Preparation of a terphenyl compound and its role as a hif inhibitor

Abstract

The application relates to application of a terphenyl compound as a HIF inhibitor, belongs to the field of pharmaceutical chemistry, and particularly relates to a terphenyl compound, including stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof and a pharmaceutical composition containing the compound as a medicine, especially as a medicine for treating and / or preventing diseases related to HIF.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a terphenyl compound, composition, and application, wherein the compound or composition has activity as a hypoxia-inducible factor (HIF) inhibitor and can be used to treat HIF-related diseases. Background Technology

[0002] Hypoxia-inducible factor (HIF) is a transcriptionally active nuclear protein that plays a crucial role in cellular adaptation to hypoxic environments. It is a heterodimer composed of HIF-1α and HIF-1β subunits. Under normal oxygen partial pressure, the HIF-1α subunit is hydroxylated by prolyl hydroxylase (PHD) and then rapidly degraded by the ubiquitin-proteasome pathway (Bruick, RKScience. 2001, 294: 1337−1340; Kamura, T. Proc. Natl. Acad. Sci. USA 2000,97: 10430−10435). However, under hypoxic conditions, the activity of PHD is inhibited, allowing the HIF-α subunit to stabilize and bind to the HIF-1β subunit, forming an active HIF transcription factor. This factor translocates into the nucleus and initiates the transcription of a series of hypoxia-responsive genes, such as the erythropoietin (EPO) gene, the vascular endothelial growth factor (VEGF) gene, and matrix metalloproteinases (MMPs) (Semenza, GL Trends Pharmacol. Sci. 2012, 33: 207−214; Wigerup, C. Pharmacol. Ther. 2016, 164: 152−169). These gene products play crucial roles in improving hypoxia, promoting angiogenesis, and regulating energy metabolism.

[0003] HIF is associated with a variety of diseases, and its abnormal activation or inactivation is closely related to the occurrence and development of many diseases. In tumor diseases, tumor cells activate the HIF signaling pathway to adapt to the hypoxic environment caused by rapid proliferation (Ke, Q. Molecular Pharmacology 2006, 70(5): 1469-1480; Li, H. Adv. Sci. 2023,2301071). HIF can promote tumor angiogenesis, enabling tumor cells to obtain sufficient oxygen and nutrients. At the same time, it can also regulate the metabolism of tumor cells, enabling them to adapt to the hypoxic environment and enhance their invasive and metastatic abilities. For example, high expression of HIF-1α has been found to be associated with poor prognosis in various solid tumors, including breast cancer, liver cancer, and lung cancer (Moon, EJ Antioxid. Redox Signaling. 2007, 9: 1237−1294; Chen, C. OncoTarget. 2017,8: 46691−46703; Kim, BJ Transl. Med. 2013, 11: 185). Therefore, HIF-1 is considered a promising target for developing new therapies against cancer metastasis. Furthermore, in ischemic diseases such as myocardial ischemia and cerebral ischemia, moderate activation of the HIF pathway can promote angiogenesis and tissue repair, showing potential therapeutic value (Zimna, A. BioMedResearch International 2015, 1-14). HIF-1 has also been reported as a target for neurodegenerative diseases (Zhang, Z. Current Medicinal Chemistry. 2011, 18(28): 4335-4343).

[0004] Terphenyls are mainly derived from fungi and actinomycetes, and in nature they primarily exist in the form of p-terphenyls. The characteristic structure of p-terphenyls consists of a central benzene ring B with two phenyl groups (rings A and C) substituted at the para-position of B. To date, more than 230 p-terphenyls have been identified, and the number is still increasing. This compound exhibits various biological activities, such as anti-inflammatory, antibacterial, antioxidant, and α-glucosidase inhibitory activities (Zhou G. Marine Life Science & Technology. 2022, 4: 62–73), but no activity against HIF has been reported, nor has its application in the preparation of drugs for the prevention or treatment of HIF-mediated diseases been observed. Summary of the Invention

[0005] The following is a summary description of some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0006] This invention provides a terphenyl compound for the treatment of diseases related to HIF activation, including but not limited to tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, and non-alcoholic fatty liver disease (NAFLD). The compound of this invention is easy to prepare, stable, and highly active, thus possessing promising clinical application prospects.

[0007] Specifically:

[0008] On one hand, the present invention relates to a terphenyl compound, characterized in that it is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, particularly for use as an HIF inhibitor, characterized in that the compound has the following structure:

[0009] Where R1 and R2 are independently and arbitrarily chosen as X represents H, D, amino, carboxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 C6H 13 Vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propynyl, butynyl, ethynylbutyryl, penynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2- Bromopropionyl, valeryl, hexanoyl, isobutenoyl, cyclopropyl, cyclopropionyl, cyclovaleryl, cyclohexanoyl, 3-pyridinecarboxyl, naphthyl, phenethylimidazolyl, pyridyl, pyrroleyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, piperidinyl, piperazine, indolyl, carbazole, benzofuranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidine base, purine base;

[0010] R3 can be arbitrarily set to H, or Z1 may be selected from 1 to 5 substituents, wherein the substituents are H, D, F, Cl, Br, I, amino, N,N-dimethylamino, N-methylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 C6H 13 Vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propynyl, butynyl, ethynylbutyryl, penynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, isobutenyl, cyclopropyl, cyclopropionyl, cyclovaleryl, cyclohexanoyl, 3-pyridinecarboxyl, naphthyl, phenethylimidazolyl, pyridyl, pyrroleyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl; Z2 is independently selected from C 3-8 Cycloalkyl, substituted or unsubstituted C 3-6 Metaheterocyclic groups, substituted or unsubstituted C 5-6 Heteroaryl, heterocyclic alkyl, heterocyclic oxy, heterocyclic amino, heterocyclic alkoxy, heterocyclic alkylamino, azidoalkoxy, fused bicyclic, fused heterobicyclic, fused heteroaryl, fused bicyclic aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 Heterocyclic group, C 5-6 The heterocyclic aryl group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclic group, aryl or 5-6 membered heteroaryl group;

[0011] L1, L2, and L3 can each be independently selected as a key, -C 1-6 Alkylene-, -vinyl-, -propenyl-, -allyl-, -n-butenyl-, -isobutenyl-, -n-pentenyl-, -isopentenyl-, -ethynyl-, -propynyl-, -propynyl-, -butynyl-, -butynyl-, -pentynyl-.

[0012] This invention relates to compounds characterized by having one of the following structures or stereoisomers, geometric isomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, with specific structures as follows:

[0013]

[0014]

[0015] On the other hand, the present invention relates to a pharmaceutical composition comprising the compounds disclosed herein. The pharmaceutical composition of the present invention further comprises pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof.

[0016] In this invention, the term "pharmaceutically acceptable salt" refers to the addition salt of a non-toxic inorganic or organic acid and / or base; see "Salt selection for basic drugs", International Journal of Pharmaceutics. 1986, 33, 201–217.

[0017] Compared with the prior art, the beneficial effects of the present invention are:

[0018] This invention discloses a terphenyl compound that can significantly reduce the response of HIF overexpression induced by hypoxia, and has good application prospects and commercial value.

[0019] The term "HIF-related diseases" refers to a series of diseases caused by the overexpression or abnormal regulation of hypoxia-inducible factor (HIF), leading to physiological dysfunction. This includes any condition where a reduction in HIF levels would bring beneficial therapeutic effects. HIF-related diseases include, but are not limited to, tumor growth and metastasis, tumor drug resistance, and diabetic nephropathy. Detailed Implementation

[0020] The following specific embodiments are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0021] Example 1: Compound 1

[0022]

[0023] 2',4''-bis(allyloxy)-3',6'-dimethoxy-[1,1':4',1''-terphenyl]-4-ol (hereinafter referred to as "Compound A") (30 mg, 0.071 mmol) was dissolved in dichloromethane (2 mL). An acid reagent (2.5 eq) was added under the conditions of DMAP catalyst and EDC dehydrating agent. The reaction was stirred for 4 h in a 45 °C water bath. TLC monitoring showed that Compound A had completely reacted. The reaction was then terminated, and the mixture was extracted three times with dichloromethane. The organic phases were combined and concentrated under reduced pressure to give a white solid, yield 91%, mp 125.3–126.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 8.0, 1.6 Hz,1H), 7.58–7.53 (overlapped, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J =10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6Hz, 1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.29 (dt, J = 5.2, 1.6 Hz, 2H), 3.97(s, 3H), 3.75 (s, 3H), 3.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 164.4, 160.0,158.1, 153.1, 150.9, 150.1, 145.1, 134.8, 134.4, 134.1, 133.4, 132.3, 132.0,132.0, 131.4, 131.0, 130.3, 130.3, 124.1, 121.1, 121.1, 120.3, 119.4, 117.9,117.6, 114.6, 114.6, 112.3, 108.2, 74.4, 69.0, 61.0, 56.2, 56.2. HRESIMS m / z553.2221 [M+H] + (calcd. for C 34 H 33 O7 + , 553.2221).

[0024] Example 2: Compound 2

[0025]

[0026] A white solid was obtained by following the preparation method in Example 1, with a yield of 98% and a mp value of 174.9–176.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.02–6.99 (overlapped, 4H), 6.70 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J= 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.2, 1.5 Hz, 2H), 4.30 (dt, J = 5.2, 1.5Hz, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ165.0, 164.0, 158.2, 153.1, 150.9, 150.1, 145.1, 134.8, 134.2, 133.4, 132.4,132.4, 132.1, 132.1, 131.4, 131.0, 130.4, 130.4, 124.1, 122.2, 121.1, 121.1,117.9, 117.6, 114.6, 114.6, 114.0, 114.0, 108.1, 74.4, 69.0, 61.0, 56.2,55.7. HRESIMS m / z 553.2220 [M+H] + (calcd. for C 34 H 33 O7 + , 553.2221).

[0027] Example 3: Compound 3

[0028]

[0029] A pale yellow solid was obtained by following the preparation method in Example 1, with a yield of 92% and a mp value of 147.7–148.9 °C. 1HNMR (400 MHz, CDCl3) δ 8.04 (dt, J = 8.0, 1.6 Hz, 1H), 7.92 (dt, J = 8.0, 1.6Hz, 1H), 7.57–7.49 (overlapped, 5H), 7.36 (td, J = 8.0, 1.6 Hz, 1H), 7.28 (d,J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.12 (m, 1H), 5.79(m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.5, 1.4 Hz, 1H),5.15 (dq, J = 17.2, 1.6 Hz, 1H), 5.09 (dq, J = 10.5, 1.4 Hz, 1H), 4.61 (dt, J= 5.5, 1.5 Hz, 2H), 4.32 (dt, J = 5.5, 1.5 Hz, 2H), 3.76 (s, 3H), 3.63 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 164.1 (d, 1 J C-F = 245.1 Hz), 164.0, 161.5,158.2, 153.1, 150.9, 149.8, 145.1, 135.0, 134.1, 133.4, 132.2, 132.2, 132.0(d, 3 J C-F = 7.4 Hz), 131.9, 130.9, 130.4, 130.4, 130.4 (d, 3 J C-F = 7.4 Hz),126.0(d, 4 J C-F = 2.9 Hz), 123.9, 120.8, 120.8, 117.9, 117.6, 117.2 (d, 2 J C-F = 23.2Hz), 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 541.2020 [M+H] + (calcd. for C 33 H30 O6F + , 541.2021).

[0030] Example 4: Compound 4

[0031]

[0032] A white solid was obtained by following the preparation method in Example 1, with a yield of 95% and a mp value of 145.9–147.2 °C. 1 H NMR (400 MHz, CDCl3) δ 8.14 (td, J = 7.6, 2.0 Hz, 1H), 7.62 (m, 1H), 7.55 (d, J =8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.25 (m,2H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.12 (m, 1H), 5.79 (m, 1H), 5.47(dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.17 (dq, J =17.2, 1.6 Hz, 1H), 5.08 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.6Hz, 2H), 4.31 (dt, J = 5.4, 1.6 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.7, 162.8 (d, 1 J C-F = 245.1 Hz), 161.2, 158.2, 153.1,150.9, 149.7, 145.1, 135.3 (d, 3 J C-F = 8.0 Hz), 134.9, 134.1, 133.4, 132.6,132.1, 132.1, 131.8, 130.9, 130.3, 130.3, 124.3 (d, 4 J C-F = 4.0 Hz), 123.9,120.9, 120.9, 117.9, 117.6, 117.4 (d, 2 JC-F = 22.3 Hz), 114.6, 114.6, 108.1,74.4, 69.0, 61.0, 56.2. HRESIMS m / z 541.2021 [M+H] + (calcd. for C 33 H 30 O6F + ,541.2021).

[0033] Example 5: Compound 5

[0034]

[0035] A white solid was obtained by following the preparation method in Example 1, with a yield of 91% and a mp value of 166.8–168.3 °C. 1 H NMR (400 MHz, CDCl3) δ 8.28–8.23 (2H, overlapped), 7.54 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.23–7.17 (2H, overlapped),7.01 (2H, d, J = 8.8 Hz), 6.70 (1H, s), 6.11 (1H, m), 5.79 (1H, m), 5.46 (1H,dq, J = 17.2, 1.6 Hz), 5.33 (1H, dq, J = 10.4, 1.6 Hz), 5.14 (1H, dq, J =17.2, 1.6 Hz), 5.08 (1H, dq, J = 10.4, 1.6 Hz), 4.61 (2H, dt, J = 5.6, 1.5Hz), 4.31 (2H, dt, J = 5.6, 1.5 Hz), 3.75 (3H, s), 3.62 (3H, s); 13 C NMR (100MHz, CDCl3) δ 167.5, 165.0, 164.3, 158.2, 153.1, 150.9, 149.9, 145.1, 135.0,134.1, 133.4, 132.9 (d, 3 J C-F = 7.9 Hz), 132.9 (d, 3 J C-F= 7.9 Hz), 132.2,132.2, 131.8, 131.0, 130.4, 130.4, 126.1 (d, 4 J C-F = 3.2 Hz), 123.9, 120.9,120.9, 117.9, 117.6, 115.9 (d, 2 J C-F = 22.1 Hz), 114.6, 114.6, 108.2, 74.4,69.0, 61.0, 56.2; HRESIMS m / z 541.2029 [M+H] + (calcd. for C 33 H 30 O6F + ,541.2021).

[0036] Example 6: Compound 6

[0037]

[0038] A white solid was obtained by following the preparation method of Example 1, with a yield of 91% and a mp value of 149.3–150.8 °C. 1 H NMR(400 MHz, CDCl3) δ 8.22 (t, J = 1.6 Hz, 1H), 8.12 (dt, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.51–7.46 (overlapped,3H), 7.27 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.11(m, 1H), 5.78 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4,1.6 Hz, 1H), 5.14 (dq, J = 17.2, 1.6 Hz, 1H), 5.08 (dt, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.6, 1.6 Hz, 2H), 4.30 (dt, J = 5.6, 1.6 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.1, 158.2, 153.1, 150.9,149.8, 145.1, 135.0, 134.9, 134.1, 133.7, 133.4, 132.2, 132.2, 131.9, 131.7,130.9, 130.4, 130.4, 130.3, 130.0, 128.4, 123.9, 120.8, 120.8, 117.9, 117.6,114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 557.1722 [M+H] + (calcd. for C 33 H 30 O6Cl + , 557.1725).

[0039] Example 7: Compound 7

[0040]

[0041] A white solid was obtained by following the preparation method in Example 1, with a yield of 90% and a mp of 168.2–169.7 °C. 1 H NMR(400 MHz, CDCl3) δ 7.81 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.47(d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.84(s, 2H), 6.70 (s, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.11 (m, 1H), 5.78 (m, 1H),5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J= 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.4, 1.5Hz, 2H), 4.29 (dt, J = 5.4, 1.5 Hz, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 3.74 (s,3H), 3.62 (s, 3H).13 C NMR (100 MHz, CDCl3) δ 165.4, 158.2, 153.6, 153.6,153.1, 150.9, 149.9, 146.5, 145.1, 140.6, 134.9, 134.1, 133.4, 132.1, 132.1,131.5, 130.9, 130.3, 130.3, 129.8, 124.0, 120.8, 120.8, 117.89, 117.54,116.8, 114.6, 114.6, 108.1, 105.6, 105.6, 74.4, 69.0, 61.1, 61.0, 56.3, 56.3,56.2. HRESIMS m / z 639.2587 [M+H] + (calcd. for C 38 H 39 O9 + , 639.2589).

[0042] Example 8: Compound 8

[0043]

[0044] A white solid was obtained according to the preparation method of Example 1, with a yield of 92%. mp 127.7–128.9 ℃. 1 H NMR(400 MHz, CDCl3) δ 8.89 (s, 1H), 8.05 (d, J = 5.6 Hz, 2H), 7.54 (d, J = 8.8Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.30–7.26 (overlapped, 3H), 7.01 (d, J =8.8 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.46 (dq, J = 17.2,1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz,1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.31(dt, J = 5.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.0, 158.2, 154.1, 153.1, 151.6, 150.9, 149.6, 145.1, 137.7, 135.0, 134.1, 133.4, 132.3, 132.3, 132.1, 130.9, 130.4, 130.4, 125.9, 123.8,123.6, 120.8, 120.8, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0,56.2. HRESIMS m / z 524.2068 [M+H] + (calcd. for C 32 H 30 O6N + , 524.2068).

[0045] Example 9: Compound 9

[0046]

[0047] A pale yellow solid was obtained by following the preparation method in Example 1, with a yield of 95% and a mp value of 148.5–149.9 °C. 1 HNMR (400 MHz, CDCl3) δ 8.89 (s, 2H), 8.05 (d, J = 5.6 Hz, 2H), 7.54 (d, J =8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.01 (d, J =8.8 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.46 (q, J = 17.2, 1.6Hz, 1H), 5.32 (dq, J = 10.4, 1.4 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.4 Hz, 1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.31 (dt, J= 5.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ163.8, 158.2, 153.1, 150.9, 150.9, 149.5, 145.1, 137.2, 135.1, 134.1, 133.4,132.3, 132.3, 132.2, 130.9, 130.4, 130.4, 123.7, 123.4, 123.5, 123.5, 120.7,120.7, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z524.2068 [M + H] + (calcd. for C 32 H 30 O6N + , 524.2068).

[0048] Example 10: Compound 10

[0049]

[0050] A pale yellow solid was obtained by following the preparation method in Example 1, with a yield of 94% and a mp of 137.2–138.6 °C. 1 HNMR (400 MHz, CDCl3) δ 8.87 (d, J = 4.7, 1.8, 0.9 Hz, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.93 (td, J = 8.0, 1.8 Hz, 1H), 7.60–7.46 (m, 5H), 7.32 (d, J = 8.8Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.10 (m, 1H), 5.75 (m, 1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.32 (dd, J = 10.4, 1.6 Hz, 1H), 5.11 (dd, J = 17.2, 1.6 Hz, 1H), 5.06 (dd, J = 10.4, 1.6 Hz, 1H), 4.60 (d, J = 5.3 Hz, 2H), 4.28 (d, J = 5.3 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.9, 158.1, 153.1, 150.9, 150.2, 149.9, 147.8, 145.0, 137.3, 134.9, 134.0, 133.4, 132.2, 132.2, 131.9, 130.9, 130.3, 130.3, 127.5, 125.9,123.9, 120.9, 120.9, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0,56.2. HRESIMS m / z 524.2065 [M+H] + (calcd. for C 32 H 30 O6N + , 524.2068).

[0051] Example 11: Compound 11

[0052]

[0053] A white solid was obtained by following the preparation method in Example 1, with a yield of 96% and a mp value of 146.2–147.8 °C. 1 H NMR(400 MHz, CDCl3) δ 9.24 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.29(t, J = 2.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.29(d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H),5.79 (m, 1H), 5.47 (dd, J = 17.2, 1.6 Hz, 1H), 5.33 (dd, J = 10.4, 1.6 Hz,1H), 5.14 (dd, J = 17.2, 1.6 Hz, 1H), 5.08 (dd, J = 10.4, 1.6 Hz, 1H), 4.61(d, J = 5.2 Hz, 2H), 4.31 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.1, 158.1, 154.5, 153.0, 150.8,149.5, 148.7, 145.0, 137.9, 134.9, 134.0, 133.3, 133.3, 132.1, 132.1, 131.9,130.8, 130.3, 130.3, 125.3, 123.7, 120.7, 120.7, 117.8, 117.5, 114.5, 114.5,108.0, 74.3, 68.9, 60.9, 56.1, 18.4. HRESIMS m / z 538.2222 [M+H] + (calcd. forC 33 H 32 O6N + , 538.2224).

[0054] Example 12: Compound 12

[0055]

[0056] A white solid was obtained by following the preparation method of Example 1, with a yield of 92% and a mp of 121.5–122.7 °C. 1 H NMR(400 MHz, CDCl3) δ 9.26 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.18 (dt, J = 8.0,2.8 Hz, 1H), 7.56–7.50 (overlapped, 4H), 7.29 (d, J = 8.8 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2,1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz,1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5 Hz, 2H), 4.32(dt, J = 5.4, 1.5 Hz, 2H), 3.76 (s, 3H), 3.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.8 (d,1 J C-F = 258.5 Hz), 160.5, 158.2, 153.0, 150.8, 149.4, 147.2(d, 3 J C-F = 4.3 Hz), 145.0, 142.8 (d, 2 J C-F = 23.2 Hz), 135.1, 134.1, 133.4,132.3, 132.3, 132.3, 130.9, 130.3, 130.3, 127.3 (d, 3 J C-F = 3.6 Hz), 124.2 (d, 2 J C-F = 19.6 Hz), 123.7, 120.6, 120.6, 117.9, 117.5, 114.6, 114.6, 108.1,74.4, 69.0, 61.0, 56.2. HRESIMS m / z 542.1985 [M+H] + (calcd. for C 32 H 29 O6NF + ,542.1973).

[0057] Example 13: Compound 13

[0058]

[0059] A white solid was obtained according to the preparation method of Example 1, with a yield of 92% and a mp of 112.1–1113.5 °C. 1HNMR (400 MHz, CDCl3) δ 9.50 (1H, d, J = 1.2 Hz), 8.86–8.83 (2H, overlapped), 7.54 (2H, d, J = 8.8, Hz), 7.51 (2H, d, J = 8.8, Hz), 7.34 (2H, d, J = 8.8,Hz), 7.00 (2H, d, J = 8.8, Hz), 6.70 (1H, s), 6.11 (1H, m), 5.75 (1H, m),5.46 (1H, dq, J = 17.2, 1.6 Hz), 5.32 (1H, dq, J = 10.5, 1.6 Hz), 5.12 (1H,dq, J = 17.2, 1.6 Hz), 5.06 (1H, dq, J = 10.5, 1.6 Hz), 4.61 (2H, dt, J =5.2, 1.6 Hz), 4.29 (2H, dt, J = 5.2, 1.6 Hz), 3.75 (3H, s), 3.62 (3H, s); 13 CNMR (100 MHz, CDCl3) δ 162.6, 158.2, 153.1, 150.9, 149.5, 148.2, 146.9,145.1, 144.8, 143.3, 135.1, 134.0, 133.4, 132.4, HRESIMS m / z 525.2029 [M + H] + (calcd. for C 31 H 29 O6N2 + , 525.2020).

[0060] Example 14: Compound 14

[0061]

[0062] A white solid was obtained according to the preparation method of Example 1, with a yield of 95%. mp 162.3–163.8 ℃. 11H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.4 Hz, 1H), 8.65 (dd, J = 5.2, 1.6 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H), 7.88 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 16.0 Hz, 1H), 6.70 (s, 1H), 6.11 (m, 1H), 5.77 (m, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.2, 1.6 Hz, 2H), 4.29 (dt, J = 5.2, 1.6 Hz, 2H), 3.74 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 164.8, 158.2, 153.1, 151.5, 150.9, 150.0, 149.7, 145.1, 142.8, 134.9, 134.5, 134.1, 133.4, 132.1, 132.1, 131.7, 130.9, 130.4, 130.4, 130.2, 124.0, 123.9, 120.8, 120.8, 119.9, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 550.2222 [M+H] + (calcd. for C 34 H 32 O6N + , 550.2224).

[0063] Example 15: Compound 15

[0064]

[0065] A white solid was obtained by following the preparation method of Example 1, with a yield of 91% and a mp of 190.1–191.6 °C. 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.6 Hz, 2H), 7.81 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.49–7.45 (overlapped, 4H), 7.23 (d, J = 8.8 Hz, 2H),7.01 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 16.0 Hz, 1H), 6.70 (s, 1H), 6.11 (m,1H), 5.77 (m, 1H), 5.46 (d, J = 17.2 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 5.12(d, J = 17.2, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 4.30(d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ164.5, 158.2, 153.1, 150.9, 150.8, 150.8, 149.6, 145.1, 143.5, 141.6, 135.0,134.1, 133.4, 132.2, 132.2, 131.9, 130.9, 130.4, 130.4, 123.9, 122.5, 122.1,122.1, 120.7, 120.7, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0,56.2. HRESIMS m / z 550.2224 [M+H] + (calcd. for C 34 H 32 O6N + , 550.2224).

[0066] Example 16: Compound 16

[0067]

[0068] A pale yellow solid was obtained by following the preparation method in Example 1, with a yield of 95%; mp 143.5–144.9 ℃. 1 HNMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 16.0 Hz, 1H), 7.76 (td, J = 7.6, 1.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 7.6, 4.8 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 7.17 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.69 (s,1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.46 (dd, J = 17.2, 1.6 Hz, 1H), 5.32 (dd, J= 10.4, 1.6 Hz, 1H), 5.13 (dd, J = 17.2, 1.6 Hz, 1H), 5.07 (dd, J = 10.4, 1.6Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.74 (s, 3H), 3.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.2, 158.2, 153.1, 152.9, 150.9,150.4, 149.9, 145.1, 145.1, 137.0, 137.0, 134.9, 134.1, 133.4, 132.1, 132.1,131.6, 131.0, 130.4, 130.4, 124.7, 124.7, 124.0, 121.9, 120.8, 117.9, 117.6,114.6, 114.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 550.2225 [M+H] + (calcd. for C 34 H 32 O6N + , 550.2224).

[0069] Example 17: Compound 17

[0070]

[0071] A pale yellow solid was obtained by following the preparation method in Example 1, with a yield of 96% and a mp of 113.9–115.3 °C. 1 HNMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 4.8, 1.6 Hz, 1H), 7.63 (dt, J = 7.6, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.42 (d, J =8.8 Hz, 2H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.00(d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.10 (m, 1H), 5.74 (m, 1H), 5.46 (dq, J =17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.11 (dq, J = 10.4, 1.6Hz, 1H), 5.05 (dq, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.4, ​​1.5 Hz, 2H), 4.27 (dt, J = 5.4, 1.5 Hz, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 3.11 (t, J = 7.6Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 170.9, 158.2,153.1, 150.9, 150.0, 149.6, 148.1, 145.0, 136.2, 135.7, 134.9, 134.1, 133.4,132.1, 132.1, 131.7, 130.9, 130.3, 130.3, 123.9, 123.6, 120.7, 120.7, 117.9,117.5, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2, 35.7, 28.2. HRESIMS m / z552.2375 [M+H] +(calcd. for C 34 H 34 O6N + , 552.2381).

[0072] Example 18: Compound 18

[0073]

[0074] A white solid was obtained by following the preparation method of Example 1, with a yield of 92% and a mp of 103.2–104.6 °C. 1 H NMR(400 MHz, CDCl3) δ 8.58 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 4.8, 2.0 Hz, 1H), 7.62 (dt, J = 8.0, 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8Hz, 2H), 7.27 (dd, J = 7.6, 4.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.00 (d, J= 8.8 Hz, 2H), 6.68 (s, 1H), 6.10 (m, 1H), 5.75 (m, 1H), 5.46 (dq, J = 17.2,1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.10 (dq, J = 17.2, 1.6 Hz, 1H), 5.05 (dq, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.2, 1.5 Hz, 2H), 4.27(dt, J = 5.2, 1.5 Hz, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 3.11 (t, J = 7.6 Hz,2H), 2.93 (t, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 170.9, 158.1, 153.0,150.0, 149.9, 149.5, 148.0, 145.0, 136.2, 135.7, 134.9, 134.0, 133.4, 132.0,132.0, 131.7, 130.9, 130.3, 130.3, 123.8, 123.6, 120.6, 120.6, 117.8, 117.5,114.6, 114.6, 108.1, 74.3, 68.9, 60.9, 56.1, 35.6, 28.2. HRESIMS m / z 552.2377[M+H] + (calcd. for C 34 H 34 O6N + , 552.2381).

[0075] Example 19: Compound 19

[0076]

[0077] A white solid was obtained by following the preparation method of Example 1, with a yield of 94% and a mp value of 137.4–138.8 °C. 1 H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 1.8, 0.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 3.6, 0.8 Hz, 1H), 7.28 (d, J = 8.8Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.61 (dd, J = 3.6, 1.8 Hz,1H), 6.11 (m, 1H), 5.77 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 4.29 (dt, J = 5.2, 1.6 Hz, 2H), 3.75(s, 3H), 3.62 (s, 3H).13 C NMR (100 MHz, CDCl3) δ 158.1, 157.0, 153.1, 150.9,149.3, 147.2, 145.0, 144.3, 134.9, 134.1, 133.4, 132.1, 132.1, 131.8, HRESIMS m / z 513.1905 [M+H] + (calcd. for C 31 H 29 O7 + , 513.1908).

[0078] Example 20: Compound 20

[0079]

[0080] A white solid was obtained by following the preparation method in Example 1, with a yield of 92% and a mp value of 126.3–127.7 °C. 1 H NMR(400 MHz, CDCl3) δ 8.22 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.0Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H), 6.70 (s, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5Hz, 2H), 4.30 (dt, J = 5.4, 1.5 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13C NMR(100 MHz, CDCl3) δ 161.5, 158.1, 153.1, 150.9, 149.5, 148.8, 145.0, 144.2,134.9, 134.1, 133.4, 132.1, 132.1, 131.6, HRESIMS m / z 513.1902 [M+H] + (calcd. for C 31 H 29 O7 + , 513.1908).

[0081] Example 21: Compound 21

[0082]

[0083] A white solid was obtained by following the preparation method in Example 1, with a yield of 95% and a mp of 148.7–149.9 °C. 1 H NMR(400 MHz, CDCl3) δ 8.34 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 5.2 Hz, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 5.2, 3.2Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.01 (2H, d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.11(m, 1H), 5.79 (m, 1H), 5.46 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 5.14 (d, J = 17.2 Hz, 1H), 5.07 (d, J = 10.4 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 4.30 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.1, 158.2, 153.1, 150.9, 149.8, 145.1, 134.9, 134.1, 134.1,133.4, 133.2, 132.1, 132.1, 131.6, HRESIMS m / z 529.1678 [M+H] + (calcd. for C 31 H 29 O6S + , 529.1679).

[0084] Example 22: Compound 22

[0085]

[0086] A white solid was obtained by following the preparation method of Example 1, with a yield of 91% and a mp value of 144.1–144.7 °C. 11H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 3.6, 1.2 Hz, 1H), 7.68 (dd, J = 4.8, 1.2 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.29 (dd, J = 8.8 Hz, 2H), 7.20 (dd, J = 4.8, 3.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.5, 1.6 Hz, 1H), 5.14 (dq, J = 17.2, 1.6 Hz, 1H), 5.08 (dq, J = 10.5, 1.6 Hz, 1H), 4.61 (dt, J = 5.6, 1.6 Hz, 1H), 4.31 (dt, J = 5.6, 1.6 Hz, 1H), 3.75 (s, 3H), 3.63 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 160.7, 158.1, 153.1, 150.9, 149.6, 145.0, 134.9, 134.7, 134.1, 133.5, 133.4, 133.2, 132.1, 132.1, 131.7, 130.9, 130.3, 130.3, 128.1, 123.9, 120.9, 120.9, 117.9, 117.6, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 529.1680 [M+H] + (calcd. for C 31 H 29 O6S + , 529.1679).

[0087] Example 23: Compound 23

[0088]

[0089] A white solid was obtained according to the preparation method of Example 1, with a yield of 96%. mp 94.2–95.7 ℃. 1 H NMR(400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.15(d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 6.11 (m, 1H), 5.75 (m, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.11 (dq, J = 17.2, 1.6 Hz, 1H), 5.05 (dq, J = 10.4, 1.6 Hz, 1H), 4.60(dt, J = 5.2, 1.6 Hz, 2H), 4.28 (dt, J = 5.2, 1.6 Hz, 2H), 4.14 (m, 2H), 3.99(m, 1H), 3.91 (m, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.38 (1H, m), 2.39 (1H,m), 2.28(1H, m). 13 C NMR (100 MHz, CDCl3) δ 172.4, 158.2, 153.1, 150.9, 149.6,145.0, 134.9, 134.1, 133.4, 132.1, 132.1, 131.7, 130.9, 130.3, HRESIMS m / z 517.2221 [M+H] + (calcd. for C 31 H 33 O7 + ,517.2221).

[0090] Example 24: Compound 24

[0091]

[0092] 3',6'-dimethoxy-[1,1':4',1''-terphenyl]-2',4,4''-triol (hereinafter referred to as "compound B") (30 mg, 0.088 mmol) was dissolved in acetone (2 mL). An ether reagent (2.5 eq) was added under K₂CO₃ catalysis. The reaction was stirred for 4 h in a 45°C water bath. TLC monitoring showed that compound B had completely reacted. The reaction was terminated, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give a white solid, yield 93%, mp 192.3–193.7 °C. 1 H NMR(400 MHz, acetone-d6) δ 8.32 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.21 (d, J =8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.75 (s,1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.57 (s, 3H), 3.56 (s, 3H); 13 C NMR (100 MHz, acetone-d6) δ 160.0, 157.2, 154.3, 152.9, 145.7, 135.0, 132.7, 132.7, 131.6,131.1, 131.1, 126.0, 125.3, 115.3, 115.3, 114.4, 114.4, 108.8, 60.8, 60.8,56.3, 55.6; HRESIMS m / z 367.1532 [M+H] + (calcd. for C 22 H 23 O5 + , 367.1540).

[0093] Example 25: Compound 25

[0094]

[0095] 4''-(allyloxy)-3',6'-dimethoxy-[1,1':4',1''-terphenyl]-2',4-diol (hereinafter referred to as "compound C") (30 mg, 0.079 mmol) was dissolved in acetone (2 mL). An ether reagent (2.5 eq) was added under K₂CO₃ catalysis. The reaction was stirred for 4 h in a 45 °C water bath. TLC monitoring was performed until compound C was completely reacted. The reaction was terminated, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to give a white solid in 81% yield. mp 144.7–145.9 °C. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.47 (s, 1H), 6.11(m, 1H), 5.95 (s, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4,1.6 Hz, 1H), 5.23 (s, 2H), 4.61 (dt, J = 7.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.51 (s, 3H), 3.45 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.3, 156.6, 153.6, 147.4,138.4, 133.4, 132.5, 132.0, 132.0, 130.7, 130.0, 130.0, 126.7, 118.0, 116.2,116.0, 116.0, 114.9, 114.9, 103.9, 94.6, 69.0, 60.9, 56.1, 56.1. HRESIMS m / z423.1801 [M+H] + (calcd. for C 25 H 27 O6 + , 423.1802).

[0096] Example 26: Compound 26

[0097]

[0098] A white solid was obtained according to the preparation method of Example 25, with a yield of 93%. mp 150.3–151.8 ℃. 1 H NMR(400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.00(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 6.10 (m, 1H),5.46 (dq, J = 17.3, 1.8 Hz, 1H), 5.33 (dq, J = 10.4, 1.8 Hz, 1H), 4.88 (s,1H), 4.80 (d, J = 17.6 Hz, 2H), 4.61 (d, J = 7.2 Hz, 2H), 4.15 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 1.53 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.1, 154.6,153.2, 151.0, 145.0, 142.0, 134.5, 133.4, 132.3, 132.3, 131.1, 130.4, 130.4,126.3, 124.4, 117.9, 114.8, 114.8, 114.6, 114.6, 113.0, 108.0, 73.3, 69.0,61.1, 56.2, 19.6. HRESIMS m / z 433.2010 [M+H] + (calcd. for C 27 H 29 O5 + , 433.2010).

[0099] Example 27: Compound 27

[0100]

[0101] A white solid was obtained according to the preparation method of Example 25, with a yield of 97%. mp 114.9–116.7 °C. 1HNMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 6.11 (m,1H), 5.46 (d, J = 17.2 Hz, 1H), 5.33(d, J = 10.4 Hz, 1H), 5.23 (t, J = 7.6Hz, 1H), 4.99 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.24 (d, J = 7.6 Hz, 2H),3.74 (s, 3H), 3.65 (s, 3H), 1.67 (s, 3H), 1.47 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.1, 154.7, 153.2, 150.9, 145.3, 138.6, 134.3, 133.4, 132.3, 132.3, 131.2, 130.4, 130.4, 126.5, 124.9, 120.4, 117.9, 114.8, 114.8, 114.6,114.6, 108.1, 69.7, 69.0, 61.0, 56.2, 25.9, 17.7. HRESIMS m / z 447.2167 [M+H] + (calcd. for C 28 H 31 O5 + , 447.2166).

[0102] Example 28: Compound 28

[0103]

[0104] A white solid was obtained according to the preparation method of Example 25, with a yield of 95%. mp 110.2–111.5 ℃. 1H NMR(400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.01(d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.71 (s, 1H), 6.10 (m, 1H),5.37 (s, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz,1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 3.91–3.81 (overlapped, 3H), 3.75 (s,3H), 3.58 (s, 3H), 3.45 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 158.3, 155.3,153.5, 150.6, 144.4, 134.6, 133.4, 132.1, 132.1, 130.6, 130.6, 130.3, 125.5,123.9, 118.0, 115.3, 115.3, 114.7, 114.7, 108.5, 74.7, 70.4, 69.0, 61.2,56.2, 44.7. HRESIMS m / z 435.1803 [M+H] + (calcd. for C 26 H 27 O6 + , 435.1802).

[0105] Example 29: Compound 29

[0106]

[0107] A white solid was obtained according to the preparation method of Example 25, with a yield of 91%. mp 120.5–122 °C. 1H NMR(400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.00(d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H),5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.04 (s,1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.49 (d, J = 2.4 Hz, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 2.38 (t, J = 2.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 158.2,154.8, 153.2, 149.7, 144.9, 134.5, 133.4, 132.3, 132.3, 130.8, 130.4, 130.4,125.8, 124.4, 117.9, 115.0, 115.0, 114.6, 114.6, 108.7, 79.3, 75.1, 69.0,61.0, 60.4, 56.3. HRESIMS m / z 417.1697 [M+H] + (calcd. for C 26 H 25 O5 + , 417.1697).

[0108] Example 30: Compound 30

[0109]

[0110] A white solid was obtained according to the preparation method of Example 25, with a yield of 94%. mp 184.5–185.8 ℃. 1H NMR(400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.00(d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.11 (m, 1H),5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.06 (s,1H), 4.61 (dt, J = 5.4, 1.6 Hz, 2H), 3.82 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.1,154.7, 153.2, 151.2, 145.2, 134.4, 133.4, 132.2, 132.2, 131.1, 130.4, 130.4,126.4, 124.6, 117.9, 114.8, 114.8, 114.6, 114.6, 108.0, 69.3, 69.0, 61.0,56.3, 15.7. HRESIMS m / z 407.1844 [M+H] + (calcd. for C 25 H 27 O5 + , 407.1853).

[0111] Example 31: Compound 31

[0112]

[0113] A colorless oil was obtained using the preparation method described in Example 25, with a yield of 97%. 1H NMR (400 MHz, CDCl3) δ7.55 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.25–7.22 (overlapped,3H), 7.10–7.07 (overlapped, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33(dq, J = 10.4, 1.6 Hz, 1H), 4.74 (s, 2H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.1, 155.3, 153.3,150.8, 145.3, 137.5, 134.5, 133.4, 132.3, 132.3, 131.1, 130.4, 130.4, HRESIMS m / z 469.2009 [M+H] + (calcd. for C 30 H 29 O5 + , 469.2010).

[0114] Example 32: Compound 32

[0115]

[0116] A white solid was obtained by following the preparation method of Example 25, with a yield of 90%. mp 157.1–158.9 °C. 1HNMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 3.74 (s, 3H), 3.70 (d, J = 6.74 Hz, 2H), 3.62 (s, 3H), 2.45 (m, 1H), 1.93–1.65 (overlapped, 4H), 1.56 (m, 2H). 13 CNMR (100 MHz, CDCl3) δ 158.1, 154.6, 153.2, 151.3, 145.2, 134.4, 133.4,132.3, 132.3, 131.2, 130.4, 130.4, 126.4, 124.6, 117.9, 114.7, 114.7, 114.6,114.6, 108.0, 76.8, 69.0, 61.0, 56.2, 35.4, 24.8, 24.8, 18.5. HRESIMS m / z447.2166 [M + H] + (calcd. for C 28 H 31 O5 + , 447.2166).

[0117] Example 33: Compound 33

[0118]

[0119] A white amorphous powder was obtained by referring to the preparation method of Example 26. 1H NMR (400 MHz, acetone-d6)δ ppm 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.78 (s, 1H), 5.25 (s, 2H), 4.86 (s, 2H), 3.74 (s, 3H), 3.55 (s, 3H), 3.47 (s, 3H), 3.00 (s, 3H). 13 C NMR (100 MHz, acetone-d6) δ 157.7 (C), 157.1 (C), 154.3 (C), 149.7 (C), 145.6 (C), 134.8,133.2 (CH×2), 132.8, 131.1 (CH×2), 126.0, 125.9, 116.8 (CH×2), 115.2 (CH×2), 109.1, 99.4 (CH2), 95.1 (CH2), 60.8 (CH3), 56.8 (CH3), 56.3 (CH3), 56.1(CH3). HR-ESI-MS m / z 425.1614 [M+H] + , (calcd for C 24 H 25 O7, 425.1595).

[0120] Example 34 HIF transcriptional repression activity test

[0121] (1) Cell model for activity testing: HCT 116 (human colon cancer cells) infected with lentiviral vector.

[0122] (2) Test Method: HCT116 cells were seeded into 24-well plates and cultured in DMEM containing 10% FBS for 24 h. After cell adhesion, VEGF 5×HRE-Firefly Luciferase plasmid and CMV-Renilla Luciferase plasmid were co-transfected into the cells using PEI transfection reagent. After plasmid expression for 24 h, the compound of this invention was added and the cells were treated under hypoxic conditions (1% O2) for 24 h. Subsequently, the cells were lysed using 1× cell lysis buffer, and a Dual-Luciferase experiment was performed using a dual-luciferase reporter assay kit to detect the effect of the compound on HIF transcriptional activity.

[0123] (3) Calculate the inhibition rate according to the following formula: Inhibition rate = (1 - Luciferase value of compound treatment group / Luciferase value of hypoxia control group) × 100%

[0124] Test results:

[0125] Table 1. Inhibitory effect of the compounds of this invention on HIF at 250 nM

[0126]

[0127] Note: In the table, "++++" indicates an inhibition rate ≥ 70%; "+++" indicates an inhibition rate of 40-69%; "++" indicates an inhibition rate of 20-39%; "+" indicates an inhibition rate of 5-19%; and "-" indicates an inhibition rate of less than 5%.

[0128] Note: This invention tested compound A in parallel. B () ), C ( (and compounds as controls)

[0129] Conclusion: Compared with compounds A, B and C, compound 1−33 of the present invention has stronger inhibitory activity against HIF transcription and can be used to treat tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases, and nervous system diseases.

[0130] It should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrated by way of example, but are not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added to the claims; all publications or patents cited in the present invention shall be used as references in the present invention.

Claims

1. A terphenyl compound, characterized in that, The compound is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially for use as an HIF inhibitor, characterized in that the compound has the following structure: R1 and R2 are independently and arbitrarily chosen as X represents H, D, amino, carboxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 C6H 13 Vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propynyl, butynyl, ethynylbutyryl, penynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2- Bromopropionyl, valeryl, hexanoyl, isobutenoyl, cyclopropyl, cyclopropionyl, cyclovaleryl, cyclohexanoyl, 3-pyridinecarboxyl, naphthyl, phenethylimidazolyl, pyridyl, pyrroleyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, piperidinyl, piperazine, indolyl, carbazole, benzofuranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidine base, purine base; R3 can be arbitrarily set to H, or Z1 may be selected from 1 to 5 substituents, wherein the substituents are H, D, F, Cl, Br, I, amino, N,N-dimethylamino, N-methylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 C6H 13 Vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propynyl, butynyl, ethynylbutyryl, penynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, isobutenyl, cyclopropyl, cyclopropionyl, cyclovaleryl, cyclohexanoyl, 3-pyridinecarboxyl, naphthyl, phenethylimidazolyl, pyridyl, pyrroleyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl; Z2 is independently selected from C 3-8 Cycloalkyl, substituted or unsubstituted C 3-6 Metaheterocyclic groups, substituted or unsubstituted C 5-6 Heteroaryl, heterocyclic alkyl, heterocyclic oxy, heterocyclic amino, heterocyclic alkoxy, heterocyclic alkylamino, azidoalkoxy, fused bicyclic, fused heterobicyclic, fused heteroaryl, fused bicyclic aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 Heterocyclic group, C 5-6 The heterocyclic aryl group may be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 cycloalkyl, 3-6 membered heterocyclic group, aryl or 5-6 membered heteroaryl group; L1, L2, and L3 can each be independently selected as a key, -C 1-6 Alkylene-, -vinyl-, -propenyl-, -allyl-, -n-butenyl-, -isobutenyl-, -n-pentenyl-, -isopentenyl-, -ethynyl-, -propynyl-, -propynyl-, -butynyl-, -butynyl-, -pentynyl-.

2. The compound according to claim 1, characterized in that, It has one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, with the specific structures as follows:

3. A drug capable of treating and / or preventing diseases related to hypoxia-inducible factor (HIF), characterized in that... It contains the compound of claim 1, wherein its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs are used as active ingredients.

4. The use of the drug of claim 2 in the treatment and / or prevention of hypoxia-inducible factor (HIF)-related diseases, wherein the diseases include those related to HIF such as tumor growth and metastasis, tumor drug resistance, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), diabetic nephropathy, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and neurological disease.

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