Chlorogenic acid simplification and its preparation, pharmaceutical composition and use thereof

Abstract

The application belongs to the technical field of medicine, and discloses a chlorogenic acid simple substance, a preparation method and a pharmaceutical composition and application thereof. Specifically relates to a compound of formula (I) or its isomer and its pharmaceutically acceptable salt, and a preparation method thereof. A new pharmaceutical composition comprises an effective dose of the compound of formula (I) and a pharmacologically acceptable carrier. The application also discloses the application of the compound in the prevention and / or treatment of tumors. The tumors include glioma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal cancer, head and neck tumor, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, rectal adenocarcinoma, leukemia and lymphoma.

Description

Technical Field

[0001] This invention relates to novel simplified chlorogenic acid compounds, their pharmaceutically usable salts, their polycrystalline and eutectic forms, their precursors or derivatives / probes with the same biological function, their preparation methods, pharmaceutical compositions containing them, and their use as medicines, especially as preventive / therapeutic agents for tumors, belonging to the field of pharmaceutical technology. Background Technology

[0002] Tumor cell growth and metastasis are often accompanied by alterations in energy metabolism, and numerous reports indicate that tumor tissue's utilization of ketone bodies can support tumor cell growth and survival. In mitochondria, a high-energy metabolic center, various enzymes are overexpressed in cancer cells, closely related to tumor recurrence, metastasis, and drug resistance. Succinyl-CoA transferase (OXCT1) is an important mitochondrial protein involved in ketone body metabolism. In recent years, OXCT1 has been found to be highly expressed or highly active in many tumor cells. In The Cancer Genome Atlas (TCGA), based on mRNA expression z-scores, increased expression of OXCT1 as a ketone body metabolic enzyme has been observed in various types of cancer. Therefore, inhibiting OXCT1, thereby cutting off the energy supply pathway for tumor cells and thus inhibiting tumor cell growth, may have promising research applications.

[0003] Specifically, succinyl-CoA acyltransferase 1 (OXCT1) is a 521-amino acid protein located in the mitochondrial matrix. It is highly expressed primarily in the heart and kidneys, but not in the liver. Therefore, under normal circumstances, ketone body breakdown can only occur in extrahepatic tissues. The activity and expression level of OXCT1 can indicate the utilization level of ketone bodies. It mainly catalyzes the transfer of coenzyme A from succinyl-CoA to acetoacetate to generate two molecules of acetoacetyl-CoA, thus being a key rate-limiting enzyme in ketone breakdown. Studies have shown that OXCT1 is abnormally expressed in various tumor tissues, catalyzing ketone body metabolism and utilization, thereby affecting tumor cell growth and metastasis. For example, recent studies have elucidated the mechanisms by which OXCT1 regulates the β-hydroxybutyrate-mediated NF-κB signaling pathway to control ketone body levels in lung cancer and promotes the malignant proliferation of non-small cell lung cancer by upregulating miR-516b-5p and upregulating SLC1A5. Furthermore, OXCT1, as a succinyltransferase, promotes hepatocellular carcinoma through succinylation of LACTB (a β-lactamase-like serine protease). Meanwhile, in MDA-MB-231 human breast cancer cells, OXCT1 overexpression leading to ketone body overuse also increases tumor growth and metastasis. Furthermore, OXCT1 is highly correlated with bladder cancer mortality; Krizia Rohena-Rivera et al. observed high expression of OXCT1 in many bladder cancer cell lines. Additionally, abnormal expression levels of OXCT1 were also observed in the metastatic colorectal cancer (CRC) cell line CC-M3. Moreover, related studies have found that OXCT1 is associated with tumor cell resistance to certain drugs; for example, OXCT1 can enhance the resistance of pancreatic ductal adenocarcinoma to gemcitabine through the NF-κB pathway.

[0004] Ketone bodies play a crucial energy support role in tumorigenesis and development. When cells are under nutrient deprivation, ketosis is activated, producing ketone bodies. These bodies are then metabolized in extrahepatic tissues and enter the tricarboxylic acid cycle to generate ATP, which supplies ATP for cell growth. OXCT1, as a key rate-limiting enzyme catalyzing ketone body metabolism, is highly expressed in many tumor tissues. Its main functions are to inhibit autophagy and apoptosis, while promoting cell proliferation, migration, mitochondrial proliferation, and intracellular ATP production, thereby influencing tumor cell growth and metastasis. Given the critical role of OXCT1 in tumorigenesis and development, the development of OXCT1 inhibitors is urgently needed; however, no relevant drugs have been reported to date.

[0005] Chlorogenic acid, a natural product, has a pro-apoptotic effect on various tumor cells. It is widely distributed in many plants, with high concentrations found in Eucommia ulmoides, honeysuckle, sunflower, coffee, and chrysanthemum. It is a phenylpropanoid compound produced by the condensation of caffeic acid and quinic acid, occurring during aerobic respiration in plants via the shikimic acid pathway. It possesses a wide range of biological activities, including antibacterial, antiviral, white blood cell-boosting, hepatoprotective, choleretic, antitumor, antihypertensive, lipid-lowering, free radical scavenging, and central nervous system stimulant effects. Previous experiments by Professor Chen Xiaoguang's research group at the Institute of Materia Medica, Chinese Academy of Medical Sciences, found that methyl chlorogenic acid exhibited improved in vitro OXCT1 inhibitory activity compared to chlorogenic acid. Based on this, they simplified the structure of methyl chlorogenic acid to obtain a series of novel simplified chlorogenic acid compounds that showed good inhibitory activity against OXCT1. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a simplified chlorogenic acid compound with antitumor activity that has excellent therapeutic effects and low toxicity, its isomers, its pharmaceutically acceptable salts, its prodrugs, and its polycrystalline or eutectic forms.

[0007] The technical problem solved by the present invention is to provide a simplified polysubstituted chlorogenic acid as shown in general formula (I), a method for its preparation, a pharmaceutical composition thereof, and its application in cancer treatment.

[0008] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0009] The first aspect of the present invention is to provide a compound as shown in general formula (I) and a pharmaceutically acceptable salt thereof:

[0010]

[0011] Including any of its tautomer forms, where:

[0012] R1, R2, and R3 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen.

[0013] R4 is independently selected from: hydrogen, methyl, ethyl, benzo[1,4]dioxane,

[0014] X is independently selected from: oxygen, nitrogen, carbon, and sulfur; when X is oxygen, nitrogen, or sulfur, X middle It is a single bond; when X is carbon, X middle It can be a single bond or a double bond;

[0015] Y is selected independently from: oxygen, nitrogen, carbon, and sulfur;

[0016] R5, R6, R7, R8, and R9 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen.

[0017] R 10 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen;

[0018] R 11 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen;

[0019] n is independently selected from 0, 1, 2, or 3;

[0020] Halogens are represented by fluorine, chlorine, bromine, and iodine.

[0021] In the implementation of derivatives of general formula (I):

[0022] Preferably, R1, R2, and R3 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen; R4 is independently selected from: hydrogen, methyl, ethyl, phenyl, benzo[1,4]dioxane,

[0023] X is independently selected from: oxygen, nitrogen, carbon, and sulfur; when X is oxygen, nitrogen, or sulfur, X middle It is a single bond; when X is carbon, X middle It can be a single or double bond; Y is independently selected from: oxygen, nitrogen; R5, R6, R7, R8, R9 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, halogen; R 10 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, halogen; R 11 The independent selection is from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen; n is independently selected from 0 or 1; halogen represents fluorine, chlorine, bromine, and iodine.

[0024] The most preferred compounds include, but are not limited to, the following compounds:

[0025]

[0026] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect:

[0027] Method 1:

[0028] When n = 1, X is oxygen or nitrogen, and Y is oxygen or nitrogen, the preparation of compound Ia is as follows:

[0029] Compound II is condensed with an amine or acid compound to give compound III. Compound III is condensed with cyclo(isopropyl)malonic acid to give compound IV. Compound IV is condensed with benzaldehyde or substituted benzaldehyde to give compound Ia.

[0030]

[0031] i. Condensation reaction; ii. Esterification reaction; iii. Aldol condensation reaction; wherein R1, R2, R3 and R4 are defined as defined in the first aspect of this invention;

[0032] Method 2:

[0033] Preparation of compound Ib when n = 0 and Y is oxygen or nitrogen:

[0034] Compound V is condensed with an amine or acid compound to give compound VI. Compound VI undergoes an ester condensation reaction with diethyl methylphosphonate to give compound VII. Compound VII reacts with benzaldehyde or substituted benzaldehyde via an HWE reaction to give compound Ib.

[0035]

[0036] i. Condensation reaction; ii. Ester condensation reaction; iii. HWE reaction; wherein R1, R2, R3 and R4 are defined as defined in the first aspect of this invention;

[0037] Method 3:

[0038] When n=1, X is carbon, X middle Preparation of compound Ic when Y is a double bond and is oxygen or nitrogen:

[0039] Compound VIII reacts with Boc anhydride to give compound IX. Compound IX undergoes an HWE reaction with commercially available compound diethylphosphonoacetate to give compound X. Compound X undergoes an ester condensation reaction with commercially available compound diethyl methyl phosphate to give compound XI. Compound XI is deprotected under acidic conditions to give compound XII. Compound XII condenses with an amine or acid compound to give compound XIII. Compound XIII reacts with benzaldehyde or substituted benzaldehyde via an HWE reaction to give compound Ic.

[0040]

[0041] i. Esterification reaction; ii. HWE reaction; iii. Ester condensation reaction; iv. Hydrolysis reaction; v. Condensation reaction; vi. HWE reaction; wherein R1, R2, R3, and R4 are defined as defined in the first aspect of this invention;

[0042] Method 4:

[0043] When n=1, X is carbon, X middle Preparation of compound Id when Y is a single bond and is oxygen or nitrogen:

[0044] Compound XIII was reduced by hydrogenation at atmospheric pressure to give compound XIV. Compound XIV was reacted with benzaldehyde or substituted benzaldehyde via HWE reaction to give compound Id.

[0045]

[0046] i. Hydrogenation reduction; ii. HWE reaction; wherein R1, R2, R3 and R4 are defined as defined in the first aspect of the present invention; Ia, Ib, Ic and Id are included in general formula I.

[0047] A third aspect of the present invention is to provide a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the above-mentioned simplified chlorogenic acid, and optionally a pharmaceutically acceptable carrier and / or excipients.

[0048] In this invention, depending on the route of administration, the pharmaceutical composition of the simplified chlorogenic acid may be selected from the following dosage forms: solution, suspension, emulsion, pill, capsule, powder, controlled release or sustained release formulation.

[0049] The simplified chlorogenic acid pharmaceutical composition of the present invention can be formulated by known methods and administered to subjects via several routes, including but not limited to parenteral, oral, local, intradermal, intramuscular, intraperitoneal, subcutaneous, intravenous, and intranasal routes.

[0050] The chlorogenic acid simplified pharmaceutical compositions of the present invention can optionally be formulated by any conventional method using one or more pharmaceutically acceptable carriers and / or excipients. Thus, the chlorogenic acid simplified composition and its pharmaceutically acceptable salts can be specifically formulated for, for example, inhalation or blowing (through the mouth or nose) or oral, sublingual, parenteral, or rectal administration.

[0051] Simplified chlorogenic acid pharmaceutical compositions can also be in the form of solutions, suspensions, emulsions, pills, capsules, powders, controlled-release or sustained-release formulations. These formulations will contain a therapeutically effective amount of the simplified chlorogenic acid, preferably in a purified form, and an appropriate carrier to provide a suitable form of administration to the patient.

[0052] A fourth aspect of this invention provides the effects of the compounds described in the first aspect of this invention, or their pharmaceutically acceptable salts, on the prevention, alleviation, and / or treatment of cancer. Any chlorogenic acid simplifications and their salts used in the prevention, alleviation, and / or treatment of cancer are within the scope of protection of this invention.

[0053] In this invention, the prevention, relief, and / or treatment of cancer are selected from those that inhibit the activity of OXCT1.

[0054] In this invention, the purified form of the chlorogenic acid simplification refers to a chlorogenic acid simplification that is substantially pure, particularly with a purity greater than 80%, preferably greater than 85%, particularly preferably greater than 90%, and even more preferably greater than 95%. The purity range of the purified form of the chlorogenic acid simplification can be, for example, 90-96%.

[0055] Beneficial technical effects:

[0056] Based on previous research results, the inventors discovered that the new compounds obtained by further structural optimization of chlorogenic acid derivatives have significantly enhanced OXCT1 inhibitory activity compared with previous chlorogenic acid derivatives, with some compounds showing an activity enhancement of nearly 85 times.

[0057] The simplified general formula (I) of chlorogenic acid is a novel monomeric compound with advantages such as low toxicity and simple preparation process; it has good application and development prospects and is an ideal new compound for the prevention, relief and / or treatment of cancer, which can be applied to the preparation of drugs and health products. Detailed Implementation

[0058] The following examples and drug activity experiments are used to further illustrate the present invention, but they do not imply any limitation on the present invention.

[0059] The following examples are used to explain the present invention, but are not intended to limit the invention in any way.

[0060]

[0061] Commercially available caffeic acid (2 g, 11.11 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide and placed in a 25°C single-necked flask. TBSCl (5.5 g, 36.66 mmol) and imidazole (5 g, 73.33 mmol) were added, and the mixture was allowed to react at room temperature for 6 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched with 10 times the volume of DMF in water, extracted with EA, and the organic phases were combined, washed with NaCl, dried overnight, filtered, and the solvent was removed by vacuum evaporation. The crude product was used directly in subsequent steps.

[0062] The crude product was dissolved in anhydrous methanol:water = 1:1 40 mL, placed in a 100 mL single-necked flask, and potassium carbonate (1.53 g, 11.11 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched with 1 M HCl, extracted with EA, the organic phases were combined, washed with NaCl, dried overnight, filtered, the solvent was removed under reduced pressure, and column chromatography (PE:EA = 15:1) was performed to give 37 4.3 g of compound as a white solid, with a yield of 95.6%.

[0063] 1H NMR(400MHz, CDCl3)δ7.66(d,J=15.9Hz,1H),7.07–7.02(m,2H),6.86–6.81(m ,1H),6.24(d,J=15.9Hz,1H),0.99(d,J=4.1Hz,18H),0.22(d,J=3.5Hz,12H).

[0064]

[0065] Compound 37 (100 mg, 0.24 mmol), EDCI (55 mg, 0.29 mmol), and methyl trans-4-hydroxycyclohexanecarboxylate (39 mg, 0.24 mmol) were dissolved in 1 mL of anhydrous dichloromethane and placed in a 10 mL single-necked flask. Et3N (83 μL, 0.6 mmol) and DMAP (5 mg) were added at 0 °C, and the reaction was carried out at 0 °C for half an hour, then moved to room temperature. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The mixture was washed with 1 M HCl, then NaHCO3, extracted with EA, and the organic phases were combined, washed with NaCl, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (PE:EA = 30:1) was performed to give compound 38 103 mg as a colorless oil, with a yield of 78.6%. [α] D 23 =1.857°(c1, MeOH); 1 H NMR (400MHz, CDCl3) δ7.55(d,J=15.9Hz,1H),7.01(dq,J=4.5,2.2Hz,2H),6.81(d,J=8.8Hz,1H),6.22(d,J=15.9Hz,1H),5.09–5.02(m,1H ),3.69(s,3H),2.43(dq,J=9.6,5.3,4.6Hz,1H),1.93(tdd,J=13.3,9.2,3.7Hz,4H),1.83–1.60(m,4H),1.05–0.94(m,18H),0.21(s,12H); 13 C NMR (100MHz, CDCl3) δ175.9,166.9,149.5,147.3,144.6,128.2,122.5,121.3,120.5,116 .3,69.4,51.8,41.5,29.2,26.0,26.0,24.1,18.6,18.6,-3.9; HRMS(ESIMS)m / z(M)calcd for C 29 H 48 O6Si2:548.29839; Found:548.30200.

[0066] Example 1

[0067]

[0068] Compound 38 (180 mg, 0.33 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran and placed in a 10 mL single-necked flask. TBAF (0.99 mL, 0.99 mmol) was added at 0 °C, and the reaction was monitored for 0.5 h. Post-treatment: The reaction was quenched with saturated NH₄Cl, extracted with EA, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (DCM:MeOH = 30:1) was performed to give compound 1 (90 mg), a white solid, in 85.2% yield. mp 126-128; [α] D 21 =12.833° (c 0.1, MeOH); 1 H NMR (400MHz, Methanol-d4) δ7.54(d,J=15.9Hz,1H),7.05(d,J=2.1Hz,1H),6.95(dd,J=8.3,2.1Hz,1H),6.78(d,J=8.1Hz,1H ),6.27(d,J=15.9Hz,1H),5.01(dt,J=5.0,2.2Hz,1H),3.68(s,3H),2.51–2.43(m,1H),1.94–1.82(m,4H),1.80–1.64(m,4H); 13 C NMR(100MHz,Methanol-d4)δ177.5,168.6,149.5,146.8,146.7,127.7,123.0,116.5,115.6,115.1,70.8,52.2,42.5,30.0,25.0; HRMS(ESIMS)m / z(M+H)+calcd for C 17 H 21 O6:321.13326; Found:321.13531.

[0069] Example 3

[0070]

[0071] Compound 1 (30 mg, 0.09 mmol) was dissolved in 0.6 mL of acetone:water = 5:1 and placed in a 100 mL single-necked flask. 0.1 mL of 3N LiOH was added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: LiOH was neutralized with 0.5N HCl, the pH was adjusted to 4-6, and the mixture was extracted with EA. The organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (DCM:MeOH = 20:1) was performed to give 316 mg of the compound as a yellow solid, with a yield of 57.1%.

[0072] mp165-167℃; [α] D 21 =1.149° (c 1.6, MeOH); 1 H NMR(400MHz, Methanol d4)δ7.54(d,J=15.9Hz,1H),7.05(d,J=2.0Hz,1H),6.95(dd,J=8.2,2.1Hz,1H),6.78(d,J=8.2Hz,1H) ,6.27(d,J=15.9Hz,1H),5.06–4.98(m,1H),2.49–2.39(m,1H),1.98–1.84(m,4H),1.83–1.66(m,4H); 13 C NMR(125MHz,MeOD)δ179.2,168.6,149.5,146.8,146.7,127.8,122.9,116.5,115.6,115.1,70.9,42.4,30.0,25.1; HRMS(ESIMS)m / z(M+H)+calcd forC 16 H 19 O6:307.11761 Found:307.11917.

[0073] Example 2

[0074]

[0075] Using caffeic acid (1 g, 5.6 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 38, compound 2 was obtained by condensation reaction, yielding 1.05 g of a powdery white solid with a yield of 67.0%.

[0076] mp220-223℃; [α] D 18 = 9.609° (c 0.2, MeOH); 1H NMR(400MHz, Methanol d4)δ7.38(d,J=15.7Hz,1H),7.00(d,J=2.0Hz,1H),6.89(dd,J=8.3,2.0Hz ,1H),6.76(d,J=8.2Hz,1H),6.34(d,J=15.7Hz,1H),3.72(tt,J=11.5,3.6H z,1H),3.65(s,3H),3.14–3.06(m,1H),2.30(ddd,J=12.1,8.8,3.3Hz,1H) ,2.01(ddt,J=13.2,6.0,3.4Hz,4H),1.59–1.45(m,2H),1.34–1.24(m,2H); 13 C NMR(125MHz,DMSO-d6)δ175.1,164.5,147.2,145.5,138.9,126.5,120.3,118.8,115.7,113.8,51.3,47.1,41.5,31.4,27.5; HRMS(ESIMS)m / z(M+H)+calcd for C 17 H 22 O5N:320.14925; Found:320.14899.

[0077] Example 4

[0078]

[0079] Using compound 2 (700 mg, 2.2 mmol) as a starting material, and following similar procedures as those used to prepare compound 3, compound 4 (1.16 g) was obtained via hydrolysis, as a yellow oily substance, with a yield of 67.0%.

[0080] [α] D 20 = 9.705° (c 0.2, MeOH); 1 H NMR (400MHz, Methanol-d4) δ7.38(d,J=15.6Hz,1H),6.99(d,J=2.1Hz,1H),6.90(dd,J=8.2,2.1Hz,1H),6.76(d,J=8.2Hz,1H),6.34(d,J=15.7Hz,1 H),3.78–3.60(m,2H),2.31–2.21(m,1H),2.04(td,J=10.9,9.7,4.6Hz,5H ),1.54(qd,J=14.1,13.6,3.7Hz,2H),1.31(qd,J=13.1,12.4,3.9Hz,3H); 13CNMR(100MHz,Methanol-d4)δ177.6,168.4,148.7,146.7,142.2,128.3,122.1,118.5,116.4,115.0,52.1,43.5,32.7,29.0; HRMS(ESIMS)m / z(M+H)+calcd for C 16 H 20 O5N:306.13360; Found:306.13358.

[0081]

[0082] Commercially available compound 4-hydroxycyclohexanecarboxylic acid (200 mg, 1.38 mmol) and aniline (138.4 μL, 1.52 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL) and placed in a 25 mL single-necked flask. EDCI (398.74 mg, 2.08 mmol) and HOBT (281.04 mg, 2.08 mmol) were added at room temperature, followed by Et3N (480.94 μL, 3.46 mmol) at 0 °C. After the addition was complete, the reaction mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The mixture was quenched with 10 times the volume of DMF in water, washed with 1 M HCl, washed with saturated NaHCO3, extracted with EA, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (PE:EA = 5:1) was performed to give 200 mg of the known compound 5A as a white solid, with a yield of 91.3%.

[0083]

[0084] The obtained compound 5A (200 mg, 0.91 mmol) was dissolved in anhydrous toluene (5 mL) and placed in a 25 mL single-necked flask. Commercially available compound cycloisopropyl malonate (131.04 mg, 0.91 mmol) was added. After the addition was complete, the reaction mixture was heated to 100 °C and refluxed for 7 h under argon protection. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction mixture was cooled to room temperature, and a white solid precipitated. Filtering yielded 222 mg of compound 5B, with a yield of 72.8%.

[0085] Example 5

[0086]

[0087] The obtained compound 5B (200 mg, 0.65 mmol) and the commercially available compound 3,4-dihydroxybenzaldehyde (99.36 mg, 0.72 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL) and placed in a 25 mL single-necked flask. A catalytic amount of piperidine (10 μL) and acetic acid (10 μL) were added. After the addition was complete, the reaction mixture was heated to 70 °C and refluxed for 5 h under argon protection. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and column chromatography (DCM:MeOH = 10:1) was performed to give compound 5 195 mg, a white solid, with a yield of 78.9%.

[0088] 1 H NMR (400MHz, DMSO) δ9.86 (s, 1H), 9.59 (s, 1H), 9.12 (s, 1H), 7.60 (d, J = 8.0Hz, 2H), 7 .47(d,J=15.8Hz,1H),7.28(t,J=7.8Hz,2H),7.08–6.95(m,3H),6.76(d,J=8.1Hz,1 H),6.24(d,J=15.9Hz,1H),4.71(tt,J=10.8,4.6Hz,1H),2.36(t,J=11.6Hz,1H),2. 14–2.00(m,2H),1.92(d,J=13.1Hz,2H),1.58(q,J=12.2Hz,2H),1.49–1.35(m,2H); 13 C NMR(101MHz,ACETONE-D6)δ206.3,174.3,166.9,148.8,146.3,145.6,140.5,140.4,129.5,127.6,124.0,122.5,120.1,120.0, 116.4,116.0,115.2,72.7,45.4,31.7,31.6,30.4,30.4,30.2,30.0,29.8,29.6,29.5,29.3,28.4; HRMS(ESIMS)m / z(M+H)+calcd forC 22 H 24 NO5:382.1648; Found:382.1649.

[0089]

[0090] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (200 mg, 1.38 mmol) and aniline (138.4 μL, 1.52 mmol), and following similar procedures to those used in the preparation of compound 5A, a condensation reaction was conducted to yield known compound 6A 195 mg, a white solid, in a yield of 90.2%.

[0091] 1 H NMR(400MHz,DMSO)δ9.80(s,1H),7.62–7.56(m,2H),7.33–7.21(m,2H),7.05–6.93(m,1H),4.58(d,J=4.4Hz,1H),3.42–3.35(m,1H),2 .24(tt,J=11.9,3.6Hz,1H),1.93–1.85(m,2H),1.83–1.74(m,2H),1.45(qd,J=13.3,3.3Hz,2H),1.16(tdd,J=13.6,10.8,3.5Hz,2H); 13 C NMR (101MHz, DMSO) δ174.1,139.5,128.6,122.9,119.0,68.3,44.1,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.7,27.7.

[0092]

[0093] Using compound 6A (200 mg, 0.65 mmol) and commercially available compound cycloisopropyl malonate (131.04 mg, 0.91 mmol) as raw materials, compound 6B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 198 mg of compound 6B as a white solid with a yield of 70.05%.

[0094] Example 6

[0095]

[0096] Using compound 6B (198 mg, 0.65 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (99.36 mg, 0.72 mmol) as raw materials, compound 6 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 180 mg of compound 6 as a white solid with a yield of 75.6%.

[0097] 1H NMR (400MHz, DMSO) δ9.86 (s, 1H), 9.59 (s, 1H), 9.12 (s, 1H), 7.60 (d, J = 8.0Hz, 2H), 7. 47(d,J=15.9Hz,1H),7.28(t,J=7.8Hz,2H),7.09–6.94(m,3H),6.76(d,J=8.1Hz,1H), 6.25(d,J=15.9Hz,1H),4.72(tt,J=10.9,4.4Hz,1H),2.36(tt,J=11.7,3.5Hz,1H),2 .10–2.00(m,2H),1.97–1.87(m,2H),1.58(qd,J=13.2,3.1Hz,2H),1.48–1.36(m,2H); 13 CNMR(101MHz,DMSO)δ173.5,166.0,148.4,145.6,145.1,139.4,128.6,125.5,123.0,121.3,119.1,115.8,1 14.9,114.3,71.8,43.6,40.1,39.9,39.7,39.5,39.3,39.1,38.9,30.7,27.2; HRMS(ESIMS)m / z(M+H)+calcd for C 22 H 24 NO5:381.1648; Found:382.1650.

[0098]

[0099] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and p-toluidine (743.07 mg, 6.94 mmol), compound 7A was obtained by condensation reaction using a similar procedure to that used in the preparation of compound 5A, yielding 1.5 g of a white solid with a yield of 93.7%.

[0100] 1 H NMR (400MHz, DMSO) δ9.91 (s, 1H), 7.56–7.45 (m, 2H), 7.06 (dd, J = 8.7, 2.4Hz, 2H), 4.62 (d, J = 4.5Hz, 1H), 3.36–3.32 (m,1H),2.33–2.20(m,4H),1.89–1.76(m,4H),1.50–1.39(m,2H),1.21–1.10(m,2H); HRMS(ESIMS)m / z(M+H)+calcd for C 14 H 20NO2:234.1486; Found:234.1489; 13 C NMR (101MHz, DMSO) δ173.9,137.1,131.6,128.9,119.0,68.3,44.0,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.7,27.7,20.4.

[0101]

[0102] Using compound 7A (400 mg, 1.72 mmol) and commercially available compound cycloisopropyl malonate (247.75 mg, 1.72 mmol) as raw materials, compound 7B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 483 mg of compound 7B as a white solid with a yield of 88.1%.

[0103] 1 H NMR (400MHz, CDCl3) δ9.76(s,1H),7.48(s,2H),7.07(d,J=8.1Hz,2H),4.64(dq,J=10.8,5.5Hz,1H),3.35(s,2H),2. 30(dd,J=13.0,9.5Hz,1H),2.23(s,3H),2.02–1.95(m,2H),1.86(s,2H),1.60–1.47(m,2H),1.36(q,J=11.7Hz,2H); 13 CNMR(101MHz,DMSO)δ172.7,167.7,165.9,136.5,132.3,131.4,128.6,118.7,72.4,43.0,41.4,29.9,26.7,20.0; HRMS(ESIMS)m / z(M+H)+calcd for C 17 H 22 NO5:320.1486; Found:320.1492.

[0104] Example 7

[0105]

[0106] Using compound 7B (100 mg, 0.31 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (33.96 mg, 0.25 mmol) as raw materials, compound 7 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 115 mg of compound 7 as a white solid with a yield of 94.3%.

[0107] 1H NMR (400MHz, DMSO-D6) δ9.77(s,1H),9.59(s,1H),9.12(s,1H),7.50–7.43(m,3H),7.11–6.98(m,4H),6.76(d,J=8.1Hz,1H),6.24(d,J=15.9Hz,1H ),4.71(s,1H),2.37–2.29(m,1H),2.23(s,3H),2.04(dd,J=11.5,3.6Hz, 2H),1.94–1.85(m,2H),1.63–1.51(m,2H),1.43(td,J=12.2,3.6Hz,3H); 13 C NMR (101MHz, DMSO) δ173.2,166.0,148.4,145.6,145.0,136.9,131.8,129.0,125.5,121.3,119.1,115.7,114. 9,114.3,71.8,43.6,40.1,39.9,39.7,39.5,39.3,39.1,38.9,30.7,27.3,20.4; HRMS(ESIMS)m / z(M+H)+calcd forC 23 H 26 NO5:396.1809; Found:396.1805.

[0108]

[0109] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 3,5-dimethoxyaniline (1.06 g, 6.94 mmol), compound 8A was obtained by condensation reaction using a similar procedure to that used in the preparation of compound 5A. The result was a white solid and the yield was 43.6%.

[0110] 1 H NMR (400MHz, METHANOL-D4) δ6.82(d,J=2.3Hz,2H),6.24(t,J=2.3Hz,1H),3.75(s,6H),3.55(tt,J=10.9,4.3Hz,1H),2.30(tt,J= 12.0,3.6Hz,1H),2.04(ddd,J=11.4,4.1,2.1Hz,2H),1.96–1.88(m,2H),1.61(tdd,J=13.4,11.9,3.2Hz,2H),1.39–1.26(m,2H); 13C NMR(101MHz,METHANOL-D4)δ175.8,161.1,140.3,98.1,95.9,69.2,54.4,48.3,4 8.1,47.9,47.7,47.5,47.3,47.1,44.9,34.2,27.7; HRMS(ESIMS)m / z(M+H)+calcd forC 15 H 22 NO4:280.1540; Found:280.1543.

[0111]

[0112] Using compound 8A (400 mg, 1.43 mmol) and commercially available compound cycloisopropyl malonate (227.04 mg, 1.58 mmol) as raw materials, compound 8B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 494 mg of compound 8B as a white solid with a yield of 94.6%.

[0113] 1 H NMR (400MHz, DMSO) δ9.82(s,1H),6.86(d,J=2.3Hz,2H),6.18(t,J=2.3Hz,1H),4.64(dt,J=11.1,6.8Hz,1H),3.69(s,6 H),2.34–2.24(m,1H),2.02–1.95(m,2H),1.88(d,J=13.2Hz,2H),1.53(q,J=12.4Hz,2H),1.37(dd,J=17.2,7.0Hz,2H); 13 C NMR(101MHz,DMSO)δ173.3,167.9,166.2,160.2,140.8,97.1,94.9,72.6,54.8,43.3,41.6,30.1,26.8; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 24 NO7:366.1508; Found:366.1506.

[0114] Example 8

[0115]

[0116] Using compound 8B (100 mg, 0.27 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (37.80 mg, 0.27 mmol) as raw materials, compound 8 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 78 mg of compound 8 as a white solid with a yield of 65.5%.

[0117] 1 H NMR (400MHz, METHANOL-D4) δ7.53(d,J=15.8Hz,1H),7.04(d,J=2.1Hz,1H),6.94(dd,J=8.3,2.1Hz,1H),6.84–6.76(m,3H),6.28–6.20(m,2H),4.79(t d,J=6.7,3.3Hz,1H),3.75(s,6H),2.38(s,1H),2.14(dd,J=12.6,4.1Hz,2H ),1.99(d,J=13.3Hz,2H),1.70(dd,J=11.9,3.2Hz,2H),1.57–1.45(m,2H); 13 C NMR(101MHz,CHLOROFORM-D)δ173.5,167.1,161.2,160.8,158.9,140.3,139.8,126.2,120.7,120.4,116.8,10 6.7,98.0,96.9,77.5,77.2,76.8,71.9,61.7,55.8,55.5,45.6,31.0,27.8,9.0; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 28 NO7:442.1874; Found:442.1860.

[0118]

[0119] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 3-ethylaniline (861.91 μL, 6.94 mmol), and following similar procedures as those used in the preparation of compound 5A, compound 9A was obtained by condensation reaction, yielding 1.18 g of compound 9A as a white solid with a yield of 69.1%.

[0120] 1H NMR (400MHz, METHANOL-D4) δ7.40 (d, J=2.0Hz, 1H), 7.35 (ddd, J=8.1, 2.2, 1.1Hz, 1H), 7.19(t,J=7.8Hz,1H),6.93(dt,J=7.6,1.4Hz,1H),3.59–3.50(m,1H),2.61(q,J=7.6H z,2H),2.35–2.25(m,1H),2.08–1.99(m,3H),1.98–1.89(m,2H),1.61(tdd,J=13.5,11 .9,3.5Hz,2H),1.37–1.27(m,3H),1.22(t,J=7.6Hz,3H); HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 22 NO2:248.1572; Found:248.1575.

[0121]

[0122] Using compound 9A (300 mg, 1.21 mmol) and commercially available compound cycloisopropyl malonate (192.26 mg, 1.33 mmol) as raw materials, compound 9B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 276 mg of compound 9B as a white solid with a yield of 68.5%.

[0123] 1 H NMR (400MHz, DMSO-D6) δ9.74(s,1H),7.43(d,J=1.9Hz,1H),7.35(d,J=8.1Hz,1H),7.13(t,J=7.8Hz,1H),6.82(d,J=7.5Hz,1H),4.61(tt,J=11.1, 4.4Hz,1H),3.31(s,2H),2.28(tt,J=11.8,3.6Hz,1H),1.99–1.79(m,4H) ,1.50(qd,J=13.3,3.2Hz,2H),1.42–1.27(m,2H),1.11(t,J=7.6Hz,3H); 13C NMR(101MHz,DMSO-D6)δ173.9,168.6,166.9,144.7,139.9,129.1,123.0,119.0,117.1,73.3,44.0, 42.4,40.7,40.5,40.3,40.1,39.8,39.6,39.4,30.9,28.8,27.6,16.1; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 24 NO5:334.1635; Found:334.1649.

[0124] Example 9

[0125]

[0126] Using compound 9B (100 mg, 0.30 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (41.43 mg, 0.30 mmol) as raw materials, compound 9 was prepared by aldol condensation reaction using similar procedures as those for compound 5, yielding 50 mg of compound 9 as a white solid with a yield of 55.6%.

[0127] 1 H NMR (400MHz, DMSO) δ9.77(s,1H),7.45(s,2H),7.41(s,1H),7.36(d,J=8.2Hz,1H),7.15(t,J=7.8Hz,1 H),7.01(d,J=2.0Hz,1H),6.99–6.94(m,1H),6.84(d,J=7.6Hz,1H),6.72(d,J=8.1Hz,1H),6.21(d,J= 15.9Hz,1H),4.68(tt,J=10.2,4.4Hz,1H),2.58–2.49(m,3H),2.31(t,J=11.6Hz,1H),2.01(q,J=6.8H z,3H),1.88(d,J=12.7Hz,3H),1.54(q,J=12.6Hz,2H),1.39(q,J=10.8Hz,2H),1.13(t,J=7.6Hz,3H); 13C NMR (101MHz, DMSO) δ173.9,166.5,148.9,146.1,145.5,144.7,139.8,129.0,126.0,123.0,121.8,118.9,117.0,116.2, 115.3,114.7,72.2,44.1,40.6,40.4,40.2,40.0,39.7,39.5,39.3,31.1,28.7,27.7,16.0; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 28 NO5:410.1964; Found:410.1962.

[0128]

[0129] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and p-benzylaniline (1.27 g, 6.94 mmol), and following similar procedures to those used in the preparation of compound 5A, compound 10A (787 mg) was obtained as a white solid via a condensation reaction, with a yield of 37.5%.

[0130] 1 H NMR(400MHz, DMSO)δ9.74(s,1H),7.55–7.46(m,2H),7.27(t,J=7.5Hz,2H),7.20–7.14(m,3H),7.14–7.09(m,2H),4.61–4.52(m,1H),3.8 6(s,2H),2.21(tt,J=11.8,3.5Hz,1H),1.87(dd,J=13.1,3.8Hz,2H),1.80–1.72(m,2H),1.43(qd,J=13.4,3.3Hz,2H),1.20–1.08(m,2H); 13 C NMR (101MHz, DMSO) δ174.1,141.8,137.7,135.9,129.0,128.8,128.6,126.1,119.4,68.5,44.3,40.7 ,40.4,40.1,40.0,39.9,39.7,39.6,39.5,39.4,39.3,39.1,34.9,27.9; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 24 NO2:310.1729; Found:310.1731.

[0131]

[0132] Using compound 10A (170 mg, 0.55 mmol) and commercially available compound cycloisopropyl malonate (87.12 mg, 0.60 mmol) as raw materials, compound 10B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 192 mg of compound 10B as a white solid with a yield of 88.5%.

[0133] 1 H NMR (400MHz, DMSO) δ9.81 (s, 1H), 7.56–7.46 (m, 2H), 7.27 (t, J = 7.5Hz, 2H), 7.22–7.16(m,3H),7.15–7.10(m,2H),4.64(tt,J=10.8,4.2Hz,1H),3.87(s ,2H),2.30(ddt,J=11.6,7.1,3.6Hz,1H),1.99(dd,J=12.8,3.9Hz,2H),1.9 3–1.83(m,2H),1.53(dt,J=13.2,10.2Hz,2H),1.36(qd,J=12.3,3.5Hz,2H); 13 C NMR (101MHz, DMSO) δ173.7,166.8,164.2,142.0,137.8,136.3,129.3,129.0,128. 8,126.3,119.7,73.2,43.8,42.3,40.9,30.8,27.5; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 26 NO5:396.1733; Found:396.1738.

[0134] Example 10

[0135]

[0136] Using compound 10B (100 mg, 0.25 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (34.51 mg, 0.25 mmol) as raw materials, compound 10 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 90 mg of compound 10 as a white solid with a yield of 76.3%.

[0137] 1H NMR (400MHz, DMSO-D6) δ7.47(d,J=8.5Hz,2H),7.43(d,J=15.8Hz,1H),7.24(t,J=7.5Hz,2H),7. 18–7.13(m,3H),7.12–7.08(m,2H),7.01(d,J=2.1Hz,1H),6.97(dd,J=8.2,2.1Hz,1H),6.73(d, J=8.1Hz,1H),6.21(d,J=15.9Hz,1H),4.73–4.61(m,1H),3.83(s,2H),2.27(dd,J=13.4,5.8Hz, 1H),2.00(d,J=11.9Hz,2H),1.86(d,J=12.8Hz,2H),1.58–1.48(m,2H),1.38(q,J=12.3Hz,2H); 13 C NMR (101MHz, DMSO) δ173.3,166.0,148.5,145.6,145.1,141.6,137.4,135.8,128.9,128.6,128.4,1 25.9,121.3,119.2,115.8,114.9,114.2,71.8,43.6,40.5,30.7,27.3; HRMS(ESIMS)m / z(M+H)+calcd for C 29 H 30 NO5:472.2122; Found:472.2118.

[0138]

[0139] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 4-ethynylaniline (813.02 mg, 6.94 mmol), and following similar procedures to those used in the preparation of compound 5A, compound 11A was obtained via a condensation reaction, yielding 650 mg of a white solid in a yield of 40.6%.

[0140] 1 H NMR (400MHz, METHANOL-D4) δ7.56 (dd, J=8.8, 2.1Hz, 2H), 7.45–7.34 (m, 2H), 3.55 (tt, J=10.7, 4.5Hz, 1H), 3.41 (d, J= 1.6Hz,1H),2.32(tt,J=11.9,3.5Hz,1H),2.08–1.99(m,2H),1.98–1.88(m,2H),1.69–1.54(m,2H),1.38–1.24(m,2H); 13C NMR (101MHz, METHANOL-D4) δ175.9,139.2,132.3,119.4,117.6,82.9,76.7,69.2,48. 3,48.1,47.9,47.7,47.5,47.3,47.1,44.8,34.1,27.7; HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 18 NO2:244.1259; Found:244.1258.

[0141]

[0142] Using compound 11A (265 mg, 1.09 mmol) and commercially available compound cycloisopropyl malonate (172.70 mg, 1.20 mmol) as raw materials, compound 11B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 302 mg of compound 11B as a white solid with a yield of 84.1%.

[0143] 1 H NMR (400MHz, DMSO) δ10.05(s,1H),7.61(d,J=8.2Hz,2H),7.39(d,J=8.4Hz,2H),4.66(d,J=13.6Hz,1H),4.06( s,1H),2.35(d,J=11.9Hz,1H),1.94(dd,J=39.5,12.3Hz,4H),1.54(q,J=12.9Hz,2H),1.37(q,J=12.5Hz,2H); 13 C NMR (101MHz, DMSO) δ174.2,168.7,166.8,140.4,132.8,119.3,116.3,84.1,80.2,73.2,43. 9,42.3,40.6,40.4,40.2,40.0,39.8,39.5,39.3,30.8,27.4; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 20 NO5:330.1263; Found:330.1267.

[0144] Example 11

[0145]

[0146] Using compound 11B (100 mg, 0.30 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (41.94 mg, 0.30 mmol) as raw materials, compound 11110 mg was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, with a yield of 90.5%.

[0147] 1 H NMR (400MHz, DMSO) δ10.05 (s, 1H), 7.63 (d, J = 8.3Hz, 2H), 7.50–7.36 (m, 3H ),7.08–6.95(m,2H),6.76(d,J=8.1Hz,1H),6.24(d,J=15.9Hz,1H),4.71(t t,J=10.2,4.3Hz,1H),4.04(s,1H),2.36(t,J=11.9Hz,1H),2.10–2.01(m,2 H),1.92(d,J=13.1Hz,2H),1.57(q,J=12.7Hz,2H),1.42(q,J=12.2Hz,2H); 13 C NMR (101MHz, DMSO) δ174.2,166.4,148.9,146.0,145.5,140.4,132.8,126.0,121.8,119.4,116.3,116.2,115.4, 114.7,84.1,80.2,72.2,44.1,40.6,40.4,40.2,40.0,39.8,39.6,39.4,31.1,27.6; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 24 NO5:406.1576; Found:406.1578.

[0148]

[0149] Starting with commercially available compound 4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 6-amino-1,4-benzodioxane (935.7 μL, 6.94 mmol), compound 12A (830 mg), a white solid, was obtained by condensation reaction using a similar procedure to that used in the preparation of compound 5A, with a yield of 43.2%.

[0150] 1H NMR (400MHz, METHANOL-D4) δ7.16(d,J=2.5Hz,1H),6.91(dd,J=8.7,2.5Hz,1H),6.75(d,J=8.7Hz,1H),4.25–4.19(m,4H),3.55(tt,J=10.9,4.3Hz,1H),2 .27(tt,J=12.0,3.6Hz,1H),2.06–2.01(m,2H),1.95–1.87(m,2H),1.60(tdd ,J=13.4,11.9,3.4Hz,2H),1.37–1.26(m,2H); HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 20 NO4:278.1384; Found:278.1387.

[0151]

[0152] Using compound 12A (500 mg, 1.80 mmol) and commercially available compound cycloisopropyl malonate (285.87 mg, 1.98 mmol) as raw materials, compound 12B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 639 mg of compound 12B as a white solid with a yield of 97.9%.

[0153] 1 H NMR (400MHz, DMSO) δ9.68(s,1H),7.22(d,J=2.5Hz,1H),6.96(dd,J=8.7,2.5Hz,1H),6.74(d,J=8.7Hz,1H),4.64(tt,J=10.7,4.3Hz,1H),4.18(q,J=5 .1Hz,4H),2.26(tt,J=11.8,3.6Hz,1H),1.98(dd,J=12.3,4.5Hz,2H),1.9 3–1.81(m,2H),1.52(qd,J=13.1,3.2Hz,2H),1.36(td,J=12.9,6.5Hz,2H); 13 C NMR (101MHz, DMSO) δ173.4,168.6,166.8,143.3,139.5,133.5,117.1,112.7,108.6,73.2,64.6,64 .4,43.8,42.3,40.6,40.4,40.2,39.9,39.7,39.5,39.3,30.8,27.5; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 22NO7:364.1318; Found:364.1320.

[0154] Example 12

[0155]

[0156] Using compound 12B (200 mg, 0.55 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (75.92 mg, 0.55 mmol) as raw materials, compound 12105 mg was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, as a white solid with a yield of 43.6%.

[0157] 1 H NMR (400MHz, DMSO) δ9.69 (s, 1H), 9.58 (s, 1H), 9.13 (s, 1H), 7.46 (d, J = 15.8Hz, 1H), 7.24 (d, J=2.5Hz,1H),7.00(dd,J=20.7,11.5Hz,4H),6.76(dd,J=8.5,4.2Hz,2H),6.24(d,J=15.9Hz ,1H),4.70(tt,J=10.3,4.3Hz,1H),4.19(q,J=5.2Hz,5H),2.29(t,J=11.6Hz,1H),2.04(dd, J=12.4,4.5Hz,2H),1.88(d,J=13.0Hz,2H),1.56(q,J=12.7Hz,2H),1.41(d,J=12.1Hz,2H); 13 C NMR (101MHz, DMSO) δ173.5,166.4,148.8,146.0,145.5,143.3,139.5,133.6,126.0,121.8,117.1,116.2,115.4,114.8, 112.8,108.7,72.2,64.6,64.4,44.0,40.6,40.4,40.2,40.0,39.8,39.6,39.4,31.1,27.7; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 26 NO7:440.1631; Found:440.1633.

[0158]

[0159] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 6-amino-1,4-benzodioxane (852.19 μL, 6.94 mmol), compound 13A was obtained as a white solid via a condensation reaction using a similar procedure to that used in the preparation of compound 5A, with a yield of 93.7%.

[0160] 1 H NMR (400MHz, DMSO) δ9.62 (s, 1H), 7.22 (d, J = 2.4Hz, 1H), 6.95 (dd, J = 8.7, 2.5Hz ,1H),6.74(d,J=8.7Hz,1H),4.56(d,J=4.4Hz,1H),4.19(tt,J=5.6,2.7Hz,4H) ,3.36(dt,J=12.9,4.5Hz,1H),2.17(tt,J=11.9,3.5Hz,1H),1.88(dt,J=12.9, 3.7Hz,2H),1.80–1.72(m,2H),1.43(qd,J=13.2,3.2Hz,2H),1.20–1.08(m,2H); 13 C NMR (101MHz, DMSO) δ173.6,142.8,139.0,133.2,116.6,112.2,108.1,68.3,64.2,63.9,44. 1,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.7,27.9,27.7; HRMS(ESIMS)m / z(M+H)+calcd forC 15 H 20 NO4:278.1314; Found:278.1315.

[0161]

[0162] Using compound 13A (180 mg, 0.65 mmol) and commercially available compound cycloisopropyl malonate (102.91 mg, 0.71 mmol) as raw materials, compound 13B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 175 mg of compound 13B as a white solid with a yield of 74.2%.

[0163] 1H NMR (400MHz, DMSO) δ9.68(s,1H),7.30–7.17(m,1H),7.01–6.91(m,1H),6.74(d,J=8.7Hz,1H),4.70–4.56(m,1H),4.18(q,J=5.3 Hz,5H),2.34–2.21(m,1H),1.98(dd,J=11.2,5.3Hz,2H),1.86(d,J=13.7Hz,3H),1.53(d,J=12.8Hz,2H),1.35(q,J=12.6Hz,3H); 13 C NMR (101MHz, DMSO) δ173.4,168.6,166.8,143.3,139.5,133.6,117.1,112.7,108.6,73.2,64.6,64 .4,43.8,42.3,40.6,40.4,40.2,40.0,39.8,39.5,39.3,30.8,27.5; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 22 NO7:364.1318; Found:364.1315.

[0164] Example 13

[0165]

[0166] Using compound 13B (100 mg, 0.28 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (37.96 mg, 0.28 mmol) as raw materials, compound 13103 mg was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, as a white solid with a yield of 83.7%.

[0167] 1 H NMR (400MHz, DMSO) δ9.68 (s, 1H), 7.46 (d, J = 15.8Hz, 1H), 7.23 (d, J = 2.4Hz, 1H), 7.07–6.92(m,3H),6.75(dd,J=8.4,3.8Hz,2H),6.24(d,J=15.9Hz,1H),4.70(tt ,J=10.5,4.4Hz,1H),4.18(p,J=4.4Hz,4H),2.29(tt,J=11.9,3.5Hz,1H),2.10– 1.98(m,2H),1.93–1.82(m,2H),1.56(qd,J=13.2,3.1Hz,2H),1.48–1.33(m,2H); 13C NMR (101MHz, DMSO) δ173.5,166.4,148.8,146.0,145.5,143.3,139.5,133.6,126.0,121.8,117.1,116.2,115.3,114.7, 112.8,108.7,72.2,64.6,64.4,44.0,40.6,40.4,40.2,40.0,39.8,39.6,39.3,31.1,27.7; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 26 NO7:440.1707; Found:440.1704.

[0168]

[0169] Starting with commercially available compound 4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 3,4-difluoroaniline (757.01 μL, 6.94 mmol), compound 14A was obtained by condensation reaction using a similar procedure to that used in the preparation of compound 5A. The result was a white solid with a yield of 31.1%.

[0170] 1 H NMR (400MHz, METHANOL-D4) δ7.72–7.65(m,1H),7.25–7.14(m,2H),3.55(tt,J=10.9,4.3Hz,1H),2.30(tt,J=12.0,3.6Hz,1H) ,2.08–2.00(m,2H),1.97–1.89(m,2H),1.61(tdd,J=13.3,11.9,3.2Hz,2H),1.37–1.26(m,2H); HRMS(ESIMS)m / z(M+H)+calcd forC 13 H 16 F2NO2:256.1142; Found:256.1144.

[0171]

[0172] Using compound 14A (400 mg, 1.57 mmol) and commercially available compound cycloisopropyl malonate (248.37 mg, 1.72 mmol) as raw materials, compound 14B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 522 mg of compound 14B as a white solid with a yield of 97.6%.

[0173] 1H NMR (400MHz, DMSO) δ10.10(s,1H),7.79(ddd,J=13.3,7.5,2.4Hz,1H),7.46–7.16(m,2H),4.62(dtt,J=19.7,11.4,4.5H z,2H),3.35(s,2H),2.35–2.25(m,2H),2.02–1.94(m,2H),1.88(s,2H),1.54(qd,J=13.3,3.2Hz,2H),1.41–1.35(m,2H); 13 C NMR (101MHz, DMSO) δ169.0,168.6,166.8,150.6,148.2,148.1,146.8,144.4,136.9,136.9,117.9,117.7,115.7,108.5,108.3,73.1,72. 9,72.1,43.9,42.3,41.4,40.6,40.4,40.1,39.9,39.7,39.5,39.3,30.8,30.7,30.2,30.1,27.4,26.6; HRMS(ESIMS)m / z(M+H)+calcdfor C 16 H 18 F2NO5: 342.1075; Found: 342.1070. Example 14

[0174]

[0175] Using compound 14B (200 mg, 0.59 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (80.93 mg, 0.59 mmol) as raw materials, compound 14212 mg was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, as a white solid with a yield of 86.2%.

[0176] 1 H NMR (400MHz, DMSO) δ7.81 (ddd, J=13.3, 7.5, 2.4Hz, 1H), 7.46 (d, J=15.8Hz, 1H) ,7.34(dt,J=25.7,9.1Hz,2H),7.08–6.97(m,2H),6.76(d,J=8.1Hz,1H),6.24( d,J=15.9Hz,1H),4.71(tt,J=10.4,4.3Hz,1H),2.38–2.28(m,1H),2.05(dd,J= 12.5,4.3Hz,2H),1.92(d,J=13.1Hz,2H),1.62–1.51(m,2H),1.48–1.35(m,2H);13 C NMR (101MHz, DMSO) δ173.7,166.0,148.4,145.6,145.1,136.5,125.5,121.3,117.5,117.3,115.8,115.3,114.9,1 14.2,108.1,107.9,71.7,43.6,40.1,39.9,39.7,39.5,39.3,39.1,38.9,30.6,27.1; HRMS(ESIMS)m / z(M+H)+calcd for C 22 H 22 F2NO5:418.1388; Found:418.1385.

[0177]

[0178] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (1 g, 6.94 mmol) and 3,4-difluoroaniline (688.19 μL, 6.94 mmol), and following similar procedures to those used in the preparation of compound 5A, compound 15A was obtained as a white solid via condensation reaction, yielding 473 mg in 26.7% yield.

[0179] 1 H NMR (400MHz, METHANOL-D4) δ7.68(ddd,J=13.0,7.4,2.3Hz,1H),7.25–7.13(m,2H),3.55(tt,J=10.9,4.3Hz,1H),2.29(tt,J=12 .0,3.6Hz,1H),2.08–2.00(m,2H),1.96–1.88(m,2H),1.60(tdd,J=13.3,11.8,3.3Hz,2H),1.31(tdd,J=13.0,10.9,3.6Hz,2H); 13 C NMR (101MHz, METHANOL-D4) δ175.8,151.0,148.5,145.2,135.7,116.8,116.7,115.6,109.1,108. 9,69.2,48.3,48.1,47.9,47.7,47.5,47.3,47.0,44.7,34.1,27.6; HRMS(ESIMS)m / z(M+H)+calcd for C 13 H 16 F2NO2:256.1140; Found:256.1144.

[0180]

[0181] Using compound 15A (300 mg, 1.18 mmol) and commercially available compound cycloisopropyl malonate (169.97 mg, 1.18 mmol) as raw materials, compound 15B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 365 mg of compound 15B as a white solid with a yield of 90.8%.

[0182] 1 H NMR (400MHz, DMSO) δ10.11(s,1H),7.79(ddd,J=13.3,7.6,2.5Hz,1H),7.40–7.25(m,2H),4.65(tt,J=10.6,4.3Hz,1H),3.35(s ,2H),2.31(tt,J=11.8,3.6Hz,1H),2.03–1.95(m,2H),1.89(d,J=13.1Hz,2H),1.54(qd,J=13.1,3.1Hz,2H),1.42–1.31(m,2H); 13 C NMR (101MHz, DMSO) δ174.1,168.6,166.8,150.5,136.9,128.6,117.9,117.8,115.7,108.5,108.3,7 3.1,43.9,42.3,40.6,40.4,40.2,40.0,39.8,39.5,39.3,30.7,27.4; HRMS(ESIMS)m / z(M+H)+calcd for C 16 H 18 F2NO5:342.1156; Found:342.1148.

[0183] Example 15

[0184]

[0185] Using compound 15B (100 mg, 0.29 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (31.75 mg, 0.23 mmol) as raw materials, compound 15 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 107 mg of compound 15 as a white solid with a yield of 88.4%.

[0186] 1H NMR (400MHz, DMSO) δ10.11 (s, 1H), 7.80 (ddd, J=13.3, 7.6, 2.4Hz, 1H), 7.46 (d, J= 15.8Hz,1H),7.33(dt,J=28.0,9.3Hz,2H),7.06–6.96(m,2H),6.76(d,J=8.1Hz,1 H),6.24(d,J=15.9Hz,1H),4.71(tt,J=10.5,4.3Hz,1H),2.41–2.25(m,1H),2.08 –2.00(m,2H),1.92(d,J=13.3Hz,2H),1.57(q,J=11.4Hz,2H),1.50–1.35(m,2H); 13 C NMR (101MHz, DMSO) δ173.9,166.2,148.6,145.8,145.3,125.7,121.5,117.7,117.5,115.9,115.5,115.1,114. 5,108.3,108.1,71.9,43.8,40.4,40.1,39.9,39.7,39.5,39.3,39.1,30.8,27.3; HRMS(ESIMS)m / z(M+H)+calcd for C 22 H 22 F2NO5:417.1388; Found:417.1386.

[0187]

[0188] Using commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (500 mg, 3.47 mmol) and 3-aminopyridine (1.08 g, 11.44 mmol) as starting materials, and N,N-dimethylacetamide as solvent, compound 16A was obtained by condensation reaction with 640 mg of the product as a white solid, with a yield of 83.9%, following a similar procedure to that used in the preparation of compound 5A.

[0189] 1H NMR (400MHz, DMSO) δ7.93(d,J=8.4Hz,1H),7.65(d,J=8.3Hz,1H),7.47(t,J=7.6Hz,1H),7.36(t,J=7.6Hz,1H),3.37(tt,J=10.9,4.3Hz,1H),3.06(q, J=7.3Hz,2H),2.28(tt,J=11.9,3.6Hz,1H),1.89(dd,J=12.1,4.2Hz,2H),1 .81(t,J=7.7Hz,1H),1.45(dt,J=13.2,10.0Hz,2H),1.17(t,J=7.2Hz,4H); 13 C NMR (101MHz, DMSO) δ175.2,144.3,143.3,141.1,128.3,127.3,126.5,124.8,124.1,119.4,110.3,68.7, 49.1,46.0,44.5,40.5,40.3,40.1,39.9,39.7,39.5,39.3,35.1,28.0,9.0; HRMS(ESIMS)m / z(M+H)+calcd for C 12 H 17 N2O2:221.1279; Found:221.1285.

[0190]

[0191] Using compound 16A (230 mg, 1.04 mmol) and commercially available compound cycloisopropyl malonate (165.56 mg, 1.15 mmol) as raw materials, compound 16B was obtained by esterification reaction using similar steps as in the preparation of compound 5B, yielding 140 mg of compound 16B as a white solid with a yield of 44.0%.

[0192] 1 H NMR (400MHz, DMSO) δ10.09(s,1H),8.82–8.64(m,1H),8.23(d,J=4.7Hz,1H),8.04(d,J=8.4Hz,1H),7.32(dd,J=8. 3,4.7Hz,1H),4.75–4.56(m,1H),2.41–2.32(m,1H),2.04–1.86(m,4H),1.56(q,J=12.9Hz,2H),1.46–1.31(m,2H); 13C NMR (101MHz, DMSO) δ174.5,168.6,166.8,144.4,141.2,136.4,126.5,124.1,73.2,43.8, 42.3,40.6,40.4,40.2,40.0,39.8,39.6,39.4,30.7,27.4; HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 19 N2O5: 307.1280; Found: 307.1288. Example 16

[0193]

[0194] Using compound 16B (100 mg, 0.33 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (45.09 mg, 0.33 mmol) as raw materials, compound 16 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 94 mg of compound 16 as a white solid with a yield of 74.6%.

[0195] 1 H NMR (400MHz, CDCl3) δ10.11(s,1H),8.75(s,1H),8.23(d,J=4.8Hz,1H),8.05(d,J=8.3 Hz,1H),7.49(s,1H),7.32(dd,J=8.3,4.6Hz,1H),7.12–6.96(m,2H),6.77(d,J=8.0Hz, 1H),6.25(d,J=15.9Hz,1H),4.72(tt,J=10.3,4.3Hz,1H),2.39(t,J=11.6Hz,1H),2.05 (dd,J=12.5,4.3Hz,2H),1.96(s,2H),1.70–1.53(m,2H),1.44(td,J=12.9,6.3Hz,2H); 13 C NMR (101MHz, DMSO) δ174.6,166.5,148.9,146.0,145.5,144.4,141.2,136.5,126.5,126.0,124.1,121.8,116. 2,115.3,114.7,72.2,44.0,40.6,40.4,40.1,39.9,39.7,39.5,39.3,31.1,27.6; HRMS(ESIMS)m / z(M+H)+calcd for C 21 H 23 N2O5:383.1602; Found:383.1601.

[0196]

[0197] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (500 mg, 3.47 mmol) and 4-aminobiphenyl (1.94 g, 11.44 mmol), and following similar procedures as those used in the preparation of compound 5A, compound 17A (955 mg) was obtained as a white solid via a condensation reaction, with a yield of 93.24%.

[0198] 1 H NMR (400MHz, DMSO) δ10.00–9.87(m,1H),8.02–7.91(m,1H),7.64–7.53(m,3H),7.48–7.24(m,5H),4.73–4.53(m,1H),3.41(dt,J= 23.1,8.1Hz,1H),2.32–2.19(m,1H),1.84(dd,J=30.2,13.9Hz,4H),1.48(dd,J=23.2,11.3Hz,2H),1.19(dd,J=24.0,12.2Hz,2H); 13 C NMR (101MHz, DMSO) δ174.8,141.2,140.7,140.5,129.7,129.4,128.0,127.1,121.8,118.6,117. 9,68.8,44.7,40.6,40.4,40.2,40.0,39.8,39.6,39.4,35.2,28.2; HRMS(ESIMS)m / z(M+H)+calcd for C 19 H 22 NO2:296.1572; Found:296.1570.

[0199]

[0200] Using compound 17A (600 mg, 2.03 mmol) and commercially available compound cycloisopropyl malonate (322.08 mg, 2.24 mmol) as raw materials, compound 17B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 570 mg of compound 17B as a white solid with a yield of 73.7%.

[0201] 1H NMR (400MHz, DMSO) δ10.00(s,1H),7.95(s,1H),7.59(t,J=7.4Hz,4H),7.46(t,J=7.5Hz,2H),7.37(dt,J=8.4,4.3Hz,2H),7.30(d,J=7.8Hz,1H ),4.65(tt,J=10.6,4.7Hz,1H),2.42–2.32(m,1H),2.05–1.96(m,2H),1.92(d,J=14.3Hz,3H),1.57(q,J=12.1Hz,2H),1.38(q,J=11.7Hz,2H); 13 C NMR (101MHz, DMSO) δ174.1,168.7,167.2,141.2,140.7,140.4,129.7,129.4,128.0,127.1,121.9,118.6,117.8,7 3.0,44.0,42.8,40.6,40.4,40.2,40.0,39.8,39.5,39.3,35.2,30.8,28.1,27.5; HRMS(ESIMS)m / z(M+H)+calcdfor C 22 H 24 NO5:382.1576; Found:382.1580.

[0202] Example 17

[0203]

[0204] Using compound 17B (100 mg, 0.26 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (36.21 mg, 0.26 mmol) as raw materials, compound 17 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 74 mg of compound 17 as a white solid with a yield of 62.3%.

[0205] 1H NMR (400MHz, DMSO) δ9.99(s,1H),9.61(s,1H),9.14(s,1H),7.96(s,1H),7.58(t,J=5.8Hz,4H) ,7.50–7.43(m,4H),7.36(dq,J=7.6,4.8Hz,2H),7.30(d,J=7.5Hz,1H),7.07–6.97(m,2H),6.7 6(d,J=8.0Hz,1H),6.25(d,J=15.9Hz,1H),4.72(tt,J=10.6,4.3Hz,1H),2.43–2.34(m,1H),2. 05(dd,J=11.9,4.8Hz,2H),1.97–1.90(m,2H),1.67–1.53(m,2H),1.46(dd,J=17.5,7.8Hz,2H); 13 C NMR (101MHz, DMSO) δ174.1,166.5,148.9,146.0,145.6,141.2,140.7,140.4,129.8,129.4,128.0,127.1,126.0,121.8,118. 6,117.9,116.2,115.4,114.7,72.2,44.1,40.6,40.4,40.2,40.0,39.8,39.5,39.3,31.1,27.7; HRMS(ESIMS)m / z(M+H)+calcd for C 28 H 28 NO5:458.1889; Found:458.1886.

[0206]

[0207] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (500 mg, 3.47 mmol) and 1-naphthylamine (1.64 g, 11.44 mmol), and following similar procedures to those used in the preparation of compound 5A, compound 18A (400 mg) was obtained via a condensation reaction as a white solid, with a yield of 42.3%.

[0208] 1H NMR (400MHz, DMSO) δ9.80 (s, 1H), 8.07–7.86 (m, 2H), 7.69 (dd, J=43.4, 7.8Hz, 2H), 7.50 (dt, J=28.8, 6.3Hz, 3H),4.65–4.50(m,1H),3.41(s,1H),1.94(d,J=12.0Hz,4H),1.53(q,J=12.9Hz,2H),1.25(t,J=12.1Hz,2H); 13 C NMR(101MHz,DMSO)δ174.7,133.7,128.1,127.9,125.9,125.7,125.5,125.1,122.7,121.8,6 8.4,43.6,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.8,27.9; HRMS(ESIMS)m / z(M+H)+calcd for C 17 H 20 NO2:270.1416; Found:270.1418.

[0209]

[0210] Using compound 18A (150 mg, 0.56 mmol) and commercially available compound cycloisopropyl malonate (88.31 mg, 0.61 mmol) as raw materials, compound 18B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B. The result was a white solid with a yield of 92.5%.

[0211] 1 H NMR(400MHz, DMSO)δ9.86(s,1H),8.08–8.00(m,1H),7.99–7.89(m,1H),7.75(d,J=8.2Hz,1H),7.64(d,J=7.4Hz,1H),7.59–7.45 (m,3H),4.69(tt,J=10.9,4.0Hz,1H),3.38(s,2H),2.63–2.54(m,1H),2.09–1.98(m,4H),1.70–1.56(m,2H),1.51–1.37(m,2H); 13C NMR (101MHz, DMSO) δ174.6,168.6,166.8,134.2,134.0,128.6,128.4,126.4,126.3,126.0,125.7,123.2,1 22.4,73.3,43.4,42.3,40.6,40.4,40.2,40.0,39.8,39.5,39.3,30.9,27.7; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 22 NO5:356.1420; Found:356.1415.

[0212] Example 18

[0213]

[0214] Using compound 18B (130 mg, 0.37 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (50.53 mg, 0.37 mmol) as raw materials, compound 18 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 50 mg of compound 18 as a white solid with a yield of 31.4%.

[0215] 1 H NMR (400MHz, DMSO-D6) δ9.85(s,1H),9.59(s,1H),9.12(s,1H),8.07–7.99(m,1H),7.96–7.89(m ,1H),7.75(d,J=8.2Hz,1H),7.64(d,J=7.4Hz,1H),7.54(dt,J=6.1,2.5Hz,2H),7.51–7.44(m,2H ),7.05(d,J=2.2Hz,1H),7.01(dd,J=8.2,2.2Hz,1H),6.76(d,J=8.1Hz,1H),6.26(d,J=15.8Hz,1 H),4.75(s,1H),2.61(s,1H),2.07(t,J=14.9Hz,4H),1.66(q,J=12.3Hz,2H),1.55–1.41(m,2H); 13C NMR (101MHz, DMSO) δ166.0,148.4,145.6,145.1,133.7,128.1,126.0,125.8,125.5,125.2,122.7,121.9,121.3,1 15.7,114.9,114.3,71.8,43.1,40.1,39.9,39.7,39.5,39.3,39.1,38.9,30.8,27.5; HRMS(ESIMS)m / z(M+H)+calcd for C 26 H 26 NO5:432.1733; Found:432.1730.

[0216]

[0217] Starting with commercially available compounds trans-4-hydroxycyclohexanecarboxylic acid (500 mg, 3.47 mmol) and 4-tert-butylaniline (1.82 ml, 11.44 mmol), and following similar procedures as those used in the preparation of compound 5A, compound 19A (900 mg) was obtained as a white solid via condensation reaction, with a yield of 94.3%.

[0218] HRMS(ESIMS)m / z(M+H)+calcd for C 17 H 26 NO2:276.1885; Found:276.1887.

[0219]

[0220] Using compound 19A (1 g, 3.63 mmol) and commercially available compound cycloisopropyl malonate (575.76 mg, 4.00 mmol) as raw materials, compound 19B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B, yielding 569 mg of compound 19B as a white solid with a yield of 52.5%.

[0221] 1 H NMR (400MHz, DMSO) δ9.79(s,1H),7.49(d,J=8.3Hz,2H),7.28(d,J=8.3Hz,2H),4.64(tt,J=10.5,4.3Hz,1H),3.32(s,2H),2.31( tt,J=11.8,3.5Hz,1H),2.05–1.95(m,2H),1.87(d,J=12.1Hz,2H),1.53(td,J=14.6,7.4Hz,2H),1.42–1.29(m,2H),1.24(s,9H); 13C NMR (101MHz, DMSO) δ173.7,168.7,167.0,145.7,137.3,125.7,119.3,73.1,43.9,42.5,40. 6,40.4,40.2,40.0,39.8,39.5,39.3,34.4,31.7,30.8,27.6; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 28 NO5:362.1889; Found:362.1885.

[0222] Example 19

[0223]

[0224] Using compound 19B (200 mg, 0.55 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (76.43 mg, 0.55 mmol) as raw materials, compound 19B was obtained by aldol condensation reaction using similar procedures as those used in the preparation of compound 5, yielding 62 mg of compound 19 as a white solid with a yield of 25.8%.

[0225] 1 H NMR(400MHz,DMSO-D6)δ9.79(s,1H),7.53–7.43(m,3H),7.32–7.27(m,2H),7.04(d ,J=2.1Hz,1H),7.01(dd,J=8.2,2.1Hz,1H),6.76(d,J=8.1Hz,1H),6.25(d,J=15.8 Hz,1H),4.72(td,J=10.8,5.4Hz,1H),2.34(t,J=11.6Hz,1H),2.04(t,J=6.3Hz,2H ),1.91(d,J=12.8Hz,2H),1.64–1.51(m,2H),1.42(q,J=11.2Hz,2H),1.25(s,9H); 13 CNMR(101MHz,DMSO)δ173.3,166.0,148.4,145.6,145.3,145.0,136.8,125.5,125.2,121.3,118.9,115.7,114.9, 114.3,71.8,43.6,40.1,39.9,39.7,39.5,39.3,39.1,38.9,34.0,31.2,30.7,27.3; HRMS(ESIMS)m / z(M+H)+calcd for C 26 H 32NO5:438.2202; Found:438.2210.

[0226] Example 20

[0227]

[0228] Using compound 8B (100 mg, 0.27 mmol) and commercially available compound 2,4-dimethoxy-3-methylbenzaldehyde (48.65 mg, 0.27 mmol) as raw materials, compound 20 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 112 mg of compound 20 as a white solid with a yield of 86.2%.

[0229] 1 H NMR (400MHz, CDCl3) δ7.90(d,J=16.1Hz,1H),7.41(d,J=8.7Hz,1H),7.23(d,J=3.5Hz, 1H), 6.78 (d, J = 2.3Hz, 2H), 6.66 (d, J = 8.7Hz, 1H), 6.38 (d, J = 16.1Hz, 1H), 6.23 (t, J = 2. 2Hz,1H),4.86(tt,J=10.8,4.3Hz,1H),3.85(s,3H),3.77(s,6H),3.73(s,3H),2.26–2 .17(m,3H),2.15(s,3H),2.07(d,J=13.7Hz,2H),1.81–1.71(m,2H),1.54–1.42(m,2H); 13 C NMR (101MHz, CDCl3) δ173.5,167.1,161.2,160.8,158.9,140.3,139.8,126.2,120.7,120.4,116.8,106.7 ,98.0,96.9,77.5,77.2,76.8,71.9,61.7,55.8,55.5,45.6,31.0,27.8,9.0; HRMS(ESIMS)m / z(M+H)+calcd for C 27 H 34 NO7:484.2346; Found:484.2330.

[0230]

[0231] Starting with commercially available compound 3-hydroxycyclohexanecarboxylic acid (200 mg, 1.38 mmol) and aniline (138.4 μL, 1.52 mmol), compound 21A (200 mg), a white solid, was obtained by condensation reaction using a similar procedure to that used in the preparation of compound 5A, with a yield of 91.3%.

[0232] HRMS(ESIMS)m / z(M+H)+calcd for C 13 H 18 NO2:220.1259; Found:220.1263.

[0233]

[0234] Using compound 21A (200 mg, 0.65 mmol) and commercially available compound cycloisopropyl malonate (131.04 mg, 0.91 mmol) as raw materials, compound 21B was obtained by esterification reaction using a similar procedure to that used in the preparation of compound 5B. The result was a white solid with a yield of 70.05%.

[0235] HRMS(ESIMS)m / z(M+H)+calcd for C 16 H 20 NO5:306.1263; Found:306.1270.

[0236] Example 21

[0237]

[0238] Using compound 21B (130 mg, 0.37 mmol) and commercially available compound 3,4-dihydroxybenzaldehyde (50.53 mg, 0.37 mmol) as raw materials, compound 21 was obtained by aldol condensation reaction using similar procedures as those for the preparation of compound 5, yielding 50 mg of compound 21 as a white solid with a yield of 31.4%.

[0239] 1 H NMR(400MHz,ACETONE-D6)δ7.61–7.50(m,2H),7.46(d,J=15.9Hz,1H),7.22–7. 10(m,2H),7.06(d,J=2.1Hz,1H),6.99–6.85(m,2H),6.78(d,J=8.1Hz,1H),6.1 8(d,J=15.9Hz,1H),5.13(t,J=3.4Hz,1H),3.94(q,J=7.1Hz,1H),2.71(ddt,J= 11.4,7.5,3.8Hz,1H),1.87–1.79(m,3H),1.81–1.73(m,2H),1.61–1.48(m,4H); 13C NMR(101MHz,ACETONE-D6)δ205.8,174.2,166.3,148.3,146.0,145.0,140.2,129.1,127.3,123.6,122.1,119.7,116.0,115.9, 114.8,69.4,60.2,40.9,33.1,30.0,30.0,29.8,29.6,29.5,29.3,29.3,29.1,28.9,20.5,14.1; HRMS(ESIMS)m / z(M+Na)+calcd for C 22 H 23 NO5Na:404.1432; Found:404.1468.

[0240]

[0241] Commercially available compound 3,4-dihydroxybenzaldehyde (2 g, 14.48 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml) in a single-necked flask. TBSCl (6.55 g, 43.44 mmol), imidazole (2.99 g, 43.44 mmol), and DMAP (177.17 mg, 1.45 mmol) were added at room temperature. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until the starting material was fully reacted. Post-treatment: The reaction was quenched with 10 times the volume of DMF in water, extracted with EA, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (PE:EA = 3:1) was performed to give 3.7 g of the known compound 39 as a yellow oil, with a yield of 84.1%.

[0242]

[0243] A commercially available compound, trans-4-(methoxycarbonyl)cyclohexyl-1-carboxylic acid (500 mg, 2.69 mmol) and aniline (0.81 mL, 8.87 mmol), was dissolved in anhydrous N,N-dimethylformamide (3 mL) in a single-necked flask. EDCI (711.63 mg, 3.71 mmol) and HOBT (501.30 mg, 3.71 mmol) were added at room temperature, followed by Et3N (0.93 mL, 6.73 mmol) at 0 °C. After the addition was complete, the reaction mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until the starting material was fully reacted. Post-treatment: The mixture was quenched with 10 times the volume of DMF in water, washed with 1N HCl, washed with saturated NaHCO3, extracted with EA, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (PE:EA = 10:1) was performed to give 40-650 mg of the known compound as a white solid, with a yield of 92.6%.

[0244] 1H NMR (400MHz, CDCl3) δ7.75(s,1H),7.53(d,J=8.0Hz,2H),7.29(d,J=7.7Hz,2H),7.07(t,J=7.4Hz,1H),3.67(s,3H),2.32(tt,J=12.1,3. 7Hz,1H),2.23(tt,J=12.0,3.6Hz,1H),2.04(ddd,J=27.0,13.8,3.6Hz,4H),1.61(qd,J=13.1,3.1Hz,2H),1.44(qd,J=12.9,3.1Hz,2H); 13 C NMR(101MHz, CDCl3)δ176.2,174.0,138.1,129.0,124.2,120.0,77.4,77.1,76.8,51.7,45.5,42.3,28.6,28.1; HRMS(ESIMS)m / z(M+H)+calcd forC 15 H 20 NO3:262.1463; Found:262.1438.

[0245]

[0246] Compound 40 (300 mg, 1.15 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) in a two-necked flask. The reaction solution was cooled to -78 °C in an acetone bath on dry ice. Under argon protection at -78 °C, n-butyllithium (1.6 M dissolved in n-hexane, 1.44 mL, 2.30 mmol) was slowly added dropwise. The reaction solution was reacted at -78 °C for 0.5 h. After the reaction was complete, diethyl methylphosphonate (0.34 mL, 2.30 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly raised to room temperature and reacted for 5 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched by slow addition of saturated ammonium chloride solution, extracted with EA, the organic phases were combined, dried overnight, filtered, the solvent was removed by vacuum distillation, and column chromatography (DCM:MeOH = 30:1) was performed to give compound 41 288 mg, a white solid, with a yield of 65.8%.

[0247] 1H NMR (400MHz, CDCl3) δ7.53(d,J=7.9Hz,2H),7.47(s,1H),7.30(t,J=7.7Hz,2H),7.09(t,J=7.3Hz,1H),4.21–4.08(m,4H),3.14(d,J=22 13C NMR (101MHz, CDCl3) δ205.0,205.0,173.8,138.2,129.1,124.3,119.9,77.5,77.4,77.2,76 .8,62.8,62.7,50.5,45.7,41.4,40.2,28.7,27.4,16.5,16.4; HRMS(ESIMS)m / z(M+H)+calcd for C 19 H 29 NO5P:382.1778; Found:382.1778.

[0248]

[0249] Compound 41 (288 mg, 0.76 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) in a two-necked flask. The reaction solution was cooled to 0 °C, and 60% sodium hydride (60.80 mg, 1.52 mmol) was slowly added under argon protection at 0 °C. The reaction solution was reacted at 0 °C for 0.5 h. After the reaction was complete, anhydrous tetrahydrofuran solution of compound 39 (250 mg, 0.76 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly raised to room temperature and reacted for 2 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched by slow dropwise addition of saturated ammonium chloride solution, extracted with EA, the organic phases were combined, dried overnight, filtered, the solvent was removed by vacuum distillation, and column chromatography (PE:EA = 20:1) was performed to give compound 42114 mg, a white solid, with a yield of 25.3%.

[0250] 1H NMR (400MHz, CDCl3) δ7.78(s,1H),7.60(d,J=8.0Hz,2H),7.50(d,J=15.9Hz,1H),7.32(t,J=7.8 Hz,2H),7.14–7.05(m,2H),7.03(d,J=2.1Hz,1H),6.83(d,J=8.2Hz,1H),6.61(d,J=15.9Hz,1H) ,2.79(tt,J=11.8,3.3Hz,1H),2.33(tt,J=12.1,3.3Hz,1H),2.15–1.99(m,5H),1.74(qd,J=13. 0,3.0Hz,2H),1.55(td,J=12.4,3.0Hz,2H),1.00(s,9H),0.99(s,9H),0.23(s,7H),0.22(s,6H); 13 C NMR (101MHz, CDCl3) δ203.0,174.0,149.9,147.3,143.2,138.2,129.0,128.0,124.1,122.8,122.5 ,121.3,121.0,119.9,77.4,77.0,76.7,47.7,45.8,28.8,28.1,25.9,25.9,18.5,18.5,-4.0,-4.1.

[0251] Example 22

[0252]

[0253] Compound 42 (90 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran in a single-necked flask. Tetrabutylammonium fluoride (124.85 μL, 0.45 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 1 h. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched by slow addition of saturated ammonium chloride solution, extracted with EA, the organic phases were combined, dried overnight, filtered, the solvent was removed by vacuum distillation, and column chromatography (DCM:MeOH = 10:1) was performed to give 2240 mg of compound as a white solid, with a yield of 72.7%.

[0254] 1H NMR(400MHz,MeOD)δ7.61(d,J=8.0Hz,3H),7.56(s,1H),7.32(t,J=7.8Hz,3H), 7.18(d,J=2.0Hz,1H),7.13–7.04(m,3H),6.86(d,J=8.2Hz,1H),6.75(d,J=15. 9Hz,1H),2.86(tt,J=12.0,3.3Hz,1H),2.49(tt,J=12.0,3.4Hz,1H),2.04(td, J=9.7,4.9Hz,4H),1.72(qd,J=13.1,3.5Hz,2H),1.52(qd,J=13.4,3.7Hz,2H); 13 C NMR(101MHz,MeOD)δ204.3,175.9,148.5,145.4,144.1,138.6,128.4,126.6,123.8,122.3,121.2,120.0,1 15.3,114.1,48.3,48.1,47.9,47.7,47.6,47.4,47.2,47.0,45.0,28.5,27.8; HRMS(ESIMS)m / z(M+H)+calcd for C 22 H 24 NO4:366.1694; Found:366.1700.

[0255]

[0256] Using commercially available compound cis-4-(methoxycarbonyl)cyclohexyl-1-carboxylic acid (500 mg, 2.69 mmol) and aniline (0.81 ml, 8.87 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 40, compound 43645 mg was obtained as a white solid via a condensation reaction, with a yield of 91.9%.

[0257] 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),7.51(d,J=7.9Hz,2H),7.27(t,J=7.9Hz,2H),7.07(t,J=7.4Hz,1H),3.67(s,3H),2.58(q, J=4.8Hz,1H),2.33(q,J=6.8Hz,1H),2.16(dq,J=14.1,4.8Hz,2H),1.79(q,J=5.7Hz,4H),1.58(ddt,J=13.9,9.6,5.3Hz,2H); 13C NMR(101MHz, CDCl3)δ175.2,173.7,138.1,128.9,124.1,120.0,77.4,77.3,77.1,76.8,51.7,44.3,39.5,26.4,26.2; HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 20 NO3:262.1463; Found:262.1438.

[0258]

[0259] Using compound 43 (300 mg, 1.15 mmol) and diethyl methylphosphonate (0.34 ml, 2.30 mmol) as raw materials, compound 44 was obtained by condensation reaction using similar steps as those for the preparation of compound 41, yielding 224 mg of compound 44 as a colorless oil with a yield of 51.6%.

[0260] 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 7.50 (d, J = 7.9Hz, 2H), 7.26 (d, J = 15.5Hz, 2H),7.04(t,J=7.4Hz,1H),4.12(dd,J=11.1,4.6Hz,4H),3.11(d,J=22.5Hz, 2H),2.74(p,J=5.3Hz,1H),2.40(tt,J=8.3,4.2Hz,1H),2.11–2.01(m,3H),1 .87(dtd,J=12.7,8.9,3.3Hz,2H),1.79–1.60(m,5H),1.31(t,J=7.2Hz,6H); 13 C NMR (101MHz, CDCl3) δ204.5,204.4,173.4,138.2,128.9,124.0,119.9,77.4,77.1,76.8,62.6,62 .6,48.1,43.5,40.3,39.0,26.4,26.1,25.4,25.2,16.4,16.3,1.0; HRMS(ESIMS)m / z(M+H)+calcd forC 19 H 29 NO5P:382.1778; Found:382.1778.

[0261]

[0262] Using compound 44 (200 mg, 0.52 mmol) and compound 39 (174.68 mg, 0.48 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 42, compound 45 was obtained by Wittig reaction in 145 mg as a white solid, with a yield of 51.06%.

[0263] 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.62(d,J=8.0Hz,2H),7.50(d,J=15.9Hz,1H),7.31(t,J=7.8Hz,2H),7.12–7.01(m,3H),6.84(d,J=8.2 Hz,1H),6.62(d,J=15.9Hz,1H),2.85–2.74(m,1H),2.37(td,J=12.0,5.9Hz,1H),2.14–2.00(m,5H),1.81–1.68(m,2H),1.58–1.47(m,2H); 13 C NMR (101MHz, CDCl3) δ203.2,174.2,149.9,147.3,143.3,138.4,128.9,128.0,124.1,122.8,122.6 ,121.3,121.0,120.0,77.4,77.1,76.8,47.7,45.7,28.8,28.1,25.9,25.9,18.5,18.4,-4.0,-4.1.

[0264] Example 23

[0265]

[0266] Using compound 45 (145 mg, 0.24 mmol) as the starting material, and following similar procedures as those used in the preparation of compound 22, compound 23 (75 mg) was obtained as a white solid via a TBS deprotection reaction, with a yield of 85.2%.

[0267] 1H NMR (400MHz, CDCl3) δ7.59(d,J=7.5Hz,3H),7.31(d,J=15.5Hz,2H),7.15(d,J=2.0Hz,1H),7.12–7.02(m,2H),6.84(d,J=8.1Hz,1H),6.73(d,J=15. 9Hz,1H),2.84(tt,J=11.9,3.2Hz,1H),2.45(tt,J=12.1,3.4Hz,1H),2.0 2(tt,J=9.4,3.7Hz,5H),1.70(qd,J=13.0,3.5Hz,2H),1.59–1.46(m,2H); 13 C NMR(101MHz,MeOD)δ204.3,175.9,148.5,145.4,144.1,138.6,128.4,126.6,123.7,122.2,121.2,120.0 ,115.2,114.1,48.3,48.1,47.9,47.6,47.4,47.2,47.0,45.0,28.5,27.8.HRMS(ESIMS)m / z(M+H)+calcd forC 22 H 24 NO4:366.1694; Found:366.1700.

[0268]

[0269] Using commercially available compound trans-4-(methoxycarbonyl)cyclohexyl-1-carboxylic acid (500 mg, 2.69 mmol) and 4-fluoroaniline (0.84 ml, 8.87 mmol) as starting materials, compound 46 was obtained by condensation reaction using similar procedures to those used in the preparation of compound 40. The result was a white solid with a yield of 90.7%.

[0270] 1 H NMR(400MHz, CDCl3) δ7.78(d,J=12.6Hz,1H),7.53–7.42(m,2H),6.96(t,J=8.7Hz,2H),3.67(s,3H),2.32(tt,J=12.1,3.6Hz,1H),2.2 2(tt,J=12.0,3.6Hz,1H),2.07(dd,J=13.4,3.4Hz,2H),2.00(dd,J=13.6,3.4Hz,2H),1.68–1.55(m,2H),1.44(qd,J=13.0,3.3Hz,2H); 13C NMR (101MHz, CDCl3) δ176.2,173.9,160.5,158.1,134.1,121.8,121.8,115.7,11 5.4,77.4,77.1,76.8,51.7,45.3,42.3,28.5,28.1; HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 19 FNO3:280.1344; Found:280.1343.

[0271]

[0272] Using compound 46 (300 mg, 1.07 mmol) and diethyl methylphosphonate (0.31 ml, 2.15 mmol) as starting materials, compound 47 was obtained by condensation reaction using similar steps as those for the preparation of compound 41, yielding 250 mg of compound 47 as a white solid with a yield of 58.5%.

[0273] 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),7.50(dd,J=8.9,4.8Hz,2H),6.96(t,J=8.6Hz,2H),4.12(pd,J=7.1,1.9Hz,4H),3.12(d,J=22.3Hz,2H), 2.61(tt,J=12.1,3.2Hz,1H),2.23(tt,J=12.1,3.2Hz,1H),2.08–1.95(m,4H),1.68–1.55(m,2H),1.42–1.33(m,2H),1.31(t,J=7.1Hz,6H); 13 C NMR (101MHz, CDCl3) δ205.0,204.9,173.9,160.4,158.0,134.4,121.7,121.6,115.6,115.3,77.4,7 7.1,76.8,62.7,62.6,50.5,45.2,41.2,40.0,28.5,27.3,16.4,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 19 H 28 FNO5P:400.1693; Found:400.1684.

[0274]

[0275] Using compound 47 (200 mg, 0.52 mmol) and compound 39 (190 mg, 0.52 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 42, compound 48 was obtained by Wittig reaction in 124 mg as a white solid, with a yield of 39.0%.

[0276] 1 H NMR (400MHz, CDCl3) δ8.20–8.12(m,1H),7.63–7.55(m,2H),7.49(d,J=15.9Hz,1H), 7.09–6.96(m,5H),6.83(d,J=8.3Hz,1H),6.61(d,J=15.9Hz,1H),2.82(tt,J=11.9,3 .4Hz,1H),2.37(tt,J=12.5,3.6Hz,1H),2.07(ddd,J=18.2,13.3,3.4Hz,5H),1.82– 1.68(m,2H),1.61–1.48(m,2H),1.00(s,9H),0.98(s,9H),0.22(s,6H),0.21(s,6H); 13 C NMR (101MHz, CDCl3) δ203.4,174.2,160.4,158.0,150.0,147.3,143.5,134.4,127.9,122.8,122.6,121.7,121.6,121.3,121 .0,115.6,115.4,77.4,77.1,76.7,47.6,45.6,28.8,28.1,25.9,25.9,18.5,18.4,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 34 H 51 FNO4Si2: 612.3341; Found: 612.3335. Example 24

[0277]

[0278] Using compound 48 (46 mg, 0.08 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 24 (22 mg) was obtained as a white solid via a TBS deprotection reaction, with a yield of 73.3%.

[0279] 1H NMR (400MHz, MeOD) δ7.58–7.51(m,4H),7.10(d,J=2.1Hz,1H),7.03(t,J=8.7Hz,4H),6.79(d,J=8.1Hz,1H),6.69(d,J=16.0Hz,1H),4.62–4. 56(m,2H),2.84(t,J=12.0Hz,1H),2.44–2.31(m,1H),2.01(d,J=2.9Hz,3H),1.98(s,2H),1.68(td,J=13.2,10.0Hz,2H),1.53–1.40(m,2H); 13 C NMR(101MHz,MeOD)δ205.7,177.1,161.8,159.4,150.0,146.9,145.6,136.2,127.9,123.6,123.2,123.1,122.6,116.6, 116.3,116.1,115.5,49.6,49.4,49.2,49.0,48.9,48.8,48.6,48.4,46.4,29.8,29.2; HRMS(ESIMS)m / z(M+H)+calcdfor C 22 H 23 FNO4:384.1584; Found:384.1606.

[0280]

[0281] Using commercially available compound cis-4-(methoxycarbonyl)cyclohexyl-1-carboxylic acid (500 mg, 2.69 mmol) and 4-fluoroaniline (0.84 ml, 8.87 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 40, compound 49 was obtained by condensation reaction, yielding 645 mg of compound 49 as a white solid in 86.0% yield.

[0282] 1 H NMR (400MHz, CDCl3) δ8.62(d,J=4.4Hz,1H),7.39(dd,J=8.8,4.9Hz,2H),6.84(t,J=8.5Hz,2H),3.55(s,3H),2.50(p,J=4.7Hz,1H), 2.29(tt,J=9.1,4.4Hz,1H), 2.06(dq,J=13.8,4.7Hz,2H), 1.69(tdd,J=18.7,11.2,7.3Hz,4H), 1.46(ddt,J=14.7,9.8,4.5Hz,2H); 13C NMR (101MHz, CDCl3) δ175.4,174.7,160.3,157.9,134.4,134.4,122.2,122.1,115.3,11 5.1,77.6,77.5,77.3,77.0,51.5,43.8,39.4,26.3,26.1; HRMS(ESIMS)m / z(M+H)+calcd for C 15 H 19 FNO3:280.1344; Found:280.1343.

[0283]

[0284] Using compound 49 (300 mg, 1.07 mmol) and diethyl methylphosphonate (0.31 ml, 2.15 mmol) as raw materials, and following similar procedures as those used in the preparation of compound 41, compound 50 was obtained by condensation reaction, yielding 259 mg of compound 50 as a colorless oil with a yield of 60.7%.

[0285] 1 H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 7.46 (dd, J = 8.9, 4.8Hz, 2H), 6.98 (t, J = 8. 5Hz,2H),4.18–4.10(m,4H),3.14(d,J=22.6Hz,2H),2.77(p,J=5.2Hz,1H),2 .40(tt,J=8.6,4.3Hz,1H),2.14–2.01(m,2H),1.93–1.83(m,2H),1.78(tt,J =9.8,3.9Hz,2H),1.68(ddt,J=14.1,9.1,4.2Hz,2H),1.32(t,J=7.1Hz,6H); 13 C NMR (101MHz, CDCl3) δ205.0,204.9,173.7,160.9,158.5,134.5,122.2,122.1,116.0,115.8,77.8,77.7, 77.5,77.2,63.1,63.0,48.4,44.0,40.7,39.5,26.8,25.9,16.8,16.7; HRMS(ESIMS)m / z(M+H)+calcdfor C 19 H 28 FNO5P:400.1693; Found:400.1684.

[0286]

[0287] Using compounds 50 (140 mg, 0.36 mmol) and 39 (159.64 mg, 0.44 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 42, compound 51 was obtained by Wittig reaction in 80 mg as a white solid, with a yield of 36.5%.

[0288] 1 H NMR(400MHz, CDCl3)δ8.03(s,1H),7.79(dd,J=8.9,4.8Hz,2H),7.73(d,J=15.9Hz,1H), 7.30(dd,J=8.3,2.1Hz,1H),7.27–7.22(m,3H),7.07(d,J=8.3Hz,1H),6.84(d,J=16.0H z,1H),3.10–2.99(m,1H),2.61–2.49(m,1H),2.31(t,J=17.4Hz,4H),1.96(td,J=18.5, 11.0Hz,3H),1.77(q,J=12.6Hz,2H),1.23(s,8H),1.22(s,11H),0.45(d,J=4.4Hz,13H); 13 C NMR (101MHz, CDCl3) δ203.1,174.0,160.5,158.1,149.9,147.3,143.3,134.2,128.0,122.8,122.5,121.7,121.6,121.3,121.0,11 5.7,115.5,77.4,77.2,77.0,76.7,47.6,45.6,29.7,28.8,28.1,25.9,25.9,18.5,18.4,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 34 H 51 FNO4Si2:612.3341; Found:612.3335.

[0289] Example 25

[0290]

[0291] Using compound 51 (50 mg, 0.08 mmol) as the starting material, and following similar procedures as those used in the preparation of compound 22, compound 25 (25 mg) was obtained as a white solid via a TBS deprotection reaction, with a yield of 80.6%.

[0292] 1H NMR (400MHz, MeOD) δ7.62–7.52(m,3H),7.12(d,J=2.1Hz,1H),7.05(dd,J=9.9,8.0Hz,3H),6.81(d,J=8.2Hz,1H),6.70(d,J=15.9Hz, 1H),2.85(td,J=12.0,6.1Hz,1H),2.38(tt,J=12.3,3.3Hz,1H),2.08–1.96(m,4H),1.70(qd,J=12.3,2.9Hz,2H),1.56–1.42(m,2H); 13 C NMR(101MHz,MeOD)δ204.2,175.7,160.4,158.0,148.6,145.5,144.2,134.8,126.5,122.2,121.8,121.7,121.2,115. 2,114.9,114.7,114.1,48.3,48.0,47.8,47.6,47.5,47.4,47.2,47.0,45.0,28.5,27.9; HRMS(ESIMS)m / z(M+H)+calcd forC 22 H 23 FNO4:384.1584; Found:384.1606.

[0293]

[0294] 3 g (21.10 mmol) of commercially available compound 4-cyclohexanone carboxylic acid was dissolved in tert-butanol (30 mL) in a single-necked flask. Di-tert-butyl dicarbonate (1.38 g, 63.31 mmol) and DMAP (3.61 g, 29.54 mmol) were added, and the mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched by slow dropwise addition of saturated ammonium chloride solution, extracted with EA, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (PE:EA = 10:1) was performed to give 2.8 g of the known compound 52 as a colorless oil, with a yield of 67.0%.

[0295] 1 H NMR (400MHz, CDCl3) δ2.64 (tt, J=9.6, 4.0Hz, 1H), 2.46 (dt, J=14.7, 5.4Hz, 2H), 2.33 (ddd, J=15.3 ,10.7,5.7Hz,2H),2.15(dq,J=12.9,4.9Hz,2H),1.98(tdd,J=14.4,8.9,3.9Hz,2H),1.46(s,9H).

[0296]

[0297] Commercially available compound diethylphosphonoacetate methyl ester (0.74 ml, 4.04 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) in a two-necked flask. The reaction solution was cooled to 0°C, and 60% sodium hydride (161.6 mg, 4.04 mmol) was slowly added under argon protection. After the addition was complete, the reaction was carried out at 0°C for 0.5 h. After the reaction was complete, an anhydrous tetrahydrofuran solution of compound 52 (400 mg, 2.02 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was raised to room temperature and reacted for 5 h. The reaction was monitored by TLC until the reactants were completely reacted. Post-treatment: The reaction was quenched by slow dropwise addition of saturated ammonium chloride solution, extracted with EA, the organic phases were combined, dried overnight, filtered, the solvent was removed by vacuum distillation, and column chromatography (PE:EA = 100:1) was performed to obtain 388 mg of the known compound 53 as a colorless oil, with a yield of 75.6%.

[0298] 1 H NMR (400MHz, CDCl3) δ5.59(s,1H),3.63(s,3H),3.53(dt,J=14.3,4.6Hz,1H),2.41(tt,J=10.4,3.9Hz,1 H),2.29(dt,J=14.0,4.6Hz,1H),2.21–2.09(m,2H),2.02–1.92(m,2H),1.71–1.52(m,2H),1.39(s,9H); 13 C NMR (101MHz, CDCl3) δ174.1,166.9,161.3,113.5,80.1,77.4,77.3,77.1,76.8,50.8,43.1,36.0,30.1,29.5,28.0,27.9.

[0299]

[0300] Using compound 53 (80 mg, 0.31 mmol) and diethyl methylphosphonate (0.09 ml, 0.63 mmol) as raw materials, compound 54 (93 mg) was obtained by condensation reaction using similar steps to those used in the preparation of compound 41, as a yellow oily substance with a yield of 80.2%.

[0301] 1H NMR (400MHz, CDCl3) δ6.09(s,1H),4.06(ddtd,J=10.5,5.2,3.7,2.0Hz,4H),3.42(dq,J=13.3,3.7Hz,1H),2.99(dq,J=22.5,1.6Hz,2H),2.37(tdp,J= 10.1,4.0,1.9Hz,1H),2.24(d,J=14.3Hz,1H),2.18–2.06(m,3H),1.98–1.8 5(m,3H),1.66–1.49(m,2H),1.34(q,J=1.6Hz,10H),1.23(p,J=2.6Hz,6H); 13 C NMR (101MHz, CDCl3) δ191.4,191.4,174.0,161.9,121.8,80.1,77.5,77.3,77.1,76.8,62.4,62.4,62.3,62. 3,44.4,43.2,42.9,36.0,35.8,30.1,29.5,28.0,28.0,27.8,16.4,16.3,16.2; HRMS(ESIMS)m / z(M+H)+calcd for C 18 H 32 O6P:375.1925; Found:375.1931.

[0302]

[0303] Compound 54 (100 mg, 0.27 mmol) was dissolved in anhydrous dichloromethane (4 mL) in a single-necked flask. Trifluoroacetic acid (24.5 μL, 0.32 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The reaction was quenched by slow addition of saturated ammonium chloride solution. The mixture was extracted with DCM, and the organic phases were combined, dried overnight, filtered, and the solvent was removed under reduced pressure. Column chromatography (DCM:MeOH = 100:1) was performed to give compound 55 80 mg as a yellow oil, with a yield of 93.0%.

[0304] 1H NMR (400MHz, CDCl3) δ6.17(s,1H),4.19–4.08(m,4H),3.52(dt,J=14.4,4.5Hz,1H),3.10(d,J=22.5Hz,2H),2.57(tt,J=10.3,3.9 Hz,1H),2.33(dt,J=13.9,4.7Hz,1H),2.26–2.16(m,2H),2.05(dt,J=17.9,6.7Hz,2H),1.77–1.61(m,2H),1.31(t,J=6.9Hz,6H); 13 C NMR (101MHz, CDCl3) δ191.5,191.4,179.1,161.7,122.0,77.4,77.0,76.7,62.7,62.7,4 4.4,43.1,41.8,36.0,29.9,29.3,29.2,28.1,16.3,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 14 H 24 O6P:319.1299; Found:319.1305.

[0305]

[0306] Using compound 55 (80 mg, 0.25 mmol) and aniline (80 μL, 0.83 mmol) as raw materials, compound 56 was obtained by condensation reaction using similar steps to those used in the preparation of compound 40. The result was a yellow oily substance with a yield of 40.8%.

[0307] 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.55(d,J=8.0Hz,2H),7.29(t,J=7.8Hz,2H),7.08(t,J=7.4Hz,1H),5.61(s,1H),4.21–4.06(m,4H),3.2 6(s,2H),3.19–3.01(m,2H),2.55–2.44(m,1H),2.44–2.26(m,2H),2.00(dd,J=17.8,7.7Hz,3H),1.91–1.79(m,1H),1.33(t,J=7.1Hz,6H); 13C NMR (101MHz, CDCl3) δ200.4,200.3,174.3,138.4,130.9,128.9,125.3,124.0,119.9,77.4,77.1,76.8 ,62.8,62.7,62.6,52.7,41.8,41.5,40.6,28.2,27.9,25.9,16.4,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 29 NO5P:394.1771; Found:394.1778.

[0308]

[0309] Compound 56 (190 mg) was dissolved in methanol in a single-necked flask. Palladium catalyst on carbon (25 mg) was added under hydrogen protection. After addition, the reaction was carried out overnight at room temperature under hydrogen protection. The reaction was monitored by TLC until the starting material was completely reacted. Post-treatment: The palladium catalyst on carbon was removed by filtration, washed with EA, the organic phases were combined, the solvent was removed by vacuum distillation, and column chromatography (PE:EA = 1:1) was performed to give 50 mg of trans-57 as a white solid and 45 mg of cis-57 as a colorless oil, with a yield of 55%. 1 H NMR (400MHz, CDCl3) δ7.58–7.48(m,3H),7.31–7.26(m,2H),7.06(t,J=7.4Hz ,1H),4.19–4.05(m,4H),3.04(d,J=22.8Hz,2H),2.51(d,J=6.4Hz,2H),2.16( tt,J=12.1,3.6Hz,1H),2.00–1.92(m,2H),1.84(tt,J=11.9,3.4Hz,3H),1.60 (qd,J=13.1,3.3Hz,2H),1.32(t,J=7.1Hz,6H),0.99(qd,J=12.8,3.0Hz,2H); 13 C NMR (101MHz, CDCl3) δ201.3,201.2,174.1,138.1,128.9,124.1,119.8,77.4,77.1,76.7,62 .6,62.6,51.2,46.1,43.4,42.1,32.6,31.9,29.2,16.4,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 31 NO5P:396.1939; Found:396.1935.cis-57: 1H NMR(400MHz, CDCl3)δ7.52(d,J=8.2Hz,3H),7.33–7.26(m,2H),7.07(t,J=7.4Hz,1H),4.12 (dddd,J=14.1,8.4,5.4,1.5Hz,4H),3.04(d,J=22.7Hz,2H),2.65(s,1H),2.40(tt,J=7.9,4 .3Hz,1H),2.17(ddd,J=11.3,6.9,4.5Hz,1H),1.87(tdd,J=14.2,9.2,5.1Hz,2H),1.69(ddt ,J=12.9,8.1,4.2Hz,2H),1.54(dtdt,J=18.0,11.1,7.0,4.0Hz,4H),1.32(t,J=7.1Hz,6H); 13 C NMR (101MHz, CDCl3) δ201.5,201.4,173.8,138.2,129.0,124.1,119.8,77.4,77.1,76.7,62 .7,62.6,48.2,43.5,42.2,29.8,29.7,28.9,25.9,16.4,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 31 NO5P:396.1939; Found:396.1934.

[0310]

[0311] Compound trans-57 (200 mg, 0.51 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) in a two-necked flask. The reaction solution was cooled to 0 °C, and sodium bis(trimethylsilyl)amino (1.2 ml, 1.02 mmol) was slowly added dropwise under argon protection at 0 °C. The reaction solution was reacted at 0 °C for 0.5 h. After the reaction was complete, anhydrous tetrahydrofuran solution of compound 39 (168.49 mg, 0.46 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to 50 °C and reacted for 2 h. The reaction was monitored by TLC until the reactants were completely reacted. Post-treatment: The reaction was quenched by slow addition of saturated ammonium chloride solution, extracted with EA, the organic phases were combined, dried overnight, filtered, the solvent was removed by vacuum distillation, and column chromatography (PE:EA = 5:1) was performed to obtain compound 58.

[0312] Example 26

[0313]

[0314] Using compound 58 (80 mg, 0.13 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 26 (40 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 75.0%.

[0315] 1 H NMR (400MHz, MeOD) δ7.55(s,1H),7.52(d,J=7.2Hz,2H),7.30(t,J=7.7Hz,2H),7.10( s,1H),7.07(d,J=7.6Hz,1H),7.03(d,J=8.3Hz,1H),6.81(d,J=8.1Hz,1H),6.64(d,J= 16.4Hz,1H),2.60(d,J=6.4Hz,2H),2.35(t,J=12.1Hz,1H),2.04(d,J=6.1Hz,1H),1.9 7–1.88(m,6H),1.62(q,J=12.9Hz,4H),1.17(t,J=12.2Hz,3H),0.91(d,J=6.9Hz,2H); 13 C NMR(101MHz,MeOD)δ201.8,176.0,148.6,145.5,144.3,138.6,128.4,126.5,123.7,123.1,122.2,120.0,115. 2,114.0,48.3,48.0,47.8,47.6,47.4,47.2,47.0,43.7,43.1,30.6,28.9,25.0; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 26 NO4:380.1850; Found:380.1856.

[0316]

[0317] Using compounds cis-57 (200 mg, 0.51 mmol) and 39 (168.49 mg, 0.46 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 59 was obtained in 88 mg via a condensation reaction as a yellow oil, with a yield of 29.0%.

[0318] 1H NMR (400MHz, CDCl3) δ7.53(d,J=7.9Hz,2H),7.43(d,J=16.1Hz,1H),7.32(t,J=7.9Hz,3H),7.1 0(t,J=7.4Hz,1H),7.04(d,J=7.2Hz,2H),6.85–6.80(m,1H),6.54(d,J=16.1Hz,1H),2.67(d,J= 7.0Hz,2H),2.44(dt,J=7.5,3.3Hz,1H),2.29–2.20(m,1H),2.01–1.90(m,2H),1.74(td,J=8.5, 3.8Hz, 3H), 1.61 (ddd, J=14.8, 8.1, 4.3Hz, 4H), 0.99 (d, J=5.4Hz, 17H), 0.22 (d, J=2.2Hz, 13H); 13 C NMR (101MHz, CDCl3) δ200.2,173.8,149.7,147.3,142.8,138.1,129.0,128.0,124.9,124.2,122.6,121.2,120.7,119.8 ,77.4,77.0,76.7,44.7,43.4,31.1,29.7,29.2,26.1,25.9,25.9,18.5,18.5,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 35 H 54 NO4Si2:608.3593; Found:608.3586.

[0319] Example 27

[0320]

[0321] Using compound 59 (80 mg, 0.13 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 27 (34 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 68.0%.

[0322] 1H NMR (400MHz, MeOD) δ7.60–7.49(m,3H),7.29(t,J=7.8Hz,2H),7.12–7.03(m,2H),7.02(dd,J=8.2,2.1Hz,1H),6.80(d,J=8.2Hz,1H),6.62(d,J=16.1H z,1H),2.75(d,J=7.3Hz,2H),2.48(dq,J=8.9,4.4Hz,1H),2.31–2.20(m,1 H),1.89(tt,J=12.5,6.8Hz,2H),1.69(t,J=4.8Hz,1H),1.68–1.60(m,5H); 13 C NMR(101MHz,MeOD)δ201.8,176.0,148.6,145.5,144.3,138.6,128.4,126.5,123.7,123.1,122.2,120.0,115. 2,114.0,48.3,48.0,47.8,47.6,47.4,47.2,47.0,43.7,43.1,30.6,28.9,25.0; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 26 NO4:380.1850; Found:380.1857.

[0323]

[0324] Using compound 55 (1 g, 3.10 mmol) and 4-tert-butylaniline (1.48 ml, 9.31 mmol) as starting materials, compound 60 (1.05 g) was obtained by condensation reaction following similar procedures to those used in the preparation of compound 40, with a yield of 75.5%.

[0325] 1 H NMR(400MHz, CDCl3)δ8.78(d,J=4.2Hz,1H),7.50–7.39(m,2H),7.20(d,J=8.6Hz ,2H),6.10(s,1H),4.10–4.04(m,4H),3.71–3.64(m,1H),3.11–2.98(m,2H),2.49 (ddt,J=11.6,7.3,3.6Hz,1H),2.24(dt,J=13.6,4.1Hz,1H),2.10(dt,J=18.0,8 .9Hz,1H),2.00–1.87(m,3H),1.73–1.56(m,2H),1.28–1.24(m,6H),1.20(s,9H); 13C NMR (101MHz, CDCl3) δ191.4,191.3,173.6,162.3,146.7,136.0,125.5,121.8,119.7,77.6,77.3,77.0,62.7,6 2.6,62.5,62.4,44.6,44.3,43.0,36.2,34.2,31.3,30.6,30.2,28.3,16.3,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 24 H 37 NO5P:450.2331; Found:450.2341.

[0326]

[0327] Using compound 60 (400 mg) as a raw material, and following similar procedures as those used in the preparation of compound 57, a hydrogenation reduction reaction was conducted to obtain 170 mg of trans-61 as a white solid and 190 mg of cis-61 as a yellow oil, with a yield of 90%.

[0328] trans-61: 1 H NMR (400MHz, CDCl3) δ7.75–7.63(m,1H),7.47–7.40(m,2H),7.27(d,J=9.1Hz,2H),4.11(p,J=7.3Hz,4H),3.03(d,J=22.8Hz,2H),2.49(d, J=6.2Hz,2H),2.21–2.06(m,1H),1.96–1.75(m,5H),1.66–1.49(m,2H),1.30(t,J=7.0Hz,6H),1.25(s,9H),0.96(td,J=14.5,7.7Hz,2H); 13 C NMR (101MHz, CDCl3) δ201.3,201.2,174.1,146.9,135.6,125.7,119.6,77.4,77.1, 76.8,62.6,62.6,51.2,45.9,43.3,42.1,34.3,32.6,31.9,31.4,29.2,16.4,16.3.

[0329] cis-61: 1H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 7.41 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.4Hz, 2H),4.07–4.00(m,4H),2.95(d,J=22.5Hz,2H),2.52(d,J=6.8Hz,2H),2.32( dp,J=8.3,4.2Hz,1H),2.06(p,J=6.0Hz,1H),1.80–1.69(m,2H),1.53(dq,J= 14.3,5.0Hz,2H),1.42(q,J=5.8Hz,4H),1.22(t,J=7.1Hz,6H),1.18(s,9H); 13 C NMR (101MHz, CDCl3) δ201.5,201.4,174.4,146.5,136.1,125.4,119.7,77.7,77.3,77.0,62.6,62 .5,48.0,43.2,43.1,42.0,34.2,31.3,29.5,28.9,25.7,16.3,16.2.HRMS(ESIMS)m / z(M+H)+calcd forC 24 H 39 NO5P:452.2488; Found:452.2495.

[0330]

[0331] Using compounds trans-61 (200 mg, 0.44 mmol) and 39 (147.56 mg, 0.40 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 62 (198 mg) was obtained as a white solid via condensation reaction, with a yield of 68.0%.

[0332] 1 H NMR (400MHz, CDCl3) δ7.47–7.39(m,4H),7.35–7.29(m,4H),7.04(d,J=7.8Hz,2H),6.83(d,J=8.0Hz,1H),6.55(d,J=16.1Hz,1H),2.54(d,J= 6.5Hz,2H),2.19(tt,J=12.2,3.6Hz,1H),2.06–1.83(m,6H),1.70–1.53(m,3H),1.29(s,9H),0.99(d,J=5.5Hz,18H),0.22(d,J=3.2Hz,12H); 13C NMR (101MHz, CDCl3) δ199.9,174.0,149.8,147.3,147.1,142.9,135.4,128.0,125.8,124.5,122.6,121.3,1 20.7,119.6,77.4,77.1,76.7,48.0,46.2,34.3,33.9,32.4,31.4,29.4,25.9,25.9,18.5,18.5,-4.0,-4.1.

[0333] Example 28

[0334]

[0335] Using compound 62 (230 mg, 0.35 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 28 (140 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 92.1%.

[0336] 1 H NMR (400MHz, MeOD) δ7.45(d,J=16.0Hz,1H),7.41–7.35(m,2H),7.29–7.17(m,2H),7.04(d,J=2.1Hz,1H),6.94(dd,J=8.1,2.2Hz,1H),6.74(d,J=8.2Hz ,1H),6.55(d,J=16.0Hz,1H),2.49(d,J=6.5Hz,2H),2.30–2.19(m,1H),1.8 6–1.76(m,5H),1.61–1.48(m,2H),1.22(d,J=1.4Hz,9H),1.09–0.99(m,2H); 13 CNMR(101MHz,MeOD)δ201.5,176.0,148.6,146.7,145.5,144.4,135.9,126.4,125.1,122.9,122.2,119.9,119.8,115.2 ,114.0,48.3,48.1,47.9,47.7,47.5,47.3,47.2,47.0,45.4,34.0,33.8,32.0,30.4,29.1; HRMS(ESIMS)m / z(M+H)+calcd for C 27 H 34 NO4:436.2410; Found:436.2419.

[0337]

[0338] Using compounds cis-61 (200 mg, 0.44 mmol) and 39 (147.56 mg, 0.40 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 63 (150 mg) was obtained as a white solid via a condensation reaction, with a yield of 51.5%.

[0339] 1 H NMR (400MHz, CDCl3) δ7.48–7.40(m,5H),7.35–7.30(m,2H),7.07–7.01(m,2H),6.83(d, J=8.9Hz,1H),6.54(d,J=16.3Hz,1H),2.67(d,J=7.0Hz,2H),2.43(dt,J=7.4,3.5Hz,1H ),2.24(q,J=6.3Hz,1H),1.93(dt,J=12.7,6.2Hz,2H),1.72(dt,J=13.7,6.4Hz,2H),1. 60(dq,J=11.8,5.8Hz,5H),1.29(s,9H),0.99(d,J=5.5Hz,18H),0.22(d,J=2.0Hz,12H); 13 C NMR (101MHz, CDCl3) δ200.3,173.8,149.7,147.3,147.1,142.8,135.5,128.0,125.8,124.9,122.6,121.2,120.7, 119.6,77.4,77.3,77.1,76.8,44.6,43.4,34.4,31.4,31.0,29.7,29.3,26.1,25.9,25.9,18.5,18.5,-4.0,-4.1.

[0340] Example 29

[0341]

[0342] Using compound 63 (80 mg, 0.12 mmol) as the starting material, and following similar procedures as those used in the preparation of compound 22, compound 29 (50 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 96.2%.

[0343] 1H NMR(400MHz,MeOD)δ7.38(d,J=16.1Hz,1H),7.32(d,J=8.7Hz,2H),7.18–7.11(m,2H), 6.97(d,J=2.0Hz,1H),6.85(dd,J=8.3,2.0Hz,1H),6.66(d,J=8.1Hz,1H),6.45(d,J=16 .0Hz,1H),3.21(s,1H),2.56(d,J=7.2Hz,2H),2.31(dp,J=8.9,3.8Hz,1H),2.13–2.02( m,1H),1.72(ddt,J=16.1,10.3,5.1Hz,2H),1.47(tt,J=12.4,5.6Hz,6H),1.12(s,9H); 13 C NMR(101MHz,MeOD)δ201.8,175.9,148.6,146.7,145.5,144.3,135.9,126.5,125.2,123.2,122.3,120.1,120.0,115.3,114. 1,48.6,48.4,48.2,47.9,47.7,47.5,47.3,47.1,43.6,43.2,33.8,30.6,30.5,28.9,25.0; HRMS(ESIMS)m / z(M+H)+calcdfor C 27 H 34 NO4:436.2410; Found:436.2415.

[0344]

[0345] Using compound 55 (400 mg, 1.24 mmol) and 4-fluoroaniline (0.35 ml, 3.73 mmol) as starting materials, compound 64 was obtained by condensation reaction using similar steps to those used in the preparation of compound 40, yielding 300 mg of compound 64 as a white solid with a yield of 78.4%.

[0346] 1H NMR (400MHz, CDCl3) δ8.41–8.31(m,1H),7.51(dd,J=8.8,4.8Hz,2H),6.93(t ,J=8.7Hz,2H),5.55(s,1H),4.16–4.04(m,4H),3.22(s,2H),3.14–2.98(m,2H) ),2.52–2.43(m,1H),2.36(t,J=13.8Hz,1H),2.24(dd,J=14.2,8.8Hz,1H),2 .00(s,1H),1.92(d,J=12.9Hz,1H),1.82–1.73(m,1H),1.30(t,J=7.0Hz,6H); 13 C NMR (101MHz, CDCl3) δ200.3,200.3,174.3,160.3,157.9,134.5,130.9,125.2,121.8,121.7,115.5,115.2,77.4,77 .1,76.8,62.8,62.7,62.7,62.6,52.7,41.9,41.3,40.6,28.2,27.8,25.8,16.3,16.3; HRMS(ESIMS)m / z(M+H)+calcd for C 20 H 28 FNO5P:412.1674 Found:412.1684.

[0347]

[0348] Using compound 64 (713 mg) as a starting material, and following similar procedures as those used in the preparation of compound 57, a hydrogenation reduction reaction was conducted to obtain 130 mg of trans-65 as a white solid and 300 mg of cis-65 as a colorless oil, with a yield of 60.3%.

[0349] trans-65: 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.46(dd,J=8.8,4.8Hz,2H),6.90(t,J=8.6Hz,2H),4.08(p,J=7.3Hz,5H),3.01(d,J=22.7Hz,2H),2.46(d,J= 6.3Hz,2H),2.14(tt,J=12.2,3.6Hz,1H),1.89–1.74(m,5H),1.55(td,J=12.8,3.3Hz,2H),1.28(t,J=7.1Hz,7H),0.92(qd,J=11.8,6.4Hz,2H); 13C NMR (101MHz, CDCl3) δ201.2,201.2,174.5,160.3,157.9,134.5,121.8,121.7,115.4,11 5.2,77.5,77.1,76.8,62.7,62.6,51.2,45.7,43.2,41.9,32.6,31.9,29.1,16.3,16.2.

[0350] cis-65: 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 7.46 (dd, J = 8.8, 4.9Hz, 2H), 6.90 (t, J = 8.6Hz ,2H),4.07(dq,J=14.8,7.1Hz,5H),3.00(d,J=22.6Hz,2H),2.58(d,J=7.0Hz,2H ),2.36(dq,J=8.0,4.1Hz,1H),2.12(dq,J=11.9,6.5Hz,1H),1.84–1.75(m,2H), 1.60(dq,J=12.5,4.7Hz,2H), 1.47(dt,J=8.2,4.7Hz,4H), 1.27(t,J=7.1Hz,7H); 13 C NMR (101MHz, CDCl3) δ201.5,201.4,174.3,160.2,157.8,134.5,121.7,121.7,115.4,11 5.2,77.5,77.1,76.8,62.7,62.6,48.1,43.3,43.2,42.0,29.6,28.9,25.7,16.3,16.2.

[0351]

[0352] Using compounds trans-65 (200 mg, 0.48 mmol) and 39 (161.14 mg, 0.44 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 66 (180 mg) was obtained as a white solid via a condensation reaction, with a yield of 60.0%.

[0353] 1H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 7.54–7.39 (m, 3H), 7.03 (d, J = 7.6Hz, 2H), 6.9 6(t,J=8.5Hz,2H),6.83(d,J=8.0Hz,1H),6.54(d,J=16.1Hz,1H),2.53(d,J=6.6 Hz,2H),2.20(tt,J=12.2,3.5Hz,1H),2.00–1.87(m,5H),1.61(qd,J=12.8,3.1H z,3H),1.10–1.02(m,2H),0.99(d,J=5.0Hz,18H),0.21(dd,J=4.3,1.1Hz,12H); 13 C NMR (101MHz, CDCl3) δ200.0,174.3,160.4,158.0,149.9,147.3,143.0,134.2,127.9,124.4,122.6,121.8,121.7,121.3,120.7 ,115.6,115.4,77.4,77.1,76.8,48.0,46.0,33.8,32.3,29.4,25.9,25.9,18.5,18.4,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 35 H 53 FNO4Si2: 626.3507; Found: 626.3492. Example 30

[0354]

[0355] Using compound 66 (80 mg, 0.13 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 30 was obtained as a yellow oily substance via a TBS deprotection reaction, with a yield of 92.3%.

[0356] 1 H NMR (400MHz, MeOD) δ7.51(q,J=8.7Hz,3H),7.09(d,J=2.2Hz,1H),7.01(t,J=8.6Hz,3H),6.79(d,J=7.9Hz,1H),6.60(d,J=15.9Hz, 1H),3.31(s,1H),2.56(d,J=6.5Hz,2H),2.36–2.25(m,1H),1.88(t,J=14.3Hz,5H),1.58(q,J=11.9Hz,2H),1.11(q,J=13.2Hz,2H); 13C NMR(101MHz,MeOD)δ201.5,176.0,148.6,145.5,144.4,134.8,126.4,122.9,122.2,121.8,121.7,115.2,114.9,1 14.7,114.0,48.3,48.1,47.8,47.6,47.4,47.3,47.2,47.0,45.4,34.0,31.9,29.1; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 25 FNO4:398.1751; Found:398.1762.

[0357]

[0358] Using compounds cis-65 (200 mg, 0.48 mmol) and 39 (161.14 mg, 0.44 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 67 (140 mg) was obtained as a white solid via a condensation reaction, with a yield of 46.7%.

[0359] 1 H NMR (400MHz, CDCl3) δ7.65 (s, 1H), 7.49 (dd, J = 8.8, 4.8Hz, 2H), 7.43 (d, J = 16.1H z,1H),7.00(d,J=16.6Hz,4H),6.82(d,J=8.1Hz,1H),6.53(d,J=16.1Hz,1H),2. 66(d,J=7.0Hz,2H),2.42(s,1H),2.27–2.19(m,1H),1.97–1.85(m,3H),1.78–1. 64(m,3H),1.59(q,J=6.7Hz,4H),0.98(d,J=5.3Hz,19H),0.21(d,J=3.4Hz,12H); 13 C NMR (101MHz, CDCl3) δ200.4,174.1,160.5,158.1,149.9,147.4,143.0,134.3,128.0,124.9,122.7,121.8,121.8,121.3,120.8 ,115.7,115.5,77.5,77.2,76.8,44.7,43.3,31.1,29.3,26.1,26.0,26.0,18.6,18.5,-4.0,-4.0; HRMS(ESIMS)m / z(M+H)+calcd for C 35 H 53FNO4Si2: 626.3463; Found: 626.3492. Example 31

[0360]

[0361] Using compound 67 (80 mg, 0.13 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 31 was obtained by deprotection reaction via TBS to produce 48 mg of a yellow oily substance, with a yield of 92.3%.

[0362] 1 H NMR(400MHz,MeOD)δ7.51–7.42(m,3H),7.03(d,J=2.0Hz,1H),6.95(dd,J=1 0.4,7.3Hz,3H),6.73(d,J=8.2Hz,1H),6.54(d,J=16.1Hz,1H),3.28(s,1H), 2.66(d,J=7.2Hz,2H),2.39(tt,J=8.9,3.9Hz,1H),2.16(qd,J=7.5,5.3Hz, 1H),1.81(tt,J=12.9,6.9Hz,2H),1.61(q,J=4.8Hz,1H),1.58–1.52(m,4H); 13 C NMR(101MHz,MeOD)δ201.8,175.9,160.4,158.0,148.6,145.5,144.3,134.8,126.5,123.1,122.2,121.9,121.8,115.2,114 .9,114.7,114.0,48.5,48.3,48.1,47.9,47.7,47.5,47.2,47.0,43.5,43.2,30.6,28.9,25.0; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 25 FNO4:398.1753; Found:398.1762.

[0363]

[0364] Using compound 64 (200 mg, 0.48 mmol) and compound 39 (161.14 mg, 0.44 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 68 was obtained in 85 mg as a yellow oily substance via a condensation reaction, with a yield of 28.4%.

[0365] 1H NMR (400MHz, CDCl3) δ8.09(s,1H),7.56–7.44(m,3H),7.07–7.01(m,2H),7.00–6.92(m,2H),6.83(d,J=8.0Hz,1H),6.60(d,J=16.0Hz,1H),5.62(s, 1H),3.29(s,2H),2.55–2.36(m,2H),2.29(d,J=18.0Hz,1H),2.02–1.94( m,1H),1.89–1.78(m,1H),0.99(d,J=4.3Hz,18H),0.21(d,J=5.1Hz,12H); 13 C NMR (101MHz, CDCl3) δ198.5,174.4,160.4,158.0,150.0,147.3,143.6,134.3,132.1,127.9,124.2,123.4,122.6,121.9,121.8,121.3,12 0.9,115.6,115.3,77.4,77.1,76.8,49.8,41.5,29.7,28.2,28.0,26.0,25.9,25.9,18.5,18.5,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 35 H 51 FNO4Si2: 624.3288; Found: 624.3335. Example 32

[0366]

[0367] Using compound 68 (85 mg, 0.14 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 32 (50 mg) was obtained as a yellow oil by a TBS deprotection reaction, with a yield of 89.3%.

[0368] 1H NMR(400MHz,MeOD)δ7.56–7.47(m,3H),7.06(d,J=2.4Hz,1H),6.98(td,J=8.8 ,2.5Hz,3H),6.77(dd,J=8.1,2.4Hz,1H),6.62(dd,J=16.0,2.4Hz,1H),5.64(s ,1H),3.28(d,J=3.2Hz,3H),2.53(tdd,J=12.3,5.5,2.6Hz,1H),2.39–2.18(m ,2H),2.17–1.99(m,2H),1.94(d,J=13.2Hz,1H),1.74(tt,J=13.7,6.8Hz,1H); 13 CNMR(101MHz,MeOD)δ199.8,175.7,160.4,158.0,148.7,145.5,144.7,134.8,131.9,126.4,124.0,122.3,121.8,121.7,115 .2,114.9,114.7,114.0,49.1,48.3,48.1,47.9,47.6,47.4,47.2,47.0,41.2,28.0,27.8,25.9; HRMS(ESIMS)m / z(M+H)+calcd for C 23 H 25 FNO4:396.1595; Found:396.1606.

[0369]

[0370] Using compound 55 (1 g, 3.10 mmol) and 3,5-dimethoxyaniline (1.43 g, 9.31 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 40, compounds Z-69 (450 mg, yellow oil) and E-69 (500 mg, yellow oil) were obtained by condensation reaction, with a yield of 67.9%.

[0371] Z-69: 1H NMR(400MHz,CDCl3)δ8.21(s,1H),6.84(d,J=2.2Hz,2H),6.16(t,J=2.2Hz,1H),5.55(d,J=4.6Hz,1H),4.10(td,J=7.2,1.8Hz,4H),3.71(s,7H),3.21(s,2H),3.09(d,J=5.6Hz,1H),3.04(d,J=5.8Hz,1H),2.49–2.18(m,4H),2.03–1.91(m,3H),1.77(ddd,J=17.3,11.4,5.4Hz,2H),1.29(t,J=7.1Hz,7H); 13 C NMR(101MHz,CDCl3)δ200.3,200.3,174.5,160.9,140.3,130.9,125.2,97.9,96.5,77.4,77.1,76.8,62.7,62.7,62.6,62.6,55.3,52.7,41.8,41.6,40.6,28.2,27.9,25.9,16.3,16.3.

[0372] E-69: 1 H NMR(400MHz,CDCl3)δ8.42(s,1H),6.82(d,J=2.3Hz,2H),6.17–6.12(m,2H),4.10(p,J=7.3Hz,4H),3.70(d,J=3.1Hz,7H),3.16–2.97(m,2H),2.54–2.46(m,1H),2.30(dt,J=14.1,4.0Hz,1H),2.17(td,J=13.1,4.6Hz,1H),2.00(dd,J=16.1,12.1Hz,3H),1.74(td,J=12.1,4.2Hz,1H),1.68–1.58(m,1H),1.29(td,J=7.1,2.9Hz,7H); 13 C NMR(101MHz,CDCl3)δ191.4,191.4,173.7,162.1,160.9,140.3,121.9,98.0,96.4,77.4,77.1,76.8,62.7,62.7,62.5,62.5,55.3,45.0,44.3,43.0,36.1,30.4,30.2,28.3,16.3,16.3.

[0373]

[0374] Using compound E-69 (700 mg) as a raw material, and following similar procedures as those used in the preparation of compound 57, compounds trans-70 (320 mg, yellow oil) and cis-70 (350 mg, yellow oil) were obtained via hydrogenation reduction reaction, with a yield of 95.7%.

[0375] trans-70: 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),6.78(d,J=2.3Hz,2H),6.12(t,J=2.2Hz,1 H),4.08–4.03(m,4H),3.67(s,6H),2.98(d,J=22.6Hz,2H),2.56(d,J=6.8Hz, 2H),2.33(dp,J=8.3,4.3Hz,1H),2.09(p,J=6.1Hz,1H),1.82–1.73(m,2H),1. 59(dq,J=8.8,4.6Hz,2H),1.46(dd,J=8.0,4.5Hz,4H),1.25(t,J=7.1Hz,6H); 13 C NMR (101MHz, CDCl3) δ201.5,201.4,174.5,160.9,140.3,98.0,96.3,77.5,77.2,76.9,62.8,62.6, 62.6,55.3,47.9,43.5,43.3,42.0,29.5,28.9,25.6,16.3,16.2; HRMS(ESIMS)m / z(M+H)+calcdfor C 22 H 35 NO7P:456.2147; Found:456.2146.cis-70: 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),6.79(d,J=2.2Hz,3H),6.12(d,J=2.3Hz,1H),4 .06(t,J=7.8Hz,4H),3.66(d,J=1.9Hz,7H),2.99(dd,J=22.6,1.9Hz,2H),2.43(d ,J=6.2Hz,2H),2.10(d,J=12.4Hz,1H),1.84(d,J=13.4Hz,2H),1.73(d,J=13.6Hz ,2H),1.52(q,J=13.3Hz,2H),1.18(dt,J=7.2,3.5Hz,1H),0.88(q,J=12.8Hz,2H); 13C NMR (101MHz, CDCl3) δ201.3,201.2,174.8,160.9,140.3,98.0,96.4,77.5,77.2,76.9,62.7,6 2.6,55.3,51.2,45.9,43.2,41.9,32.5,31.8,29.1,16.3,16.2; HRMS(ESIMS)m / z(M+H)+calcd for C 22 H 35 NO7P:456.2145; Found:456.2146.

[0376]

[0377] Using compounds E-69 (150 mg, 0.33 mmol) and 39 (109.86 mg, 0.30 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 71 was obtained via a condensation reaction, yielding 80 mg of a yellow oily substance in a yield of 40.0%.

[0378] 1 H NMR(400MHz, CDCl3)δ7.47(d,J=16.1Hz,1H),7.40(s,1H),7.08–7.00(m,2H), 6.83(d,J=7.1Hz,3H),6.59(d,J=16.0Hz,1H),6.23(s,1H),5.65(s,1H),3.77 (s,6H),3.30(s,2H),2.41(dt,J=36.3,13.9Hz,3H),2.12(s,2H),2.02(d,J=1 2.1Hz,1H),1.92–1.79(m,1H),0.99(d,J=4.8Hz,18H),0.22(d,J=4.0Hz,12H); 13 CNMR (101MHz, CDCl3) δ198.2,174.1,161.0,149.9,147.3,143.4,139.9,132.3,128.0,124.1,123.4,122.6,121.3,120.9,97.9,9 6.8,77.4,77.2,77.0,76.7,55.4,49.8,42.1,28.3,28.0,26.0,25.9,25.9,18.5,18.5,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 37 H 56 NO6Si2:666.3605; Found:666.3641.

[0379] Example 33

[0380]

[0381] Using compound 71 (50 mg, 0.08 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 33 (25 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 71.4%.

[0382] 1 H NMR(400MHz,MeOD)δ7.55(d,J=16.0Hz,1H),7.10(d,J=2.1Hz,1H),7.00(dd,J =8.2,2.0Hz,1H),6.85–6.79(m,3H),6.66(d,J=16.0Hz,1H),6.22(d,J=2.3Hz, 1H),5.68(d,J=4.4Hz,1H),3.74(s,6H),2.63–2.52(m,1H),2.40–2.24(m,2H) ,2.12(q,J=21.9Hz,2H),1.97(d,J=12.4Hz,1H),1.76(qd,J=12.0,5.6Hz,1H); 13 C NMR(101MHz,MeOD)δ199.8,175.9,161.0,148.6,145.5,144.6,140.3,131.9,126.4,124.0,122.3,121.8,115.2,114.0,98 .0,95.8,54.3,49.1,48.3,48.1,47.8,47.6,47.4,47.2,47.0,41.4,29.4,28.0,27.8,25.9; HRMS(ESIMS)m / z(M+H)+calcd for C 25 H 28 NO6:438.1923; Found:438.1911.

[0383]

[0384] Using compounds Z-69 (150 mg, 0.33 mmol) and 39 (109.86 mg, 0.30 mmol) as raw materials, and following similar procedures as those used in the preparation of compound 58, compound 72 was obtained via a condensation reaction, yielding 86 mg of a yellow oily substance in a yield of 41.5%.

[0385] 1H NMR (400MHz, CDCl3) δ7.52–7.34(m,2H),7.04(dq,J=9.0,2.6Hz,2H),6.83(q,J =3.4Hz,4H),6.59(dd,J=16.0,3.2Hz,1H),6.26–6.16(m,1H),5.65(s,1H),3.7 7(d,J=3.2Hz,6H),3.30(s,2H),2.54–2.28(m,3H),2.12(s,2H),2.02(d,J=12. 9Hz, 1H), 1.87 (d, J = 9.9Hz, 1H), 0.99 (t, J = 4.0Hz, 18H), 0.21 (t, J = 3.6Hz, 12H); 13 C NMR (101MHz, CDCl3) δ198.2,174.1,161.0,149.9,147.3,143.4,139.9,132.3,128.0,124.1,123.4,122.6,121.3,120.9,97.9,9 6.8,77.4,77.2,77.0,76.7,55.4,49.8,42.1,28.3,28.0,26.0,25.9,25.9,18.5,18.5,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 37 H 56 NO6Si2: 666.3600; Found: 666.3641. Example 34

[0386]

[0387] Using compound 72 (50 mg, 0.08 mmol) as a starting material, and following similar procedures as those used in the preparation of compound 22, compound 34 (20 mg) was obtained via a TBS deprotection reaction as a yellow oil, with a yield of 69.4%.

[0388] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=15.9Hz,1H),7.08(d,J=2.1Hz,1H),6.99(dd,J=8.2,2.1Hz,1H),6.84–6.77(m,4H),6.65(d,J=16.0Hz,1H),6.22 (t,J=2.3Hz,1H),5.67(d,J=4.6Hz,1H),3.73(s,6H),2.52(d,J=14.5Hz, 1H),2.41–2.07(m,5H),2.07–1.91(m,2H),1.76(qd,J=11.9,5.6Hz,1H);13 C NMR (101MHz, CDCl3) δ203.7,179.8,165.0,152.6,149.5,148.6,144.2,135.8,133.4,130.3,127.9,126.2,125.7,119.1,117.9,1 01.9,99.8,58.3,53.0,52.4,52.2,52.0,51.8,51.6,51.3,51.1,50.9,45.3,32.0,31.8,29.9,28.7; HRMS(ESIMS)m / z(M+H)+calcd for C 25 H 28 NO6:438.1918; Found:438.1911.

[0389]

[0390] Using compounds trans-70 (190 mg, 0.42 mmol) and 39 (139.16 mg, 0.38 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 73 (120 mg) was obtained via a condensation reaction as a yellow oily substance, with a yield of 42.9%.

[0391] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=4.9Hz,1H),7.42(d,J=16.4Hz,1H),7.03(dd,J=6.5,2.1Hz,2H),6.87–6 .79(m,3H),6.53(d,J=16.2Hz,1H),6.20(t,J=2.2Hz,1H),5.27(d,J=1.5Hz,1H),3.73(d,J=1.6Hz,6H), 2.66(d,J=6.9Hz,2H),2.40(td,J=7.8,4.0Hz,1H),2.25(p,J=6.0Hz,1H),1.91(dq,J=13.7,6.9Hz,2H), 1.69(dq,J=12.7,4.8Hz,2H),1.57(d,J=17.9Hz,4H),0.98(dd,J=5.1,1.6Hz,19H),0.22–0.19(m,12H); 13CNMR(101MHz, CDCl3)δ200.3,174.4,161.0,149.8,147.3,142.9,140.1,128.0,124.8,122.6,121.2,120.7,97.9,96 .6,77.4,77.1,76.8,55.3,44.4,43.7,30.8,29.2,25.9,25.9,18.5,18.4,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 37 H 58 NO6Si2: 668.3749; Found: 668.3797. Example 35

[0392]

[0393] Using compound 73 (100 mg, 0.16 mmol) as the starting material, and following similar procedures as those used in the preparation of compound 22, compound 35 was obtained by deprotection reaction via TBS to produce 40 mg of a yellow oily substance, with a yield of 57.1%.

[0394] 1 H NMR(400MHz,MeOD)δ7.51(d,J=16.0Hz,1H),7.10(d,J=2.1Hz,1H),6.99(dd,J=8.2 ,2.0Hz,1H),6.83(d,J=2.2Hz,2H),6.80(d,J=8.2Hz,1H),6.59(d,J=16.1Hz,1H), 6.20(d,J=2.3Hz,1H),3.72(s,6H),2.69(d,J=7.2Hz,2H),2.44(tt,J=8.8,3.8Hz, 1H),2.20(dd,J=8.7,4.1Hz,1H),1.91–1.79(m,2H),1.62(dp,J=24.4,5.0Hz,6H); 13 C NMR(101MHz,MeOD)δ201.8,176.1,161.0,148.5,145.5,144.3,140.3,126.5,123.1,122.3,115.3,114.1,98.1,95. 8,54.4,48.5,48.3,48.1,47.9,47.7,47.5,47.3,47.1,43.8,43.2,30.6,28.9,25.0; HRMS(ESIMS)m / z(M+H)+calcd for C 25 H 30 NO6:440.2057; Found:440.2068.

[0395]

[0396] Using compounds cis-70 (190 mg, 0.42 mmol) and 39 (139.16 mg, 0.38 mmol) as starting materials, and following similar procedures as those used in the preparation of compound 58, compound 74 (130 mg) was obtained via a condensation reaction as a yellow oily substance, with a yield of 46.4%.

[0397] 1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.42 (d, J = 16.1Hz, 1H), 7.03 (d, J = 8.3Hz, 2H), 6.8 2(dd,J=5.0,2.9Hz,3H),6.54(d,J=16.1Hz,1H),6.20(t,J=2.2Hz,1H),3.73(s,7H), 2.52(d,J=6.5Hz,2H),2.22–2.13(m,1H),1.97(s,2H),1.88(d,J=12.7Hz,2H),1.66– 1.54(m,2H),1.03(d,J=11.0Hz,1H),0.98(d,J=5.1Hz,19H),0.21(d,J=4.1Hz,12H); 13 CNMR(101MHz, CDCl3)δ200.0,174.5,161.0,149.8,147.3,143.0,140.1,128.0,124.5,122.6,121.3,120.7,97.9,96.7 ,77.4,77.1,76.8,55.3,48.0,46.3,33.8,32.3,29.3,25.9,25.9,18.5,18.4,-4.0,-4.1; HRMS(ESIMS)m / z(M+H)+calcd for C 37 H 58 NO6Si2: 668.3748; Found: 668.3797. Example 36

[0398]

[0399] Using compound 74 (120 mg, 0.18 mmol) as the starting material, and following similar procedures as those used in the preparation of compound 22, compound 36 (70 mg) was obtained as a yellow oil by a TBS deprotection reaction, with a yield of 88.6%.

[0400] 1H NMR (400MHz, MeOD) δ7.44(d,J=16.0Hz,1H),7.04(d,J=2.1Hz,1H),6.94(dd,J =8.2,2.0Hz,1H),6.78–6.73(m,3H),6.54(d,J=16.0Hz,1H),6.16(t,J=2.3Hz, 1H),3.67(s,6H),2.48(d,J=6.5Hz,2H),2.24(tt,J=12.3,3.3Hz,1H),1.80(d dd,J=17.4,13.1,3.6Hz,5H),1.58–1.45(m,2H),1.03(qd,J=11.7,6.2Hz,2H); 13 CNMR(101MHz,MeOD)δ201.5,176.1,161.0,148.6,145.5,144.3,140.3,126.4,122.9,122.2,115.2,114.0,98.0, 95.8,54.3,48.3,48.1,47.9,47.7,47.4,47.3,47.2,47.0,45.6,34.0,31.9,29.1; HRMS(ESIMS)m / z(M+H)+calcd for C 25 H 30 NO6:440.2058; Found:440.2068.

[0401] Pharmacological experiments

[0402] Experimental example: chlorogenic acid simplified compound OXCT1 target IC 50 Measurement

[0403] (I) Method

[0404] Screening methods for OXCT1 small molecule inhibitors

[0405] 100 μL of recombinant human OXCT1 protein solution (final concentration 250 μM) and 10 μL of compounds at different concentrations were added to eight-connected tubes. The control group consisted of 100 μL of screening buffer solution without OXCT1 protein and 10 μL of compounds at different concentrations added to eight-connected tubes. The remaining procedures were the same as the experimental group: incubation at 37°C for 1 h, followed by the addition of 45 μL of succinyl-CoA solution (final concentration 125 μM), incubation at room temperature for 1 min, addition of 45 μL of lithium acetoacetate solution (final concentration 2 mM), and then transfer of 95 μL to a 384-well plate (two parallel wells per sample group). The absorbance at 313 nM was measured using a microplate reader. Inhibition rate % = 1 - (test compound group - blank compound control group) / (enzyme reaction group - blank solution group) * 100%. The IC50 of the compounds was calculated using Graphpad.50 value.

[0406] (II) Results

[0407] IC is calculated based on OD313 50 The values ​​are shown in Table 1 below. Experimental results show that compounds 6, 8, 10, 12, 13, 15, 21, 22, 23, and 24 exhibited inhibitory activity against OXCT1 reaching 10%. -7 It exhibits good OXCT1 inhibitory activity at the M level.

[0408] Table 1 Results of in vitro target screening

[0409]

[0410]

Claims

1. A compound as shown in general formula I, or an isomer thereof, and a pharmaceutically acceptable salt thereof: Including any of its tautomer forms, where: R1, R2, and R3 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen. R4 is independently selected from: hydrogen, methyl, ethyl, benzo[1,4]dioxane, X is independently selected from: oxygen, nitrogen, carbon, and sulfur; when X is oxygen, nitrogen, or sulfur, X middle It is a single bond; when X is carbon, X middle It can be a single bond or a double bond; Y is selected independently from: oxygen, nitrogen, carbon, and sulfur; R5, R6, R7, R8, and R9 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen. R 10 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen; R 11 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen; n is independently selected from 0, 1, 2, or 3; Halogens are represented by fluorine, chlorine, bromine, and iodine.

2. The compound according to claim 1, or its isomers and pharmaceutically acceptable salts thereof, characterized in that: R1, R2, and R3 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen. R4 is independently selected from: hydrogen, methyl, ethyl, phenyl, benzo[1,4]dioxane, X is independently selected from: oxygen, nitrogen, carbon, and sulfur; when X is oxygen, nitrogen, or sulfur, X middle It is a single bond; when X is carbon, X middle It can be a single bond or a double bond; Y is independently selected from: oxygen and nitrogen; R5, R6, R7, R8, and R9 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, vinyl, ethynyl, cyano, nitro, and halogen. R 10 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen; R 11 Independently selected from hydrogen, methyl, ethyl, methoxy, cyano, nitro, and halogen; n is independently selected from 0 or 1; Halogens are represented by fluorine, chlorine, bromine, and iodine.

3. The compound or its isomer according to any one of claims 1-2, and its pharmaceutically acceptable salt, characterized in that, The compound is selected from 4. The compound or its isomer according to any one of claims 1-3, and its pharmaceutically acceptable salt, characterized in that, The pharmaceutically acceptable salts include: sodium salts, potassium salts, calcium salts, magnesium salts, lithium salts, ammonium salts, or salts of organic bases that can provide physiologically acceptable cations.

5. A method for preparing the compound according to any one of claims 1-3, characterized by comprising the following steps: Method 1: When n = 1, X is oxygen or nitrogen, and Y is oxygen or nitrogen, the preparation of compound Ia is as follows: Compound II is condensed with an amine or acid compound to give compound III. Compound III is condensed with cyclo(isopropyl)malonic acid to give compound IV. Compound IV is condensed with benzaldehyde or substituted benzaldehyde to give compound Ia. i. Condensation reaction; ii. esterification reaction; iii. aldol condensation reaction; wherein R1, R2, R3 and R4 are defined as defined in claims 1-3; Method 2: Preparation of compound Ib when n = 0 and Y is oxygen or nitrogen: Compound V is condensed with an amine or acid compound to give compound VI. Compound VI undergoes an ester condensation reaction with diethyl methylphosphonate to give compound VII. Compound VII reacts with benzaldehyde or substituted benzaldehyde via an HWE reaction to give compound Ib. i. Condensation reaction; ii. Ester condensation reaction; iii. HWE reaction; wherein R1, R2, R3 and R4 are defined as defined in claims 1-3; Method 3: When n=1, X is carbon, X middle Preparation of compound Ic when Y is a double bond and is oxygen or nitrogen: Compound VIII reacts with Boc anhydride to give compound IX. Compound IX undergoes an HWE reaction with commercially available compound diethylphosphonoacetate to give compound X. Compound X undergoes an ester condensation reaction with commercially available compound diethyl methyl phosphate to give compound XI. Compound XI is deprotected under acidic conditions to give compound XII. Compound XII condenses with an amine or acid compound to give compound XIII. Compound XIII reacts with benzaldehyde or substituted benzaldehyde via an HWE reaction to give compound Ic. i. esterification reaction; ii. HWE reaction; iii. ester condensation reaction; iv. hydrolysis reaction; v. condensation reaction; vi. HWE reaction; wherein R1, R2, R3 and R4 are defined as in claims 1-3; Method 4: When n=1, X is carbon, X middle Preparation of compound Id when Y is a single bond and is oxygen or nitrogen: Compound XIII was reduced by hydrogenation at atmospheric pressure to give compound XIV. Compound XIV was reacted with benzaldehyde or substituted benzaldehyde via HWE reaction to give compound Id. i. Hydrogenation reduction; ii. HWE reaction; wherein R1, R2, R3 and R4 are defined as defined in claims 1-3; Ia, Ib, Ic and Id are included in general formula I.

6. A pharmaceutical composition comprising an effective dose of the compound of any one of claims 1-4 or an isomer thereof, a pharmaceutically acceptable salt thereof, and a pharmacodynamically acceptable carrier thereof.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition includes tablets, capsules, pills, or injections.

8. The use of any compound of claims 1-4 or its isomers and pharmaceutically acceptable salts in the preparation of a drug for the prevention and / or treatment of tumors.

9. The application according to claim 8, characterized in that, The tumors mentioned are selected from gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, head and neck tumors, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, or rectal adenocarcinoma.

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