Preparation of terphenyl compound and effect of terphenyl compound as HIF inhibitor

Abstract

The invention relates to an application of a terphenyl compound as an HIF inhibitor, belongs to the field of medicinal chemistry, and particularly relates to a terphenyl compound which comprises a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, solvate, metabolite and ester of the terphenyl compound. The pharmaceutically acceptable salt or the prodrug thereof and the pharmaceutical composition containing the compound are used as medicines, especially used for treating and / or preventing related diseases caused by HIF.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a terphenyl compound, a composition and an application, wherein the compound or the composition has the activity of being a hypoxia-inducible factor (HIF) inhibitor and can be used for treating HIF-related diseases. Background Art

[0002] Hypoxia-inducible factor (HIF) is a nuclear protein with transcriptional activity, which plays a key role in the process of cell adaptation to the hypoxic environment. It is a heterodimer composed of HIF-1α and HIF-1β subunits. Under normal oxygen partial pressure, the HIF-α subunit will be hydroxylated by prolyl hydroxylase (PHD) and then rapidly degraded by the ubiquitin-proteasome pathway (Bruick, R. K. Science. 2001, 294: 1337-1340; Kamura, T. Proc. Natl. Acad. Sci. U.S.A. 2000, 97: 10430-10435). However, under hypoxic conditions, the activity of PHD is inhibited, the HIF-α subunit is stabilized and binds to the HIF-1β subunit to form an active HIF transcription factor, which 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, matrix metalloproteinases (MMPs), etc. (Semenza, G. L. Trends Pharmacol. Sci. 2012, 33: 207-214; Wigerup, C. Pharmacol. Ther. 2016, 164: 152-169). These gene products play a crucial role in improving hypoxia, promoting angiogenesis, regulating energy metabolism, etc.

[0003] HIF is associated with a variety of diseases, and the abnormal activation or inactivation of HIF is closely related to the occurrence and development of many diseases. In tumor diseases, in order to adapt to the hypoxic environment caused by rapid proliferation, tumor cells will activate the HIF signaling pathway (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 enhancing their invasion and metastasis abilities. For example, in various solid tumors such as breast cancer, liver cancer, and lung cancer, high expression of HIF-1α has been found to be associated with poor prognosis of tumors (Moon, E. J. Antioxid. Redox Signaling. 2007, 9: 1237-1294; Chen, C. OncoTarget. 2017, 8: 46691-46703; Kim, B. J. Transl. Med. 2013, 11: 185). Therefore, HIF-1 is considered a promising target for developing new anti-cancer metastasis therapies. In addition, in ischemic diseases such as myocardial ischemia and cerebral ischemia, moderate activation of the HIF pathway can promote angiogenesis and tissue repair, with potential therapeutic value (Zimna, A. BioMed Research 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 mainly come from fungi and actinomycetes and mainly exist in the form of p-terphenyls in nature. The structural feature of terphenyl is composed of a central benzene ring B and two phenyl groups (ring A and C) substituted at the para position of benzene ring B. So far, more than 230 terphenyls have been identified, and the number is still increasing. This compound shows various biological activities such as anti-inflammatory, antibacterial, antioxidant, and α-glucosidase inhibitory effects (Zhou G. Marine Life Science & Technology. 2022, 4: 62–73), but it has not been reported to have the activity of inhibiting HIF, and there is no application of it in the preparation of drugs for preventing or treating HIF-mediated diseases. Summary of the Invention

[0005] The following only generally describes some aspects of the present invention and is not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there is a difference between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0006] The present invention provides a terphenyl compound for treating 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, non-alcoholic fatty liver disease (NAFLD), etc. The compounds of the present invention are easy to prepare, have stable properties and strong activities, and thus have good clinical application prospects.

[0007] Specifically:

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

[0009] Wherein R1 and R2 are each independently optionally X is 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, propargyl, butynyl, ethynylbutyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxypropyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, methacryloyl, cyclopropyl, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indolyl, carbazolyl, benzofuryl, tetrahydrofuran, tetrahydropyran, pyrimidine base, purine base;

[0010] R3 is optionally H, Wherein Z1 is optionally 1-5 substituents, and the substituents are H, D, F, Cl, Br, I, amino, N,N-dimethylamino, N-methylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H11 ,C6H 13 ,vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propargyl, butynyl, ethynylbutyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxypropyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, methacryloyl, cyclopropyl, cyclopropanoyl, cyclopentanoyl, cyclohexanoyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl; Z2 is independently optionally selected from C 3-8 cycloalkyl, substituted or unsubstituted C 3-6 -membered heterocyclic group, substituted or unsubstituted C 5-6 -membered heteroaryl, heterocycloalkyl, heterocyclic oxy, heterocyclic amino, heterocyclic alkoxy, heterocyclic alkanamino, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 heterocyclic group, C 5-6 heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxy, 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;

[0011] L1, L2, L3 are each independently optionally a bond, -C 1-6 alkylene-, -vinyl-, -propenyl-, -allyl-, -n-butenyl-, -isobutenyl-, -n-pentenyl-, -isopentenyl-, -ethynyl-, -propynyl-, -propargyl-, -butynyl-, -ethynylbutyl-, -pentynyl-.

[0012] The present invention relates to a compound characterized by having one of the following structures or its stereoisomers, geometric isomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or its prodrugs, and the specific structures are as follows:

[0013]

[0014] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound disclosed in the present invention. The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0015] The term "pharmaceutically acceptable salt" in the present invention refers to non-toxic addition salts of inorganic or organic acids and / or bases; see "Salt selection for basic drugs", International Journal of Pharmaceutics. 1986, 33, 201–217.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0017] The present invention discloses a terphenyl compound which can significantly reduce the reaction of HIF overexpression caused by hypoxia, and has good application prospects and commercial value.

[0018] The "HIF-related disease" refers to a series of diseases caused by the overexpression or abnormal regulation of hypoxia-inducible factor (HIF), which in turn leads to disorders of the body's physiological functions, including any disease in which a decrease in HIF levels will bring beneficial effects. HIF-related diseases include, but are not limited to, tumor growth and metastasis, tumor drug resistance, diabetic nephropathy, etc. Detailed implementation manners

[0019] The following specific examples are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0020] Example 1: Compound 1

[0021]

[0022] Dissolve 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) in dichloromethane (2 mL). Under the conditions of catalyst DMAP and dehydrating agent EDC, add an acid reagent (2.5 eq), and stir and react at 45 °C in a water bath for 4 h. Monitor by TLC plate. When Compound A has reacted completely, terminate the reaction. Extract with dichloromethane three times, combine the organic phases, and concentrate under reduced pressure to obtain a white solid with a yield of 91% and mp 125.3–126.9 °C. 11H 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 = 8.4 Hz, 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, 1.6 Hz, 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 13C 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 / z 553.2221 [M+H] + (calcd. for C 34 H 33 O7 + , 553.2221).

[0023] Example 2: Compound 2

[0024]

[0025] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 98%, mp 174.9–176.3 °C. 11H 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, 1.5 Hz, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 165.0, 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).

[0026] Example 3: Compound 3

[0027]

[0028] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 92%, mp 147.7–148.9 °C. 11H NMR (400 MHz, CDCl3) δ 8.04 (dt, J = 8.0, 1.6 Hz, 1H), 7.92 (dt, J = 8.0, 1.6 Hz, 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 13C 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 = 23.2 Hz), 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 H 30 O6F + , 541.2021).

[0029] Example 4: Compound 4

[0030]

[0031] A white solid was obtained according to the preparation method of Example 1, with a yield of 95% and mp 145.9–147.2 °C. 1 1H 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, 1.6 Hz, 2H), 4.31 (dt, J = 5.4, 1.6 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13 13C 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 J C-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).

[0032] Example 5: Compound 5

[0033]

[0034] A white solid was obtained according to the preparation method of Example 1, with a yield of 91% and mp 166.8–168.3 °C. 1 1H 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, 1.5 Hz), 4.31 (2H, dt, J = 5.6, 1.5 Hz), 3.75 (3H, s), 3.62 (3H, s); 13 13C NMR (100 MHz, 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).

[0035] Example 6: Compound 6

[0036]

[0037] A white solid was obtained according to the preparation method of Example 1, with a yield of 91% and mp 149.3–150.8 °C. 1 1H 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). 13 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).

[0038] Example 7: Compound 7

[0039]

[0040] A white solid was obtained according to the preparation method of Example 1, with a yield of 90% and mp 168.2–169.7 °C. 11H 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, 1.5 Hz, 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 13C 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).

[0041] Example 8: Compound 8

[0042]

[0043] A white solid was obtained according to the preparation method of Reference Example 1, with a yield of 92%. mp 127.7–128.9 °C. 11H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.05 (d, J = 5.6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.30–7.26 (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). 13 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).

[0044] Example 9: Compound 9

[0045]

[0046] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 95%, mp 148.5–149.9 °C. 11H NMR (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, 1.6 Hz, 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). 13 13C NMR (100 MHz, CDCl3) δ 163.8, 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 / z 524.2068 [M+H] + (calcd. for C 32 H 30 O6N + , 524.2068).

[0047] Example 10: Compound 10

[0048]

[0049] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 94%, mp 137.2–138.6 °C. 11H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 4.7, 1.8, 0.9 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.93 (td, J = 8.0, 1.8 Hz, 1H), 7.60–7.46 (m, 5H), 7.32 (d, J = 8.8 Hz, 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). 13 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).

[0050] Example 11: Compound 11

[0051]

[0052] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 96%, mp 146.2–147.8 °C. 11H 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). 13 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. for C 33 H 32 O6N + , 538.2224).

[0053] Example 12: Compound 12

[0054]

[0055] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 92%, mp 121.5–122.7 °C. 11H 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 13C 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).

[0056] Example 13: Compound 13

[0057]

[0058] A white solid was obtained according to the preparation method of Example 1, with a yield of 92%, m.p. 112.1–113.5 °C,1 1H NMR (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 13C NMR (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, 132.3, 132.3, 130.9, 130.4, 130.4, 123.8, 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 525.2029 [M + H] + (calcd. for C 31 H 29 O6N2 + , 525.2020).

[0059] Example 14: Compound 14

[0060]

[0061] A white solid was obtained according to the preparation method of Example 1, with a yield of 95%. mp 162.3–163.8 °C. 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).

[0062] Example 15: Compound 15

[0063]

[0064] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 91%, mp 190.1–191.6 °C. 11H 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 13C NMR (100 MHz, CDCl3) δ 164.5, 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).

[0065] Example 16: Compound 16

[0066]

[0067] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 95%; mp 143.5–144.9 °C. 11H NMR (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 = 8.0 Hz, 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, 1.6 Hz, 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 13C 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).

[0068] Example 17: Compound 17

[0069]

[0070] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 96%, mp 113.9–115.3 °C. 11H NMR (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, 1.6 Hz, 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 = 7.6 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H). 13 13C 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 / z 552.2375 [M+H] + (calcd. for C 34 H 34 O6N + , 552.2381).

[0071] Example 18: Compound 18

[0072]

[0073] A white solid was obtained according to the preparation method of Example 1, with a yield of 92%, mp 103.2–104.6 °C. 11H 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 = 8.8 Hz, 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). 13 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).

[0074] Example 19: Compound 19

[0075]

[0076] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 94%, mp 137.4–138.8 °C. 11H 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 = 8.8 Hz, 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 (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), 4.29 (dt, J = 5.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C 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, 130.9, 130.3, 130.3, 123.9, 120.8, 120.8, 119.4, 117.9, 117.6, 114.6, 114.6, 112.3, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 513.1905 [M+H] + (calcd. for C 31 H 29 O7 + , 513.1908).

[0077] Example 20: Compound 20

[0078]

[0079] A white solid was obtained according to the preparation method of Reference Example 1, with a yield of 92%, mp 126.3–127.7 °C. 11H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 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, 1.5 Hz, 2H), 4.30 (dt, J = 5.4, 1.5 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13 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, 130.9, 130.3, 130.3, 123.9, 120.9, 120.9, 119.1, 117.9, 117.6, 114.6, 114.6, 110.2, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 513.1902 [M+H] + (calcd. for C 31 H 29 O7 + , 513.1908).

[0080] Example 21: Compound 21

[0081]

[0082] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 95%, mp 148.7–149.9 °C. 11H 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, 3.2 Hz, 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). 13 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, 131.0, 130.4, 130.4, 128.4, 126.5, 124.0, 121.0, 121.0, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 529.1678 [M+H] + (calcd. for C 31 H 29 O6S + , 529.1679).

[0083] Example 22: Compound 22

[0084]

[0085] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 91%, mp 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).

[0086] Example 23: Compound 23

[0087]

[0088] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 96%. mp 94.2–95.7 °C. 11H 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 13C 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, 130.3, 123.8, 120.6, 120.6, 117.9, 117.5, 114.6, 114.6, 108.1, 74.4, 70.5, 69.0, 68.50, 61.0, 56.2, 44.1, 29.8. HRESIMS m / z 517.2221 [M + H] + (calcd. for C 31 H 33 O7 + , 517.2221).

[0089] Example 24: Compound 24

[0090]

[0091] Dissolve 3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4,4”-triol (hereinafter referred to as “Compound B”) (30 mg, 0.088 mmol) in acetone (2 mL). Under the condition of catalyst K2CO3, add the ether reagent (2.5 eq). Under the condition of a 45 °C water bath, stir and react for 4 h. Monitor by TLC plate. After Compound B has reacted completely, terminate the reaction. Extract with ethyl acetate three times. Combine the organic phases and concentrate under reduced pressure to obtain a white solid, with a yield of 93%, m.p. 192.3–193.7 °C, 11H 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 13C 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).

[0092] Example 25: Compound 25

[0093]

[0094] Dissolve 4"-(allyloxy)-3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4-diol (hereinafter referred to as "Compound C") (30 mg, 0.079 mmol) in acetone (2 mL). Under the condition of catalyst K2CO3, add an ether reagent (2.5 eq). Under the condition of a 45 °C water bath, stir and react for 4 h. Monitor by TLC plate. After Compound C has reacted completely, terminate the reaction. Extract with ethyl acetate three times. Combine the organic phases and concentrate under reduced pressure to obtain a white solid with a yield of 81%. mp 144.7–145.9 °C. 11H 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 13C 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 / z 423.1801 [M + H] + (calcd. for C 25 H 27 O6 + , 423.1802).

[0095] Example 26: Compound 26

[0096]

[0097] A white solid was obtained according to the preparation method of Reference Example 25, with a yield of 93%. mp 150.3–151.8 °C. 1 1H 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). 1313C 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).

[0098] Example 27: Compound 27

[0099]

[0100] A white solid was obtained by referring to the preparation method of Example 25, with a yield of 97%. mp 114.9–116.7 °C. 1 1H NMR (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 = 7.6 Hz, 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 13C 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).

[0101] Example 28: Compound 28

[0102]

[0103] A white solid was obtained according to the preparation method of Reference Example 25, with a yield of 95%. mp 110.2–111.5 °C. 1 H NMR(400MHz,CDCl3)δ7.53(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),6.71(s,1H),6.10(m,1H),5.37(s,1H),5.46(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),4.61(dt,J=5.2,1.6Hz,2H),3.91–3.81(overlapped,3H),3.75(s,3H),3.58(s,3H),3.45(m,2H). 13 C NMR(100MHz,CDCl3)δ158.3,155.3,153.5,150.6,144.4,134.6,133.4,132.1,132.1,130.6,130.6,130.3,125.5,123.9,118.0,115.3,115.3,114.7,114.7,108.5,74.7,70.4,69.0,61.2,56.2,44.7.HRESIMS m / z435.1803[M+H] + (calcd.for C 26 H 27 O6 + ,435.1802).

[0104] Example 29: Compound 29

[0105]

[0106] A white solid was obtained according to the preparation method of Reference Example 25, with a yield of 91%. mp 120.5–122 °C. 11H 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 13C 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).

[0107] Example 30: Compound 30

[0108]

[0109] A white solid was obtained by referring to the preparation method of Example 25, with a yield of 94%. mp 184.5–185.8 °C. 1 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). 1313C 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).

[0110] Example 31: Compound 31

[0111]

[0112] Obtained as a colorless oil according to the preparation method of Reference Example 25, with a yield of 97%. 1 1H NMR (400 MHz, CDCl3) δ 7.55 (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 = 8.8 Hz, 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 13C 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, 130.4, 128.6, 128.6, 128.3, 128.3, 127.9, 125.9, 124.9, 117.9, 115.0, 114.6, 114.6, 108.4, 75.2, 69.0, 61.2, 56.3. HRESIMS m / z 469.2009 [M+H] + (calcd. for C 30 H 29 O5 + , 469.2010).

[0113] Example 32: Compound 32

[0114]

[0115] A white solid was obtained according to the preparation method of Reference Example 25, with a yield of 90%. mp 157.1–158.9 °C. 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), 6.67 (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), 4.91 (s, 1H), 4.60 (dt, J = 5.2, 1.6 Hz, 2H), 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 C NMR (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 / z 447.2166 [M+H] + (calcd. for C 28 H 31 O5 + , 447.2166).

[0116] Example 33: Compound 33

[0117]

[0118] A white amorphous powder was obtained according to the preparation method of Reference Example 26. 11H 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 = 8.8 Hz, 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 13C 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).

[0119] Example 34 HIF Transcription Inhibition Activity Test

[0120] (1) Active test cell model: HCT 116 (human colon cancer cells) infected with lentiviral vector.

[0121] (2) Test method: Seed HCT116 cells into 24-well plates and culture them in DMEM containing 10% FBS for 24 h. After the cells adhere, co-transfect the VEGF 5×HRE-Firefly Luciferase plasmid and the CMV-Renilla Luciferase plasmid into the cells using the transfection reagent PEI. After 24 h of plasmid expression, add the compound of the present invention and treat the cells under hypoxic conditions (1% O2) for 24 h. Subsequently, lyse the cells using 1× cell lysis buffer and perform the Dual-Luciferase experiment using the Dual-Luciferase Reporter Assay Kit to detect the effect of the compound on HIF transcriptional activity.

[0122] (3) Calculate the inhibition rate according to the following formula: Inhibition rate = (1 - Luciferase value of the compound treatment group / Luciferase value of the hypoxic control group) × 100%

[0123] Test results:

[0124] Table 1 Inhibitory effect of the compounds of the present invention on HIF at 250 nM

[0125]

[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%; "-" indicates an inhibition rate < 5%.

[0128] Note: The compounds of the present invention were tested in parallel and the compounds as controls.

[0129] Conclusion: Compared with compounds A, B, and C, the compounds 1 - 33 of the present invention have stronger inhibitory HIF transcriptional activity and can be used to treat diseases 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 diseases, and neurological diseases.

[0130] It should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrative, but 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 in the claims; all publications or patents cited in the present invention will be used as references for the present invention.

Claims

1. A terphenyl compound, characterized in that, It is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially for use as a HIF inhibitor, characterized in that the compound has the following structure: wherein R1 and R2 are each independently optionally X is 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, propargyl, butynyl, butynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoyl, methacryloyl, cyclopropyl, cyclopropanoyl, cyclopentanoyl, cyclohexanoyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indolyl, carbazolyl, benzofuranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidine base, purine base; R3 is optionally H, wherein Z1 is optionally 1 to 5 substituents selected from 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, propargyl, butynyl, butynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, methacryloyl, cyclopropyl, cyclopropanoyl, cyclopentanoyl, cyclohexanoyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl; Z2 is independently optionally selected from C 3-8 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-6 heteroaryl group, heterocycloalkyl, heterocyclic oxy group, heterocyclic amino group, heterocyclic alkoxy group, heterocyclic alkylamino group, azidoalkoxy group, fused bicyclic group, fused heterobicyclic group, fused heteroaryl group, fused bicyclic aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 heterocyclic group, C 5-6 heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxy, 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; L1, L2, and L3 are each independently optionally a bond, -C 1-6 alkylene-, -vinyl-, -propenyl-, -allyl-, -n-butenyl-, -isobutenyl-, -n-pentenyl-, -isopentenyl-, -ethynyl-, -propargyl-, -propynyl-, -butynyl-, -butynyl-, -pentynyl.

2. The compound according to claim 1, wherein It has one of the following structures or its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the specific structure is as follows:

3. A drug capable of treating and / or preventing diseases associated with hypoxia-inducible factor (HIF), characterized in that It contains the compound described in claim 1, its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof as an active ingredient.

4. Use of the drug described in claim 2 in the treatment and / or prevention of diseases caused by hypoxia-inducible factor (HIF), and the diseases include those HIF-related diseases 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 diseases, and nervous system diseases.

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