Selective estrogen receptor down-regulator compound, preparation method and use

Abstract

The present invention discloses a selective estrogen receptor down-regulator compound, a preparation method and a use thereof. The invention relates to the field of pharmaceutical chemistry; the compound disclosed in the present invention is an orally available estrogen receptor down-regulator, whose activity is at the nanomolar level, and has a very significant effect on the prevention of tumors such as breast cancer; the cyclin-dependent kinase (CDK) 4 / 6 inhibitor described in the present invention belongs to a new class of drugs, which plays an important role in the treatment of HR+, HER2-breast cancer patients, and can be used in combination with an estrogen receptor down-regulator to exert an anti-tumor effect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of selective estrogen receptor down-regulator compounds, preparation methods and uses thereof. Background Art

[0002] Estrogen plays a role in protein synthesis, coagulation, lipid balance, fluid balance, melanin, gastrointestinal function, lung function, cognition, immune response and heart disease. Estrogen receptors (ER) are ligand-activated transcriptional regulatory proteins that mediate the induction of a variety of biological effects by interacting with endogenous estrogens (including 17β-estradiol and estrogens). ER has been found to have two subtypes, ERα and ERβ, and both subtypes are involved in the regulation and development of the female reproductive tract. ER and estrogens regulate biological processes through several different pathways. The classical pathway involves the binding of ligand-activated ER to specific DNA sequence motifs of estrogen response elements (EREs). The goal of drug development is to develop new compounds that modulate estrogen activity by acting as antagonists or agonists or as partial antagonists or partial agonists. Fulvestrant is an example of a complete estrogen receptor antagonist without agonist activity, which is a selective estrogen receptor downregulator (SERD), disclosed by Imperial Chemical Industries (ICI) in US Patent No. 4,659,516 and sold by Astra Zeneca under the trade name Faslodex. It is used to treat hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after anti-estrogen therapy. Fulvestrant has limited water solubility and can only be injected intramuscularly (TM), not orally. Patient compliance is poor and clinical use is limited. Another class of anti-estrogen is selective estrogen receptor modulators (SERMs), which act as antagonists or agonists in a gene-specific or tissue-specific manner. The goal of SERM therapy is to provide favorable targeted anti-estrogen activity and avoid adverse off-target effects or exhibit incidental favorable estrogen side effects (J Med Chem 2020, 63, 15094-15114.). An example of a SERM is tamoxifen, originally marketed by AstraZeneca under the trade name Nolvadex and also disclosed by ICI in US Patent No. 4,659,516. (See also US Patent Nos. 6,774,122 and 7,456,160). Tamoxifen is used for further breast cancer after breast cancer treatment and for treating lymph node-positive breast cancer in women after mastectomy and radiotherapy. Tamoxifen can affect bone health, can cause osteopenia (bone thinning) in premenopausal women, and may be beneficial for bone health in postmenopausal women. Its serious side effects include increasing the risk of uterine cancer in postmenopausal women and "tumor flares" in women with breast cancer that spreads to the bone. In addition to these side effects, acquired drug resistance is also a problem. In some cases, ER-positive breast cancer not only becomes tamoxifen-resistant, but also tamoxifen becomes an agonist that induces tumor proliferation.The third-line treatment of breast cancer includes steroidal and nonsteroidal aromatase inhibitors (AIs), which block the production of estrogen and thus block ER-dependent growth. These drugs (which include letrozole, anastrozole, and exemestane) have the risk of removing all estrogen from women after menopause, thereby increasing the risk of osteopenia, osteoporosis, and fractures (J Med Chem 2019, 62, 11301-11323.).

[0003] A variety of SERDs, SERMs and AIs have been disclosed. The SERM raloxifene was disclosed by Eli Lilly in 1981 (US Patent Nos. 4,418,068; 5,478,847; 5,393,763 and 5,457,117) for preventing breast cancer and treating osteoporosis. In June 2011, Aragon Pharmaceuticals disclosed benzopyran derivatives and acolbifene analogs for treating tamoxifen-resistant breast cancer (see WO2011 / 156518, US Patent Nos. 8,455,534 and 8,299,112). Genentech discloses a series of tetrahydropyrido [3,4-b] indole-1-yl compounds with estrogen receptor modulating activity in US2016 / 0175289 and discloses three compounds (one of which, GDN-0810) in US2015 / 0258080 for combined therapy of estrogen receptor modulation. AstraZeneca is currently developing AZD9496, a novel oral selective estrogen receptor down-regulator for patients with estrogen receptor-positive breast cancer (WO 2014 / 191726). Considering the usually catastrophic effects of estrogen regulation disorders (including cancer, tumors and especially breast cancer), there is still a strong demand for the production of new drugs with significant anti-estrogen efficacy without unacceptable side effects. Summary of the invention

[0004] In view of the above problems, the present invention provides a novel selective estrogen receptor down-regulator compound (SERD).

[0005] Another object of the present invention is to provide a preparation method and use of the selective estrogen receptor down-regulator compound.

[0006] The technical solution of the present invention is: the present invention discloses a selective estrogen receptor down-regulator compound, characterized in that the chemical structural formula of the compound is as shown in formula (I):

[0007]

[0008] Where:

[0009] m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4;

[0010] X is selected from -O-, -CH2-, -S-, -NR 17 , -CHF-, -CF2- and cycloalkyl; Y is selected from -C(O)-, -CF2-, cycloalkyl, -CH2- and -CHF-;

[0011] Ring B is selected from phenyl, biphenyl, naphthyl, quinolyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl; Ring A is selected from phenyl, heteroaryl, phenylthio, 5- or 6-membered monocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;

[0012] R1 is selected from -CH=CHCOOR 17 、-NR 17 (CO)COOR 17 、-COOR 17 , cycloalkyl-COOR 17 、-C2-C6 alkenylene-COOR 17 、-C2-C6 alkynylene-COOR 17 、-CH=CHC(O)R 16 , -COOH, -NH(CO)COOH, -CH=CHCOOH, -NR 17 (CO)C(O)R 16 、-C(O)R 16 , -cycloalkyl-C(O)R 16 、-C2-C6 alkenylene-C(O)R 16 and -C2-C6 alkynylene-C(O)R 16 ;

[0013] R2 and R3 are selected from -OR 15 、-SR 15 、-N(R 15 )2, hydrogen, aryl, heteroaryl, halogen, -CN, -NO2, haloalkyl, cycloalkyl, thiol, nitroso, C1-C6 alkyl, hydroxyl, -O(C1-C6 alkyl), -O(C1-C6 fluoroalkyl), -SF5, -B(OH)2, -B(OR 15 )2. -C(O)OR 15 、-C(O)R 16 、-C(S)R 16 、-OSO2OR 15 、-OSO2R 16 、-NHSO2OR 15 、-NHSO2R 16 、-N(alkyl)SO2OR15 、-N(alkyl)SO2R 16 、-OP(O)(OR 15 )2.-OP(O)(R 16 )2、-P(O)(OR 15 )3. -P(O)(R 16 )3. -P(O)OR 15 、-P(O)R 16 、-SO2R 16 、-SO2OR 15 , alkyne, alkene, arylalkyl, aryloxy, heteroarylalkyl and C1-C6 fluoroalkyl;

[0014] Among them, R 15 R is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; 16 is independently selected at each occurrence from -N(R 15 )2. -SR 15 、-OR 15 ; R 17 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C(O)R 15 、-C(S)R 15 、-C(O)R 16 、-C(S)R 16 and heteroaryl.

[0015] Furthermore, the R1 is selected from -COOH, -NH(CO)COOH or -CH=CHCOOH.

[0016] Further, the ring A is phenyl or a 5- or 6-membered monocyclic heteroaryl.

[0017] Furthermore, the ring B is phenyl, biphenyl, naphthyl or quinolyl.

[0018] Further, the compound is any one of the following:

[0019]

[0020] Further, its specific synthetic route is as follows:

[0021] Synthetic route 1:

[0022]

[0023] Synthetic line 2:

[0024]

[0025] Furthermore, a pharmaceutical composition contains a therapeutically effective amount of the selective estrogen receptor down-regulator compound and a pharmaceutically acceptable carrier.

[0026] Furthermore, the selective estrogen receptor down-regulator compound is used in the preparation of a drug for treating estrogen-related disorders.

[0027] Furthermore, in the use described, the estrogen-related disorder is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, lung cancer, cancer that has metastasized to the bone, or bone loss; the breast cancer is hormone receptor-positive metastatic breast cancer, tamoxifen-resistant breast cancer, or triple-negative breast cancer.

[0028] The cyclin-dependent kinase (CDK) 4 / 6 inhibitors of the present invention belong to a new class of drugs that interrupt the proliferation of malignant cells by inhibiting the progression of the cell cycle. The three inhibitors, palbociclib, ribociclib and abemaciclib, have recently been approved for the treatment of breast cancer in various settings and combination regimens. Based on their impressive efficacy, all three CDK4 / 6 inhibitors now play an important role in the treatment of HR+, HER2- breast cancer patients.

[0029] The combination therapy with CDK4 / 6 includes but is not limited to three inhibitors: palbociclib, ribociclib and abemaciclib.

[0030] The beneficial effect of the present invention is that the compound disclosed in the present invention is an orally administrable estrogen receptor down-regulator, the activity of which reaches the nanomolar level, and has a very significant effect on the prevention of tumors such as breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is a Western blot analysis diagram in an embodiment of the present invention;

[0032] Figure 2 is an immunofluorescence analysis diagram in an embodiment of the present invention;

[0033] Figure 3 In the present embodiment, a bar graph showing the effects of compound 10 and 21 group, fulvestrant and tamoxifen group and control group on ERE luciferase transcriptional activity in MCF-7 cells is shown, the y-axis is the relevant ERE luciferase transcriptional activity, and the x-axis is the compound 10 and 21 group, fulvestrant and tamoxifen group and control group;

[0034] Figure 4is a graph showing that compounds 10 and 21 induce G0 / G1 phase arrest of MCF-7 cell cycle in the examples of the present invention, the y-axis is the number of MCF-7 cells, and the x-axis is the region range of the cell cycle. After treatment with 10 and 21 for 24 hours, MCF-7 cells were collected, stained with PI, and analyzed by flow cytometry. Compared with the control group DMSO, *p<0.05, **p<0.01;

[0035] Figure 5 is a bar graph showing the effects of compounds 10 and 21 on the ER signaling pathway in the examples of the present invention, the y-axis is the expression of GREB1, PGR, and TFF1 genes in MCF-7 cells, and the x-axis is the region range of cell cycles treated with different concentrations of compounds, N=3, ns>0.05, *p<0.05, **p<0.01, ***p<0.001;

[0036] Figure 6 is a graph showing an in vivo PK study of compound 10 in an embodiment of the present invention, wherein the y-axis is the concentration of compound 10 in mouse blood, and the x-axis is the corresponding time, and a complete PK (including intravenous injection of 5 mg / kg and oral administration of 20 mg / kg) was performed on compound 10 that exhibited the best antiproliferative properties in the in vitro test;

[0037] Figure 7 The graphs and histograms of the compound control group, group 10, group 21, fulvestrant group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, and 21+ribociclib group in the embodiments of the present invention show the changes in mouse transplanted tumor volume and mouse body weight, as well as the changes in mouse tumor volume and tumor-bearing size over time in the oral control group, group 10, group 21, fulvestrant group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, and 21+ribociclib group 7A is a graph of mouse breast cancer tumors after 30 days of administration; in FIG. 7B, the y-axis is the mouse weight and the x-axis is time; in FIG. 7C and FIG. 7D, the y-axis is the mouse transplanted tumor volume and tumor weight, and the x-axis is the corresponding control group, compound 10 group, 21 group, fulvestrant group, ribociclib group, fulvestrant + ribociclib group, 10 + ribociclib group, 21 + ribociclib group; in FIG. 7E, the y-axis is the mouse transplanted tumor volume, and the x-axis is time. The long diameter (a) and short diameter (b) of the tumor were measured with a vernier caliper, and the tumor volume was calculated according to the following formula: V = 1 / 2 × a × b 2 When the average tumor volume reaches 100 mm3 At about 14:00 p.m., the mice were randomly divided into 8 groups (n=8 in each group), named as control group, fulvestrant group, 10 group, 21 group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, 21+ribociclib group; the mice in the fulvestrant group were subcutaneously injected with fulvestrant 250 mg / kg once a week; the mice in the 10 group were orally administered with 10 60 mg / kg every day; the mice in the 21 group were intragastrically administered with 21 60 mg / kg every day; the mice were orally administered with ribociclib 60 mg / kg every day. The mice in the fulvestrant+ribociclib group were orally administered with ribociclib 60 mg / kg every day, and a single subcutaneous injection of fulvestrant 250 mg / kg was given weekly; the mice in the 10+ribociclib group were orally administered with 10 60 mg / kg and ribociclib 60 mg / kg every day. Mice in the 21+ribociclib group were orally administered 21 and ribociclib 60 mg / kg daily; the body weight and tumor volume of the mice were recorded every 5 days during the 30 days of administration;

[0038] Figure 8 HE-stained sections showing the effects on mouse heart, liver, spleen, lung and kidney tissues in the examples of the present invention, the heart, liver, spleen, kidney and rat uterus were selected for histological examination, the tissues were dissected, embedded in paraffin, sliced ​​(6 μm thick), and the slices were stained with hematoxylin and eosin (H&E);

[0039] Fig. 9 is a curve graph showing the effects of the control group, fulvestrant group, 10 group, 21 group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, and 21+ribociclib group on the expression of Ki67, ER, and PR in mouse tumor tissues in the examples of the present invention, Fig. 9 In A, 9B, and 9C, the y-axis of the line graphs is the expression index of Ki67, ER, and PR in mouse tumor tissues, and the x-axis is the control group, fulvestrant group, 10 group, 21 group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, and 21+ribociclib group, *p<0.05, **p<0.01;

[0040] Fig.1010A is an H&E staining image and a cubic graph showing the effects of compound 10 and 21 groups, estrogen group, fulvestrant group and control group on the endometrium of female rat pups in the examples of the present invention. 10B is an H&E staining image, the y-axis of FIG. 10B is the ratio of wet weight of uterus to body weight of female rat pups, and the x-axis is compound 10 and 21 groups, estrogen group, fulvestrant group and control group. DETAILED DESCRIPTION

[0041] In order to more clearly illustrate the technical solution of the present invention, the technical solution of the present invention is further described in detail below:

[0042]

[0043] The following table shows the types of intermediates synthesized in reaction route 1:

[0044]

[0045]

[0046] Synthesis step 1

[0047] Intermediate 1: 7-(Benzyloxy)-4-hydroxyquinoline-3-carboxylic acid ethyl ester

[0048] The synthesis steps of intermediate 1 are as follows: Tribenzyloxyaniline (2 g, 10.00 mmol) is placed in a 100 ml round-bottom flask, and then diethyl ethoxymethylenemalonate (3.256 g, 15.00 mmol) is added, and the mixture is placed in an oil bath at 120°C for 2 h, and the generated ethanol is removed with a water separator; then 25 ml of diphenyl ether is added, and the mixture is heated to 250°C and reacted for 5 h, and the reaction end point is monitored by TLC; after the reaction is completed, 40 ml of n-hexane is added to the reaction solution after it is cooled, and a solid precipitates. The solid is filtered, and the filter cake is washed with ethanol and dried to obtain a brown solid with a yield of 51.4%. 1 H NMR (500MHz, DMSO-d6) δ12.12(s,1H),8.47(d,J=4.5Hz,1H),8.06(d,J=9.6Hz,1H),7.49(d,J=7.2Hz,2H),7.42(t, J=7.4Hz,2H),7.36(t,J=7.3Hz,1H),7.10–7.06(m,2H),5.22(s,2H),4.19(q,J=7.0Hz,2H),1.27(t,J=7.1Hz,3H).

[0049]

[0050] Synthesis step 2

[0051] Intermediate 2: 7-(Benzyloxy)-4-chloroquinoline-3-carboxylic acid ethyl ester

[0052] The synthesis steps of intermediate 2 are as follows: compound 1 (1 g, 3.09 mmol) was added to a 100 ml round-bottom flask, and then 6 ml of toluene, SOCl2 (11 g, 92.77 mmol), and 1 ml of DMF were added. The temperature was raised to 70°C and refluxed for 8 h. The reaction end point was monitored by TLC. After the reaction was completed, the reaction solution was cooled and added dropwise to an ice-water mixture to remove excess SOCl2, and then extracted with DCM for 3 times. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The yellow solid was separated by silica gel column chromatography with a yield of 58.7%. 1 HNMR(500MHz,DMSO-d6)δ9.10(s,1H),8.30(d,J=9.2Hz,1H),7.63(d,J=2.6Hz,1H),7.58–7.51(m,4H), 7.43(t,J=7.5Hz,3H),7.37(t,J=7.3Hz,2H),5.36(s,2H),4.41(q,J=7.1Hz,3H),1.38(t,J=7.1Hz,4H). 13 C NMR (126MHz, CDCl3) δ164.49,161.86,151.31,150.96,143.87,135.72,128.79,128.46,12 7.84,126.97,121.99,121.53,120.84,108.73,77.32,77.07,76.81,70.79,61.99,14.35.

[0053]

[0054] Synthesis step 3

[0055] Intermediate 3: (7-(Benzyloxy)-4-chloroquinolin-3-yl)methanol

[0056] The synthesis steps of intermediate 3 are as follows: compound 2 (620 mg, 1.81 mmol) was added to a 100 ml round-bottom flask, and then 6 ml of anhydrous THF was added and stirred evenly; 1 mol / L diisobutylaluminum hydride (5.44 ml, 5.44 mmol) was added dropwise under ice bath conditions; after the addition was completed, the mixture was stirred at room temperature for 20 minutes, and the reaction end point was monitored by TLC; after the reaction was completed, saturated potassium sodium tartrate aqueous solution was added to the reaction solution under ice bath conditions, and the mixture was stirred overnight to decompose the aluminum salt; the reaction solution was extracted with EA 3 times, the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid with a yield of 86.4%. 1H NMR (500MHz, DMSO-d6) δ8.89(s,1H),8.12(d,J=9.2Hz,1H),7.56(d,J=2.6Hz,1H),7.52(d,J=7.4Hz,3H),7.47(dd,J=9 .3,2.5Hz,1H),7.42(t,J=7.5Hz,2H),7.36(t,J=7.3Hz,1H),5.57(t,J=5.7Hz,1H),5.31(s,2H),4.77(d,J=5.6Hz,2H). 13 C NMR(126MHz,Chloroform-d)δ160.43,150.69,150.17,141.03,136.17,128. 94,128.84,128.44,127.88,125.42,121.48,121.38,108.54,70.48,61.07.

[0057]

[0058] Synthesis step 4

[0059] Intermediate 4: 7-(Benzyloxy)-4-chloroquinoline-3-carboxaldehyde

[0060] The synthesis steps of intermediate 4 are as follows: compound 3 (450 mg, 1.50 mmol) was added to a 100 ml round-bottom flask, and then 6 ml of anhydrous DCM was added and stirred evenly; Dess-Martin oxidant (1.27 g, 3.00 mmol) was slowly added under ice bath conditions, and then reacted at room temperature for 20 minutes; TLC was used to monitor the reaction endpoint, and after the reaction was completed, saturated sodium bicarbonate aqueous solution was added to the reaction solution under ice bath conditions to remove excess oxidant and acetic acid; the reaction solution was extracted with DCM three times, the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid with a yield of 87%. 1 H NMR (500MHz, DMSO-d6) δ10.49(s,1H),9.08(s,1H),8.33(d,J=9.3Hz,1H),7.65(d,J=2.5Hz,1H),7.58( dd,J=9.3,2.6Hz,1H),7.53(d,J=7.1Hz,2H),7.43(t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),5.38(s,2H). 13C NMR(126MHz,Chloroform-d)δ188.97,163.03,152.99,149.42,147.89,135. 65,128.93,128.65,127.89,126.66,123.10,122.26,120.78,109.39,70.85.

[0061]

[0062] Synthesis steps 1-5

[0063] Synthesis steps of intermediate 1-5-aq:

[0064] Add 6.72 mmol of the Br-substituted aromatic hydrocarbon of ring A into a dried 50 ml round-bottom flask, and then add 6 ml of anhydrous THF, Mg powder (163.2 mg, 6.72 mmol), and a catalytic amount of iodine in sequence. Under N2 protection, heat to 80°C and reflux for 3 h. After the reaction solution is cooled, slowly dropwise add the reaction solution to an anhydrous THF solution of compound 4 (400 mg, 1.34 mmol) under ice bath conditions. After the addition is complete, react at room temperature for 10 minutes. Monitor the reaction endpoint by TLC. After the reaction is completed, add 1 M dilute hydrochloric acid to the reaction solution under ice bath conditions to remove excess Mg powder and Mg salt. Extract the reaction solution with EA 3 times, collect the organic phase, dry it with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and separate it by silica gel column chromatography to obtain a yellow solid or oil.

[0065] Intermediate 1-5-a: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(phenyl)methanol

[0066] 1 H NMR (500MHz, DMSO-d6) δ8.97(s,1H),8.12(d,J=9.3Hz,1H),7.55(d,J=2.6Hz,1H),7.51(d,J=7.3Hz,3H),7.47(dd,J=9.2,2.6H z,1H),7.44–7.39(m,9H),7.37–7.29(m,3H),7.24(t,J=7.3Hz,1H),6.40(d,J=4.2Hz,1H),6.25(d,J=4.1Hz,1H),5.31(s,2H). 13CNMR(126MHz,Chloroform-d)δ160.48,149.93,149.79,142.06,140.17,136.19,131.72,128 .86,128.84,128.43,128.20,127.86,126.76,125.66,121.45,121.24,108.64,71.94,70.51.

[0067] The following intermediates were prepared by a similar process to steps 1-5 using appropriate starting materials:

[0068] Intermediate 1-5-b: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(3-fluorophenyl)methanol

[0069] 1 H NMR (500MHz, DMSO-d6) δ8.94(s,1H),8.13(d,J=9.3Hz,1H),7.56(d,J=2.6Hz,1H),7.51(d,J=7.2Hz,2H),7.48(dd,J=9.2,2.6Hz,1H),7.41(t,J=7.4 Hz,2H),7.38–7.32(m,2H),7.28(d,J=10.2Hz,1H),7.21(d,J=7.7Hz,1H), 7.09(td,J=8.5,2.7Hz,1H), 6.53(d,J=4.4Hz,1H), 6.27(d,J=4.3Hz,1H). 13 C NMR(126MHz,Chloroform-d)δ163.10(d,J=246.4Hz),160.64,149.81,149.73,144.67(d,J=6.1Hz),140.31,136.12,131.42,130.36(d,J=8.2H z),128.85,128.45,127.86,125.71,122.21(d,J=2.7Hz),121.62,121. 16,114.99(d,J=21.1Hz),113.69(d,J=22.4Hz),108.52,71.11,70.54.

[0070] Intermediate 1-5-c: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluorophenyl)methanol

[0071] 1H NMR(500MHz,Chloroform-d)δ8.99(s,1H),8.10(d,J=9.2Hz,1H),7.51–7.46(m,3H),7 .44–7.38(m,4H),7.37–7.33(m,2H),7.02(t,J=8.7Hz,2H),6.42(s,1H),5.19(s,2H). 13 C NMR(126MHz,Chloroform-d)δ162.49(d,J=247.0Hz),160.62,149.66,149.60,140.25,137.84(d,J=3.1Hz),136.12,131 .65,128.85,128.53(d,J=8.2Hz),128.46,127.87,125.65,121.63,121.20,115.72(d,J=21.6Hz),108.47,71.26,70.55.

[0072] Intermediate 1-5-d: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-(trifluoromethyl)phenyl)methanol

[0073] 1 H NMR(500MHz,Chloroform-d)δ8.85(s,1H),8.07(d,J=9.2Hz,1H),7.68(d,J=7.8Hz,1H),7.54–7 .49(m,2H),7.47–7.43(m,3H),7.42–7.35(m,3H),7.35–7.29(m,2H),6.74(s,1H),5.16(s,2H). 13 C NMR(126MHz,Chloroform-d)δ160.62,149.78,149.70,141.11,140.11,136.10,132.40,130.78,129. 06,128.77,128.37,128.30,127.82,126.47,126.42,125.60,121.58,121.39,108.19,70.46,67.75.

[0074] Intermediate 1-5-e: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanol

[0075] 1H NMR (500MHz, DMSO-d6) δ8.94(s,1H),8.13(d,J=9.3Hz,1H),7.70(d,J=8.3Hz,2H),7.65(d,J=8.2Hz,2H),7.56(d,J=2.6Hz,1H),7.51(d,J=7. 3Hz,2H),7.48(dd,J=9.2,2.6Hz,1H),7.41(t,J=7.5Hz,2H),7.35(t,J=7.3Hz,1H),6.62(d,J=4.3Hz,1H),6.34(d,J=4.1Hz,1H),5.31(s,2H). 13 C NMR(126MHz,DMSO-d6)δ159.79,150.24,149.31,147.83,140.49,138.18,136.43,132.15,128 .51,128.03,127.85,127.18,125.35,125.31,125.25,121.23,120.01,109.13,69.74,69.51.

[0076] Intermediate 1-5-f: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-(trifluoromethoxy)phenyl)methanol

[0077] 1 H NMR(500MHz,Chloroform-d)δ8.93(s,1H),8.06(d,J=9.3Hz,1H),7.47(d,J=7.9Hz,5H),7 .40(t,J=7.4Hz,2H),7.37–7.30(m,2H),7.17(d,J=8.3Hz,2H),6.43(s,1H),5.16(s,2H). 13 C NMR(126MHz,Chloroform-d)δ160.65,149.67,149.60,148.86,140.77,140.26,136.09,131. 60,128.84,128.46,128.14,127.86,125.65,121.65,121.21,121.12,108.37,70.93,70.53.

[0078] Intermediate 1-5-g: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-methoxyphenyl)methanol

[0079] 1H NMR(500MHz,Chloroform-d)δ9.06(s,1H),8.09(d,J=9.2Hz,1H),7.52–7.46(m,3H),7.40(t,J =7.4Hz,2H),7.37–7.31(m,4H),6.86(d,J=8.8Hz,2H),6.37(s,1H),5.18(s,2H),3.77(s,3H). 13 C NMR(126MHz,Chloroform-d)δ160.42,159.45,149.75,149.67,140.04,136.21,134.31,131.97, 128.83,128.42,128.19,127.88,125.58,121.41,121.28,114.20,108.51,71.63,70.50,55.42.

[0080] Intermediate 1-5-h: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(thiophen-2-yl)methanol

[0081] 1 H NMR(500MHz,Chloroform-d)δ9.08(s,1H),8.10(d,J=9.2Hz,1H),7.52–7.46(m,3H),7.41(t,J= 7.4Hz,2H),7.37–7.32(m,2H),7.29–7.26(m,1H),6.95–6.92(m,2H),6.65(s,1H),5.19(s,2H). 13 C NMR(126MHz,Chloroform-d)δ160.62,149.82,149.50,146.12,140.12,136.15,131.38,128. 85,128.45,127.88,127.00,125.93,125.69,125.32,121.57,121.12,108.53,70.54,68.28.

[0082] Intermediate 1-5-i: benzofuran-5-yl(7-(benzyloxy)-4-chloroquinolin-3-yl)methanol

[0083] 1H NMR(500MHz,Chloroform-d)δ9.11(s,1H),8.05(d,J=9.3Hz,1H),7.64(s,1H),7.58(s,1H),7.55( s,1H),7.45(d,J=7.5Hz,2H),7.43–7.30(m,7H),6.69(d,J=2.2Hz,1H),6.50(s,1H),5.15(s,2H). 13 C NMR(126MHz,Chloroform-d)δ160.78,154.63,148.99,145.80,136.73,136.03,132.49,131.18,128.80, 128.43,127.93,127.77,125.64,123.43,121.80,121.39,119.72,111.72,107.52,106.84,71.94,70.59.

[0084] Intermediate 1-5-j: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-ethylphenyl)methanol

[0085] 1 H NMR(500MHz,Chloroform-d)δ8.83(s,1H),8.09(d,J=9.2Hz,1H),7.50–7.45(m,3H),7.43–7.35(m,4H),7.33( dd,J=9.2,2.5Hz,1H),7.29–7.17(m,3H),6.59(s,1H),5.15(s,2H),2.79–2.58(m,2H),1.19(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ160.50,150.36,149.81,141.89,140.84,138.99,136.19,131.32,128.99,128 .82,128.45,128.42,127.89,126.74,126.36,125.61,121.47,121.28,108.44,70.49,68.73,27.05,15.18.

[0086] Intermediate 1-5-k: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-isopropylphenyl)methanol

[0087] 1H NMR(500MHz,Chloroform-d)δ8.82(s,1H),8.10(d,J=9.2Hz,1H),7.52–7.45(m,3H),7.41(t,J=7.4Hz,2H),7.38–7.28(m, 5H),7.18(t,J=7.9Hz,1H),6.68(s,1H),5.16(s,2H),3.27(p,J=6.8Hz,1H),1.29(d,J=6.7Hz,3H),1.06(d,J=6.8Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ160.49,150.45,149.87,146.82,140.67,138.02,136.16,131.47,128.84,128.67 ,128.44,127.91,126.66,126.20,126.07,125.62,121.49,121.26,108.47,70.49,68.62,28.67,24.52,23.74.

[0088] Intermediate 1-5-1: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2,6-dimethylphenyl)methanol

[0089] 1 H NMR(500MHz,Chloroform-d)δ9.01(s,1H),8.11(d,J=9.3Hz,1H),7.50–7.46(m,3H),7.43–7.39(m,2H ),7.37–7.32(m,2H),7.14–7.10(m,1H),7.02(d,J=7.6Hz,2H),6.58(s,1H),5.18(s,2H),2.31(s,6H). 13 C NMR(126MHz,Chloroform-d)δ160.30,150.50,149.64,140.41,137.10,136.83,136.11,130.73, 129.65,128.71,128.30,128.26,127.77,125.22,121.36,121.27,108.34,70.38,69.69,21.24.

[0090] Intermediate 1-5-m: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(3,5-dimethylphenyl)methanol

[0091] 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.03(d,J=9.2Hz,1H),7.57(d,J=2.5Hz,1H),7.49(d,J=7.2Hz,2H),7.41(t,J=7 .3Hz,2H),7.38–7.35(m,1H),7.30(dd,J=9.2,2.5Hz,1H),7.05(s,2H),6.88(s,1H),6.33(s,1H),5.16(s,2H),2.27(s,6H). 13 C NMR(126MHz,Chloroform-d)δ160.50,149.36,141.96,141.19,138.26,137.48,136.08,132.48, 129.66,128.72,128.34,127.91,125.54,124.54,123.92,121.48,107.50,71.52,70.47,21.41.

[0092] Intermediate 1-5-n: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2,4-dimethylphenyl)methanol

[0093] 1 H NMR(500MHz,Chloroform-d)δ8.93(s,1H),8.11(d,J=9.2Hz,1H),7.61(d,J=2.5Hz,1H),7.49(d,J=7.2Hz,2H),7.40(t,J=7 .3Hz,2H),7.37–7.32(m,2H),7.19(d,J=7.7Hz,1H),7.01–6.96(m,2H),6.49(s,1H),5.21(s,2H),2.32(s,3H),2.29(s,3H). 13 C NMR(126MHz,Chloroform-d)δ160.71,149.66,141.45,137.99,136.61,136.13,135.85,131.73,128.82 ,128.43,128.03,127.94,127.13,126.65,125.63,121.71,121.42,107.83,70.60,69.11,21.16,19.26.

[0094] Intermediate 1-5-o: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluoro-2-methylphenyl)methanol

[0095] 1H NMR(500MHz,Chloroform-d)δ8.75(s,1H),8.02(d,J=9.3Hz,1H),7.49–7.45(m,2H),7.43–7.38(m,3H),7. 38–7.34(m,1H),7.33–7.27(m,2H),6.87–6.81(m,2H),6.41(s,1H),5.11(s,2H),4.80(s,1H),2.24(s,3H). 13 C NMR (126MHz, Chloroform-d) δ 162.23 (d, J = 246.3Hz), 160.57, 149.87, 149.39, 141.08, 138.36 (d, J = 8.0Hz), 136.06, 135.59 (d, J = 2.8Hz), 131.02, 128.79,128.42,128.34(d,J=8.5Hz),127.88,125.55,121.59,121.16,1 17.45(d,J=21.2Hz),112.92(d,J=20.9Hz),107.94,70.45,68.40,19.29.

[0096] Intermediate 1-5-p: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-chloro-2-methylphenyl)methanol

[0097] 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),8.09(d,J=9.3Hz,1H),7.52–7.46(m,3H),7.40(t ,J=7.4Hz,2H),7.37–7.30(m,3H),7.18–7.14(m,2H),6.45(s,1H),5.18(s,2H),2.25(s,3H). 13 C NMR(126MHz,Chloroform-d)δ160.74,149.78,149.57,141.44,141.29,138.14,137.78,136.07,133.77, 130.70,130.55,128.84,128.47,128.03,126.49,125.66,121.77,121.25,108.14,70.56,68.69,19.18.

[0098] Intermediate 1-5-q: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluoro-2,6-dimethylphenyl)methanol

[0099] 1 H NMR(500MHz,Chloroform-d)δ9.00(s,1H),8.12(d,J=9.3Hz,1H),7.51(d,J=2.5Hz,1H),7.49(d,J=7.1Hz,2 H),7.41(t,J=7.4Hz,2H),7.38–7.33(m,2H),6.74(d,J=9.3Hz,2H),6.54(s,1H),5.20(s,2H),2.31(s,6H). 13 C NMR(126MHz,Chloroform-d)δ161.99(d,J=246.6Hz),160.58,150.24,149.68,144.40,139.86(d,J=8.2Hz),136.16,132.84(d,J=3 .3Hz),130.55,128.86,128.46,127.88,125.36,121.59,121.47,116.13(d,J=20.5Hz),108.41,70.57,69.28,21.51(d,J=1.6Hz).

[0100]

[0101] Synthesis steps 1-6

[0102] Synthesis steps of intermediate 1-6-aq:

[0103] Add 1-5-aq (1.02 mmol) to a 100 ml round-bottom flask, add 6 ml of anhydrous DCM, and stir evenly; slowly add Dess-Martin oxidant (2.04 mmol) under ice bath condition, and then react at room temperature for 20 minutes; monitor the reaction endpoint by TLC, and after the reaction is completed, add saturated sodium bicarbonate aqueous solution to the reaction solution under ice bath condition to remove excess oxidant and acetic acid; extract the reaction solution with DCM for 3 times, collect the organic phase, dry it with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and separate it by silica gel column chromatography to obtain a yellow solid or oil.

[0104] Intermediate 1-6-a: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(phenyl)methanone

[0105] 1H NMR(500MHz,Chloroform-d)δ8.77(s,1H),8.24(d,J=9.2Hz,1H),7.86(d,J=7.7Hz,2H),7.64(t,J=7.4H z,1H),7.60(d,J=2.5Hz,1H),7.53–7.47(m,4H),7.47–7.41(m,3H),7.37(t,J=7.4Hz,1H),5.27(s,2H). 13 C NMR(126MHz,Chloroform-d)δ193.69,161.39,151.17,149.15,140.36,136.77,135.89,134. 06,130.12,129.28,128.86,128.81,128.44,127.76,126.09,122.11,120.97,109.01,70.56.

[0106] Intermediate 1-6-b: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(3-fluorophenyl)methanone

[0107] 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),8.22(d,J=9.2Hz,1H),7.60–7.56(m ,3H),7.50(d,J=7.1Hz,2H),7.47–7.40(m,4H),7.39–7.30(m,2H),5.26(s,2H). 13 C NMR(126MHz,Chloroform-d)δ192.58(d,J=2.4Hz),162.98(d,J=248.9Hz),161.64,151.37,149.03,140.61,138.96(d,J=6.4Hz),135.87,130.60(d,J =7.7Hz),128.87,128.75,128.52,127.82,126.18,126.10(d,J=3.0Hz),12 2.35, 121.15 (d, J = 21.5Hz), 120.95, 116.47 (d, J = 22.6Hz), 109.05, 70.66.

[0108] Intermediate 1-6-c: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluorophenyl)methanone

[0109] 1H NMR(500MHz,Chloroform-d)δ8.75(s,1H),8.23(d,J=9.2Hz,1H),7.92–7.84(m,2H),7.57(d,J=2.5Hz,1 H),7.51(d,J=7.1Hz,2H),7.48–7.41(m,3H),7.37(t,J=7.3Hz,1H),7.17(t,J=8.6Hz,2H),5.27(s,2H). 13 C NMR(126MHz,Chloroform-d)δ192.24,166.46(d,J=257.0Hz),161.58,151.30,149.02,140.41,135.92,133.30(d,J=3.0H z), 132.92 (d, J = 9.6Hz), 129.10, 128.91, 128.56, 127.86, 126.17, 122.35, 121.02, 116.24 (d, J = 22.1Hz), 109.06, 70.69.

[0110] Intermediate 1-6-d: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-(trifluoromethyl)phenyl)methanone

[0111] 1 H NMR(500MHz,Chloroform-d)δ8.93(s,1H),8.24(d,J=9.3Hz,1H),7.84(d,J=7.7Hz,1H),7.6 9–7.59(m,2H),7.54(d,J=2.5Hz,1H),7.51–7.40(m,6H),7.37(t,J=7.3Hz,1H),5.26(s,2H). 13 C NMR(126MHz,Chloroform-d)δ193.36,162.31,152.14,151.31,143.19,139.00,135.79,131.95,131.24,1 29.15,128.92,128.60,127.87,127.40,127.36,127.25,126.95,124.68,122.31,121.12,109.10,70.76.

[0112] Intermediate 1-6-e: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-(trifluoromethyl)phenyl)methanone

[0113] 1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.23(d,J=9.2Hz,1H),7.96(d,J=8.1Hz,2H),7.76(d,J=8.2Hz,2H),7.61(d,J= 2.5Hz,1H),7.51(d,J=7.3Hz,2H),7.47(dd,J=9.3,2.5Hz,1H),7.43(t,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),5.28(s,2H). 13 CNMR(126MHz,Chloroform-d)δ192.90,151.44,149.09,140.95,139.71,135.84,130.35, 128.92,128.59,128.47,127.87,126.26,126.03,126.00,122.56,120.96,108.99,70.75.

[0114] Intermediate 1-6-f: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-(trifluoromethoxy)phenyl)methanone

[0115] 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),8.23(d,J=9.2Hz,1H),7.91(d,J=8.8Hz,2H),7.58(d,J=2.6Hz ,1H),7.51(d,J=7.1Hz,2H),7.48–7.40(m,3H),7.37(t,J=7.3Hz,1H),7.32(d,J=8.3Hz,2H),5.27(s,2H). 13 C NMR(126MHz,Chloroform-d)δ192.30,161.68,153.41,151.45,149.06,140.51,135.92,135.07,1 32.21,128.92,128.82,128.57,127.85,126.19,122.41,121.44,120.99,120.61,109.15,70.72.

[0116] Intermediate 1-6-g: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-methoxyphenyl)methanone

[0117] 1H NMR(500MHz,Chloroform-d)δ8.74(s,1H),8.23(d,J=9.2Hz,1H),7.83(d,J=8.8Hz,2H),7.57(d,J=2.6Hz,1H),7 .51(d,J=7.1Hz,2H),7.46–7.40(m,3H),7.37(t,J=7.2Hz,1H),6.96(d,J=8.9Hz,2H),5.26(s,2H),3.89(s,3H). 13 C NMR(126MHz,Chloroform-d)δ192.18,164.54,161.32,151.06,149.09,140.08,136.01,132.73, 129.86,129.77,128.89,128.52,127.85,126.11,122.13,121.13,114.24,109.04,70.64,55.74.

[0118] Intermediate 1-6-h: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(thiophen-2-yl)methanone

[0119] 1 H NMR(500MHz,Chloroform-d)δ8.82(s,1H),8.25(d,J=9.3Hz,1H),7.81(d,J=4.9Hz,1H),7.57(d,J=2.5H z,1H),7.50(d,J=7.0Hz,2H),7.49–7.40(m,4H),7.38(d,J=7.2Hz,1H),7.17–7.14(m,1H),5.26(s,2H). 13 C NMR(126MHz,Chloroform-d)δ185.40,161.51,151.23,148.64,143.99,140.34,136.27,136. 22,135.94,129.42,128.91,128.66,128.55,127.86,126.30,122.30,121.21,109.02,70.67.

[0120] Intermediate 1-6-i: benzofuran-5-yl (7-(benzyloxy)-4-chloroquinolin-3-yl)methanone

[0121] 1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.23(d,J=9.3Hz,1H),8.09(d,J=1.8Hz,1H),7.91(dd,J=8.7,1.8Hz,1H),7.70(d,J=2 .2Hz,1H),7.61–7.56(m,2H),7.51(d,J=7.1Hz,2H),7.46–7.40(m,3H),7.37(t,J=7.3Hz,1H),6.82(d,J=2.2Hz,1H),5.27(s,2H). 13 C NMR(126MHz,Chloroform-d)δ193.27,161.35,158.11,151.13,149.11,146.86,140.22,135.94,132.31,129. 81,128.86,128.49,127.89,127.81,126.64,126.12,125.00,122.15,121.07,112.06,109.03,107.45,70.60.

[0122] Intermediate 1-6-j: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-ethylphenyl)methanone

[0123] 1 H NMR(500MHz,Chloroform-d)δ8.82(s,1H),8.23(d,J=9.3Hz,1H),7.56(d,J=2.5Hz,1H),7.52–7.46(m,3 H),7.45–7.31(m,6H),7.20(t,J=7.5Hz,1H),5.26(s,2H),2.97(q,J=7.5Hz,2H),1.30(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ195.92,161.67,151.49,150.37,145.59,141.31,137.23,135.94,132.44,131 .05,130.64,130.01,128.90,128.54,127.84,126.51,125.83,122.14,121.16,109.07,70.67,27.05,15.95.

[0124] Intermediate 1-6-k: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2-isopropylphenyl)methanone

[0125] 1H NMR(500MHz,Chloroform-d)δ8.85(s,1H),8.24(d,J=9.3Hz,1H),7.57–7.48(m,5H),7.45–7.40(m,3H ),7.37(t,J=7.3Hz,1H),7.28–7.24(m,2H),7.21–7.16(m,1H),5.26(s,2H),1.31(s,3H),1.29(s,3H). 13 C NMR(126MHz,Chloroform-d)δ196.34,161.76,151.60,150.74,149.52,141.69,137.75,135.88,132.15,129 .80,129.72,128.89,128.54,127.84,126.97,126.63,125.57,122.14,121.17,109.01,70.66,29.61,24.21.

[0126] Intermediate 1-6-1: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2,6-dimethylphenyl)methanone

[0127] 1 H NMR(500MHz,Chloroform-d)δ8.93(s,1H),8.31(d,J=9.3Hz,1H),7.54(d,J=2.6Hz,1H),7.49(d,J=7.2Hz,2 H),7.44–7.39(m,3H),7.36(t,J=7.3Hz,1H),7.27(t,1H),7.09(d,J=7.7Hz,2H),5.25(s,2H),2.20(s,6H). 13 C NMR(126MHz,Chloroform-d)δ197.69,162.06,151.91,151.47,142.86,140.05,135.70,134. 63,129.64,128.74,128.40,128.18,127.68,127.11,122.01,121.37,108.89,70.56,19.81.

[0128] Intermediate 1-6-m: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(3,5-dimethylphenyl)methanone

[0129] 1H NMR(500MHz,Chloroform-d)δ8.75(s,1H),8.20(d,J=9.2Hz,1H),7.57(d,J=2.6Hz,1H),7.49(d,J=7.4 Hz,2H),7.47(s,2H),7.44–7.38(m,3H),7.34(t,J=7.3Hz,1H),7.25(s,1H),5.24(s,2H),2.33(s,6H). 13 C NMR(126MHz,Chloroform-d)δ193.84,161.21,151.00,149.06,140.15,138.54,136.80,135.87, 135.79,129.59,128.72,128.33,127.85,127.66,126.03,121.92,120.95,108.95,70.46,21.15.

[0130] Intermediate 1-6-n: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(2,4-dimethylphenyl)methanone

[0131] 1 H NMR(500MHz,Chloroform-d)δ8.77(s,1H),8.21(d,J=9.2Hz,1H),7.56(d,J=2.6Hz,1H),7.50(d,J=7.2Hz,2H),7.45–7.40(m, 3H),7.36(t,J=7.3Hz,1H),7.26(d,J=7.9Hz,1H),7.16(s,1H),7.00(d,J=7.8Hz,1H),5.25(s,2H),2.61(s,3H),2.38(s,3H). 13 CNMR(126MHz,Chloroform-d)δ195.35,161.45,151.22,149.83,143.45,140.63,140.17,135.97,134.24,133 .14,132.17,130.66,128.88,128.51,127.83,126.56,126.30,122.06,121.13,109.02,70.63,21.68,21.51.

[0132] Intermediate 1-6-o: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluoro-2-methylphenyl)methanone

[0133] 1H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.20(d,J=9.3Hz,1H),7.55(d,J=2.5Hz,1H),7.49(d,J=7.2Hz, 2H),7.43–7.34(m,5H),7.04(dd,J=9.7,2.6Hz,1H),6.88(td,J=8.3,2.6Hz,1H),5.25(s,2H),2.62(s,3H). 13 C NMR(126MHz,Chloroform-d)δ194.40,164.73(d,J=254.8Hz),161.61,151.40,149.76,143.50(d,J=9.1Hz),140.80,135.88,134.09(d,J=9.6Hz), 133.46(d,J=2.9Hz),130.04,128.86,128.50,127.80,126.30,122.19,12 0.99,119.14(d,J=21.5Hz),112.91(d,J=21.4Hz),109.03,70.63,21.55.

[0134] Intermediate 1-6-p: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-chloro-2-methylphenyl)methanone

[0135] 1 H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.21(d,J=9.2Hz,1H),7.56(d,J=2.5Hz,1H),7.50(d,J=7.1Hz,2H),7. 46–7.40(m,3H),7.39–7.34(m,2H),7.29(d,J=8.3Hz,1H),7.19(dd,J=8.3,2.1Hz,1H),5.26(s,2H),2.58(s,3H). 13 C NMR(126MHz,Chloroform-d)δ194.75,161.79,151.38,149.75,141.65,141.19,138.52,135.84,135.65, 132.55,132.19,129.74,128.90,128.57,127.86,126.41,126.15,122.35,121.03,108.92,70.70,21.19.

[0136] Intermediate 1-6-q: (7-(Benzyloxy)-4-chloroquinolin-3-yl)(4-fluoro-2,6-dimethylphenyl)methanone

[0137] 1 H NMR(500MHz,Chloroform-d)δ8.91(s,1H),8.28(d,J=9.3Hz,1H),7.52(d,J=2.5Hz,1H),7.47(d,J=7 .1Hz,2H),7.43–7.38(m,3H),7.34(t,J=7.3Hz,1H),6.78(d,J=9.3Hz,2H),5.24(s,2H),2.16(s,6H). 13 C NMR(126MHz,Chloroform-d)δ196.83,162.96(d,J=248.9Hz),162.18,152.04,151.32,142.85,137.84(d,J=8.7Hz),136.27(d,J=3 .1Hz),135.71,128.80,128.47,127.73,127.60,127.12,122.15,121.30,115.06(d,J=21.2Hz),108.96,70.63,20.06(d,J=1.7Hz).

[0138]

[0139] Synthesis steps 1-7

[0140] Synthesis steps of intermediate 1-7-aq:

[0141] Add 1-6-aq (0.68 mmol) to a 100 ml round-bottom flask, add 6 ml of DMF, then add cesium carbonate (2.04 mmol) and trans-p-coumaric acid methyl ester (0.714 mmol), stir evenly, heat to 70 ° C, and reflux for 1 h; monitor the reaction end point by TLC, after the reaction is completed, spin off DMF, and then add an appropriate amount of dilute hydrochloric acid to remove excess cesium carbonate; the reaction solution is extracted 3 times with EA, the organic phase is collected, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid or oil.

[0142] Intermediate 1-7-a: Methyl (E)-3-(4-((3-benzoyl-7(benzyloxy)quinolin-4-yl)oxy)phenyl)acrylic acid

[0143] 1H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 7.93 (d, J = 9.2Hz, 1H), 7.70–7.62 (m, 4H), 7.56–7.49 (m, 5H), 7.48–7. 40(m,5H),7.36(t,J=7.3Hz,1H),6.62(d,J=8.8Hz,2H),6.47(d,J=16.0Hz,1H),5.37(s,2H),3.69(s,3H). 13 C NMR(126MHz,Chloroform-d)δ193.20,167.44,161.87,159.35,157.16,153.41,152.13,143.72,137.42,135.94,133.48,129. 65,129.56,129.46,128.82,128.45,128.43,127.78,124.41,121.36,120.78,117.26,116.99,116.78,108.96,70.54,51.74.

[0144] Intermediate 1-7-b: Methyl (E)-3-(4-((7-(benzyloxy)-3-(3-fluorobenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0145] 1 H NMR(500MHz,Chloroform-d)δ8.95(s,1H),8.01(d,J=9.3Hz,1H),7.60(d,J=2.5Hz,1H),7.54(d,J=16.0Hz,1H),7.51–7.46(m,2H),7.4 3–7.33(m,5H),7.31(dd,J=9.2,2.4Hz,1H),7.29–7.22(m,4H),6.52(d,J=8.8Hz,2H),6.26(d,J=16.0Hz,1H),5.25(s,2H),3.76(s,3H). 13C NMR(126MHz,Chloroform-d)δ192.00,167.38,162.63(d,J=248.4Hz),162.02,159.27,157 .23,153.62,151.92,143.57,139.50(d,J=6.4Hz),135.88,130.08(d,J=7.6Hz),129.70,12 9.65(d,J=9.9Hz),128.82,128.45,127.76,125.38(d,J=3.0Hz),124.44,121.47,120.41(d ,J=21.6Hz),120.29,117.16,117.13,116.69,115.93(d,J=22.5Hz),109.03,70.55,51.74.

[0146] Intermediate 1-7-c: Methyl (E)-3-(4-((7-(benzyloxy)-3-(4-fluorobenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0147] 1 H NMR(500MHz,Chloroform-d)δ8.93(s,1H),8.01(d,J=9.2Hz,2H),7.65–7.58(m,3H),7.53(d,J=16.0Hz,1H),7.48(d,J=7.5Hz,2H),7.41–7.36( m,2H),7.35–7.28(m,2H),7.24(d,J=2.2Hz,1H),7.04(t,J=7.5Hz,2H), 6.52(d,J=6.6Hz,2H),6.25(d,J=16.0Hz,1H),5.24(s,2H),3.75(s,3H). 13 C NMR(126MHz,Chloroform-d)δ191.51,167.31,165.93(d,J=256.0Hz),162.6 0,161.90,159.12,156.96,153.31,151.81,143.51,135.81,133.73(d,J=2.7 Hz),132.13(d,J=9.4Hz),129.61,129.50,128.72,128.36,127.69,124.31,1 21.40,120.43,117.05,116.62,115.57(d,J=22.0Hz),108.80,70.45,51.65.

[0148] Intermediate 1-7-d: Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0149] 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),7.73(d,J=9.3Hz,1H),7.64(d,J=7.9Hz,1H),7.60(d,J=2.4Hz,1H),7.56(d,J=16.0Hz,1H),7.50–7 .45(m,3H),7.44–7.34(m,4H),7.29–7.26(m,2H),7.24–7.19(m,2H),6 .37(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),5.25(s,2H),3.78(s,3H). 13 C NMR(126MHz,Chloroform-d)δ192.42,167.52,162.56,159.35,158.41,154.56,152.98,143.74,139.39,135.78,131.43,130.20, 129.66,129.37,128.91,128.60,127.86,127.83,127.43,125.20,121.55,120.65,117.14,116.99,115.65,109.40,70.72,51.83.

[0150] Intermediate 1-7-e: Methyl (E)-3-(4-((7-(benzyloxy)-3-(4-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0151] 1 H NMR(500MHz,Chloroform-d)δ8.99(s,1H),8.00(d,J=9.1Hz,1H),7.66(d,J=8.1 Hz,2H),7.63–7.58(m,3H),7.53(d,J=16.0Hz,1H),7.48(d,J=7.2Hz,2H),7.40( t,J=7.3Hz,2H),7.37–7.33(m,1H),7.31(dd,J=9.2,2.5Hz,1H),7.23(d,J=8.7H z,2H),6.44(d,J=8.8Hz,2H),6.25(d,J=16.0Hz,1H),5.25(s,2H),3.76(s,3H). 13C NMR(126MHz,Chloroform-d)δ192.31,167.32,162.18,159.15,157.33,153.85,152.02,143.43,140.40,135.83,129.70,129.62, 129.58,128.81,128.46,127.75,125.40,125.37,124.45,121.57,119.93,117.25,117.06,116.62,116.43,109.08,70.56,53.52.

[0152] Intermediate 1-7-f: Methyl (E)-3-(4-((7-(benzyloxy)-3-(4-(trifluoromethoxy)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0153] 1 H NMR(500MHz,Chloroform-d)δ8.98(s,1H),8.04(d,J=9.2Hz,1H),7.66–7.60(m,3H),7.55(d,J=16.0Hz,1H),7.49(d,J=7.1Hz,2H),7.42(t,J =7.0Hz,2H),7.38–7.31(m,2H),7.24(s,2H),7.20(d,J=8.3Hz,2H),6.48(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),5.26(s,2H),3.79(s,3H). 13 C NMR(126MHz,Chloroform-d)δ191.74,167.49,162.28,159.17,157.37,153.52,151.97,144.81,143.59,135.88,135.83,131.47, 130.13,129.76,128.91,128.57,127.86,124.54,121.71,120.43,117.34,117.21,116.66,116.17,115.11,108.88,70.69,51.86.

[0154] Intermediate 1-7-g: Methyl (E)-3-(4-((7-(benzyloxy)-3-(4-methoxybenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0155] 1H NMR(500MHz,Chloroform-d)δ8.92(s,1H),8.02(d,J=9.1Hz,1H),7.64–7.59(m,3H ),7.55(d,J=16.0Hz,1H),7.50(d,J=7.1Hz,2H),7.42(t,J=7.4Hz,2H),7.37(t,J=7 .3Hz,1H),7.32(dd,J=9.2,2.5Hz,1H),7.28–7.26(m,2H),6.86(d,J=8.9Hz,2H),6. 57(d,J=8.8Hz,2H),6.26(d,J=16.0Hz,1H),5.27(s,2H),3.88(s,3H),3.78(s,3H). 13 C NMR(126MHz,Chloroform-d)δ191.67,167.56,164.14,161.72,159.44,156.76,153.26,152.08,143.87,136.05,132.19,130.38, 129.70,129.50,128.89,128.51,127.86,124.39,121.45,121.35,117.39,116.97,116.95,113.79,109.02,70.59,55.70,51.82.

[0156] Intermediate 1-7-h: Methyl (E)-3-(4-((7-(benzyloxy)-3-(thiophene-2-carbonyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0157] 1 H NMR(500MHz,Chloroform-d)δ8.95(s,1H),8.02(d,J=9.2Hz,1H),7.67(d,J=4.9Hz, 1H),7.59(d,J=2.5Hz,1H),7.55(d,J=16.0Hz,1H),7.52(d,J=3.8Hz,1H),7.48(d,J= 7.1Hz,2H),7.40(t,J=7.4Hz,2H),7.34(t,J=7.3Hz,1H),7.32–7.27(m,3H),7.11–7 .08(m,1H),6.68(d,J=8.8Hz,2H),6.26(d,J=16.0Hz,1H),5.24(s,2H),3.76(s,3H). 13CNMR(126MHz,Chloroform-d)δ184.54,167.41,161.74,159.37,156.84,153.23,151.24,144.02,143.72,135.91,135.57,135 .24,129.71,129.57,128.79,128.42,128.17,127.75,124.37,121.36,121.20,117.33,117.04,117.00,108.93,70.49,51.70.

[0158] Intermediate 1-7-i: Methyl (E)-3-(4-((3-(benzofuran-5-carbonyl)-7-(benzyloxy)quinolin-4-yl)oxy)phenyl)acrylic acid

[0159] 1 H NMR(500MHz,Chloroform-d)δ8.97(s,1H),8.02(d,J=9.2Hz,1H),7.88(s,1H),7.67(s,1H),7.64–7.58(m,2H),7.55–7.43(m,4H),7.40(t,J=7.3 Hz,2H),7.37–7.29(m,2H),7.20(d,J=8.3Hz,2H),6.76(d,J=2.1Hz,1H), 6.49(d,J=8.3Hz,2H),6.22(d,J=16.0Hz,1H),5.25(s,2H),3.75(s,3H). 13 C NMR(126MHz,Chloroform-d)δ192.72,167.40,161.72,159.32,157.72,156.89,153.29,152.08,146.61,143.69,135.93,132.87,129.58,129. 41,128.79,128.42,127.75,127.45,126.15,124.37,124.18,121.29,1 21.23,117.26,116.90,116.80,111.51,108.95,107.31,70.48,51.72.

[0160] Intermediate 1-7-j: Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0161] 1H NMR(500MHz,Chloroform-d)δ9.10(s,1H),7.94(d,J=9.2Hz,1H),7.60(d,J=2 .5Hz,1H),7.56(d,J=16.0Hz,1H),7.48(d,J=7.4Hz,2H),7.42–7.32(m,4H),7 .30–7.23(m,4H),7.19–7.10(m,2H),6.39(d,J=8.8Hz,2H),6.27(d,J=15.9Hz ,1H),5.24(s,2H),3.77(s,3H),2.33(q,J=7.5Hz,2H),1.03(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ194.69,167.49,162.12,159.56,157.35,153.70,152.97,144.78,143.73,137.72,135.88,131.79,130.12 ,129.67,129.64,129.37,128.46,127.78,125.36,124.66,121.78,1 21.39,117.38,116.89,116.15,108.96,70.56,51.76,26.28,15.57.

[0162] Intermediate 1-7-k: Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-isopropylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0163] 1 H NMR(500MHz,Chloroform-d)δ9.14(s,1H),7.86(d,J=9.2Hz,1H),7.59(d,J=2.5Hz,1H),7.55( d,J=16.0Hz,1H),7.46(d,J=7.3Hz,2H),7.41–7.29(m,5H),7.27(d,J=9.1Hz,2H),7.24(dd,J= 9.2,2.5Hz,1H),7.20(d,J=7.5Hz,1H),7.07(td,J=7.5,1.2Hz,1H),6.45(d,J=8.7Hz,2H),6.2 6(d,J=16.0Hz,1H),5.23(s,2H),3.75(s,3H),2.98(p,J=6.8Hz,1H),1.03(s,3H),1.02(s,3H). 13C NMR(126MHz,Chloroform-d)δ194.96,171.11,167.40,162.05,159.54,157.12,153.88,153.11,148.66,143.70,137.82,135.81,131.46,129 .67,129.18,128.77,128.41,127.72,126.13,125.11,124.74,122.18 ,121.34,117.32,116.74,115.76,109.08,70.50,51.68,29.70,24.06.

[0164] Intermediate 1-7-1: Methyl (E)-3-(4-((7-(benzyloxy)-3-(2,6-dimethylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0165] 1 H NMR(500MHz,Chloroform-d)δ9.29(s,1H),7.75(d,J=9.2Hz,1H),7.59–7.55(m,2H) ,7.47(d,J=7.2Hz,2H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.3Hz,1H),7.27(d,J=9.3 Hz,2H),7.21(dd,J=9.2,2.5Hz,1H),7.05(t,J=7.6Hz,1H),6.86(d,J=7.6Hz,2H),6 .42(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),5.24(s,2H),3.78(s,3H),1.99(s,6H). 13 CNMR(126MHz,Chloroform-d)δ196.97,167.58,162.45,159.66,158.28,154.39,153.34,143.91,140.79,135.79,134.03,129.47 ,129.09,129.06,128.88,128.55,127.86,127.82,125.32,121.49,121.30,117.57,116.71,115.57,109.28,70.67,51.80,19.65.

[0166] Intermediate 1-7-m: methyl (E)-3-(4-((7-(benzyloxy)-3-(3,5-dimethylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0167] 1 H NMR(500MHz,Chloroform-d)δ8.94(s,1H),8.03(d,J=9.2Hz,1H),7.62(d,J=2.6Hz ,1H),7.56(d,J=16.0Hz,1H),7.49(d,J=7.1Hz,2H),7.42(t,J=7.3Hz,2H),7.36(t ,J=7.3Hz,1H),7.32(dd,J=9.2,2.5Hz,1H),7.27(d,J=8.8Hz,2H),7.17(s,3H),6. 57(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),5.26(s,2H),3.79(s,3H),2.27(s,6H). 13 C NMR(126MHz,Chloroform-d)δ193.63,167.57,161.91,159.49,157.36,153.12,152.04,143.85,138.24,137.58,135.97,135.23, 130.12,129.65,129.49,128.89,128.52,127.85,127.32,124.62,121.41,117.44,116.97,116.22,108.78,70.62,51.84,21.23.

[0168] Intermediate 1-7-n: methyl (E)-3-(4-((7-(benzyloxy)-3-(2,4-dimethylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0169] 1 H NMR(500MHz,Chloroform-d)δ9.03(s,1H),8.01(d,J=9.2Hz,1H),7.60(d,J=2.4Hz,1H),7.57(d,J= 16.0Hz,1H),7.48(d,J=7.2Hz,2H),7.40(t,J=8.1Hz,2H),7.35(t,J=7.2Hz,1H),7.31(dd,J=9.2,2. 5Hz,1H),7.27(d,J=8.8Hz,2H),7.22(d,J=7.8Hz,1H),6.96(d,J=8.0Hz,1H),6.93(s,1H),6.44(d, J=8.7Hz,2H),6.28(d,J=16.0Hz,1H),5.24(s,2H),3.79(d,J=1.2Hz,3H),2.35(s,3H),2.01(s,3H). 13C NMR(126MHz,Chloroform-d)δ194.34,167.63,162.13,159.49,157.36,152.67,144.94,143.83,142.79,135.90,132.42,131.29,130.13 ,129.69,129.56,128.88,128.52,127.86,126.20,124.59,121.51,1 16.99,116.55,116.19,114.90,108.63,70.62,51.87,21.64,20.35.

[0170] Intermediate 1-7-o: Methyl (E)-3-(4-((7-(benzyloxy)-3-(4-fluoro-2-methylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0171] 1 H NMR(500MHz,Chloroform-d)δ9.04(s,1H),7.98(d,J=9.1Hz,1H),7.59(d,J=2.5Hz,1H),7.55(d,J=16.0Hz,1H),7.46(d,J=7.4Hz,2H),7.38(t,J=7.5H z,2H),7.35–7.30(m,2H),7.30–7.25(m,3H),6.86–6.77(m,2H),6.40(d,J= 8.7Hz,2H),6.27(d,J=16.0Hz,1H),5.23(s,2H),3.76(s,3H),1.99(s,3H). 13 C NMR(126MHz,Chloroform-d)δ193.17,167.35,164.33(d,J=253.7Hz),162.13,159.32,15 7.11,153.62,152.58,143.48,142.75(d,J=8.9Hz),135.81,134.01(d,J=2.8Hz),133.15( d, J=9.5Hz),129.66,129.57,128.76,128.40,127.72,124.44,121.43,121.27,118.22(d ,J=21.3Hz),117.18,117.08,116.18,112.40(d,J=21.6Hz),108.86,70.50,51.71,20.25.

[0172] Intermediate 1-7-p: methyl (E)-3-(4-((7-(benzyloxy)-3-(4-chloro-2-methylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0173] 1 H NMR(500MHz,Chloroform-d)δ9.07(s,1H),7.99(d,J=9.2Hz,1H),7.61(d,J=2.4Hz ,1H),7.57(d,J=16.0Hz,1H),7.48(d,J=7.3Hz,2H),7.44–7.39(m,2H),7.36(t,J=7 .3Hz,1H),7.33–7.28(m,3H),7.24(d,J=8.3Hz,1H),7.15–7.09(m,2H),6.41(d,J=8 .8Hz,2H),6.29(d,J=16.0Hz,1H),5.25(s,2H),3.79(d,J=1.9Hz,3H),1.99(s,3H). 13 CNMR(126MHz,Chloroform-d)δ193.60,167.53,162.38,159.40,157.46,153.72,152.61,144.86,143.60,141.04,137.83,136.23,135.83 ,131.77,131.40,130.13,129.78,129.70,128.90,128.56,127.86,1 25.73,124.62,121.68,117.23,116.24,108.85,70.66,51.89,20.02.

[0174] Intermediate 1-7-q: methyl (E)-3-(4-((7-(benzyloxy)-3-(4-fluoro-2,6-dimethylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0175] 1H NMR(500MHz,Chloroform-d)δ9.31(s,1H),7.75(d,J=9.2Hz,1H),7.61–7.54( m,2H),7.46(d,J=7.1Hz,2H),7.39(t,J=7.3Hz,2H),7.33(t,J=7.3Hz,1H),7.2 9(d,J=8.8Hz,2H),7.21(dd,J=9.2,2.5Hz,1H),6.56(d,J=9.4Hz,2H),6.43(d ,J=8.7Hz,2H),6.29(d,J=16.0Hz,1H),5.23(s,2H),3.76(s,3H),1.97(s,6H). 13 C NMR(126MHz,Chloroform-d)δ195.86,167.39,162.47(d,J=247.7Hz),162.45, 159.54,158.08,154.43,153.08,143.65,137.05(d,J=8.5Hz),136.96(d,J=3. 1Hz),135.70,129.43,129.19,128.79,128.46,127.72,125.19,121.49,121.2 5,117.37,116.84,115.33,114.47(d,J=21.2Hz),109.29,70.58,51.69,19.72.

[0176]

[0177] Synthesis steps 1-8

[0178] Synthesis steps of intermediate 1-8-aq:

[0179] Add 1-7-aq (0.60 mmol) to a 100 ml round-bottom flask, add 6 ml of DCM, stir evenly, and protect with N2; slowly drop 1 mol / L boron tribromide (1.20 mmol) under ice bath conditions, and react for 5 minutes after the addition is complete; monitor the reaction endpoint by TLC, and after the reaction is complete, add excess anhydrous methanol to quench the unreacted boron tribromide and the boron complex formed by decomposition; evaporate the reaction solution to dryness under reduced pressure, and separate by silica gel column chromatography to obtain a yellow solid or oily substance.

[0180] Intermediate 1-8-a: Methyl (E)-3-(4-((3-benzoyl-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0181] 1H NMR (500MHz, DMSO-d6) δ10.74(s,1H),8.84(s,1H),7.89(d,J=9.1Hz,1H),7.67–7.59(m,3H),7.56–7.50(m,3H),7.46(t,J= 7.7Hz, 2H), 7.40 (d, J = 2.4Hz, 1H), 7.24 (dd, J = 9.1, 2.4Hz, 1H), 6.59 (d, J = 8.5Hz, 2H), 6.47 (d, J = 16.0Hz, 1H), 3.69 (s, 3H). 13 CNMR(126MHz,Chloroform-d)δ192.98,167.62,161.89,159.32,158.25,152.16,151.45,143.82,137.42, 133.62,129.77,129.66,128.57,126.69,125.00,121.29,120.07,117.14,116.98,116.56,109.52,51.88.

[0182] Intermediate 1-8-b: Methyl (E)-3-(4((3-(3-fluorobenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0183] 1 H NMR(500MHz,Chloroform-d)δ8.88(s,1H),7.99(d,J=9.1Hz,1H),7.59(d,J=2.3Hz,1H),7.54(d,J=16.0Hz,1H),7.36(q,J= 6.6,5.4Hz,2H),7.29–7.23(m,4H),7.19(dd,J=9.1,2.3Hz,1H),6.53(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),3.78(s,3H). 13 CNMR(126MHz,Chloroform-d)δ191.86,167.61,162.66(d,J=248.4Hz),162. 06,159.15,158.19,152.60,151.42,143.67,139.45(d,J=6.3Hz),130.17(d ,J=7.7Hz),129.76,125.38(d,J=2.9Hz),125.08,121.48,120.53(d,J=21.3 Hz), 119.53, 117.23, 116.81, 116.46, 115.92 (d, J = 22.6Hz), 109.85, 51.86.

[0184] Intermediate 1-8-c: Methyl (E)-3-(4((3-(4-fluorobenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0185] 1 H NMR(500MHz,Chloroform-d)δ8.90(s,1H),7.98(d,J=9.2Hz,1H),7.67–7.62(m,2H),7.58–7.52(m,2H),7.29(d,J=8.8Hz,2H) ,7.12(dd,J=9.1,2.3Hz,1H),7.07(t,J=8.6Hz,2H),6.57(d,J=8.8Hz,2H),6.28(d,J=16.0Hz,1H),3.79(s,3H),3.50(s,1H). 13 CNMR(126MHz,Chloroform-d)δ191.28,167.41,166.04(d,J=256.6Hz),161.46,159.02,157.88,152.20,151.35,143.51,133.70(d,J= 2.9Hz), 132.18 (d, J = 9.2Hz), 129.73, 129.68, 125.01, 121.16, 119.88, 117.23, 116.78, 116.55, 115.69 (d, J = 21.9Hz), 109.75, 51.77.

[0186] Intermediate 1-8-d: Methyl (E)-3-(4-((7-hydroxy-3-(2-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0187] 1 H NMR (500MHz, DMSO-d6) δ10.99(s,1H),9.10(s,1H),7.75(d,J=7.9Hz,1H),7.64(d,J=9.1Hz,1H),7.62–7.58(m,1H),7.57–7 .50(m,5H),7.40(d,J=2.4Hz,1H),7.18(dd,J=9.1,2.4Hz,1H),6.47(d,J=16.0Hz,1H),6.44(d,J=8.6Hz,2H),3.69(s,3H). 13C NMR (126MHz, DMSO-d6) δ192.01,166.76,162.00,158.99,158.02,153.94,152.05,144.82,143.63,132.10,130.68 ,130.38,130.06,128.81,128.08,125.40,120.97,116.66,115.82,115.48,115.11,113.95,110.88,56.09,18.59.

[0188] Intermediate 1-8-e: Methyl (E)-3-(4-((7-hydroxy-3-(4-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0189] 1 H NMR(500MHz,Chloroform-d)δ8.94(s,1H),7.95(d,J=9.2Hz,1H),7.71(d,J=8.1Hz,2H),7.65(d,J=8.2Hz,2H),7.55(d,J=16.0Hz ,1H),7.45(s,1H),7.28(d,J=8.8Hz,2H),7.04(dd,J=9.2,2.1Hz,1H),6.52(d,J=8.8Hz,2H),6.29(d,J=16.0Hz,1H),3.79(s,3H). 13 CNMR(126MHz,Chloroform-d)δ191.96,167.49,162.24,159.07,158.57,152.31,151.40,143.46,140.35, 130.00,129.87,129.69,125.59,125.57,125.28,121.54,119.43,117.56,116.71,116.56,109.44,51.94.

[0190] Intermediate 1-8-f: Methyl (E)-3-(4-((7-hydroxy-3-(4-(trifluoromethoxy)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0191] 1H NMR(500MHz,Chloroform-d)δ8.93(s,1H),7.99(d,J=9.1Hz,1H),7.64(d,J=8.7Hz,2H),7.58–7.51(m,2H),7.27(d,J=7. 7Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 7.14 (dd, J = 9.1, 2.2Hz, 1H), 6.52 (d, J = 8.6Hz, 2H), 6.28 (d, J = 16.0Hz, 1H), 3.79 (s, 3H). 13 C NMR(126MHz,Chloroform-d)δ191.47,167.58,161.90,159.05,151.50,144.90,143.59,135.76,131.48,130. 12,129.95,129.81,128.22,125.23,121.43,120.48,117.46,116.79,116.64,116.10,115.67,109.76,51.93.

[0192] Intermediate 1-8-g: Methyl (E)-3-(4-((7-hydroxy-3-(4-methoxybenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0193] 1 H NMR(500MHz,Chloroform-d)δ8.83(s,1H),7.93(d,J=9.1Hz,1H),7.61(d,J=8.9Hz,2H),7.56–7.50(m,2H),7.28–7.26(m,2H) ,7.08(dd,J=9.2,2.3Hz,1H),6.85(d,J=8.9Hz,2H),6.61(d,J=8.8Hz,2H),6.25(d,J=16.0Hz,1H),5.28(s,6H),3.49(s,1H). 13 CNMR(126MHz,Chloroform-d)δ191.16,167.58,164.20,162.00,159.14,158.10,151.47,150.88,143.78, 132.16,130.11,129.68,124.90,121.44,120.45,117.11,117.04,116.56,113.83,109.10,55.67,51.81.

[0194] Intermediate 1-8-h: Methyl (E)-3-(4-((7-hydroxy-3-(thiophene-2-carbonyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0195] 1 H NMR (500MHz, DMSO-d6) δ10.71(s,1H),8.89(s,1H),8.09(dd,J=4.9,1.2Hz,1H),7.90(d,J=9.1Hz,1H),7.70(dd,J=3.8,1.2Hz ,1H),7.59–7.53(m,3H),7.40(d,J=2.5Hz,1H),7.29–7.21(m,2H),6.74(d,J=8.8Hz,2H),6.49(d,J=16.1Hz,1H),3.69(s,3H). 13 CNMR(126MHz,DMSO-d6)δ184.30,166.74,160.87,159.27,155.84,152.85,150.75,143.61,143.35,136 .77,136.49,130.24,129.02,128.96,124.45,120.78,120.70,116.82,116.60,115.51,110.64,51.46.

[0196] Intermediate 1-8-i: Methyl (E)-3-(4-((3-(benzofuran-5-carbonyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0197] 1 H NMR(500MHz,Chloroform-d)δ8.91(s,1H),7.97(d,J=9.1Hz,1H),7.93(d,J=1.8Hz,1H),7.70(d,J=2.2Hz,1H),7.63(dd,J=8.6,1.9Hz,1H),7.52–7.45(m, 2H),7.43–7.34(m,1H),7.23(d,J=8.7Hz,2H),7.10(dd,J=9.1,2.3Hz,1H),6 .82–6.79(m,1H),6.57(d,J=8.8Hz,2H),6.24(d,J=16.0Hz,1H),3.78(s,3H). 13C NMR(126MHz,Chloroform-d)δ192.29,167.56,162.11,159.16,158.44,157.89,146.78,143.72,132.81,129.82,129.72,1 28.89,127.88,127.65,126.21,125.14,124.36,120.53,117.20,117.14,116.96,116.67,111.73,109.08,107.44,51.88.

[0198] Intermediate 1-8-j: Methyl (E)-3-(4-((3-(2-ethylbenzoyl)7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0199] 1 H NMR(500MHz,Chloroform-d)δ9.01(s,1H),7.89(d,J=9.1Hz,1H),7.61–7.52(m,2H),7.42–7.33(m,2H),7.28(d,J=8.4Hz,2H),7.21–7.14(m ,2H),7.07(dd,J=9.2,2.2Hz,1H),6.46(d,J=8.5Hz,2H),6.28(d,J=15.9Hz,1H),3.79(s,3H),2.33(q,J=7.5Hz,2H),1.03(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ193.89,167.63,162.76,159.36,158.89,151.68,151.50,145.04,143.75,137.35,132.08, 130.29,130.08,129.80,125.52,125.42,121.83,121.10,117.13,116.79,116.42,116.13,108.90,51.90,26.33,15.59.

[0200] Intermediate 1-8-k: Methyl (E)-3-(4-((7-hydroxy-3-(2-isopropylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid

[0201] 1H NMR(500MHz,Chloroform-d)δ9.01(s,1H),7.76(d,J=9.2Hz,1H),7.57(d,J=1 6.0Hz,1H),7.41–7.35(m,2H),7.34–7.30(m,3H),7.27(d,J=8.0Hz,1H),7.11 (t,J=7.5Hz,1H),6.93(dd,J=9.1,2.2Hz,1H),6.55(d,J=8.4Hz,2H),6.28(d, J=16.0Hz,1H),3.78(s,3H),2.99(p,J=6.8Hz,1H),1.04(s,3H),1.03(s,3H). 13 C NMR(126MHz,Chloroform-d)δ194.53,167.66,162.52,159.52,158.41,152.25,148.82,143.85,137.65,131.66,130.08, 129.83,129.47,129.27,126.30,125.42,125.29,121.55,116.92,116.64,116.12,116.03,109.17,51.88,29.81,24.15.

[0202] Intermediate 1-8-1: Methyl (E)-3-(4-((3-(2,6-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0203] 1 H NMR(500MHz,Chloroform-d)δ9.18(s,1H),7.68(d,J=9.2Hz,1H),7.59(d,J=16.0Hz,1H),7.40(d,J=2.4Hz,1H),7.31(d,J=8.7Hz,2H),7.05( t,J=7.6Hz,1H),6.93(dd,J=9.2,2.3Hz,1H),6.86(d,J=7.7Hz,2H),6.49(d,J=8.6Hz,2H),6.30(d,J=16.0Hz,1H),3.79(s,3H),2.01(s,6H). 13C NMR(126MHz,Chloroform-d)δ196.54,167.74,162.78,159.54,159.33,152.77,152.52,143.96,140.45,134. 02,130.08,129.56,129.27,127.92,125.96,121.53,120.67,116.79,116.10,115.69,109.50,51.91,19.68.

[0204] Intermediate 1-8-m: methyl (E)-3-(4-((3-(3,5-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0205] 1 H NMR(500MHz,Chloroform-d)δ8.86(s,1H),7.92(d,J=9.1Hz,1H),7.57(d,J=16.0Hz,1H),7.45(d,J=2.4Hz,1H),7.29(d,J=8.8Hz,2 H),7.20(s,2H),7.17(s,1H),7.04(dd,J=9.2,2.3Hz,1H),6.62(d,J=8.8Hz,2H),6.28(d,J=16.0Hz,1H),3.79(s,3H),2.27(s,6H). 13 CNMR(126MHz,Chloroform-d)δ193.42,167.67,161.83,159.41,158.30,151.90,151.36,143.88,138.32,137 .59,135.27,130.10,129.71,129.62,127.30,125.16,121.20,120.47,117.08,116.64,116.11,51.89,21.20.

[0206] Intermediate 1-8-n: methyl (E)-3-(4-((3-(2,4-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0207] 1H NMR(500MHz,Chloroform-d)δ8.95(s,1H),7.95(d,J=9.1Hz,1H),7.60–7.53(m,2H),7.28(d,J=8.7Hz,2H),7.25(d,J=8.2Hz,1H),7.15(d ,J=9.1Hz,1H),6.96(d,J=7.9Hz,1H),6.92(s,1H),6.44(d,J=8.8Hz,2H),6.28(d,J=16.0Hz,1H),3.78(s,3H),2.34(s,3H),1.99(s,3H). 13 C NMR(126MHz,Chloroform-d)δ194.17,167.66,161.91,159.44,158.01,152.53,152.23,143.84,142.75,139.42,134.90, 132.37,131.22,129.69,129.58,126.20,125.09,121.29,121.28,116.97,116.70,116.55,109.70,51.86,21.61,20.25.

[0208] Intermediate 1-8-o: Methyl (E)-3-(4-((3-(4-fluoro-2-methylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0209] 1 H NMR(500MHz,Chloroform-d)δ8.97(s,1H),7.88(d,J=9.1Hz,1H),7.57(d,J=15.9Hz,1H),7.46–7.38(m,2H),7.31(d,J=8.7Hz,2H),7.00(dd,J= 9.1,2.3Hz,1H),6.88(td,J=8.3,2.6Hz,1H),6.47(d,J=8.8Hz,2H),6.2 9(d,J=15.9Hz,1H),5.29(s,1H),3.97(s,1H),3.79(s,3H),2.01(s,3H). 13C NMR(126MHz,Chloroform-d)δ192.96,167.61,164.49(d,J=254.0Hz),162.44,1 59.33,158.17,152.36,151.96,143.63,142.94(d,J=9.0Hz),133.99(d,J=2.9H z), 133.32 (d, J = 9.5Hz), 130.08, 129.83, 129.81, 125.12, 121.49, 120.71, 118. 38(d,J=21.3Hz),117.25,116.38,112.57(d,J=21.4Hz),109.35,51.91,20.32.

[0210] Intermediate 1-8-p: methyl (E)-3-(4-((3-(4-chloro-2-methylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0211] 1 H NMR(500MHz,Chloroform-d)δ8.99(s,1H),7.96(d,J=9.1Hz,1H),7.65–7.54(m,2H),7.36–7.30(m,3H),7.17(dd ,J=8.3,2.1Hz,1H),7.14–7.08(m,2H),6.48(d,J=8.7Hz,2H),6.31(d,J=16.0Hz,1H),3.80(s,3H),1.98(s,3H). 13 C NMR (126MHz, Chloroform-d) δ192.74,167.52,162.81,159.15,158.93,151.46,151.33,143.49,141.27,138.12,135. 87,131.91,131.52,130.10,129.87,125.86,125.42,121.94,120.61,117.51,116.79,116.49,108.87,51.94,20.04.

[0212] Intermediate 1-8-q: methyl (E)-3-(4-((3-(4-fluoro-2,6-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0213] 1H NMR(500MHz,Chloroform-d)δ9.21(s,1H),7.70(d,J=9.2Hz,1H),7.59(d,J=15.7Hz,1H),7.44–7.43(m,1H),7.33(d,J=8.8Hz,2H ),7.26–7.23(m,1H),6.58(d,J=9.3Hz,2H),6.49(d,J=8.8Hz,2H),6.31(d,J=15.9Hz,1H),4.04(s,1H),3.80(s,3H),2.00(s,6H). 13 C NMR(126MHz,Chloroform-d)δ195.62,167.65,162.66(d,J=248.1Hz),162.37,159.56,158.20,153.09,152.61,143.77,137.18(d, J=8.6Hz),130.12,129.60,129.51,126.02,121.42,120.91,117.09,116.95,116.08,114.68(d,J=21.2Hz),110.01,51.93,19.87.

[0214]

[0215] The following table shows the types of intermediates synthesized in reaction route 2

[0216]

[0217] Synthesis step 2-1

[0218] Synthesis steps of intermediate 2-1-d:

[0219] Place o-ethylphenol (1 g, 8.18 mmol) in a 100 ml round-bottom flask, add 6 ml THF to dissolve, add NBS (1.45 g, 8.15 mmol) under ice bath conditions, and add a few drops of dilute sulfuric acid as a catalyst; react at room temperature for 48 h, monitor the reaction endpoint by TLC, and after the reaction is completed, extract the reaction solution with EA and H2O for 3 times, collect the organic phase, dry it with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and separate it by silica gel column chromatography to obtain a transparent oil.

[0220] Intermediate 2-1-d 4-bromo-2-ethylphenol

[0221] 1H NMR(500MHz,Chloroform-d)δ7.25(d,J=2.6Hz,1H),7.17(dd,J=8.5,2.5Hz,1H), 6.64(d,J=8.5Hz,1H),4.80(s,1H),2.60(q,J=7.5Hz,2H),1.23(t,J=7.6Hz,3H). 13 CNMR(126MHz,Chloroform-d)δ152.61,132.47,132.11,129.77,116.94,113.03,22.95,13.81.

[0222]

[0223] Synthesis step 2-2

[0224] Synthesis steps of intermediate 2-2-ag:

[0225] Add 2-1-ag (5.36 mmol) to a 100 ml round-bottom flask, add 6 ml of DMF, stir evenly, then add methyl acrylate (16.08 mmol), bis(triphenylphosphine)palladium dichloride (0.536 mmol), triethylamine (10.72 mmol), oil bath at 135°C, N2 protection, react for 4 hours. TLC monitors the end point of the reaction. After the reaction is completed, the reaction solution is extracted 3 times with EA and H2O, the organic phase is collected, dried with anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a transparent oil.

[0226] Intermediate 2-2-a Methyl (E)-3-(4-hydroxy-3-methylphenyl) acrylic acid

[0227] 1 H NMR(500MHz,DMSO-d6)δ9.95(s,1H),7.52(d,J=15.9Hz,1H),7.46(s,1H),7.36(d,J= 8.3Hz,1H),6.80(d,J=8.3Hz,1H),6.37(d,J=15.9Hz,1H),3.68(s,3H),2.12(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.12,158.13,145.04,130.96,127.98,124.91,124.60,114.88,113.60,51.23,15.87.

[0228] Intermediate 2-2-b Methyl (E)-3-(4-hydroxy-2-methylphenyl) acrylic acid

[0229] 1 H NMR(500MHz,DMSO-d6)δ9.90(s,1H),7.78(d,J=15.7Hz,1H),7.60(d,J=9.1H z,1H),6.66–6.61(m,2H),6.33(d,J=15.8Hz,1H),3.69(s,3H),2.31(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.11,159.54,141.67,139.69,128.48,123.58,117.24,114.70,113.82,51.29,19.45.

[0230] Intermediate 2-2-c Methyl (E)-3-(3-fluoro-4-hydroxyphenyl)acrylic acid

[0231] 1 H NMR (500MHz, DMSO-d6) δ10.47(s,1H),7.62(dd,J=12.5,2.1Hz,1H),7.55(d,J=16.0Hz,1H ),7.36(dd,J=8.2,2.1Hz,1H),6.96(t,J=8.7Hz,1H),6.49(d,J=16.0Hz,1H),3.69(s,3H). 13 C NMR(126MHz,DMSO-d6)δ166.87,151.07(d,J=241.5Hz),147.34(d,J=12.4Hz),143.78(d,J=2.3Hz),1 26.03(d,J=2.7Hz), 125.91(d,J=6.6Hz), 117.80(d,J=3.3Hz), 115.66, 115.63(d,J=18.6Hz), 51.35.

[0232] Intermediate 2-2-d Methyl (E)-3-(3-ethyl-4-hydroxyphenyl) acrylic acid

[0233] 1 H NMR(500MHz,Chloroform-d)δ7.64(d,J=16.0Hz,1H),7.32(d,J=2.2Hz,1H),7.26–7.23(m,1H),6.80 (d,J=8.3Hz,1H),6.30(d,J=15.9Hz,1H),3.81(s,3H),2.65(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H). 13C NMR (126MHz, Chloroform-d) δ168.55,156.24,145.55,130.91,129.60,127.62,127.06,115.70,114.63,51.86,23.05,13.92.

[0234] Intermediate 2-2-e methyl (E)-3-(4-hydroxy-3-methoxyphenyl) acrylic acid

[0235] 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=15.9Hz,1H),7.05(dd,J=8.2,1.9Hz,1H),7.01( d,J=1.9Hz,1H),6.90(d,J=8.1Hz,1H),6.28(d,J=15.9Hz,1H),3.90(s,3H),3.78(s,3H). 13 C NMR (126MHz, Chloroform-d) δ167.87,148.18,146.96,145.10,127.01,123.12,115.21,114.90,109.55,56.04,51.71.

[0236] Intermediate 2-2-f Methyl (E)-3-(4-hydroxy-3,5-dimethoxyphenyl) acrylic acid

[0237] 1 H NMR (500MHz, Chloroform-d) δ7.58(d,J=16.0Hz,1H),7.17(s,2H),6.28(d,J=15.9Hz,1H),5.13(s,1H),3.79(s,3H),2.26(s,6H). 13 C NMR (126MHz, Chloroform-d) δ168.14,154.63,145.19,128.99,126.66,123.69,114.84,51.71,16.03.

[0238] Intermediate 2-2-g Methyl (E)-3-(4-hydroxy-2,6-dimethoxyphenyl)acrylic acid

[0239] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.74(d,J=16.3Hz,1H),6.52(s,2H),6.05(d,J=16.3Hz,1H),3.71(s,3H),2.26(s,6H). 13C NMR (126MHz, DMSO-d6) δ166.94,157.71,142.36,139.10,123.75,120.13,115.51,51.37,21.28.

[0240]

[0241] Synthesis steps 2-3

[0242] Synthesis steps of intermediate 2-3-ag:

[0243] Add 1-6-j (0.99 mmol) and 2-2-ag (1.04 mmol) to a 100 ml round-bottom flask, add 6 ml of DMF, stir evenly, then add anhydrous potassium carbonate (1.48 mmol), heat to 70 ° C, protect with N2, and react for 2 hours; monitor the reaction end point by TLC. After the reaction is completed, add dilute hydrochloric acid to the reaction solution to remove potassium carbonate, extract with EA and H2O 3 times, collect the organic phase, dry with anhydrous sodium sulfate, evaporate under reduced pressure, and separate by silica gel column chromatography to obtain a yellow solid or oil.

[0244] Intermediate 2-3-a Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-3-methylphenyl)acrylic acid

[0245] 1 H NMR(500MHz,Chloroform-d)δ9.11(s,1H),7.92(d,J=9.2Hz,1H),7.66(s,1H),7.5 6(d,J=16.0Hz,1H),7.51(d,J=7.8Hz,2H),7.45–7.34(m,4H),7.32–7.27(m,2H),7. 22(d,J=7.4Hz,2H),7.14(t,J=7.5Hz,1H),7.09(d,J=8.5Hz,1H),6.32–6.23(m,2H ),5.28(s,2H),3.79(s,3H),2.40–2.24(m,2H),1.79(s,3H),1.01(t,J=7.5Hz,3H). 13C NMR(126MHz,Chloroform-d)δ194.96,167.52,162.02,158.01,157.39,153. 60,152.65,144.78,143.98,137.95,135.87,131.72,130.82,130.16,129.68 ,129.10,128.78,128.42,127.87,127.77,127.23,125.33,124.45,122.26,121.32,117.29,116.54,113.85,108.90,70.53,51.68,26.00,15.50,15.41.

[0246] Intermediate 2-3-b Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-2-methylphenyl)acrylic acid

[0247] 1 H NMR(500MHz,Chloroform-d)δ9.10(s,1H),7.97(d,J=9.2Hz,1H),7.82(d,J=15.9Hz,1H),7.60(d,J=2.4Hz,1H),7.50(d,J=7.3Hz,2H),7.44–7.34(m ,4H),7.31–7.27(m,3H),7.19–7.12(m,2H),6.27–6.15(m,3H),5.27(s,2H ),3.79(s,3H),2.32(q,J=7.5Hz,2H),2.23(s,3H),1.03(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ194.77,167.63,162.13,159.26,157.51,153. 83,153.15,144.94,141.46,139.94,137.72,135.99,131.75,130.28,129.58 ,128.90,128.53,128.37,128.09,127.85,125.40,124.76,121.63,121.33,117.91,117.83,117.54,113.83,109.06,70.62,51.82,26.36,19.90,15.62.

[0248] Intermediate 2-3-c Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-3-fluorophenyl)acrylic acid

[0249] 1 H NMR(500MHz,Chloroform-d)δ9.04(s,1H),8.01(d,J=9.2Hz,1H),7.60(d,J=2.5Hz,1H), 7.53–7.47(m,3H),7.45–7.34(m,4H),7.31(dd,J=9.2,2.5Hz,1H),7.30–7.27(m,1H),7.2 1(d,J=7.7Hz,1H),7.16–7.10(m,2H),7.01(d,J=8.5Hz,1H),6.46(t,J=8.4Hz,1H),6.27( d,J=15.9Hz,1H),5.27(s,2H),3.79(s,3H),2.40(q,J=7.5Hz,2H),1.07(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ194.64,167.18,162.19,157.21,153.76,152.93,151.00, 147.14(d,J=11.4Hz),144.72,142.76,137.36,135.93,132.06,130.57(d,J=6.3Hz),130 .26,129.85,128.91,128.56,127.86,125.59,124.82(d,J=3.2Hz),124.46,121.59,121 .39,118.31,117.23,116.99,115.72(d,J=18.4Hz),109.09,70.65,51.96,26.45,15.72.

[0250] Intermediate 2-3-d Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-3-ethylphenyl)acrylic acid

[0251] 1H NMR(500MHz,Chloroform-d)δ9.08(s,1H),7.86(d,J=9.1Hz,1H),7.61(d,J=2.4Hz,1H),7.56(d, J=16.0Hz,1H),7.49(d,J=7.3Hz,2H),7.42(t,J=7.4Hz,2H),7.39–7.34(m,2H),7.29–7.26(m,2H) ,7.24(d,J=2.2Hz,1H),7.19(d,J=7.7Hz,1H),7.14–7.07(m,2H),6.30–6.23(m,2H),5.26(s,2H) ,3.79(s,3H),2.39–2.23(m,2H),2.21–2.05(m,2H),1.07(t,J=7.5Hz,3H),1.00(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ195.19,167.68,162.04,157.81,157.37,153.81 ,152.79,144.87,144.27,138.04,135.97,133.50,131.79,130.23,129.79,12 9.33,129.05,128.90,128.54,127.85,127.22,125.43,124.54,122.63,121.40,117.42,116.56,113.97,109.13,70.63,51.79,26.13,22.32,15.61,13.59.

[0252] Intermediate 2-3-e methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-3-methoxyphenyl)acrylic acid

[0253] 1H NMR(500MHz,Chloroform-d)δ9.00(s,1H),8.04(d,J=9.3Hz,1H),7.57(d,J=2.5Hz,1H),7.54(d,J=16.0Hz, 1H),7.49(d,J=7.0Hz,2H),7.41(t,J=7.3Hz,2H),7.39–7.33(m,2H),7.31(d,J=7.6Hz,1H),7.28(dd,J=9.3 ,2.5Hz,1H),7.17–7.12(m,2H),6.85(d,J=1.9Hz,1H),6.82(dd,J=8.3,2.0Hz,1H),6.34(d,J=8.3Hz,1H),6 .27(d,J=16.0Hz,1H),5.25(s,2H),3.79(s,3H),3.57(s,3H),2.31(q,J=7.5Hz,2H),1.04(t,J=7.5Hz,3H). 13 CNMR(126MHz,Chloroform-d)δ194.79,167.47,162.03,157.96,153.58,152 .90,149.12,148.94,145.08,144.13,137.40,136.02,131.65,130.71,130.2 8,129.52,128.86,128.48,127.85,125.46,124.81,121.57,121.28,121.15,117.23,117.08,116.27,110.81,108.87,70.57,55.78,51.84,26.38,15.65.

[0254] Intermediate 2-3-fmethyl(E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-3,5-dimethoxyphenyl)acrylic acid

[0255] 1H NMR(500MHz,Chloroform-d)δ8.63(s,1H),8.23(d,J=9.2Hz,1H),7.57(d,J=2.5Hz, 1H),7.53–7.47(m,3H),7.42(t,J=7.5Hz,2H),7.39–7.31(m,3H),7.28–7.23(m,1H) ,7.16(d,J=7.6Hz,1H),7.09(t,J=7.5Hz,1H),6.93(s,2H),6.27(d,J=16.0Hz,1H), 5.26(s,2H),3.80(s,3H),2.32(q,J=7.4Hz,2H),1.79(s,6H),1.07(t,J=7.4Hz,3H). 13 CNMR(126MHz,Chloroform-d)δ194.58,167.51,161.28,157.51,154.00,152.36,151.87,146.53,143.99,136.39,136.18,132.50,131.38,13 0.49,130.32,129.19,128.83,128.40,127.79,125.36,124.24,120.5 2,119.15,117.37,115.87,108.82,70.45,51.80,27.14,16.87,15.64.

[0256] Intermediate 2-3-g Methyl (E)-3-(4-((7-(benzyloxy)-3-(2-ethylbenzoyl)quinolin-4-yl)oxy)-2,6-dimethoxyphenyl)acrylic acid

[0257] 1 H NMR(500MHz,Chloroform-d)δ9.09(s,1H),8.00(d,J=9.2Hz,1H),7.71(d,J=16 .3Hz,1H),7.60(d,J=2.5Hz,1H),7.50(d,J=7.3Hz,2H),7.45–7.34(m,4H),7.32 –7.27(m,2H),7.16(t,J=6.8Hz,2H),6.05(s,2H),5.97(d,J=16.3Hz,1H),5.27 (s,2H),3.80(s,3H),2.32(q,J=7.5Hz,2H),2.14(s,6H),1.05(t,J=7.5Hz,3H). 13C NMR(126MHz,Chloroform-d)δ194.74,167.37,162.12,157.75,157.65,153.79,153.22,145.07,142.57,139.06,137.63,136.06,131.67,130.43 ,129.49,128.90,128.81,128.52,127.85,125.39,124.85,123.09,121. 46,121.21,117.72,115.62,109.04,70.62,51.84,26.41,21.32,15.63.

[0258]

[0259] Synthesis steps 2-4

[0260] Synthesis steps of intermediate 2-4-ag:

[0261] Add 2-3-ag (0.34mmol) to a 100ml round-bottom flask, add 6ml of DCM, stir evenly, and protect with N2. Slowly add 1mol / L boron tribromide (0.68mmol) under ice bath conditions, and react for 5 minutes after the addition is complete. TLC monitors the reaction endpoint. After the reaction is complete, add excess anhydrous methanol to quench the unreacted boron tribromide and the boron complex formed by decomposition. The reaction solution is evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain a yellow solid or oil.

[0262] Intermediate 2-4-a Methyl (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3-methylphenyl)acrylic acid

[0263] 1 H NMR(500MHz,Chloroform-d)δ8.98(s,1H),7.80(d,J=9.1Hz,1H),7.58–7.50(m,2H), 7.41–7.34(m,2H),7.24–7.19(m,2H),7.17(t,J=7.5Hz,1H),7.12(dd,J=8.5,2.3Hz, 1H),7.01(dd,J=9.1,2.3Hz,1H),6.35(d,J=8.5Hz,1H),6.28(d,J=15.9Hz,1H),5.29 (s,1H),3.79(d,J=2.0Hz,3H),2.35–2.25(m,2H),1.82(s,3H),1.00(t,J=7.5Hz,3H). 13C NMR(126MHz,Chloroform-d)δ194.35,167.74,162.58,158.88,157.92,151.62,151.49,145.03,144.07,137.72,131.98,131.02, 130.34,129.83,129.50,128.13,127.38,125.51,125.12,121.67,121.63,116.79,116.70,114.23,108.94,51.87,26.09,15.56.

[0264] Intermediate 2-4-b Methyl (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-2-methylphenyl)acrylic acid

[0265] 1 H NMR(500MHz,Chloroform-d)δ9.00(s,1H),7.87(d,J=9.2Hz,1H),7.83(d,J=15.8 Hz,1H),7.44–7.37(m,3H),7.33(d,J=8.7Hz,1H),7.22–7.15(m,2H),6.97(dd,J= 9.2,2.3Hz,1H),6.32(dd,J=8.7,2.7Hz,1H),6.27(d,J=2.7Hz,1H),6.23(d,J=15 .8Hz,1H),3.80(s,3H),2.32(q,J=7.5Hz,2H),2.25(s,3H),1.04(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ194.09,167.69,162.43,159.12,158.75,152.06,151.90,145.10,141.45,140.06,137.46,131.91,130 .41,129.65,128.66,128.19,125.51,125.40,121.46,120.98,118.07,118.02,116.83,114.04,109.06,51.88,26.38,19.90,15.61.

[0266] Intermediate 2-4-c Methyl (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3-fluorophenyl)acrylic acid

[0267] 1H NMR(500MHz,Chloroform-d)δ8.91(s,1H),8.06(d,J=9.2Hz,1H),7.84(d,J=2.3 Hz,1H),7.50(d,J=16.0Hz,1H),7.45–7.38(m,1H),7.34–7.31(m,1H),7.26–7.15 (m,4H),7.11(dd,J=11.4,2.0Hz,1H),7.08–7.04(m,1H),6.63(t,J=8.3Hz,1H),6 .28(d,J=16.0Hz,1H),3.80(s,3H),2.41(q,J=7.5Hz,2H),1.07(t,J=7.5Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ193.02,166.85,166.50,162.62,150.93,150.23,143.88,142.54,136.59,132.16,130.81(d,J=6.7Hz),130.30,12 9.65,126.02,125.64,125.16,121.67,120.25,118.43,117.79(d,J=3 .6Hz),117.42,115.93,115.65,115.53,108.15,51.53,25.61,15.46.

[0268] Intermediate 2-4-d Methyl (E)-3-(3-ethyl-4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid

[0269] 1 H NMR(500MHz,Chloroform-d)δ8.96(s,1H),7.96–7.88(m,2H),7.56(d,J=15.9Hz,1H),7.39(t,J=7.5Hz,1H),7.33(d,J=7.5Hz,1H),7.25–7.11(m,6 H),6.40(d,J=8.5Hz,1H),6.29(d,J=16.1Hz,1H),3.79(s,3H),2.38–2.2 4(m,2H),2.22–2.07(m,2H),1.09(t,J=7.5Hz,3H),1.00(t,J=7.5Hz,3H). 13C NMR(126MHz,Chloroform-d)δ193.26,167.63,163.52,160.14,157.21,149.92,145.43,144.01,137.00,133.95,132.33,130.50,13 0.20,130.03,129.25,127.26,125.64,125.52,122.65,121.69,117.11,117.04,114.64,107.86,51.88,26.21,22.38,15.57,13.59.

[0270] Intermediate 2-4-e methyl (E) -3- (4- ( (3- (2-ethylbenzoyl) -7-hydroxyquinolin-4-yl) oxygen) -3-methoxyphenyl) acrylic acid

[0271] 1 H NMR(500MHz,Chloroform-d)δ8.90(s,1H),7.96(d,J=9.2Hz,1H),7.55(d,J=1 6.0Hz,1H),7.43(s,1H),7.37(d,J=7.6Hz,2H),7.17(t,J=8.4Hz,2H),7.03(dd ,J=9.1,2.2Hz,1H),6.89–6.83(m,2H),6.46(d,J=8.2Hz,1H),6.28(d,J=15.9H z,1H),3.80(s,3H),3.59(s,3H),2.32(q,J=7.4Hz,2H),1.04(t,J=7.5Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ194.34,167.55,162.04,159.05,152.10,152.00,149.21,148.72,145.18,144.18,137.24,131.75,130 .87,130.52,129.58,125.55,125.39,121.64,121.13,120.51,117.17,116.75,116.44,110.95,109.41,55.81,51.90,26.43,15.66.

[0272] Intermediate 2-4-fmethyl(E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3,5-dimethoxyphenyl)acrylic acid

[0273] 1H NMR(500MHz,Chloroform-d)δ8.57(s,1H),8.23(d,J=9.2Hz,1H),7.49(d,J=16.0Hz,1H),7.40(t,J=7.5Hz,1H),7.30(t,J=8.0Hz,3 H),7.20–7.12(m,2H),6.94(s,2H),6.27(d,J=16.0Hz,1H),3.81(s,3H),2.36(q,J=7.4Hz,2H),1.87(s,6H),1.06(t,J=7.4Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ192.44,167.49,162.96,160.53,153.56,148.38,147.92,146.93,143.74,135.54,133.07,132 .62,132.14,130.64,130.55,129.29,125.65,125.12,122.20,118.73,117.96,115.16,107.30,51.93,27.29,16.94,15.62.

[0274] Intermediate 2-4-g methyl (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-2,6-dimethoxyphenyl)acrylic acid

[0275] 1 H NMR(500MHz,Chloroform-d)δ8.96(s,1H),8.00(d,J=9.1Hz,1H),7.67(d,J=16.3Hz,1H),7.53(d,J=2.4Hz,1H),7.39(t,J=8.1Hz,1H),7.29–7.26(m,1H) ,7.21(dd,J=9.1,2.4Hz,1H),7.17–7.11(m,2H),6.04(s,2H),5.94(d,J=16. 3Hz,1H),3.78(s,3H),2.30–2.24(m,2H),2.11(s,6H),1.02(t,J=7.5Hz,3H). 13C NMR(126MHz,Chloroform-d)δ193.89,167.42,162.61,159.17,157.26,151.66,145.22,142.50,139.44,139.09,137.08,131 .89,130.44,129.55,129.10,125.44,123.14,121.62,120.56,116.91,115.71,115.60,108.85,51.86,26.37,21.20,15.52.

[0276] Synthesis process of representative compounds

[0277]

[0278] Synthesis step 9

[0279] Synthesis steps of compounds 1 to 24:

[0280] Add 1-8a-q or 2-4-ag (0.68 mmol) to a 100 ml round-bottom flask, add 6 ml of THF, and stir evenly; dissolve LiOH (3.40 mmol) in 2 ml of water to prepare a NaOH solution; add the NaOH solution dropwise to the reaction solution under an ice bath, and react at room temperature for 15 hours after the addition; monitor the reaction endpoint by TLC, and after the reaction is completed, add dilute hydrochloric acid dropwise under an ice bath to adjust the pH to 1; extract the reaction solution with EA 3 times, collect the organic phase, dry it with anhydrous sodium sulfate, evaporate it under reduced pressure, and separate it by silica gel column chromatography to obtain a white or cyan solid.

[0281] Compounds 1 to 24 were prepared by a process similar to step 9 using appropriate starting materials; the characterizations of these compounds are as follows: Compounds 1 to 17 were synthesized by reaction scheme 1

[0282] Compound 1: (E)-3-(4-((3-benzoyl-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0283] The compound is obtained by reacting intermediate 1-8-a. 1H NMR(500MHz,DMSO-d6)δ12.26(s,1H),10.78(s,1H),8.85(s,1H),7.90(d,J=9.1Hz,1H),7.66–7.61(m,3H),7.50 –7.44(m,6H),7.41(d,J=2.4Hz,1H),7.26(dd,J=9.1,2.4Hz,1H),6.59(d,J=8.8Hz,2H),6.36(d,J=16.0Hz,1H). 13 CNMR(126MHz,DMSO)δ192.88,167.91,161.10,158.95,156.37,153.03,151.49,142.68,137.07,133.68,129.94, 129.36,129.28,128.65,124.53,120.83,120.27,118.68,116.36,115.46,110.67.ESI-MS(-)[m / z]:410.58[MH] - .

[0284] Compound 2: (E)-3-(4((3-(3-fluorobenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0285] The compound is obtained by reacting intermediate 1-8-b. 1 H NMR(500MHz,DMSO-d6)δ8.85(s,1H),7.90(d,J=9.1Hz,1H),7.52–7.45(m,5H),7.43(d,J=16.0Hz,1H),7.40(d, J=2.4Hz,1H),7.36(d,J=9.1Hz,1H),7.25(dd,J=9.1,2.4Hz,1H),6.61(d,J=8.8Hz,2H),6.36(d,J=16.0Hz,1H). 13C NMR (126MHz, DMSO) δ192.18,192.16,168.51,163.37,161.79,161.41,159.2 1,157.04,153.64,151.91,142.63,142.61,142.60,139.85,139.80,131.26, 131.20,130.27,129.87,126.08,126.05,125.01,121.25,120.91,120.74,12 0.00,119.72,116.71,115.82,115.64,111.10.ESI-MS(-)[m / z]:428.77[MH] - .

[0286] Compound 3: (E)-3-(4((3-(4-fluorobenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0287] The compound is obtained by reaction of intermediate 1-8-c. 1 H NMR (500MHz, Methanol-d4) δ8.80(s,1H),8.02(d,J=9.1Hz,1H),7.64(dd,J=8.8,5.4Hz,2H),7.51(d,J=16.0Hz,1H),7.40(d,J=2. 4Hz, 1H), 7.35 (d, J = 8.8Hz, 2H), 7.24 (dd, J = 9.1, 2.4Hz, 1H), 7.13 (t, J = 8.7Hz, 2H), 6.54 (d, J = 8.8Hz, 2H), 6.30 (d, J = 16.0Hz, 1H). 13 C NMR (126MHz, MeOD) δ193.12,170.33,168.47,166.45,163.25,160.41,158.97,154.20,152.73,144.96,135.31,135.29,133.47,133. 39,131.18,131.07,130.88,125.83,122.01,121.15,118.80,117.93,117.51,116.69,116.52,110.79.ESI-MS(-)[m / z]:428.82[MH] - .

[0288] Compound 4: (E)-3-(4-((7-hydroxy-3-(2-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0289] The compound is obtained by reaction of intermediate 1-8-d. 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),7.75(d,J=7.9Hz,1H),7.63–7.56(m,2H),7.54–7.47(m,2H),7.41(d,J =8.5Hz,2H),7.38–7.33(m,2H),7.15(dd,J=9.2,2.4Hz,1H),6.40(d,J=8.5Hz,2H),6.33(d,J=15.9Hz,1H). 13 C NMR (126MHz, DMSO) δ192.07,158.48,158.06,154.26,152.03,149.51,138.92,132.09,130.58,129.54,129. 44,128.02,125.81,125.29,121.39,119.07,115.47,115.38,114.73,111.04.ESI-MS(-)[m / z]:478.81[MH] - .

[0290] Compound 5: (E)-3-(4-((7-hydroxy-3-(4-(trifluoromethyl)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0291] The compound is obtained by reacting intermediate 1-8-e. 1 H NMR(500MHz,DMSO-d6)δ10.91(s,1H),8.91(s,1H),7.92(d,J=9.1Hz,1H),7.79(s,4H) ,7.50–7.39(m,4H),7.29–7.22(m,1H),6.56(d,J=8.3Hz,2H),6.35(d,J=16.0Hz,1H). 13 C NMR (126MHz, DMSO) δ192.14,167.62,161.52,158.79,157.02,152.97,151.45,142.89,140.52,130.01,129.86,129. 36,125.55,125.54,124.87,124.76,120.96,119.45,118.35,116.24,115.42,110.42.ESI-MS(-)[m / z]:478.55[MH] - .

[0292] Compound 6: (E)-3-(4-((7-hydroxy-3-(4-(trifluoromethoxy)benzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0293] The compound is obtained by reaction of intermediate 1-8-f. 1 H NMR(500MHz,DMSO-d6)δ10.90(s,1H),8.92(s,1H),7.95(d,J=9.1Hz,1H),7.73(d,J=8.8Hz,2H) ,7.51–7.37(m,6H),7.28(dd,J=9.1,2.4Hz,1H),6.59(d,J=8.8Hz,2H),6.35(d,J=16.0Hz,1H). 13 C NMR (126MHz, DMSO) δ191.19,167.47,161.50,158.60,156.99,152.20,151.67,151.02,142.75,135.86,131.58,129. 85,129.37,124.67,120.92,120.59,119.47,118.84,118.32,116.29,115.41,109.85.ESI-MS(-)[m / z]:494.76[MH] - .

[0294] Compound 7: (E)-3-(4-((7-hydroxy-3-(4-methoxybenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0295] The compound is obtained by reacting intermediate 1-8-g. 1 H NMR (500MHz, DMSO-d6) δ8.80(s,1H),7.88(d,J=9.1Hz,1H),7.63(d,J=8.8Hz,2H),7.49(d,J=8.6Hz,2H),7.45(d,J=16.0Hz,1H),7. 40(d,J=2.4Hz,1H),7.24(dd,J=9.1,2.4Hz,1H),6.99(d,J=8.8Hz,2H),6.62(d,J=8.6Hz,2H),6.35(d,J=16.0Hz,1H),3.84(s,3H). 13C NMR (126MHz, DMSO) δ191.01,167.72,163.64,160.73,158.93,155.76,152.73,151.22,142.78,131.90,129.89, 129.73,129.17,124.31,120.83,120.67,116.37,115.46,113.94,110.60,55.66.ESI-MS(-)[m / z]:440.80[MH] - .

[0296] Compound 8: (E)-3-(4-((7-hydroxy-3-(thiophene-2-carbonyl)quinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0297] The compound is obtained by reaction of intermediate 1-8-h. 1 H NMR (500MHz, DMSO-d6) δ8.88(s,1H),8.08(d,J=4.9Hz,1H),7.90(d,J=9.1Hz,1H),7.70(d,J=3.8Hz,1H),7.52(d,J=8.7 Hz,2H),7.46(d,J=16.0Hz,1H),7.40(d,J=2.4Hz,1H),7.28–7.21(m,2H),6.73(d,J=8.6Hz,2H),6.37(d,J=16.0Hz,1H). 13 C NMR (126MHz, DMSO) δ184.26,167.74,160.88,158.97,155.85,152.80,150.68,143.31,142.66,136.68,136.40, 129.91,129.26,128.89,124.39,120.74,120.60,118.53,116.53,115.44,110.58.ESI-MS(-)[m / z]:416.52[MH] - .

[0298] Compound 9: (E)-3-(4-((3-(Benzofuran-5-carbonyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0299] The compound is obtained by reacting intermediate 1-8-i. 1H NMR (500MHz, Methanol-d4) δ8.72(s,1H),7.91(d,J=9.0Hz,1H),7.77(d,J=1.8Hz,1H),7.74(d,J=2.3Hz,1H),7.45(dd,J=8.7,1.8Hz, 1H),7.38(d,J=8.7Hz,1H),7.34–7.28(m,2H),7.17–7.09(m,3H),6.77(d,J=2.2Hz,1H),6.37(d,J=8.8Hz,2H),6.17(d,J=15.9Hz,1H). 13 C NMR(126MHz,MeOD)δ194.33,171.80,163.04,160.07,159.14,158.95,153.97,152.74,148.29,143.43,134.13,131.45,130.44, 128.94,127.02,125.79,125.26,121.87,121.60,120.71,117.96,117.54,112.34,110.75,108.30.ESI-MS(-)[m / z]:450.81[MH] - .

[0300] Compound 10: (E)-3-(4-((3-(2-ethylbenzoyl)7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0301] The compound is obtained by reacting intermediate 1-8-j. 1 H NMR (500MHz, DMSO-d6) δ12.28(s,1H),10.80(s,1H),8.92(s,1H),7.82(d,J=9.1Hz,1H),7.60–7.36(m,5H),7.33(d,J=7. 7Hz,1H),7.28–7.11(m,3H),6.44(d,J=8.2Hz,2H),6.36(d,J=16.0Hz,1H),2.31(q,J=7.6Hz,2H),0.95(t,J=7.5Hz,3H). 13C NMR (126MHz, DMSO) δ194.45,167.58,161.33,159.07,156.71,153.38,152.16,143.39,142.96,137.73,131.54,129.89,129 .64,129.37,129.03,125.44,124.74,120.73,118.01,115.71,115.41,110.68,25.48,15.41.ESI-MS(-)[m / z]:438.90[MH] - .

[0302] Compound 11: (E)-3-(4-((7-hydroxy-3-(2-isopropylbenzoyl)quinolin-4-yl)oxy)phenyl)acrylic acid: the specific structure is shown in the structural summary of compounds 1 to 24;

[0303] The compound is obtained by reacting intermediate 1-8-k. 1 H NMR(500MHz,DMSO-d6)δ12.20(s,1H),10.84(s,1H),8.96(s,1H),7.76(d,J=9 .1Hz,1H),7.54–7.47(m,4H),7.47–7.41(m,2H),7.40–7.34(m,2H),7.28(d,J =7.5Hz,1H),7.20(dd,J=9.1,2.4Hz,1H),7.14(t,J=7.4Hz,1H),6.51(d,J=8. 8Hz, 2H), 6.36 (d, J = 16.0Hz, 1H), 2.88 (p, J = 6.8Hz, 1H), 0.98 (d, J = 6.8Hz, 6H). 13 CNMR(126MHz,DMSO)δ194.73,167.62,161.44,159.10,156.66,153.56,152.32,147.47,144.19,143.01,137.93,131.29,130.11,12 9.98,128.97,128.73,126.00,125.23,121.07,120.80,117.96,115.75,115.46,110.77,29.29,23.77.ESI-MS(-)[m / z]:452.24[MH] - .

[0304] Compound 12: (E)-3-(4-((3-(2,6-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0305] The compound is obtained by reaction of intermediate 1-8-1. 1 H NMR (500MHz, DMSO-d6) δ12.23(s,1H),10.94(s,1H),9.07(s,1H),7.66(d,J=9.2Hz,1H),7.57–7.44(m,3H),7.38(d,J=2.4Hz,1H),7 .18(dd,J=9.2,2.4Hz,1H),7.10(t,J=7.6Hz,1H),6.93(d,J=7.7Hz,2H),6.48(d,J=8.4Hz,2H),6.37(d,J=16.0Hz,1H),1.93(s,6H). 13 C NMR (126MHz, DMSO) δ196.30,167.63,161.85,159.15,157.62,153.96,152.18,143.09,140.59,133.27,129.71,128 .76,128.74,127.55,125.43,120.92,120.07,117.84,115.43,115.23,110.89,19.07.ESI-MS(-)[m / z]:438.24[MH] - .

[0306] Compound 13: (E)-3-(4-((3-(3,5-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0307] The compound is obtained by reaction of intermediate 1-8-m. 1 H NMR(500MHz,DMSO-d6)δ11.06(s,1H),8.91(s,1H),7.95(d,J=9.1Hz,1H),7.52–7.44(m,4H),7.29(dd,J =9.2, 2.3Hz, 1H), 7.25 (s, 1H), 7.20 (s, 2H), 6.69 (d, J = 8.8Hz, 2H), 6.38 (d, J = 16.0Hz, 1H), 2.24 (s, 6H). 13C NMR (126MHz, DMSO) δ192.37,167.58,161.74,158.66,150.35,142.90,137.90,137.04,135.01,130.11,129.86,129 .48,126.88,126.72,125.00,121.15,120.45,118.33,116.81,115.70,101.94,20.60.ESI-MS(-)[m / z]:438.78[MH] - .

[0308] Compound 14: (E)-3-(4-((3-(2,4-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0309] The compound is obtained by reacting intermediate 1-8-n. 1 H NMR (500MHz, DMSO-d6) δ10.82(s,1H),8.86(s,1H),7.89(d,J=9.1Hz,1H),7.53–7.44(m,3H),7.40(s,1H),7.24( d,J=6.3Hz,2H),7.02(d,J=7.2Hz,2H),6.47(d,J=8.3Hz,2H),6.37(d,J=16.0Hz,1H),2.31(s,3H),1.96(s,3H). 13 CNMR(126MHz,DMSO)δ193.96,167.63,161.27,159.03,156.62,152.93,151.88,143.00,142.03,138.02,134.92,131.93,130.79 ,129.91,129.20,126.18,124.61,121.07,120.80,118.12,116.04,115.58,110.44,21.05,19.65.ESI-MS(-)[m / z]:438.79[MH] - .

[0310] Compound 15: (E)-3-(4-((3-(4-fluoro-2-methylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0311] The compound is obtained by reaction of intermediate 1-8-o. 1H NMR (500MHz, DMSO-d6) δ8.91(s,1H),7.88(d,J=9.1Hz,1H),7.51(d,J=8.7Hz,2H),7.47(d,J=15.8Hz,2H),7.45–7.42(m,1H),7. 39(d,J=2.4Hz,1H),7.23(dd,J=9.1,2.4Hz,1H),7.08–7.00(m,2H),6.46(d,J=8.7Hz,2H),6.37(d,J=16.0Hz,1H),1.96(s,3H). 13 C NMR(126MHz,DMSO)δ193.12,167.73,164.46,162.47,161.42,158.92,15 6.60,153.37,152.04,142.71,141.66,141.58,134.43,134.41,133.09, 133.02,129.94,129.30,124.64,120.78,120.39,117.90,117.73,115.8 0,115.37,112.52,112.35,110.65,19.45.ESI-MS(-)[m / z]:442.59[MH] - .

[0312] Compound 16: (E)-3-(4-((3-(4-chloro-2-methylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0313] The compound is obtained by reaction of intermediate 1-8-p. 1 H NMR (500MHz, DMSO-d6) δ12.27(s,1H),10.84(s,1H),8.93(s,1H),7.87(d,J=9.0Hz,1H),7.55–7.44(m, 3H),7.43–7.34(m,2H),7.32–7.19(m,3H),6.46(d,J=8.6Hz,2H),6.39(d,J=16.0Hz,1H),1.94(s,3H). 13C NMR (126MHz, DMSO) δ193.39,167.61,161.51,158.94,156.82,153.36,151.98,142.92,140.03,136.64,136.06,131.72,130 .70,129.98,129.26,125.56,124.72,120.82,120.27,118.21,115.76,115.38,110.60,19.09.ESI-MS(-)[m / z]:458.19[MH] - .

[0314] Compound 17: (E)-3-(4-((3-(4-fluoro-2,6-dimethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0315] The compound is obtained by reacting intermediate 1-8-q. 1 H NMR (500MHz, DMSO-d6) δ12.16(s,1H),11.00(s,1H),9.11(s,1H),7.65(d,J=9.1Hz,1H),7.52–7.46(m,3H),7.38(d,J=2. 4Hz, 1H), 7.18 (dd, J = 9.1, 2.4Hz, 1H), 6.76 (d, J = 9.9Hz, 2H), 6.50 (d, J = 8.5Hz, 2H), 6.37 (d, J = 16.0Hz, 1H), 1.95 (s, 7H). 13 C NMR (126MHz, DMSO) δ195.50,167.65,162.60,161.94,160.65,159.05,157.57,154.02,152.07,143.01,137.17,137.14,136.65,136 .58,129.68,128.85,125.41,120.97,120.17,117.98,115.32,115.11,114.18,114.00,110.93,19.08.ESI-MS(-)[m / z]:456.61[MH] - Compounds 18 to 24 were synthesized by reaction route 2

[0316] Compound 18: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3-methylphenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0317] The compound is obtained by reaction of intermediate 2-4-a.1 H NMR (500MHz, DMSO-d6) δ12.16(s,1H),10.83(s,1H),8.94(s,1H),7.80(d,J=9.1Hz,1H),7.50–7.38(m,4H),7.32(d,J=7.3Hz,1H),7.26(d, J=7.6Hz,2H),7.23–7.16(m,2H),6.34(d,J=16.0Hz,1H),6.20(d,J=8.5Hz,1H),2.23(d,J=7.7Hz,2H),1.72(s,3H),0.90(t,J=7.5Hz,3H). 13 C NMR (126MHz, DMSO) δ194.71,167.62,161.32,157.59,156.77,153.39,151.98,143.40,143.14,138.04,131.49,130.69,129.68,129.40,12 8.69,127.50,126.95,125.43,124.60,121.08,120.70,117.74,115.30,113.32,110.68,25.20,15.31,14.88.ESI-MS(-)[m / z]:452.27[MH] - .

[0318] Compound 19: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-2-methylphenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0319] The compound is obtained by reaction of intermediate 2-4-b. 1 H NMR (500MHz, DMSO-d6) δ12.24(s,1H),10.83(s,1H),8.91(s,1H),7.86(d,J=9.1H z,1H),7.66(d,J=15.8Hz,1H),7.51(d,J=8.3Hz,1H),7.45(t,J=7.5Hz,1H),7.38 (d,J=2.4Hz,1H),7.33(d,J=7.6Hz,1H),7.22(m,J=12.7,8.8,6.1Hz,3H),6.28(d d,J=11.8,3.6Hz,3H),2.28(q,J=7.4Hz,2H),2.19(s,3H),0.95(t,J=7.5Hz,3H). 13C NMR (126MHz, DMSO) δ194.35,167.62,161.35,158.73,156.86,153.34,152.25,143.60,140.14,139.47,137.56,131.58,129.80,128.23 ,127.71,125.47,124.77,120.71,120.50,118.97,117.33,115.54,113.46,110.64,25.53,19.17,15.46.ESI-MS(-)[m / z]:452.26[MH] - .

[0320] Compound 20: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3-fluorophenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0321] The compound is obtained by reaction of intermediate 2-4-c. 1 H NMR (500MHz, DMSO-d6) δ12.36(s,1H),10.88(s,1H),8.88(s,1H),7.89(d,J=9.1Hz,1H),7.62(d,J=12.1Hz,1H),7.48–7.36(m,3H),7.32(d,J=7 .7Hz,1H),7.29–7.21(m,3H),7.17(t,J=7.5Hz,1H),6.57(t,J=8.6Hz,1H),6.45(d,J=16.0Hz,1H),2.35(q,J=7.5Hz,2H),0.98(t,J=7.5Hz,3H). 13 C NMR (126MHz, DMSO) δ194.29,167.44,161.45,156.54,153.29,152.14,150.13,146.39,146.30,143.32,141.98,137.40,131.66,129.68,129 .49,125.54,125.35,125.33,124.49,120.93,120.20,119.63,116.84,115.87,115.02,110.67,25.53,15.50.ESI-MS(-)[m / z]:456.21[MH] - .

[0322] Compound 21: (E)-3-(3-ethyl-4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)phenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0323] The compound is obtained by reaction of intermediate 2-4-d. 1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.74(d,J=9.1Hz,1H),7.50–7.38(m,5H),7.33(d,J=7.8Hz,1H),7.24(m,J=19.5,9.5,4.8 Hz,4H),6.36(d,J=15.9Hz,1H),6.23(d,J=8.5Hz,1H),2.26(s,2H),2.09(s,2H),1.02(t,J=7.5Hz,3H),0.90(t,J=7.5Hz,3H). 13 C NMR (126MHz, DMSO) δ194.74,167.61,161.24,157.20,156.66,153.36,151.94,143.42,143.22,137.95,132.49,131.49,129.69,129.44,129.1 1,128.88,127.34,125.45,124.44,121.35,120.77,117.77,115.31,11 3.50,110.73,25.24,21.64,15.33,13.46.ESI-MS(-)[m / z]:466.29[MH] - .

[0324] Compound 22: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3-methoxyphenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0325] The compound is obtained by reaction of intermediate 2-4-e. 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H),7.84(d,J=9.2Hz,1H),7.46–7.37(m,3H),7.27(d,J=7.4Hz,1H),7.25–7.20(m,3H),7.16(t,J=7.5 Hz,1H),6.95(d,J=8.3Hz,1H),6.43(d,J=15.9Hz,1H),6.36(d,J=8.3Hz,1H),3.55(s,3H),2.29(q,J=7.5Hz,2H),0.98(t,J=7.5Hz,3H).13 C NMR (126MHz, DMSO) δ194.49,161.25,157.41,153.09,151.93,148.65,148.08,143.64,137.25,131.48,130.30,130.13,129.26 ,125.44,124.48,121.29,120.56,120.18,115.80,115.13,111.48,110.58,55.66,25.54,15.42.ESI-MS(-)[m / z]:468.25[MH] - .

[0326] Compound 23: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-3,5-dimethoxyphenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0327] The compound is obtained by reaction of intermediate 2-4-f. 1 H NMR (500MHz, DMSO-d6) δ12.35(s,1H),10.60(s,1H),8.53(s,1H),8.12(d,J=9.1Hz,1H),7.45(td,J=7.3,1.7Hz,1H),7.39(d,J=15.9 Hz,1H),7.34(d,J=2.5Hz,1H),7.26–7.14(m,6H),6.36(d,J=16.0Hz,1H),2.24(q,J=7.4Hz,2H),1.70(s,6H),0.98(t,J=7.4Hz,3H). 13 C NMR (126MHz, DMSO) δ194.43,167.59,160.42,156.94,153.39,152.00,151.15,145.08,143.02,136.28,132.41,131.96,131.05,12 9.93,129.45,129.24,125.67,124.21,119.93,118.67,118.13,113.95,110.38,26.17,16.18,15.42.ESI-MS(-)[m / z]:466.28[MH] - .

[0328] Compound 24: (E)-3-(4-((3-(2-ethylbenzoyl)-7-hydroxyquinolin-4-yl)oxy)-2,6-dimethoxyphenyl)acrylic acid: For the specific structure, see the structural summary of compounds 1 to 24;

[0329] The compound is obtained by reacting intermediate 2-4-g. 1 H NMR(500MHz,DMSO-d6)δ12.40(s,1H),10.77(s,1H),8.89(s,1H),7.89(d,J =9.0Hz,1H),7.56(d,J=16.3Hz,1H),7.45(t,J=7.4Hz,1H),7.38(d,J=2.4H z,1H),7.33(d,J=7.5Hz,1H),7.23(dd,J=8.9,2.4Hz,3H),6.14(s,2H),5.9 5(d,J=16.3Hz,1H),2.31–2.23(m,3H),2.10(s,6H),0.97(t,J=7.5Hz,3H). 13 CNMR(126MHz,DMSO)δ194.23,167.31,161.29,157.08,157.03,153.26,152.30,143.80,141.13,138.58,137.35,131.53,129.95,12 9.28,128.24,125.44,124.75,124.02,120.58,120.22,115.70,115.12,110.58,25.56,20.74,15.46.ESI-MS(-)[m / z]:466.28[MH] - .

[0330]

[0331] Summary of the structures of compounds 1 to 24

[0332] Pharmacological experiments:

[0333] (1) Survival of MCF-7 cells or Ishikawa cells

[0334] MTT assay for cell viability: Before each experiment, the culture medium of MCF-7 was replaced with RPMI-1640 without phenol red and FBS treated with activated carbon was used to remove estrogen for 2 days; 1000-2000 MCF-7 cells were seeded into each well of a 96-well plate and cultured overnight to allow the cells to adhere; all compounds were dissolved in DMSO, and the control group was treated with 0.1% DMSO treatment, after treatment, the cells were incubated for 96 to 120 hours; 5% MTT (5 mg / mL, phosphate buffered saline (PBS)) reagent was added to the cells, and after incubation for about 4 hours, the culture medium was discarded, and 200 μL DMSO was added (the absorbance was measured at 490 nm after shaking on a shaker for about 10 minutes) and shaken for about 10 minutes; finally, the absorbance was measured at 490 nm; the growth inhibition rate of the compound was calculated by the MTT method as (Ac-As) / (Ac-Ab)×100%, where Ac is the absorbance of the control well; the absorbance of the sample well is As; and Ab is the absorbance of the blank well. The MTT method was used to detect the viability of ishikawa cells, and 3000-4000 ishikawa cells were inoculated into a 96-well plate and cultured overnight to allow the cells to adhere to the wall; all compounds were dissolved in DMSO, and the control group was treated with 0.1% DMSO treatment, 20μM compound treatment for 72h, 5% MTT (5mg / mL, phosphate buffered saline (PBS)) reagent was added to the cells, incubated for about 4h, the culture medium was discarded, 200μL DMSO was added, and the cells were shaken for about 10 minutes (the absorbance was measured at 490nm after shaking on a shaker for about 10 minutes); finally, the absorbance was measured at 490nm. The growth inhibition rate of the compound calculated by the MTT method is (Ac-As) / (Ac-Ab)×100%, where Ac is the absorbance of the control well; the absorbance of the sample well is As; and Ab is the absorbance of the blank well. The results are shown in Table 1.

[0335] Table 1 Antiproliferative activity of quinoline SERD compounds in MCF-7 and Ishikawa cells

[0336]

[0337]

[0338] (2) Protein immunoblotting:

[0339] MCF-7 cells were cultured with phenol red-free medium and activated carbon-treated FBS for 2 days before the experiment; when the cells were cultured to 80% density in a 6-well plate, control and test compounds were added for 24 hours; the cells were then washed with pre-cooled PBS, and cell lysis buffer was added to lyse the cells to extract intracellular proteins (then, the cells were washed in cold PBS and then resuspended in cell radioimmunoprecipitation assay (RIPA) lysis buffer to prepare cell extracts); the sample was loaded according to the calculated protein concentration; the electrophoresis conditions were 20 mA, 120 minutes. The transfer conditions are 100V, 90 minutes, and the operation must be performed in an ice bath environment; after blocking with 5% skim milk at room temperature for 2 hours, wash 3 times with PBST, 10 minutes each time; then dilute the primary antibody with the primary antibody diluent according to the appropriate ratio (use PBST to prepare 5% bovine serum albumin, dilute various specific antibodies ERα at 1:1000, and use 5% bovine serum albumin as a diluent), incubate overnight at 4°C; recover the primary antibody, incubate the secondary antibody on a shaker for 2 hours, and then wash 3 times with PBST (after incubating the secondary antibody on a shaker for 2 hours at room temperature, rinse the membrane 3 times with PBST); finally, evenly drop the ECL luminescent liquid on the membrane surface (mix it with ECL chemiluminescence and evenly sprinkle it on the membrane surface), and use a gel imager to image and analyze the bands. The results are shown in Figure 1 .

[0340] (3) Immunofluorescence detection

[0341] MCF-7 cells were cultured in hormone-free conditions (FBS without phenol red 1640 and activated carbon treatment) 48 hours before the experiment; cells were cultured overnight in 24-well culture plates (4×104 cells per well); after adherence, cells were treated with the test compound and cultured for 24 hours; all samples were fixed and then blocked. After incubation with the corresponding diluted antibodies at 4°C overnight, secondary antibodies coupled to fluorophores were added; then, cells were rinsed three times with PBS; cell nuclei were stained with DAPI, and then immunofluorescence was detected using a fluorescence microscope (Leica, Dim8). The results are shown in Figure 2 .

[0342] Estrogen response element (ERE) luciferase assay in MCF-7 cells:

[0343] MCF-7 cells were cultured in hormone-free conditions (no phenol red 1640 and charcoal-stripped FBS) 48 h before the experiment. Cells were seeded in 96-well plates at a density of 1.5 × 104 cells / well and co-transfected with 100 ng of ERE-luciferase plasmid (3X ERE TATA luc was a gift from Donald McDonnell (Addgene plasmid#11354; http: / / n2t.net / addgene:11354; RRID:Addgene_11354)). According to the instructions, Lipofecta minute 8000 transfection reagent (Beyotime) was used in RPIM 1640 medium for 24 h. After 24 h, the cells were treated with the corresponding compounds for 24 h, and the luciferase activity was measured using the luciferase assay system (Beyotime) 24 h later. The results are shown in Figure 3 .

[0344] (4) Cell cycle arrest

[0345] MCF-7 cells were cultured in hormone-free conditions (FBS without phenol red 1640 and activated carbon treatment) 48 h before the experiment; cells were seeded in 6-well plates at a density of 5×105 cells / well, and after 24 h of treatment with the corresponding compounds, cells were collected and processed according to the instructions of the Keygen Cell Cycle Detection Kit, and then detected using a flow cytometer; the results are shown in Figure 4 .

[0346] (5) qPCR detection

[0347] RNA was extracted using a total RNA extraction kit (converted to cDNA using the III 1st Strand cDNA Synthesis SuperMix for qPCR (gDNA digester plus) according to the manufacturer's recommendations.) Quantitative real-time PCR was performed on a 7500 RT-PCR system using qPCR SYBR Green Master Mix was used for qPCR. β-actin was used as a normalization control, and the relative difference in gene expression was calculated using the ΔΔCt method.

[0348] (6) Pharmacokinetic experiments on target compounds

[0349] 6 SPF female ICR mice, 6-8 weeks old, weighing 18-22g, animal license number: SCXK (Beijing) 2021-0006; the experimental animals were adaptively raised for one week after receipt, and then pharmacokinetic studies were carried out; the temperature of the animal room was 20-26°C; the humidity was 40-70%; 12h light and dark alternation; free drinking water and food; fasting for 12h before the start of the animal experiment; the present invention adopts a single-dose single-cycle administration scheme, selects 6 healthy and suitable animals, and divides them into 2 groups, recorded as groups 1 and 2; administration The scheme is shown in Table 2. After administration, blood was collected from the jugular vein. The specific collection time points are shown in the time points in Table 3 below. Sampling requirements and processing: blood was collected using sodium heparin anticoagulation tubes and placed in a wet ice environment for more than 15 minutes, 6000r / min, centrifuged for 3 minutes, plasma was separated, and stored at -20°C for testing. The concentration of samples of each animal at each time point was determined by LC-MS / MS. For samples with high concentrations exceeding the detection limit, blank plasma was used to dilute to the quantitative range concentration and then measure. Microsoft Excel 2010 spreadsheet software was used for data management, and WinNolin 8.2 software was used to calculate pharmacokinetic parameters. The absolute bioavailability calculation formula is:

[0350] F(%)=(Doseiv×AUC oral(0-∞) ) / (Doseoral×AUC iv(0-∞) )×100%.

[0351] Calculation of pharmacokinetic parameters: According to the blood drug concentration-time data of each test animal measured in the experiment, the main pharmacokinetic parameters of the test substance are obtained, including T max (peak time), C max (peak concentration), t 1 / 2 (elimination half-life), AUC

[0352] (area under the blood drug concentration-time curve) and other parameter values.

[0353] Table 2 Dosage regimen

[0354]

[0355] After administration, blood was collected from the jugular vein. The specific collection time points are shown in the following Table 3.

[0356] Table 3 Blood sample collection design

[0357]

[0358] The results are shown in Tables 4 and 5. Figure 7 .

[0359] Table 4 In vivo pharmacokinetic data of compound 10

[0360]

[0361] Table 5 Blood concentration of compound 10 after oral or intravenous injection*

[0362]

[0363] *Compound 10 was intragastrically administered at 5 mg / kg (intravenous injection) and 20 mg / kg (oral administration) in water with PEG400 / CMC=1:9. The data are the average blood concentrations of three mice at different time points. ND: No data

[0364] (7) Establishment of nude mouse subcutaneous transplant tumor model and determination of mouse weight and tumor volume related indicators

[0365] Female nude mice and female immature SD rats were maintained under specific pathogen-free conditions; all animals were handled in strict accordance with the Guide for the Care and Use of Laboratory Animals and the Principles of the Use and Care of Vertebrate Animals, and all animal work was approved by the Institutional Animal Care Committee of the Beijing Institute of Biotechnology. Animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals issued by the Ministry of Science and Technology of the People's Republic of China.

[0366] Tumor inoculation was performed by subcutaneously injecting nude mice with MCF-7 cells (1×106) suspended in PBS. During the experiment, nude mice were subcutaneously injected with estrogen (0.15 mg / ml / day). The long diameter (a) and short diameter (b) of the tumor were measured with a vernier caliper, and the tumor volume was calculated according to the formula V = 1 / 2×a×b 2 When the average tumor volume reaches 100 mm 3At about 14:00 p.m., the mice were randomly divided into 8 groups (n=8 in each group), named as control group, fulvestrant group, 10 group, 21 group, ribociclib group, fulvestrant+ribociclib group, 10+ribociclib group, 21+ribociclib group. The mice in the fulvestrant group were subcutaneously injected with fulvestrant 250 mg / kg once a week; the mice in the 10 group were orally administered with 10 60 mg / kg every day; and the mice in the 21 group were intragastrically administered with 21 60 mg / kg every day. The mice were orally administered with ribociclib 60 mg / kg every day. Mice in the fulvestrant+ribociclib group were orally administered ribociclib 60 mg / kg daily and given a single subcutaneous injection of fulvestrant 250 mg / kg weekly; mice in the 10+ribociclib group were orally administered 10 60 mg / kg and ribociclib 60 mg / kg daily; mice in the 21+ribociclib group were orally administered 21 and ribociclib 60 mg / kg daily; within 30 days of administration, the weight and tumor volume of mice were recorded every 5 days; mice were sacrificed, and the tumors, hearts, livers, spleens, and kidneys were removed. Figure 7 .

[0367] (8) HE staining sections

[0368] The rat heart, liver, spleen, kidney and uterus were selected for histological examination. The tissues were dissected, embedded in paraffin, and sliced ​​(6 μm thick); the slices were stained with hematoxylin and eosin (H&E).

[0369] 1) Place the prepared tissue paraffin sections in a constant temperature electric furnace and bake at 60°C for 3 hours;

[0370] 2) The dried paraffin sections were dewaxed in xylene I and xylene II for 5 minutes, then immersed in 100% ethanol, 95% ethanol, 90% ethanol, 80% ethanol and 70% ethanol for 1 minute, and washed with distilled water for 2 minutes;

[0371] 3) Hematoxylin staining for 5 minutes, hydrochloric acid ethanol differentiation for 30 seconds, and rinse with water;

[0372] 4) Stain with eosin dye solution for 1 minute and wash off the residual dye solution;

[0373] 5) 70% ethanol for 30 seconds; 80% ethanol for 30 seconds; 90% ethanol twice, 3 minutes each time. Absolute ethanol twice, 5 minutes each time. Xylene transparent, neutral glue seal, observe under a microscope. The results are shown in Figure 8 .

[0374] (9) Immunohistochemistry

[0375] The tumor tissue was fixed with 4% formalin for 24 hours, embedded in paraffin, and then 6 μm sections were cut and mounted on plus slides; the sections were dewaxed in xylene and then exposed to graded alcohols (100%, 95%, 70%, 50%, water) for hydration; the slides were immersed in antigen retrieval solution and heated for 10 minutes; after cooling to room temperature, the slides were infiltrated in TBST for 15 minutes, rinsed with water, and then incubated with 3% hydrogen peroxide for 10 minutes to inactivate endogenous peroxidase activity; to block nonspecific binding, the slides were incubated with blocking solution for 30 minutes; and incubated with Ki67 primary antibody (dilution ratio of 1:500), ER primary antibody (dilution ratio of 1:250) or PR primary antibody (dilution ratio of 1:100) at 4°C overnight. For the negative control, the primary antibody was replaced by blocking solution; after washing the primary antibody with TBST, peroxidase-labeled goat anti-rabbit immunoglobulin-coupled polymer was added for 30 minutes; for signal detection, Elite abc-color reagent was used for incubation for 30 minutes, and diaminobenzidine mixture was used for incubation for 5 minutes; hematoxylin was used for counter staining, graded alcohol dehydration was performed, and observation was performed under a microscope. The results are shown in Fig. 9 .

[0376] (10) Determination of uterine wet weight

[0377] Before the experiment, 15 3-week-old female immature SD rats weighing about 100 g were adaptively raised for 7 days; control, 10, and 21 were orally administered (60 mg / kg) once a day for 2 consecutive days; Fulvestrant was subcutaneously injected at a dose of 2 mg / kg once a day for 2 consecutive days; the uterus of rats in each group was collected on the first day after the experiment; peripheral fat tissue was removed, and the rat uterus was rinsed 2 to 3 times with PBS, drained, stored, and weighed. The wet weight of the uterus was recorded and the uterine coefficient was calculated.

[0378] Uterine coefficient = uterine wet weight (g) / body weight (g) × 100. The results are shown in Fig.10 .

[0379] The above are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, some improvements and modifications without departing from the principle of the present invention should be regarded as the protection scope of the present invention.

Claims

1. A selective estrogen receptor down-regulator compound, characterized in that The chemical structural formula of the compound is shown in formula (I): Where: m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; X is selected from -O-; Y is selected from -C(O)-; Ring B is selected from phenyl; Ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl; R1 is selected from -CH=CHCOOH; R2 and R3 are selected from hydrogen, C1-C6 alkyl, halogen.

2. A selective estrogen receptor down-regulator compound, characterized in that The compound is any of the following:

3. The method for preparing the selective estrogen receptor down-regulator compound according to claim 1, wherein the specific synthetic route is as follows: Synthetic route 1: Synthesis route 2:

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more selective estrogen receptor down-regulator compounds as described in claim 1 and a pharmaceutically acceptable carrier.

5. Use of the selective estrogen receptor down-regulator compound according to claim 1 in the preparation of a drug for treating estrogen-related disorders.

6. The use according to claim 5, characterized in that The estrogen-related disorder is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, lung cancer, cancer that has metastasized to the bone, or bone loss.

7. The use according to claim 6, characterized in that The breast cancer is hormone receptor-positive metastatic breast cancer, tamoxifen-resistant breast cancer or triple-negative breast cancer.

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