Benzofuran terphenyl HIF inhibitor as well as preparation method and application thereof

Abstract

The invention relates to application of a benzofuran terphenyl compound in medicines, 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 benzofuran terphenyl compound, a composition and an application thereof. 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, tumor cells activate the HIF signaling pathway in order 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 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. Additionally, 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). There are also research reports on HIF-1 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 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 exhibits various biological activities, such as anti - inflammatory, antibacterial, antioxidant, and α - glucosidase inhibitory effects (Zhou G. Marine Life Science & Technology. 2022, 4: 62–73). Chen et al. reported that the benzofuran terphenyl compound candidusin A found from the marine compound library is a potent AMPK activator and can be used as a new potential candidate for the treatment of non - alcoholic steatohepatitis (NASH) (Chen J. Marine Life Science & Technology. 2023, 5: 196), but this type of compound has not been reported to have the activity of inhibiting HIF transcription, and there is no application of it in the preparation of drugs for preventing or treating HIF - mediated diseases. Summary of the Invention

[0005] Only some aspects of the present invention are generally described below and are 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 benzofuran terphenyl compound for treating diseases related to HIF overexpression, 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 have stable properties and strong activities, so they have good clinical application prospects.

[0007] Specifically:

[0008] On the one hand, the present invention relates to a benzofuran 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 of the compound represented by formula (I), especially for use as an HIF inhibitor, characterized in that the compound has the following structure:

[0009] Wherein R1 and R2 are each independently optionally methyl, ethyl, and CD3; R3 is each independently optionally wherein 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, but-2-ynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxypropyl, 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, benzofuryl, tetrahydrofuryl, tetrahydropyranyl, pyrimidine base, purine base; Z1 is optionally 1-5 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, but-2-ynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxypropyl, 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; Z2 is independently optionally selected from 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, but-2-ynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxypropyl, 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, C1-8 Alkyl, C 3-8 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocyclic group, substituted or unsubstituted C 5-6 Heteroaryl, heterocycloalkyl, heterocyclic group - oxy, heterocyclic group - amino, heterocyclic group - alkoxy, heterocyclic group - alkylamino, azido - alkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic group aliphatic substituent, biaryl, teraryl, fused biaryl, fused teraryl, 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, hydroxyl, amino, cyano, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3 - 6 membered heterocyclic group, aryl or 5 - 6 membered heteroaryl substituent;

[0010] 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 -, - butynyl -, - pentynyl -;

[0011] When R1 and R2 are both methyl, R3 cannot be H.

[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 a non - toxic addition salt of an inorganic or organic acid and / or base; 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:

[0017] The present invention discloses the application of a benzofuran terphenyl compound as an HIF inhibitor, which has good application prospects and commercial value.

[0018] The "HIF-related diseases" refer 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 diseases 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. Specific Embodiments

[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 7-(4-hydroxyphenyl)-6,9-dimethoxydibenzo[b,d]furan-2,3-diol (hereinafter referred to as "Compound A") (30 mg, 0.085 mmol) in deuterated acetone (2 mL). Under the condition of an appropriate amount of catalyst phosphorus pentoxide and in a 50 °C water bath, stir and react for 4 h. Monitor by TLC plate. When Compound A has reacted completely, terminate the reaction. Extract with dichloromethane 3 times, combine the organic phases, and concentrate under reduced pressure to obtain Compound 1. 1 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.01 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 5.04 (s, 1H), 3.99 (s, 3H), 3.85 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 155.0, 151.1, 150.2, 149.5, 147.3, 144.4, 136.7, 131.3, 130.9, 130.9, 130.8, 118.8, 116.0, 115.3, 115.3, 115.3, 105.7, 101.4, 93.7, 61.2, 56.0, 25.9, 25.9. ESIMS m / z 399.17.

[0023] Example 2: Compound 2

[0024]

[0025] Dissolve 4-(6,9-dimethoxy-2,2-dimethylbenzo[b][1,3]dioxolo[4,5-f]benzofuran-7-yl)phenol (hereinafter referred to as "Compound B") (30 mg, 0.076 mmol) in dichloromethane (2 mL). Under the conditions of catalyst DMAP and dehydrating agent EDC, add an acid reagent (2.5 eq). Under the condition of a 45 °C water bath, stir and react 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 Compound 2. 1 H NMR (400 MHz, Acetone-d6) δ 9.35 (d, J = 1.2 Hz, 1H), 8.90 (dd, J = 4.9, 1.2 Hz, 1H), 8.53 (dt, J = 8.0, 2.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.65 (dd, J = 8.0, 4.9 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 7.15 (s, 1H), 6.89 (s, 1H), 4.10 (s, 3H), 3.91 (s, 3H), 2.82 (s, 3H), 1.73 (s, 6H). 13 C NMR (100 MHz, Acetone) δ 164.7, 155.1, 151.9, 151.8, 151.0, 151.0, 150.0, 148.5, 145.5, 138.2, 137.5, 137.4, 131.5, 131.5, 131.1, 126.6, 124.7, 122.4, 122.4, 119.8, 116.5, 116.3, 106.7, 101.8, 94.4, 61.3, 56.4, 25.8, 25.8. ESIMS m / z 498.16.

[0026] Example 3: Compound 3

[0027]

[0028] Obtained by referring to the preparation method of Example 2. 1 H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 4.4 Hz, 2H), 8.04 (d, J = 4.4 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.69 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 1.74 (s, 6H). 1313C NMR (100 MHz, CDCl3) δ 164.0, 151.2, 151.0, 151.0, 150.2, 149.7, 149.3, 147.5, 144.5, 137.0, 137.0, 136.8, 130.9, 130.9, 129.9, 123.4, 123.4, 121.3, 121.3, 118.8, 116.0, 115.9, 105.7, 101.5, 93.7, 61.4, 56.0, 26.0, 26.0. ESIMS m / z 498.16.

[0029] Example 4: Compound 4

[0030]

[0031] Obtained by referring to the preparation method of Example 2, 1 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.94 (td, J = 8.0, 1.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.58 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.70 (s, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 164.1, 151.2, 150.3, 150.2, 150.2, 149.4, 147.7, 147.4, 144.5, 137.4, 136.9, 136.7, 130.8, 130.8, 130.1, 127.6, 126.1, 121.5, 121.5, 118.8, 116.0, 115.8, 105.8, 101.5, 93.7, 61.4, 56.0, 26.0, 26.0. ESIMS m / z 498.16.

[0032] Example 5: Compound 5

[0033]

[0034] Obtained by referring to the preparation method of Example 2, 11H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.93 (dt, J = 8.0, 2.0 Hz, 1H), 7.87 (d, J = 16.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.75 (d, J = 16.0 Hz, 1H), 6.68 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 164.9, 151.5, 151.2, 150.2, 150.1, 149.9, 149.3, 147.4, 144.5, 143.0, 136.8, 136.5, 134.6, 130.7, 130.7, 130.1, 130.1, 124.0, 121.4, 121.4, 119.7, 118.8, 115.9, 115.8, 105.7, 101.5, 93.7, 61.3, 56.0, 25.9, 25.9. ESIMS m / z 524.17.

[0035] Example 6: Compound 6

[0036]

[0037] Obtained by referring to the preparation method of Example 2 1 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 16.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 6.0 Hz, 2H), 7.43 (s, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.83 (d, J = 16.0 Hz, 1H), 6.68 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 1.73 (s, 6H). 1313C NMR (100 MHz, CDCl3) δ 164.7, 151.2, 150.9, 150.9, 150.9, 150.2, 149.8, 149.3, 147.4, 144.5, 143.8, 141.4, 136.8, 136.6, 130.8, 130.8, 130.0, 122.2, 122.1, 121.3, 118.8, 115.9, 115.9, 115.9, 105.7, 101.5, 93.7, 61.3, 56.0, 25.9, 25.9. ESIMS m / z 524.17.

[0038] Example 7: Compound 7

[0039]

[0040] Obtained by referring to the preparation method of Example 2 1 1H NMR (400 MHz, CDCl3) δ 8.70 (dt, J = 4.7, 1.5 Hz, 1H), 7.90 (d, J = 15.6 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 7.9 Hz, 1H), 7.43 (s, 1H), 7.31 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 15.6 Hz, 1H), 7.01 (s, 1H), 6.69 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 165.4, 152.8, 151.21, 150.4, 150.2, 150.0, 149.4, 147.4, 145.3, 144.5, 137.0, 136.8, 136.4, 130.7, 130.7, 130.2, 124.7, 124.7, 121.7, 121.4, 121.4, 118.8, 116.0, 115.8, 105.8, 101.5, 93.7, 61.3, 56.0, 25.9, 25.9. ESIMS m / z 524.17.

[0041] Example 8: Compound 8

[0042]

[0043] Obtained by referring to the preparation method of Example 2 11H NMR (400 MHz, CDCl3) δ 8.25 ((d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.70 (s, 1H), 4.01 (s, 3H), 3.89 (s, 3H), 1.74 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 165.5, 151.2, 150.2, 147.4, 144.5, 136.9, 134.0, 133.8, 136.5, 133.8, 130.8, 130.8, 130.4, 130.4, 130.2, 129.8, 128.8, 128.8, 121.6, 121.6, 118.8, 105.8, 101.5, 93.7, 61.4, 56.0, 29.8, 29.8. ESIMS m / z 497.16.

[0044] Example 9: Compound 9

[0045]

[0046] Obtained by referring to the preparation method of Example 2 1 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 16.0 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.65–7.58 (overlapped, 2H), 7.46–7.42 (overlapped, 4H), 7.28 (d, J = 8.8 Hz, 2H), 7.02 (s, 1H), 6.71 (s, 1H), 6.69 (d, J = 16 Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 1.75 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 165.6, 151.2, 150.1, 150.0, 149.3, 147.4, 146.8, 144.5, 136.8, 136.3, 134.3, 130.9, 130.7, 130.7, 130.2, 129.1, 129.1, 128.4, 128.4, 121.5, 121.5, 118.8, 117.4, 115.9, 115.7, 105.8, 101.5, 93.7, 61.3, 56.0, 25.9, 25.9. ESIMS m / z 523.18.

[0047] Example 10: Compound 10

[0048]

[0049] Obtained by referring to the preparation method of Example 2 1 H NMR(400MHz,CDCl3)δ7.85(d,J=15.8Hz,1H),7.66(d,J=8.1Hz,2H),7.51(d,J=8.4Hz,2H),7.44(s,1H),7.27(d,J=5.5Hz,2H),7.03(s,1H),6.77–6.67(overlapped,3H),6.45(d,J=15.8Hz,1H),4.01(s,3H),3.89(s,3H),3.05(s,6H),1.75(s,6H). 13 C NMR(100MHz,CDCl3)δ166.5,152.2,151.2,150.4,150.1,149.4,147.4,147.4,144.5,136.8,135.9,130.6,130.6,130.4,130.3,130.3,122.1,121.6,121.6,118.8,116.0,115.7,111.9,111.9,111.4,105.8,101.5,93.7,61.3,56.0,40.2,40.2,25.9,25.9.ESIMS m / z 566.22.

[0050] Example 11: Compound 11

[0051]

[0052] Obtained by referring to the preparation method of Example 2 1 H NMR(400MHz,Chloroform-d)δ9.26(t,J=1.6Hz,1H),8.75(d,J=2.8Hz,1H),8.18(ddd,J=8.5,2.9,1.7Hz,1H),7.70(d,J=8.8Hz,2H),7.43(s,1H),7.32(d,J=8.8Hz,2H),7.01(s,1H),6.69(s,1H),4.01(s,3H),3.90(s,3H),1.74(s,6H). 1313C NMR (100 MHz, CDCl3) δ 163.0, 160.6, 158.0, 151.2, 150.2, 149.5, 149.3, 147.5, 147.3, 144.5, 142.9, 137.1, 136.8, 130.9, 130.9, 129.82, 127.2, 124.2, 121.3, 121.3, 118.8, 115.9, 105.7, 101.5, 93.7, 61.4, 56.0, 25.9, 25.9. ESIMS m / z 516.15.

[0053] Example 12: Compound 12

[0054]

[0055] Dissolve Compound B (30 mg, 0.076 mmol) in acetone (3 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 dichloromethane three times. Combine the organic phases and concentrate under reduced pressure to obtain Compound 12. 1 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 7.50–7.46 (overlapped, 2H), 7.44–7.38 (overlapped, 3H), 7.36 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.66 (s, 1H), 5.13 (s, 2H), 3.99 (s, 3H), 3.86 (s, 3H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 158.2, 151.1, 150.1, 149.5, 147.3, 144.4, 137.2, 136.7, 131.4, 130.8, 130.7, 130.7, 128.8, 128.8, 128.2, 127.7, 127.7, 118.7, 116.1, 115.3, 114.8, 114.8, 105.7, 101.4, 93.7, 70.2, 61.2, 56.0, 25.9, 25.9. ESIMS m / z 483.18.

[0056] Example 13: Compound 13

[0057]

[0058] Obtained by referring to the preparation method of Example 12 11H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 7.41 (s, 1H), 7.03–6.99 (overlapped, 3H), 6.65 (s, 1H), 4.29 (dd, J = 11.0, 3.2 Hz, 1H), 4.04 (dd, J = 11.0, 5.6 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 3H), 3.40 (m, 1H), 2.94 (dd, J = 4.9, 4.1 Hz, 1H), 2.80 (dd, J = 4.9, 2.7 Hz, 1H), 1.73 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 157.9, 151.2, 150.1, 149.5, 147.3, 144.5, 136.7, 131.7, 130.8, 130.8, 130.7, 118.7, 116.0, 115.4, 114.6, 114.6, 105.7, 101.5, 93.7, 69.0, 61.2, 56.0, 50.3, 44.9, 26.0, 26.0. ESIMS m / z 449.16.

[0059] Example 14: Compound 14

[0060]

[0061] Obtained by referring to the preparation method of Example 12 1 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 18.8 Hz, 2H), 7.43 (s, 1H), 7.03–6.98 (overlapped, 3H), 6.67 (s, 1H), 6.11 (m, 1H), 5.47 (dq, J = 17.2, 1.7 Hz, 1H), 5.33 (dq, J = 10.5, 1.4 Hz, 1H), 4.61 (dt, J = 5.3, 1.6 Hz, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 1.74 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 158.0, 151.1, 150.1, 149.5, 147.2, 144.4, 136.7, 133.5, 131.3, 130.8, 130.7, 130.7, 118.7, 117.9, 116.0, 115.3, 114.6, 114.6, 105.68, 101.4, 93.7, 69.0, 61.2, 56.0, 25.9, 25.9. ESIMS m / z 433.17.

[0062] Example 15: Compound 15

[0063]

[0064] Obtained by referring to the preparation method of Example 12 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J=8.8Hz,2H),7.42(s,1H),7.07(d,J=8.8Hz,2H),7.01(s,1H),6.66(s,1H),4.76(d,J=2.4Hz,2H),3.99(s,3H),3.86(s,3H),2.56(t,J=2.4Hz,1H),1.73(s,6H). 13 C NMR(100MHz,CDCl3)δ157.0,151.2,150.1,149.5,147.3,144.4,136.7,132.1,130.7,130.7,130.6,118.7,116.0,115.4,114.8,114.8,105.7,101.4,93.7,78.8,75.7,61.2,56.0,56.0,25.9,25.9.ESIMS m / z 431.15.

[0065] Example 16: Compound 16

[0066]

[0067] Obtained by referring to the preparation method of Example 12 1 H NMR(400MHz,CDCl3)δ7.55(d,J=8.8Hz,2H),7.42(s,1H),7.03–6.99(overlapped,3H),6.66(s,1H),5.14(s,1H),5.02(s,1H),4.50(s,2H),4.00(s,3H),3.85(s,3H),1.87(s,3H),1.73(s,6H). 13 C NMR(100MHz,CDCl3)δ158.2,151.1,150.1,149.5,147.3,144.4,141.1,136.7,131.2,130.8,130.6,130.6,118.7,116.1,115.2,114.7,114.7,112.9,105.7,101.4,93.7,72.0,61.2,56.0,25.9,25.9,19.6.ESIMS m / z 447.18.

[0068] Example 17: Compound 17

[0069]

[0070] Obtained according to the preparation method of Example 2 1 H NMR(400MHz,CDCl3)δ7.61(d,J=8.8Hz,2H),7.42(s,1H),7.20(d,J=8.8Hz,2H),7.01(s,1H),6.67(s,1H),3.99(s,3H),3.85(s,3H),3.14(s,3H),3.04(s,3H),1.73(s,6H). 13 C NMR(100MHz,CDCl3)δ155.1,151.2,150.8,150.1,149.4,147.3,144.4,136.8,135.6,130.5,130.5,130.4,121.6,121.6,118.7,116.0,115.6,105.8,101.5,93.7,61.3,56.0,36.8,36.6,25.9,25.9.ESIMS m / z 464.17.

[0071] Example 18: Compound 19

[0072]

[0073] Obtained according to the preparation method of Example 2 1 H NMR(400MHz,CDCl3)δ7.63(d,J=8.8Hz,2H),7.42(s,1H),7.19(d,J=8.8Hz,2H),7.01(s,1H),6.67(s,1H),5.96(m,1H),3.99(s,3H),3.86(s,3H),2.26(d,J=1.3Hz,3H),2.01(d,J=1.3Hz,3H),1.73(s,6H). 13 C NMR(100MHz,CDCl3)δ165.1,160.2,151.2,150.1,145.0,149.4,147.4,144.5,136.8,136.0,130.6,130.6,130.3,121.7,

[0074] 121.7,118.8,116.0,115.7,115.4,105.8,101.5,93.7,61.3,56.0,27.8,25.9,20.65.ESIMS m / z475.18.

[0075] Example 19: Test for HIF Transcription Inhibitory Activity

[0076] (1) Active test cell model: HCT 116 (human colon cancer cells) infected with lentiviral vector.

[0077] (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 a Dual-Luciferase assay kit to detect the effect of the compound on HIF transcriptional activity.

[0078] (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%

[0079] Test results:

[0080] Table 1 Inhibitory effect of the compounds of the present invention on HIF at 1 μM

[0081] Compound Inhibition rate (%) Compound Inhibition rate (%) 1 ++++ 12 ++++ 2 ++++ 13 ++++ 3 ++++ 14 ++++ 4 ++++ 15 ++++ 5 ++++ 16 ++++ 6 ++++ 17 ++++ 7 ++++ 18 ++++ 8 ++++ 19 ++++ 9 ++++ 20 ++++ 10 ++++ 21 ++++ 11 ++++

[0082] Note: In the table, "++++" indicates that the inhibition rate ≥ 70%; "+++" indicates that the inhibition rate is 40 - 69%; "++" indicates that the inhibition rate is 20 - 39%; "+" indicates that the inhibition rate is 5 - 19%; "-" indicates that the inhibition rate is less than 5%.

[0083] Conclusion: At a concentration of 1 μM, compounds 1 - 21 of the present invention have strong inhibitory activity on HIF transcription 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.

[0084] 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 benzofuran terphenyl compound, characterized in that, Use of 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 as a HIF inhibitor, characterized in that the compound has the following structure: wherein R1 and R2 are each independently optionally methyl, ethyl and CD3; R3 is each independently optionally wherein 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, valeryl, hexanoyl, methacryloyl, cyclopropyl, cyclopropanoyl, cyclopentanoyl, cyclohexanoyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indolyl, carbazolyl, benzofuryl, tetrahydrofuran, tetrahydropyran, pyrimidine base, purine base; 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, 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 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, C 1-8 alkyl, C 3-8 cycloalkyl, substituted or unsubstituted C 3-6 membered heterocyclic group, substituted or unsubstituted C 5-6 membered heteroaryl, heterocycloalkyl, heterocyclic group oxy, heterocyclic group amino, heterocyclic group alkoxy, heterocyclic group alkanamino, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic group aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 heterocyclic group, C 5-6 heteroaryl may each independently optionally be substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, aryl or 5-6 membered heteroaryl; L1, L2, L3 are each independently optionally a bond, -C 1-6 alkylene-, -vinyl-, -propenyl-, -allyl-, -n-butenyl-, -isobutenyl-, -n-pentenyl-, -isopentenyl-, -ethynyl-, -propargyl-, -propynyl-, -butynyl-, -but-2-ynyl-, -pentynyl; When R1 and R2 are both methyl, R3 cannot be H.

2. The compound according to claim 1, characterized in that, 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 structures are 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 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 related to hypoxia-inducible factor (HIF), and 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 diseases, and nervous system diseases.

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