td,J=7.7,1.9Hz,1H),7.3 7(dt,J=7.9,1.1Hz,1H),7.24(ddd,J=7.5,4.8,1.2Hz,1H),7.18–7.02(m,2H),4.49(t,J=6.6Hz,2H),3.22(t,J=6.6Hz,2H).

[0186] (2) Synthesis of intermediate V3

[0187] Intermediate IV3 (3.97 mmol) was added to solution A, followed by sodium borohydride (11.91 mmol). The mixture was stirred at room temperature for 2 hours. When the reaction was complete as indicated by TLC, 1 mol / L hydrochloric acid was added to quench the reaction until no more gas was released. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution. The methanol in the system was then removed by rotary evaporation, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain white solid V3, with a yield of 100%. 1 H NMR (400MHz, DMSO-d6) δ8.51(ddd,J=4.9,1.9,0.9Hz,1H),7.72(td,J=7.6,1.9Hz,1H),7.36(dt,J=7.9,1.1Hz,1H),7.27– 7.16 (m, 3H), 6.92–6.82 (m, 2H), 5.03 (t, J = 5.7Hz, 1H), 4.40 (d, J = 5.7Hz, 2H), 4.33 (t, J = 6.7Hz, 2H), 3.17 (t, J = 6.7Hz, 2H).

[0188] (3) Synthesis of intermediate VI3

[0189] A tetrahydrofuran solution of intermediate V3 (27.11 mmol) was cooled to 0 °C, and thionyl chloride (30.35 mmol) was slowly added dropwise, followed by stirring overnight at room temperature. Once TLC showed the reaction was complete, the solution was directly evaporated to dryness without further purification to obtain intermediate VI3.

[0190] (4) Target compound I 18 Synthesis

[0191] A solution of 9H-pyrido[2,3-b]indole (416.17 μmol) was obtained by stirring in anhydrous N,N-dimethylformamide under argon protection, followed by the addition of sodium hydride (1.87 mmol). After stirring the solution at 0 °C for 1 h, compound VI3 (457.79 μmol) was added, and the mixture was stirred at room temperature for 4 h. When TLC showed the reaction was complete, ice water was added, and the mixture was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound as a white solid I. 18 The yield was 83%.

[0192] 1 H NMR (300MHz, Chloroform-d) δ8.51 (dt, J=4.9, 1.4Hz, 2H), 8.33 (dd, J=7.7, 1. 6Hz,1H),8.07(dt,J=7.8,1.0Hz,1H),7.57(td,J=7.7,1.9Hz,1H),7.49–7.38( m,1H),7.38–7.32(m,1H),7.30–7.14(m,5H),7.11(ddd,J=7.6,4.9,1.2Hz,1H) ,6.86–6.72(m,2H),5.62(s,2H),4.28(t,J=6.6Hz,2H),3.20(t,J=6.6Hz,2H).

[0193] 13 C NMR(75MHz,Chloroform-d)δ158.45,158.09,149.27,146.15,139.51,136.48,129.54,128.34,128.19, 126.74,123.79,121.61,121.01,120.61,119.95,115.87,115.26,114.72,109.92,67.08,44.45,37.97.

[0194] application

[0195] 1. Detection of the inhibitory effect of compound I on colorectal cancer cell lines using the CCK-8 assay.

[0196] Using bardoxifene as a positive control, a 20 μM concentration was prepared for initial screening, and its inhibitory rate on HT29 cells at 20 μM was calculated. Compound I was prepared at the same concentration for initial screening, and compounds exhibiting lower inhibitory rates than bardoxifene were used for secondary screening. The concentration gradients of bardoxifene and compound I in the secondary screening were set at 0.94, 1.88, 3.75, 7.50, 15.00, and 30.00 μM. Both rounds of screening were applied to the colorectal cancer cell line HT29, with an initial cell number of 4000 cells per well. Cell viability was directly measured at 48 hours to determine the final IC50 of the compounds. 50 .

[0197] Cell viability = [(Experimental group readings - Blank group readings) / (Control group readings - Blank group readings)] × 100%.

[0198] Table 1 Inhibitory effect of compound I on HT29

[0199]

[0200]

[0201] 2. Growth inhibitory effect of compound I6 on HT29 cells

[0202] HT29 cells were seeded at 1000 cells per well in six-well plates. Different concentrations of I6 (1 μM, 2 μM, 4 μM, 8 μM, and 12 μM) were administered to the cells, along with a 0.1% DMSO control group. After 48 hours of treatment, the cells were washed with pre-cooled PBS and cultured for 10-14 days to allow them to aggregate. The cells were then fixed with 4% paraformaldehyde, stained with 1% crystal violet, and counted using Image J. The results are as follows:

[0203] In summary, based on the effect of badoxifene on GP130, we designed and synthesized a series of compounds I. In vitro studies on colorectal cancer cells HT29 showed that they could significantly inhibit the occurrence and development of colorectal cancer cells; this provides a possibility for the development of small-molecule antitumor drugs for colorectal cancer and has good application prospects.

Claims

1. A bardoxifene derivative, characterized in that, It has the structure shown in equation (I): Wherein, the A group is , or ; The B group is or ; n is 1, 2, or 3; When the B group is When, group A is or .

2. A bardoxifene derivative, characterized in that, The badoxifen derivative has any of the following compound structures: 、 、 、 。 3. The use of any one of the bardoxifene derivatives according to claims 1 to 2 in the preparation of a drug for treating tumors.

Images