Benzofurans or their pharmaceutically acceptable salts, their preparation methods and applications

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to benzofuran compounds or their pharmaceutically acceptable salts, their preparation methods, and applications. The benzofuran compounds of this invention can significantly inhibit the activity of phosphodiesterase 4 and can be used to prepare drugs for treating inflammatory diseases, autoimmune diseases, or neuropsychiatric disorders, especially for stroke and ischemic dementia-related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. More specifically, it relates to benzofuran compounds or pharmaceutically acceptable salts thereof, methods of their preparation, and applications. Background Technology

[0002] Cyclic nucleotide phosphodiesterases (PDEs) specifically utilize cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) as substrates to catalyze the hydrolysis of cAMP and / or cGMP to generate the corresponding inactive AMP and / or GMP, thereby controlling their intracellular concentrations and influencing various physiological processes and metabolic functions. The PDE family comprises 11 subtypes (PDE1–PDE11), which can be classified into three categories based on their substrates: cAMP-specific hydrolases (PDE4, PDE7, and PDE8), cGMP-specific hydrolases (PDE5, PDE6, and PDE9), and dual hydrolases (PDE1, PDE2, PDE3, PDE10, and PDE11). PDE4 and PDE9 can regulate many physiological activities, such as energy metabolism, memory, immune response, vision, smell and growth of various cell types, by regulating cAMP and cGMP, activating protein kinase A (PKA) and protein kinase G (PKG) pathways.

[0003] PDE4 (phosphodiesterase 4) has four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. Except for PDE4C, the other three subtypes are highly expressed in the cerebral cortex, olfactory bulb, hippocampus, and brainstem. Numerous studies have confirmed that PDE4 is widely involved in various neuronal activities. PDE4 inhibitors can improve cognitive function by inhibiting PDE4 enzyme activity, upregulating cAMP concentration, thereby activating the cAMP / PKA / CREB pathway, regulating BDNF concentration, promoting synaptic growth, increasing synaptic plasticity and neuronal survival. Furthermore, upregulation of cAMP concentration can inhibit NF-κB nuclear translocation, thereby downregulating intracellular inflammatory factors (such as TNF-α, IL-1, and IL-6), alleviating neuroinflammation, and reducing inflammation-induced neuronal damage and apoptosis. PDE4 inhibitors have been used in research on various diseases, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, Alzheimer's disease, schizophrenia, and depression.

[0004] Currently, only three PDE4 inhibitors are available on the market: roflumilast, apremilast, and criborrol. Furthermore, all three have experienced varying degrees of adverse reactions in actual clinical applications. Therefore, the number of available PDE4 inhibitors is very limited, and further research and development of novel PDE4 inhibitors remains necessary. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the limited types of existing PDE4 inhibitors and to provide benzofuran compounds or their pharmaceutically acceptable salts.

[0006] The object of this invention is to provide a method for preparing benzofuran compounds or pharmaceutically acceptable salts thereof.

[0007] Another object of the present invention is to provide the use of the benzofuran compounds or pharmaceutically acceptable salts thereof in the preparation of phosphodiesterase 4 inhibitors.

[0008] Another object of the present invention is to provide the use of the said benzofuran compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating phosphodiesterase 4-related diseases.

[0009] Another object of the present invention is to provide a phosphodiesterase 4 inhibitor.

[0010] The above-mentioned objective of this invention is achieved through the following technical solution:

[0011] This invention protects benzofuran compounds or pharmaceutically acceptable salts thereof, said benzofuran compounds having the structure shown in formula (I) or formula (II):

[0012]

[0013] C 1-6 In alkylates, without R 1 Select the substitute or C. 1-6 Monoalkyl or polyalkyl 1 indivual -6 Alkyl C oxygen 1- 6-alkyl C-oxygen 3- base 6 Cycloalkylation; group, C 3-6 One of the heterocyclic groups;

[0014] X, Y, Z, and A are each independently selected from C and N;

[0015] R 2 Selected from H, hydroxyl or C 1-6 alkyl;

[0016] R 3 R 4 Each is independently selected from H, hydroxyl, carbonyl, C 1-6 Alkyl, C 3-6 cycloalkyl, benzyl, C 5-9 Heterocyclic group or C 5-9 Mixed aromatics;

[0017] R 5R 6 Each is independently selected from H or C 1-6 alkyl;

[0018] Ar is a five-membered heterocycle, which is unsubstituted or via one or more carbonyl groups, C 1-6 Alkyl substitution.

[0019] Preferably, the R 1 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-5 One of cycloalkyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolidinyl, and hexahydropiperidinyl; C 1-3 Alkyl groups that are unsubstituted or via one or more C16 groups 1-3 Alkyl substitution;

[0020] R 3 R 4 Each is independently selected from H, hydroxyl, carbonyl, C 1-3 Alkyl, C 3-5 cycloalkyl, benzyl;

[0021] Ar is a five-membered heterocycle, which is unsubstituted or via one or more carbonyl groups, C 1-4 Alkyl substitution, wherein the heteroatom in the five-membered heterocycle is one or more of oxygen and nitrogen atoms.

[0022] Preferably, when the benzofuran compound has the structural formula described in formula (I), Choose from any of the following structures:

[0023] Alternatively, when the benzofuran compound has the structural formula described in formula (II), Choose from any of the following structures:

[0024] Preferably, R 1 It is cyclopropane; when the benzofuran compound has the structure described in formula (I), Choose from any of the following structures: or

[0025] When the benzofuran compound has the structural formula described in formula (II) The inventors discovered through research that when When the structure is selected from the above, the prepared compound has better phosphodiesterase 4 inhibitory activity.

[0026] More preferably, R 1It is cyclopropane; when the benzofuran compound has the structure described in formula (I), Choose from any of the following structures: or

[0027] When the benzofuran compound has the structural formula described in formula (II) The inventors discovered through research that when When selected from the above structures, the prepared compounds exhibit excellent phosphodiesterase 4 inhibitory activity, with an IC50 value of [missing information]. 50 Below 26.3 nM.

[0028] This invention also protects a method for preparing the benzofuran compound or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0029] S1. Prepare compounds of formula (III) or formula (IV);

[0030] S2. The compound of formula (I) is obtained by coupling a compound of formula (III) or formula (IV) with a compound of formula (VI); or the compound of formula (II) is obtained by coupling a compound of formula (IV) with a compound of formula (V).

[0031]

[0032] In its description, benzene and furan W class are compound B (O H) drugs. 2 、Learn B (P can be in) 2 The method for preparing the Br salt is to obtain the compound shown in formula (I) or formula (II) by salt formation reaction.

[0033] Preferably, the coupling reaction is as follows: the above-mentioned compound (III) or compound (IV) is mixed with compound (VI), palladium catalyst, and basic reagent in a solvent, and the reaction is carried out at 85-95°C under inert gas protection, followed by post-treatment to obtain the compound shown in formula (I); or the above-mentioned compound (IV) is mixed with compound (V), palladium catalyst, and basic reagent in a solvent, and the reaction is carried out at 85-95°C under inert gas protection, followed by post-treatment to obtain the compound shown in formula (II).

[0034] Preferably, the palladium catalyst is a commonly used palladium catalyst in coupling reactions; preferably, the palladium catalyst is selected from divalent palladium catalysts, including but not limited to Pd(dppf)Cl2, etc.

[0035] Preferably, the alkaline reagent is a commonly used alkaline reagent in the art; specifically, the alkaline reagent includes, but is not limited to, potassium carbonate.

[0036] Preferably, the solvent is a mixed solution of water and organic matter commonly used in the art; specifically, the solvent is a mixed solution of dioxane and water.

[0037] The post-processing described in this invention is a common post-processing method in the field of compound separation and purification, including but not limited to column chromatography; specifically, the column chromatography is elution using an eluent with a volume ratio of ethyl acetate to petroleum ether of 1:1 to 5.

[0038] Additionally, the present invention protects the use of the benzofuran compounds or pharmaceutically acceptable salts thereof in the preparation of phosphodiesterase 4 inhibitors.

[0039] Furthermore, this invention also protects the use of the benzofuran compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating phosphodiesterase 4-related diseases.

[0040] Preferably, the phosphodiesterase 4-related diseases are allergic diseases, autoimmune diseases, central nervous system diseases, or diseases caused by local ischemic reflux due to heart failure, shock, and cerebrovascular diseases.

[0041] Preferably, the allergic disease is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or nephritis; the autoimmune disease is rheumatoid arthritis, multiple sclerosis, Crohn's disease, or systemic lupus erythematosus; and the central nervous system disease is depression, amnesia, or dementia.

[0042] The present invention also protects the use of the benzofuran compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of stroke and ischemic dementia-related diseases.

[0043] This invention provides a phosphodiesterase 4 inhibitor containing any of the benzofuran compounds described in this invention or a pharmaceutically acceptable salt thereof.

[0044] The present invention has the following beneficial effects:

[0045] The benzofuran compounds provided by this invention exhibit good inhibitory activity against PDE4 and can be used to treat diseases mediated by abnormal PDE4 expression, such as allergic diseases, autoimmune diseases, central nervous system diseases, or diseases caused by ischemic backflow due to heart failure, shock, and cerebrovascular diseases. Simultaneously, the benzofuran compounds also have significant therapeutic effects on ischemic stroke (cerebral infarction). Attached Figure Description

[0046] Figure 1 This is a dose-response curve showing the inhibition rate of different concentrations of the compound prepared in Example 20 on PDE4 enzyme.

[0047] Figure 2This is a diagram showing the cytotoxicity experiment of the compound prepared in Example 20.

[0048] Figure 3 This is a schematic diagram illustrating the protective effect of the compound prepared in Example 20 against HT-22 cell damage in an oxygen-glucose deprivation / reoxygenation model (OGD / R). Detailed Implementation

[0049] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0050] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0051] In this invention, C 1-6 Alkyl groups refer to saturated alkyl groups with a total number of carbon atoms of 1-6, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups; for example, straight-chain alkyl groups with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, and branched alkyl groups with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6. C 1-3 Alkyl groups have a similar explanation, the difference being the number of carbon atoms.

[0052] C 1-6 Alkoxy groups refer to alkoxy groups with a total number of 1-6 carbon atoms, including C. 1-6 straight-chain alkoxy, C 1-6 Branched alkoxy groups; for example, straight-chain alkoxy groups with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6, and branched-chain alkoxy groups with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6. C 1-3 Alkoxy groups have a similar explanation, the difference being the number of carbon atoms.

[0053] C 3-6 Cycloalkyl groups are saturated hydrocarbon groups consisting of a monocyclic ring of carbon atoms and hydrogen atoms, with a total number of carbon atoms of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0054] C 3-6 A heterocyclic group is a group remaining after removing one hydrogen atom from a monocyclic or fused ring with 3 to 6 ring atoms. It contains at least one N, O, or S ring atom, with the remaining ring atoms being C. Such a ring can be saturated or unsaturated (e.g., having one or more double bonds), but it does not possess a fully conjugated π-electron system. Examples include ethylene oxide, tetrahydropyran ring, tetrahydrofuran ring, tetrahydropyrrole ring, and hexahydropiperidine ring. 5-9 Heterocyclic groups have a similar explanation, the difference being the number of ring atoms.

[0055] C 5-9 Heteroaryl refers to a group that has 5 to 9 ring atoms, which is the remaining group after removing one hydrogen atom from a monocyclic or fused ring. It contains at least one N, O, or S ring atom, and the remaining ring atoms are C, and has a fully conjugated π-electron system. Examples include pyrrole, furanyl, thiophene, pyridinyl, quinolinyl, and isoquinolinyl.

[0056] The term "pharmaceutically acceptable salt" as used in this invention refers to the salt of the compounds described in this invention, and more specifically, to the salt prepared from compounds with specific substituents discovered in this invention and a relatively non-toxic acid. The acid includes inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, sulfuric acid, phosphonic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and similar acids.

[0057] Example 1

[0058] Synthetic route of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)benzene-1,3-diol (compound 1):

[0059]

[0060] Step 1: Synthesis of 3-bromo-2-hydroxymethyl-6-methoxyphenol (compounds 1-2, CAS No.: 35090-65-4):

[0061] Compound 1-1, 6-bromo-2-hydroxy-3-methoxybenzaldehyde (22 mmol, 1.0 equiv.), was dissolved in methanol (100 mL). Sodium borohydride (22 mmol, 1.0 equiv.) was slowly added in portions under ice bath conditions. After being cooled to room temperature and stirred for 6 hours, dilute hydrochloric acid (20 mL) was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether (1:5, v / v) as the eluent to give intermediate 1-2 (96% yield).

[0062] NMR data of intermediates 1-2:

[0063] 1 H NMR (400MHz, CDCl3) δ7.04 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.90 (s, 2H), 3.86 (s, 3H). 13C NMR (101MHz, CDCl3) δ145.46,125.29,123.26,114.99,111.41,60.83,56.19.

[0064] Step 2: Synthesis of 3-bromo-2-((bromotriphenylphosphino)methyl)-6-methoxyphenol (compounds 1-3):

[0065] Compounds 1-2 (20 mmol, 1.0 equiv.) were dissolved in acetonitrile (100 mL), and triphenylphosphine bromide (20 mmol, 1.0 equiv.) was added. The mixture was heated to 82 °C and stirred for 3 hours, with the reaction monitored by thin-layer chromatography (TLC). After the reaction was complete, most of the acetonitrile was evaporated under reduced pressure, and an appropriate amount of ethyl acetate was added. The mixture was filtered to give intermediate 1-3 (white solid, yield 89%).

[0066] Step 3: Synthesis of 4-bromo-2-cyclopropyl-7-methoxybenzofuran (compounds 1-4):

[0067] Compounds 1-3 (10 mmol, 1.0 equiv.) were dissolved in toluene (50 mL), and cyclopropylformyl chloride (11 mmol, 1.1 equiv.) and triethylamine (24 mmol, 2.4 equiv.) were added. The mixture was heated to 110 °C and stirred for 3 hours. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was filtered, and the filtrate was extracted with ethyl acetate after adding an appropriate amount of water. The upper organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (n-hexane:ethyl acetate = 200:1, v / v) to give intermediate 1-4 (white solid, yield 85%).

[0068] NMR data of intermediates 1-4:

[0069] 1 H NMR (400MHz, CDCl3) δ7.21(d,J=8.5Hz,1H),6.60(d,J=8.5Hz,1H),6.34(s,1H),3.96(s,3H),2.09–1.99(m,1H),1.05–0.90(m,4H). 13 C NMR (101MHz, CDCl3) δ161.60,144.26,143.00,131.52,125.50,106.70,103.72,100.59,56.18,9.23,7.54.

[0070] Step 4: Synthesis of 2-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compounds 1-5):

[0071] Compounds 1-4 (5 mmol, 1.0 equiv.), pinacol diboronate (15 mmol, 3.0 equiv.), Pd(dppf)Cl2 (0.25 mmol, 0.05 equiv.), and potassium acetate (15 mmol, 3.0 equiv.) were dissolved in dimethyl sulfoxide (25 mL). The mixture was stirred at 80 °C under argon protection for 12 hours, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:100 (v / v) as the eluent to give intermediate 1-5 (white solid, yield 72%).

[0072] NMR data of intermediates 1-5:

[0073] 1 H NMR (400MHz, CDCl3) δ7.59(d,J=8.0Hz,1H),6.74(s,1H),6.72(d,J=8.0Hz,1H),4.01(s,3H),2.12–2.01(m,1H),1.36(s,12H),1.04–0.94(m,4H). 13 CNMR (101MHz, CDCl3) δ161.19,147.06,142.61,136.11,131.55,105.01,102.34,83.29,55.85,24.90,9.26,7.23.

[0074] Step 5: Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)benzene-1,3-diol (compound 1):

[0075] Compounds 1-5 (0.5 mmol, 1.0 equiv.), 5-bromobenzene-1,3-diol (0.6 mmol, 1.2 equiv.), Pd(dppf)Cl2 (0.025 mmol, 0.05 equiv.), and potassium carbonate (1 mmol, 2 equiv.) were dissolved in a dioxane / water mixture (dioxane:water = 4:1, 5 mL). The mixture was stirred at 90 °C under argon protection for 12 hours, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:3 (v / v) as the eluent to obtain compound 1 (white solid, yield 42%).

[0076] NMR data for compound 1:

[0077] 1 H NMR(400MHz, CDCl3) δ7.14(d,J=7.9Hz,1H),6.76(d,J=7.4Hz,1H),6.62(s,2H),6.51 (s,1H),6.35(s,1H),5.21(s,2H),4.02(s,3H),2.08–2.01(m,1H),1.02–0.87(m,4H). 13 C NMR (101MHz, CDCl3) δ 161.40, 156.83, 144.33, 143.34, 142.91, 128.75, 126.01, 122.50, 107.92, 105.72, 101.27, 99.97, 56.08, 9.22, 7.39. Example 2

[0078] Synthetic route of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridine (compound 2):

[0079]

[0080] Compounds 1-4 (0.5 mmol, 1.0 equiv.), pyridine-4-boronic acid (0.6 mmol, 1.2 equiv.), Pd(dppf)Cl2 ((1,5-cyclooctadiene)rhodium(I) dimer, 0.025 mmol, 0.05 equiv.), and potassium carbonate (1 mmol, 2 equiv.) were dissolved in a dioxane / water mixture (dioxane:water = 4:1, 5 mL). The mixture was stirred at 90 °C under argon protection for 12 hours, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:5 (v / v) as the eluent to obtain compound 2 (white solid, yield 55%).

[0081] NMR data for compound 2:

[0082] 1 H NMR (400MHz, CDCl3) δ8.66(s,2H),7.48(d,J=4.6Hz,2H),7.25(d,J=8.9Hz,1H),6.8 2(d,J=8.3Hz,1H),6.53(s,1H),4.04(s,3H),2.09–2.04(m,1H),1.06–0.94(m,4H). 13C NMR (101MHz, CDCl3) δ162.13,150.05,147.71,145.37,143.51,128.83,123.51,123.06,122.71,105.87,99.51,56.11,9.30,7.56.

[0083] Example 3

[0084] Synthesis of 3-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridine (compound 3):

[0085] Compound 3 was synthesized according to the method described in Example 2, except that pyridine-4-boronic acid in Example 2 was replaced with pyridine-3-boronic acid. The structure of compound 3 is shown below:

[0086]

[0087] NMR data for compound 3:

[0088] 1 H NMR (400MHz, CDCl3) δ8.82(s,1H),8.56(d,J=4.2Hz,1H),7.88–7.80(m,1H),7.37–7.34(m,1H),7.16(d ,J=8.2Hz,1H),6.81(d,J=8.2Hz,1H),6.46(s,1H),4.02(s,3H),2.09–2.01(m,1H),1.06–0.87(m,4H). 13 C NMR (101MHz, CDCl3) δ161.89,149.09,147.76,144.80,143.44,135.78,135.13,128.95,123.41,122.90,105.90,99.37,56.05,9.24,7.47.

[0089] Example 4

[0090] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyrimidine (compound 4):

[0091] Compound 4 was synthesized according to the method described in Example 2, except that pyridine-4-boronic acid in Example 2 was replaced with pyrimidine-5-boronic acid. The structure of compound 4 is shown below:

[0092]

[0093] NMR data for compound 4:

[0094] 1 H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 8.94 (s, 2H), 7.19 (d, J = 8.2Hz, 1H), 6.85 (d, J=8.2Hz,1H),6.46(s,1H),4.04(s,3H),2.11–2.05(m,1H),1.08–0.93(m,4H). 13 C NMR (101MHz, CDCl3) δ162.58,156.79,155.56,145.51,143.55,133.79,129.02,123.14,118.93,106.16,98.92,56.15,9.32,7.66.

[0095] Example 5

[0096] Synthesis of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-2-methylpyridine (compound 5):

[0097] Compound 5 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 4-bromo-2-methylpyridine to prepare compound 5, the structure of which is shown below:

[0098]

[0099] NMR data for compound 5:

[0100] 1 H NMR (400MHz, CDCl3) δ8.53(d,J=5.2Hz,1H),7.34(s,1H),7.29(d,J=5.1Hz,1H),7.23(d,J=8.3Hz,1H) ,6.81(d,J=8.3Hz,1H),6.51(s,1H),4.03(s,3H),2.62(s,3H),2.11–2.03(m,1H),1.06–0.93(m,4H). 13 C NMR (101MHz, CDCl3) δ161.96,158.61,149.33,148.09,145.25,143.48,128.8 3,123.81,122.99,122.20,119.98,105.81,99.62,56.09,24.58,9.31,7.53.

[0101] Example 6

[0102] Synthesis of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-2,6-dimethylpyridine (compound 6):

[0103] Compound 6 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 4-bromo-2,6-dimethylpyridine to obtain compound 6, the structure of which is shown below:

[0104]

[0105] NMR data for compound 6:

[0106] 1 H NMR (400MHz, CDCl3) δ7.21(d,J=8.1Hz,1H),7.15(s,2H),6.79(d,J=8.1Hz,1H) ,6.50(s,1H),4.03(s,3H),2.59(s,6H),2.11–2.02(m,1H),1.05–0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ161.78,157.90,145.13,143.46,122.92,119.41,105.77,99.74,56.09,24.58,9.31,7.49.

[0107] Example 7

[0108] Synthesis of 2-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-3,5-dimethylpyrazine (compound 7):

[0109] Compound 7 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 2-bromo-3,5-dimethylpyrazine to prepare compound 7, the structure of which is shown below:

[0110]

[0111] NMR data for compound 7:

[0112] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.19 (d, J = 8.1Hz, 1H), 6.80 (d, J = 8.1Hz, 1H), 6.23 (s,1H),4.04(s,3H),2.59(s,3H),2.52(s,3H),2.05–2.00(m,1H),0.99–0.92(m,4H). 13C NMR (101MHz, CDCl3) δ161.77,150.64,149.78,144.98,143.27,140.96,130.02,124.08,123.15,105.26,100.01,56.08,22.77,21.22,9.25,7.39.

[0113] Example 8

[0114] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-2,3-dimethylpyrazine (compound 8)

[0115] Compound 8 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-2,3-dimethylpyrazine to prepare compound 8, the structure of which is shown below:

[0116]

[0117] NMR data for compound 8:

[0118] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),7.57(d,J=8.2Hz,1H),6.91(s,1H),6.82(d,J=8.2Hz ,1H),4.03(s,3H),2.63(s,3H),2.58(s,3H),2.15–2.03(m,1H),1.06–0.92(m,4H).13C NMR (101MHz, CDCl3) δ161.87,151.43,149.99,149.11,145.58,139.11,129.16,122.74,121.86,105.70,100.85,56.08,22.26,21.67,9.32,7.43.

[0119] Example 9

[0120] Synthesis of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridin-2-ol (compound 9):

[0121] Compound 9 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 4-bromopyridin-2-ol to prepare compound 9, the structure of which is shown below:

[0122]

[0123] NMR data for compound 8:

[0124] 1 H NMR (400MHz, CDCl3) δ13.32(s,1H),7.46(d,J=6.6Hz,1H),7.25(d,J=7.2Hz,1H),6.8 2–6.77(m,2H),6.61–6.53(m,2H),4.03(s,3H),2.11–2.01(m,1H),1.06–0.90(m,4H). 13 C NMR (101MHz, CDCl3) δ165.74,162.29,153.54,145.74,143.45,134.25,12 8.82,122.99,122.90,117.14,107.90,105.69,99.64,56.11,9.28,7.63.

[0125] Example 10

[0126] Synthesis of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-ethylpyridin-2(1H)-one (compound 10):

[0127] Compound 10 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 4-bromo-1-ethylpyridin-2(1H)-one to prepare compound 10, the structure of which is shown below:

[0128]

[0129] NMR data for compound 10:

[0130] 1 H NMR (400MHz, CDCl3) δ7.31(d,J=7.0Hz,1H),7.20(d,J=8.3Hz,1H),6.76(d,J=8.4Hz,2H),6.55(s,1H ),6.43–6.41(m,1H),4.06–3.97(m,5H),2.08–2.01(m,1H),1.39(t,J=7.2Hz,3H),1.01–0.95(m,4H). 13 C NMR (101MHz, CDCl3) δ162.64,162.09,150.95,145.52,143.41,136.49,128.72,1 22.80,122.70,117.81,106.96,105.65,99.68,56.06,44.42,14.72,9.23,7.55.

[0131] Example 11

[0132] Synthesis of 1-cyclopentyl-4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridin-2(1H)-one (compound 11):

[0133] Compound 11 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-1-cyclopentylpyridin-2(1H)-one (intermediate 11-2), and the structure of compound 11 is shown below:

[0134]

[0135] NMR data for compound 11:

[0136] 1 H NMR(400MHz, CDCl3)δ7.36(d,J=7.2Hz,1H),7.20(d,J=8.3Hz,1H),6.77–6.74(m,2H),6.55(s,1H),6.47–6.43(m,1H),5.39 –5.31(m,1H),4.01(s,3H),2.26–2.16(m,2H),2.09–2.01(m,1H),1.90–1.82(m,2H),1.80–1.64(m,4H),1.03–0.91(m,4H). 13 C NMR (101MHz, CDCl3) δ163.05,162.07,150.02,145.50,133.14,128.74,122.81, 122.67,117.29,107.05,105.65,99.70,56.05,55.73,32.25,24.40,9.23,7.54.

[0137] Synthesis of 4-bromo-1-cyclopentylpyridin-2(1H)-one (intermediate 11-2):

[0138]

[0139] Compound 11-1, 4-bromopyridin-2(1H)-one (5 mmol, 1.0 equiv.), was dissolved in DMF (20 mL), and bromocyclopentane (10 mmol, 2.0 equiv.) and cesium carbonate (10 mmol, 2.0 equiv.) were added. After stirring at room temperature for 2 hours, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:20 (v / v) as the eluent to obtain intermediate 11-2 (yield 8%).

[0140] NMR data of intermediate 11-2:

[0141] 1 H NMR (400MHz, CDCl3) δ7.16 (d, J=7.4Hz, 1H), 6.76 (s, 1H), 6.33 (dd, J=7.4, 1.8Hz, 1H), 5.13 –5.15(m,1H),2.17–2.11(m,2H),1.87–1.76(m,2H),1.76–1.70(m,2H),1.64–1.54(m,2H). 13 C NMR (101MHz, CDCl3) δ161.60,134.50,133.66,122.48,110.39,56.17,32.14,24.25.

[0142] Example 12

[0143] Synthesis of 1-benzyl-4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridin-2(1H)-one (compound 12):

[0144] Compound 12 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-1-benzylpyridin-2(1H)-one (CAS No.: 1781092-40-7), and the structure of compound 12 was prepared as shown below:

[0145]

[0146] NMR data for compound 12:

[0147] 1H NMR (400MHz, CDCl3) δ7.40–7.28(m,6H),7.21(d,J=8.3Hz,1H),6.82(d,J=1.5Hz,1H),6.77(d,J=8.3Hz ,1H),6.56(s,1H),6.42–6.40(m,1H),5.19(s,2H),4.02(s,3H),2.09–2.01(m,1H),1.05–0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ162.87,162.17,151.06,145.63,143.44,136.69,136.49,128.88,128.7 6,128.21,127.98,122.80,122.70,117.84,107.10,105.68,99.71,56.08,51.55,9.26,7.59.

[0148] Example 13

[0149] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridin-2-ol (compound 13):

[0150] Compound 13 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromobenzene-1,3-diol was replaced with 5-bromopyridin-2-ol. The results are shown below:

[0151]

[0152] NMR data for compound 13:

[0153] 1 H NMR (400MHz, CDCl3) δ13.47(s,1H),7.77(dd,J=9.4,2.5Hz,1H),7.60(s,1H),7.04(d,J=8.2Hz,1H),6.77 (d,J=8.3Hz,1H),6.72(d,J=9.4Hz,1H),6.40(s,1H),4.02(s,3H),2.11–2.03(m,1H),1.05–0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ164.59,161.87,144.45,143.46,142.73,132.43,12 8.45,121.82,121.45,120.40,120.12,105.87,99.19,56.10,9.26,7.52.

[0154] Example 14

[0155] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl))-6-methylpyridin-2-ol (compound 14):

[0156] Compound 14 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-6-methylpyridin-2-ol to prepare compound 14, the structure of which is shown below:

[0157]

[0158] NMR data for compound 14:

[0159] 1 H NMR (400MHz, CDCl3) δ13.46(s,1H),7.44(d,J=9.2Hz,1H),6.93(d,J=8.1Hz,1H),6.75(d,J=8.2Hz,1H ),6.51(d,J=9.2Hz,1H),6.10(s,1H),4.02(s,3H),2.29(s,3H),2.06–1.99(m,1H),1.02–0.89(m,4H). 13 C NMR (101MHz, CDCl3) δ161.52,144.60,144.25,143.19,143.00,130.22,124.09,122.11,118.00,116.38,105.52,99.59,56.08,17.71,9.25,7.49.

[0160] Example 15

[0161] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-methylpyridin-2(1H)-one (compound 15):

[0162] Compound 15 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-1-methylpyridin-2(1H)-one to prepare compound 15, the structure of which is shown below:

[0163]

[0164] NMR data for compound 15:

[0165] 1H NMR (400MHz, CDCl3) δ7.59(d,J=9.4Hz,1H),7.42(s,1H),7.00(d,J=8.2Hz,1H),6.75(d,J=8.2Hz,1H) ,6.67(d,J=9.3Hz,1H),6.35(s,1H),4.00(s,3H),3.62(s,3H),2.10–2.01(m,1H),1.05–0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ162.30,161.67,144.39,143.40,140.60,136.09,128.5 2,121.76,121.56,120.41,119.31,105.82,99.19,56.08,37.89,9.25,7.46.

[0166] Example 16

[0167] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-ethylpyridin-2(1H)-one (compound 16):

[0168] Compound 16 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-1-ethylpyridin-2(1H)-one to prepare compound 16, the structure of which is shown below:

[0169]

[0170] NMR data for compound 16:

[0171] 1 H NMR (400MHz, CDCl3) δ7.58–7.56(m,1H),7.42(d,J=2.4Hz,1H),7.01(d,J=8.2Hz,1H),6.75(d,J=8.2Hz,1H),6.66(d,J =9.3Hz,1H),6.36(s,1H),4.09–4.04(m,2H),4.01(s,3H),2.10–2.02(m,1H),1.41(t,J=7.2Hz,3H),1.05–0.93(m,4H). 13C NMR (101MHz, CDCl3) δ161.65,161.60,144.37,143.42,140.28,134.83,128.50,1 21.76,121.72,120.81,119.43,105.83,99.26,56.10,45.03,14.83,9.27,7.47.

[0172] Example 17

[0173] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-cyclopentylpyridin-2(1H)-one (compound 17):

[0174] Compound 17 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-1-cyclopentylpyridin-2(1H)-one (CAS No.: 1425045-03-9), and the structure of compound 17 is shown below:

[0175]

[0176] NMR data for compound 17:

[0177] 1 H NMR (400MHz, CDCl3) δ7.55–7.53(m,1H),7.46(d,J=2.3Hz,1H),7.01(d,J=8.2Hz,1H),6.76(d,J=8.2Hz,1H),6.66(d,J=9.3Hz,1H),6.33 (s,1H),5.46–5.34(m,1H),4.01(s,3H),2.25–2.20(m,2H),2.10–2.03(m,1H),1.90–1.82(m,2H),1.80–1.66(m,4H),1.04–0.93(m,4H). 13 C NMR (101MHz, CDCl3) δ161.70,144.36,143.42,139.45,131.56,128.50,122.15, 121.68,120.27,119.50,105.84,99.19,56.11,32.44,24.81,24.42,9.29,7.51.

[0178] Example 18

[0179] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-benzylpyridin-2(1H)-one (compound 18):

[0180] Compound 18 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-1-benzylpyridin-2(1H)-one (CAS No.: 217448-53-8), and the structure of compound 18 is shown below:

[0181]

[0182] NMR data for compound 18:

[0183] 1 H NMR (400MHz, CDCl3) δ7.59–7.56(m,1H),7.41–7.30(m,6H),6.96(d,J=8.2Hz,1H),6.73(d,J=1.2Hz,1H ),6.70(d,J=2.8Hz,1H),6.11(s,1H),5.22(s,2H),3.98(s,3H),2.05–1.96(m,1H),1.01–0.85(m,4H). 13 C NMR (101MHz, CDCl3) δ 161.77, 161.69, 144.34, 143.40, 140.32, 136.46, 134.90, 128.93, 128.34, 128.10, 121.59, 151.54, 120.92, 119.28, 105.80, 98.99, 56.06, 51.82, 9.17, 7.47. Example 19

[0184] Synthesis of 6-(2-cyclopropyl-7-methoxybenzofuran-4-yl)isobenzofuran-1(3H)-one (compound 19):

[0185] Compound 19 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 6-bromoisobenzofuran-1(3H)-one, and the structure of compound 19 is shown below:

[0186]

[0187] NMR data for compound 19:

[0188] 1H NMR (400MHz, CDCl3) δ8.10(s,1H),7.89(d,J=7.8Hz,1H),7.56(d,J=7.8Hz,1H),7.20(d,J=8.0Hz,1H) ,6.82(d,J=8.1Hz,1H),6.47(s,1H),5.38(s,2H),4.04(s,3H),2.13–2.02(m,1H),1.07–0.90(m,4H). 13 C NMR (101MHz, CDCl3) δ171.19,161.98,144.87,144.63,143.46,141.72,134.16,128.8 9,126.35,124.80,124.75,123.08,122.28,105.90,99.46,69.64,56.12,9.29,7.50.

[0189] Example 20

[0190] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)isobenzofuran-1(3H)-one (compound 20):

[0191] Compound 20 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromoisobenzofuran-1(3H)-one to prepare compound 20, the structure of which is shown below:

[0192]

[0193] NMR data for compound 20:

[0194] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.64(s,1H),7.23(d,J=8.2Hz,1H) ,6.83(d,J=8.3Hz,1H),6.47(s,1H),5.38(s,2H),4.05(s,3H),2.11–2.04(m,1H),1.05–0.94(m,4H). 13 C NMR (101MHz, CDCl3) δ171.06,162.14,147.29,146.60,145.19,143.47,129.28,128.9 9,125.93,124.92,123.79,123.40,121.25,105.91,99.50,69.61,56.13,9.31,7.56.

[0195] Example 21

[0196] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl))-3-methylisobenzofuran-1(3H)-one (compound 21):

[0197] Compound 21 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-3-methylisobenzofuran-1(3H)-one, and compound 21 was prepared as shown below:

[0198]

[0199] NMR data for compound 21:

[0200] 1 H NMR (400MHz, CDCl3) δ7.95(d,J=7.6Hz,1H),7.71(d,J=7.7Hz,1H),7.57(s,1H),7.23(d,J=8.1Hz,1H),6.83(d,J=8. 0Hz,1H),6.46(s,1H),5.66–5.58(m,1H),4.05(s,3H),2.12–2.02(m,1H),1.69(d,J=6.1Hz,3H),1.06–0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ170.41,162.09,146.60,145.17,143.45,129.26,128.99,125. 85,125.01,123.82,123.38,120.76,105.90,99.53,77.64,56.13,20.49,9.32,7.56.

[0201] Example 22

[0202] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl))-3-ethylisobenzofuran-1(3H)-one (compound 22):

[0203] Compound 22 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromo)-3-ethylisobenzofuran-1(3H)-one (intermediate 22-2), and the structure of compound 22 is shown below:

[0204]

[0205] NMR data for compound 22:

[0206] 1 H NMR (400MHz, CDCl3) δ7.95(d,J=7.6Hz,1H),7.72(d,J=7.6Hz,1H),7.57(s,1H),7.23(d,J=8.0Hz,1H),6.83(d,J= 8.1Hz,1H),6.46(s,1H),5.53–5.47(m,1H),4.05(s,3H),2.25–2.02(m,2H),1,91–1.84(m,1H),1.12–0.92(m,7H). 13 C NMR (101MHz, CDCl3) δ162.10,150.51,146.49,145.17,129.27,129.00,125.85,125 .05,124.39,123.39,120.95,105.90,99.55,82.25,56.14,27.81,9.33,8.98,7.55.

[0207] Synthesis of 5-bromo)-3-ethylisobenzofuran-1(3H)-one (intermediate 22-2):

[0208]

[0209] Compound 22-1, 5-bromo-3-hydroxyisobenzofuran-1(3H)-one (1 mmol, 1.0 equiv.), and ethyl magnesium bromide (1.1 mmol, 1.1 equiv.) were dissolved in anhydrous tetrahydrofuran (5 mL). The mixture was refluxed and stirred for 1 hour under argon protection, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:20 (v / v) as the eluent to give intermediate 22-2 (white solid, yield 86%).

[0210] NMR data for intermediate 22-2:

[0211] 1 H NMR (400MHz, CDCl3) δ7.75(d,J=8.0Hz,1H),7.66(d,J=7.9Hz,1H),7.60(s,1H),5.42(s,1H),2.18–1.78(m,2H),1.00(t,J=7.3Hz,3H). 13C NMR (101MHz, CDCl3) δ 151.43, 132.70, 129.22, 127.01, 125.24, 81.62, 27.54, 8.76. Example 23

[0212] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl))-3-propylisobenzofuran-1(3H)-one (compound 23):

[0213] Compound 23 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromo)-3-propylisobenzofuran-1(3H)-one (intermediate 23-1), and the structure of compound 23 is shown below:

[0214]

[0215] NMR data for compound 23:

[0216] 1 H NMR (400MHz, CDCl3) δ7.93(d,J=7.9Hz,1H),7.70(d,J=7.9Hz,1H),7.56(s,1H),7.22(d,J=8.2Hz,1H),6.82(d,J=8.3Hz,1H ),6.46(s,1H),5.54–5.51(m,1H),4.04(s,3H),2.12–2.00(m,2H),1.84–1.75(m,1H),1.62–1.48(m,2H),1.06–0.92(m,7H). 13 C NMR (101MHz, CDCl3) δ170.59,162.03,150.86,146.42,145.12,143.42,129.17,128.95,125.78,12 5.00,124.13,123.36,120.91,105.87,99.52,81.14,56.09,36.89,18.28,13.79,9.29,7.54,7.51.

[0217] Synthesis of 5-bromo)-3-propylisobenzofuran-1(3H)-one (intermediate 23-1):

[0218]

[0219] Compound 22-1, 5-bromo-3-hydroxyisobenzofuran-1(3H)-one (1 mmol, 1.0 equiv.), and propylmagnesium bromide (1.1 mmol, 1.1 equiv.) were dissolved in anhydrous tetrahydrofuran (5 mL). The mixture was refluxed and stirred for 1 hour under argon protection, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography using ethyl acetate / petroleum ether = 1:20 (v / v) as the eluent to give intermediate 22-2 (white solid, yield 81%).

[0220] NMR data of intermediate 23-1:

[0221] 1 H NMR(400MHz, CDCl3)δ7.74(d,J=8.0Hz,1H),7.65(d,J=7.9Hz,1H),7.60(s,1H),5.49–5.38 (m,1H),2.06–1.90(m,1H),1.81–1.68(m,1H),1.58–1.43(m,2H),0.98(t,J=7.1Hz,3H).). 13 C NMR (101MHz, CDCl3) δ169.58,151.81,132.63,129.18,126.99,125.21,125.09,80.57,36.63,18.15,13.71.

[0222] Example 24

[0223] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl))-3-butylisobenzofuran-1(3H)-one (compound 24):

[0224] Compound 24 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-3-butylisobenzofuran-1(3H)-one (CAS No.: 950681-35-3), and the structure of compound 24 is shown below:

[0225]

[0226] 1H NMR (400MHz, CDCl3) δ7.94(d,J=7.9Hz,1H),7.71(d,J=7.9Hz,1H),7.56(s,1H),7.23(d,J=8.2Hz,1H),6.83(d,J=8.3Hz,1H),6.46(s,1H),5.55– 5.50(m,1H),4.04(s,3H),2.15–2.03(m,2H),1.86–1.78(m,1H),1.56–1 .48(m,2H),1.42–1.36(m,2H),1.05–0.97(m,4H),0.92(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.62,162.07,150.86,146.44,145.15,129.20,128.98,125.82,125.04,12 4.19,123.37,120.93,105.89,99.53,81.34,56.12,34.53,26.92,22.44,13.86,9.31,7.56,7.52.

[0227] Example 25

[0228] Synthesis of 6-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1-methyl-1,2-dihydro-3H-indazole-3-one (compound 25):

[0229] Compound 25 was synthesized according to the method described in Example 1, except that the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 6-bromo-1-methyl-1,2-dihydro-3H-indazole-3-one (CAS No.: 1226985-36-9), and the structure of compound 25 is shown below:

[0230]

[0231] NMR data for compound 25:

[0232] 1 H NMR (400MHz, CDCl3) δ10.73(s,1H),7.69(d,J=8.3Hz,1H),7.51(s,1H),7.29(d,J=8.2Hz,1H),7.18(d,J=8.3 Hz,1H),6.94(d,J=8.3Hz,1H),6.75(s,1H),3.95(s,3H),3.79(s,3H),2.19–2.11(m,1H),1.05–0.89(m,4H). 13C NMR (101MHz, CDCl3) δ161.20,154.58,144.44,143.03,138.83,128.78,126.60,12 3.58,120.72,119.70,111.60,108.35,106.68,100.64,56.19,35.32,9.47,7.78.

[0233] Example 26

[0234] Synthesis of 6-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1H-indazole (compound 26):

[0235] Compound 26 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 6-bromo-1H-indazole to prepare compound 26, the structure of which is shown below:

[0236]

[0237] NMR data of compound 26

[0238] 1 H NMR (400MHz, CDCl3) δ10.67(s,1H),8.15(s,1H),7.84(d,J=8.0Hz,1H),7.43(d,J=7.9Hz,1H),7.25(d ,J=8.0Hz,1H),6.83(d,J=7.7Hz,1H),6.54(s,1H),4.05(s,3H),2.13–2.02(m,1H),1.04–0.94(m,4H). 13 C NMR (101MHz, CDCl3) δ161.50,144.37,140.68,139.24,134.68,129.07,126.7 3,123.05,122.39,122.03,120.79,108.63,105.78,99.91,56.06,9.25,7.40.

[0239] Example 27

[0240] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)-1H-indazole (compound 27):

[0241] Compound 27 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromo-1H-indazole to prepare compound 27, the structure of which is shown below:

[0242]

[0243] NMR data for compound 27:

[0244] 1 H NMR (400MHz, CDCl3) δ10.40(s,1H),8.15(s,1H),7.91(s,1H),7.64–7.56(m,2H),7.21(d,J=8.2 Hz,1H),6.82(d,J=8.2Hz,1H),6.50(s,1H),4.04(s,3H),2.09–2.01(m,1H),1.03–0.91(m,4H). 13 C NMR (101MHz, CDCl3) δ161.39,144.07,143.45,139.20,135.15,133.52,129.06,12 8.13,126.93,123.76,122.82,119.76,109.76,105.82,99.90,56.10,9.27,7.39.

[0245] Example 28

[0246] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)benzo[d]oxazol-2(3H)-one (compound 28):

[0247] Compound 28 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromobenzo[d]oxazol-2(3H)-one to prepare compound 28, the structure of which is shown below:

[0248]

[0249] NMR data for compound 28:

[0250] 1 H NMR(400MHz, CDCl3)δ9.16(d,J=11.3Hz,1H),7.33–7.25(m,3H),7.13(d,J=7.9Hz,1H), 6.80(d,J=7.8Hz,1H),6.45(s,1H),4.03(s,3H),2.15–2.00(m,1H),1.04–0.94(m,4H). 13C NMR (101MHz, CDCl3) δ161.69,155.82,144.43,142.84,136.95,129.56,128.8 4,125.82,122.82,122.78,110.20,109.62,105.78,99.63,56.11,9.28,7.46.

[0251] Example 29

[0252] Synthesis of 6-(2-cyclopropyl-7-methoxybenzofuran-4-yl)benzo[d]oxazol-2(3H)-one (compound 29):

[0253] Compound 29 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 6-bromobenzo[d]oxazol-2(3H)-one to prepare compound 29, the structure of which is shown below:

[0254]

[0255] NMR data for compound 29:

[0256] 1 H NMR(400MHz, CDCl3)δ9.02(s,1H),7.42(s,1H),7.37(d,J=8.0Hz,1H),7.19–7.09(m,2H) ,6.80(d,J=8.2Hz,1H),6.46(s,1H),4.03(s,3H),2.12–2.02(m,1H),1.09–0.91(m,4H). 13 C NMR (101MHz, CDCl3) δ161.70,155.53,144.42,144.30,143.43,135.73,128.80,12 7.82,125.75,124.10,122.69,109.98,109.83,105.81,99.60,56.12,9.28,7.47.

[0257] Example 30

[0258] Synthesis of 5-(2-cyclopropyl-7-methoxybenzofuran-4-yl)indol-2-one (compound 30):

[0259] Compound 30 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromoindol-2-one to prepare compound 30, the structure of which is shown below:

[0260]

[0261] NMR data for compound 30:

[0262] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),7.41(d,J=9.5Hz,2H),7.12(d,J=8.1Hz,1H),6.96(d,J=7.8Hz,1H) ,6.79(d,J=8.2Hz,1H),6.45(s,1H),4.02(s,3H),3.62(s,2H),2.12–1.99(m,2H),1.05–0.96(m,4H). 13 C NMR (101MHz, CDCl3) δ177.48,161.38,144.09,143.42,141.13,134.83,128.71,127.8 0,126.45,125.71,124.55,122.35,109.72,105.76,99.79,56.08,36.32,9.26,7.40.

[0263] Example 31

[0264] Synthesis of 6-(2-cyclopropyl-7-methoxybenzofuran-4-yl)indol-2-one (compound 31):

[0265] Compound 31 was synthesized according to the method described in Example 1, except that in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 6-bromoindol-2-one to prepare compound 31.

[0266]

[0267] NMR data for compound 31:

[0268] 1 H NMR (400MHz, CDCl3) δ9.13(s,1H),7.28(d,J=7.7Hz,1H),7.20(d,J=7.6Hz,1H),7.14(d,J=8.2Hz,1H),7.09 (s,1H),6.78(d,J=8.2Hz,1H),6.48(s,1H),4.02(s,3H),3.59(s,2H),2.09–2.03(m,1H),1.03–0.92(m,4H). 13C NMR (101MHz, CDCl3) δ 177.77, 161.47, 144.41, 143.43, 142.85, 140.43, 128.81, 126.35, 124.68, 123.58, 122.65, 122.34, 109.49, 105.78, 99.86, 56.09, 36.05, 9.27, 7.40. Example 32

[0269] Synthetic route of 5-(2-isopropyl-7-methoxybenzofuran-4-yl)pyridin-2-ol (compound 32):

[0270]

[0271] Compound 32 was synthesized according to the method described in Example 1, except that the cyclopropylformyl chloride in step 3 of Example 1 was replaced with isobutyryl chloride to prepare intermediate 32-1, and intermediate 32-2 was obtained sequentially. Then, the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridin-2-ol to prepare compound 32.

[0272] NMR data for compound 32: 1 H NMR (400MHz, CDCl3) δ13.64(s,1H),7.78(d,J=8.7Hz,1H),7.64(s,1H),7.05(d,J=8.2Hz,1H),6.79(d,J =8.2Hz,1H),6.73(d,J=9.3Hz,1H),6.43(s,1H),4.03(s,3H),3.16–3.09(m,1H),1.36(d,J=6.9Hz,6H). 13 C NMR (101MHz, CDCl3) δ166.05,164.70,144.62,143.68,142.79,132.56,128 .29,121.82,121.75,120.44,120.09,105.99,98.87,56.10,28.27,21.07.

[0273] NMR data for compound 32-1: 1 H NMR (400MHz, CDCl3) δ7.23(d,J=8.5Hz,1H),6.63(d,J=8.5Hz,1H),6.39(s,1H),3.98(s,3H),3.16–3.07(m,1H),1.36(d,J=6.9Hz,6H). 13C NMR (101MHz, CDCl3) δ165.81,144.47,143.32,131.36,125.42,106.86,104.11,100.46,56.22,28.25,20.93.

[0274] NMR data for compound 32-2: 1 H NMR (400MHz, CDCl3) δ7.61(d,J=8.0Hz,1H),6.77(s,1H),6.74(d,J=8.0Hz,1H),4.02(s,3H),3.20–3.06(m,1H),1.40–1.35(m,18H). 13 C NMR (101MHz, CDCl3) δ165.42,147.28,142.85,135.94,131.53,105.14,101.91,83.33,55.90,28.29,24.94,21.09.

[0275] Example 33

[0276] Synthetic route of 5-(2-propyl-7-methoxybenzofuran-4-yl)pyridin-2-ol (compound 33):

[0277]

[0278] Compound 33 was synthesized according to the method described in Example 1, except that in step 3 of Example 1, cyclopropylformyl chloride was replaced with butyryl chloride to prepare intermediate 33-1, and intermediate 33-2 was obtained sequentially. Then, 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridin-2-ol to prepare compound 33.

[0279] NMR data for compound 33: 1 H NMR (400MHz, CDCl3) δ13.60(s,1H),7.77(d,J=8.8Hz,1H),7.64(s,1H),7.05(d,J=8.2Hz,1H),6.78(d,J=8.2Hz,1H ),6.72(d,J=9.3Hz,1H),6.46(s,1H),4.02(s,3H),2.77(t,J=7.4Hz,2H),1.84–1.72(m,2H),1.00(t,J=7.4Hz,3H). 13C NMR (101MHz, CDCl3) δ160.59,144.57,143.75,142.73,132.54,128.36,121. 73,121.65,120.46,120.07,105.86,101.10,56.07(s),30.37,21.12,13.73.

[0280] NMR data for compound 33-1: 1 H NMR(400MHz, CDCl3) δ7.23(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.41(s,1H) ,3.98(s,3H),2.76(t,J=7.5Hz,2H),1.86–1.71(m,2H),1.01(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ160.41,144.43,143.37,131.48,125.47,106.74,103.98,102.54,56.21,30.35,21.00,13.71.

[0281] NMR data for compound 33-2: 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.0Hz,1H),6.82(s,1H),6.74(d,J=8.0Hz,1H),4.02( s,3H),2.78(t,J=7.5Hz,2H),1.87–1.75(m,2H),1.37(s,12H),1.02(t,J=7.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ160.06,147.23,142.90,136.07,131.51,105.02,104.15,83.31,55.86,30.48,24.93,21.25,13.84.

[0282] Example 34

[0283] Synthetic route of 5-(2-cyclobutyl-7-methoxybenzofuran-4-yl)pyridine-2-ol (compound 34):

[0284]

[0285] Compound 34 was synthesized according to the method described in Example 1, except that the cyclopropylformyl chloride in step 3 of Example 1 was replaced with cyclobutylformyl chloride to prepare intermediate 34-1, and intermediate 34-2 was obtained sequentially. Then, the 5-bromophenyl-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridin-2-ol to prepare compound 34.

[0286] NMR data for compound 34: 1 H NMR (400MHz, CDCl3) δ13.67(s,1H),7.80–7.77(m,1H),7.62(d,J=2.2Hz,1H),7.05(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),6 .73(d,J=9.3Hz,1H),6.45(s,1H),4.03(s,3H),3.31–3.20(m,1H),2.16–2.07(m,2H),1.85–1.75(m,4H),1.73–1.65(m,2H). 13 C NMR (101MHz, CDCl3) δ164.68,164.43,144.57,143.75,142.79,132.53,128.32 ,121.73,121.70,120.46,120.08,105.91,99.37,56.10,38.98,31.87,25.32.

[0287] NMR data for compound 34-1: 1 H NMR(400MHz, CDCl3) δ7.22(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),6.40(s,1H),3.98 (s,3H),3.31–3.17(m,1H),2.17–2.06(m,2H),1.87–1.75(m,4H),1.75–1.64(m,2H). 13 C NMR (101MHz, CDCl3) δ164.19,144.39,143.35,131.37,125.37,106.75,103.97,100.88,56.18,38.90,31.73,25.24.

[0288] NMR data for compound 34-2: 1H NMR (400MHz, CDCl3) δ7.61(d,J=8.0Hz,1H),6.80(s,1H),6.74(d,J=8.0Hz,1H),4.02(s,3H) ,3.31–3.20(m,1H),2.16–2.11(m,2H),1.89–1.82(m,4H),1.72–1.65(m,2H),1.37(s,12H). 13 C NMR (101MHz, CDCl3) δ163.72,147.21,142.91,135.96,131.48,105.05,102.43,83.29,55.86,39.06,31.81,25.37,24.91.

[0289] Example 35

[0290] Synthetic route of 5-(2-cyclopentyl-7-methoxybenzofuran-4-yl)pyridine-2-ol (compound 35):

[0291]

[0292] Compound 35 was synthesized according to the method described in Example 1, except that in step 3 of Example 1, cyclopropylformyl chloride was replaced with cyclopentylformyl chloride to prepare intermediate 35-1, and intermediate 35-2 was obtained sequentially. Then, 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridin-2-ol to prepare compound 35.

[0293] NMR data for compound 35: 1 H NMR (400MHz, CDCl3) δ13.57(s,1H),7.80–7.78(m,1H),7.63(d,J=2.0Hz,1H),7.06(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),6 .73(d,J=9.3Hz,1H),6.50(s,1H),4.03(s,3H),3.73–3.64(m,1H),3.41–2.31(m,4H),2.14–2.03(m,1H),2.01–1.92(m,1H). 13 C NMR (101MHz, CDCl3) δ164.63,163.57,144.62,143.78,142.74,132.48,128.30 ,121.76,121.73,120.40,120.09,105.94,99.76,56.07,33.67,27.98,18.60.

[0294] NMR data for compound 35-1: 1 H NMR(400MHz, CDCl3) δ7.23(d,J=8.5Hz,1H),6.63(d,J=8.5Hz,1H),6.45(s,1H),3.98 (s,3H),3.72–3.60(m,1H),2.41–2.33(m,4H),2.13–2.05(m,1H),2.01–1.92(m,1H). 13 C NMR (101MHz, CDCl3) δ163.32,144.46,143.39,131.38,125.42,106.79,104.07,101.24,56.18,33.62,27.87,18.62.

[0295] NMR data for compound 35-2: 1 H NMR (400MHz, CDCl3) δ7.62(d,J=8.0Hz,1H),6.83(s,1H),6.74(d,J=8.0Hz,1H),4. 02(s,3H),3.74–3.65(m,1H),2.43–2.35(m,4H),2.12–1.90(m,2H),1.37(s,12H). 13 C NMR (101MHz, CDCl3) δ162.91,147.27,142.96,135.94,131.51,105.11,102.80,83.31,55.85,33.81,27.93,24.91,18.62.

[0296] Example 36

[0297] Synthetic route of 5-(7-methoxy-2-(methoxymethyl)benzofuran-4-yl)pyridin-2-ol (compound 36):

[0298]

[0299] Compound 36 was synthesized according to the method described in Example 1, except that in step 3 of Example 1, cyclopropylformyl chloride was replaced with 2-methoxyacetyl chloride to prepare intermediate 36-1, and intermediate 36-2 was obtained sequentially. Then, in step 5 of Example 1, 5-bromophenyl-1,3-diol was replaced with 5-bromopyridin-2-ol to prepare compound 36.

[0300] NMR data for compound 36: 1H NMR (400MHz, CDCl3) δ13.39(s,1H),7.80–7.76(m,1H),7.61(s,1H),7.10(d,J=8.2Hz,1H),6.8 5(d,J=8.2Hz,1H),6.78(s,1H),6.72(d,J=9.4Hz,1H),4.58(s,2H),4.03(s,3H),3.45(s,3H). 13 C NMR (101MHz, CDCl3) δ164.53,155.36,144.95,142.61,132.50,127.56,122.34,122.09,120.20,120.06,106.85,104.52,66.83,58.42,56.09.

[0301] NMR data for compound 36-1: 1 H NMR (400MHz, CDCl3) δ7.27(d,J=8.5Hz,1H),6.73(s,1H),6.68(d,J=8.5Hz,1H),4.57(s,2H),3.98(s,3H),3.44(s,3H). 13 CNMR(101MHz, CDCl3)δ155.06,144.81,144.05,130.66,125.87,107.69,105.98,104.51,66.72,58.39,56.19.

[0302] NMR data for compound 36-2: 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.0Hz,1H),7.15(s,1H),6.79(d,J=8.0Hz,1H),4.59(s,2H),4.02(s,3H),3.44(s,3H),1.36(s,12H). 13 C NMR (101MHz, CDCl3) δ154.64,147.65,143.66,135.06,131.85,107.91,105.98,83.39,66.91,58.24,55.87,24.90.

[0303] Example 37

[0304] Synthetic route of 5-(7-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzofuran-4-yl)pyridin-2-ol (compound 37):

[0305]

[0306] Compound 37 was synthesized according to the method described in Example 1, except that in step 3 of Example 1, the cyclopropylformyl chloride was replaced with tetrahydro-2H-pyran-4-carbonyl chloride to prepare 4-bromo-7-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzofuran (intermediate 37-1), which then yielded 2-(7-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate 37-2). Then, in step 5 of Example 1, the 5-bromophenyl-1,3-diol was replaced with 5-bromopyridin-2-ol to prepare compound 37.

[0307] NMR data for compound 37: 1 H NMR (400MHz, CDCl3) δ13.44(s,1H),7.77(d,J=9.1Hz,1H),7.61(s,1H),7.07(d,J=8.1Hz,1H),6.81(d,J=8.2Hz,1H),6.73(d,J =9.3Hz,1H),6.46(s,1H),4.10–4.00(m,5H),3.55(t,J=11.4Hz,2H),3.11–3.04(m,1H),2.09–2.02(m,2H),1.91–1.81(m,2H). 13 C NMR (101MHz, CDCl3) δ162.96,144.67,143.67,142.71,132.49,121.93,120.26,120.19,106.22,99.54,67.41,56.09,34.88,31.0.

[0308] NMR data for compound 37-1: 1 H NMR(400MHz, CDCl3)δ7.24(d,J=8.5Hz,1H),6.64(d,J=8.5Hz,1H),6.42(s,1H),4.10–4.04(m, 2H),3.98(s,3H),3.59–3.51(m,2H),3.08–3.01(m,1H),2.09–2.01(m,2H),1.91–1.81(m,2H). 13 C NMR (101MHz, CDCl3) δ162.67,144.50,143.26,131.09,125.60,107.04,104.17,101.12,67.37,56.18,34.78,30.87.

[0309] NMR data for compound 37-2: 1H NMR (400MHz, CDCl3) δ7.63(d,J=8.0Hz,1H),6.81(s,1H),6.76(d,J=8.0Hz,1H),4.12–4.05(m,2H),4. 02(s,3H),3.57–3.51(m,2H),3.10–3.01(m,1H),2.08–2.02(m,2H),1.96–1.84(m,2H),1.37(s,12H). 13 C NMR (101MHz, CDCl3) δ162.33,147.32,142.80,135.61,131.68,105.34,102.60,83.36,67.54,55.87,34.91,31.07,24.90.

[0310] The specific structures of the compounds prepared in Examples 1-37 above are shown in the table below:

[0311] Table 1. Compound Structures

[0312]

[0313]

[0314]

[0315]

[0316] Example 38: Enzyme inhibitory activity test of phosphodiesterase 4 (PDE4D)

[0317] (1) Establishment of in vitro screening method and model for PDE4D enzyme activity inhibition: The inhibitory activity of PDE4D kinase was detected by time-resolved fluorescence resonance energy transfer method. Apremilast was used as a control drug, and its half-maximal inhibitory rate (IC50) in this model was determined. 50 The value, the result is consistent with the IC reported in multiple literatures. 50 Similar values ​​indicate that the screening model has been successfully constructed.

[0318] (2) Dissolve compounds 1-37 of the present invention separately in DMSO to prepare a 10 mM stock solution. Continue to serially dilute with DMSO and add to the final reaction system, ensuring the DMSO concentration is lower than 1%. The reaction system consists of PDE4D enzyme, BSA (bovine serum albumin), the PDE4D-specific fluorescent substrate FAM-cAMP, and reaction buffer. After all components are mixed together, react at room temperature for 60 minutes. After the reaction, add a specific phosphate-binding antibody and incubate at room temperature for another 60 minutes. Then, detect the fluorescence polarization signal using a SpectraMax M5 multi-functional microplate reader from MD Corporation. The excitation wavelength is 485 nm, and the emission wavelength is 528 nm. Substitute the values ​​into the following formula to calculate the percentage of activity:

[0319] Activity % = {(FP drug – FP background) / (FP enzyme – FP background)} × 100%

[0320] IC of the compound 50 Value testing was conducted, and the dose-response curves of different concentrations of compounds on the enzyme were fitted using nonlinear regression and normalization methods with Prism GraphPad software.

[0321] Table 2. Inhibitory activity of each embodiment against PDE4D (IC50) 50 ,nM) a

[0322]

[0323]

[0324] a Note: All data are averages of three independent experiments.

[0325] b Note: Inhibition rate of PDE4D at a concentration of 100 nM.

[0326] As shown in Table 2, the benzofuran compounds prepared in this invention all exhibit inhibitory activity against PDE4D. Among them, nine compounds have IC50 values... 50 Values ​​less than 60.5 nM; 7 compounds showed satisfactory inhibitory activity against PDE4D (IC50). 50 <40 nM), for example, compound 2 (IC). 50 =6.0nM), 5(IC) 50 =26.2nM), 9(IC) 50 =32.6nM), 10(IC) 50 =37.1nM), 13(IC 50 =6.3nM), 15(IC) 50 =15.1nM) and 20(IC)50 =23.8 nM). Among them, compounds 2 and 13 showed significantly better inhibitory activity against PDE4D than the positive control drug Apremilast (IC50). 50 =10.1 nM). As can be seen from the table, the compounds of the present invention have good PDE4D enzyme inhibitory activity and can be used to treat related diseases mediated by abnormal PDE4 expression.

[0327] Example 39: Toxicity experiment of compound 20 on mouse hippocampal neurons

[0328] Experimental materials: Compound 20 prepared in Example 20, and culture medium containing 10% fetal bovine serum;

[0329] Preparation of culture media containing different concentrations of compound 20: Compound 20 of the present invention is dissolved in DMSO and then added to the culture medium to obtain a mixed solution. The final concentration of compound 20 in the mixed solution is controlled to be 0.625, 1.25, 2.5, 5, 10, 20, 40, and 80 μmol / L, and the volume concentration of DMSO in the mixed solution is 0.1%.

[0330] Experimental Methods: Logarithmic growth phase mouse hippocampal neurons (HT-22 cells) were collected, digested, centrifuged, and resuspended. The cell suspension concentration was adjusted, and the cell suspension was seeded into 96-well plates, with 20,000 cells per well. The culture medium was 10% fetal bovine serum, and the edges of the 96-well plates were filled with sterile PBS. The cells were incubated in an incubator for 12 hours until they were completely adhered. The original culture medium in the wells was removed, and culture medium containing different concentrations of compound 20 was added. The control group (C) wells were filled with 10% fetal bovine serum. The culture medium and DMSO were added to bring the final concentration of the solution in each well to 0.1% DMSO. The plates were then incubated for 48 hours. After the experimental treatment, the 96-well plates were removed from the incubator, and 10% (5 mg / mL) thiazolyl blue solution was added to each well. The plates were incubated for 4 hours, the culture medium was carefully discarded, and 150 μL of DMSO solution was added to each well. The plates were then shaken for 10 minutes using a microplate reader, and the absorbance of each well was measured at 570 nm. The cell viability of each group was calculated. Cell viability = (experimental wells - blank wells) / (control wells - blank wells) × 100%.

[0331] Experimental results are as follows Figure 2 As shown, compound 20 has no obvious toxicity to HT-22 cells.

[0332] Example 40: Effect of Compound 20 on HT-22 Cell Viability in the OGD / R Model

[0333] Experimental materials: Compound 20 prepared in Example 20;

[0334] Preparation of serum-free pure culture medium containing different concentrations of compound 20: The preparation method is the same as in Example 39, except that the culture medium prepared is a serum-free pure culture medium.

[0335] Preparation of sugar-free culture medium containing different concentrations of compound 20: The preparation method is the same as in Example 39, except that the culture medium is sugar-free.

[0336] All the culture media involved in this embodiment contain the same volume concentration of DMSO.

[0337] Experimental methods:

[0338] The OGD / R model is a classic and widely accepted in vitro cell model used to evaluate whether compounds have the ability to combat cerebral ischemia-reperfusion injury. HT-22 is a mouse hippocampal neuronal cell line used to replace primary cultured neurons.

[0339] In this experiment, HT-22 cells were seeded in 96-well plates and cultured overnight in an incubator. They were then divided into the following groups: OGD / R group, drug-treated groups (three different concentrations of OGD / R + compound 20), and control group. HT-22 cells were then subjected to serum deprivation treatment for 1 hour: the liquid in each well was aspirated and replaced with serum-free pure culture medium (the drug-treated groups were replaced with serum-free pure culture medium containing different concentrations of compound 20); after 1 hour of this treatment, the culture medium was aspirated, and the cells were gently washed three times with PBS, then aspirated again and replaced with glucose-free culture medium (the drug-treated groups were replaced with glucose-free culture medium containing different concentrations of compound 20, and the control group was replaced with high-glucose culture medium). The 96-well plates were then placed in an anoxic chamber (the control group was cultured in a normal incubator for 6 hours), and the aeration tube was opened to introduce gas (a mixture of 95% nitrogen and 5% carbon dioxide) for 5 minutes at a rate of 10 L / min. Finally, the aeration tube was closed, and the cells were incubated at 37°C for 6 hours. After the above treatment, remove the 96-well plate and replace the culture medium with normal culture medium (containing 10% fetal bovine serum). After incubation for 24 hours, remove the treated 96-well plate from the incubator, add 10% volume of thiazolyl blue solution (5 mg / mL) to each well, and incubate for 4 hours. Carefully discard the culture medium, add 150 μL of DMSO solution to each well, shake the 96-well plate with a microplate reader for 10 minutes, and measure the absorbance of each well at 570 nm. Then calculate the cell viability of each group. Cell viability = (experimental wells - blank wells) / (control wells - blank wells) × 100%.

[0340] like Figure 3As shown, compound 20 at doses of 0.3125 μmol / L and 0.625 μmol / L reversed the decrease in HT-22 cell viability after OGD modeling. This indicates that compound 20 has a significant therapeutic effect on ischemic stroke (cerebral infarction).

[0341] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A benzofuran compound or a pharmaceutically acceptable salt thereof, characterized in that, The benzofuran compounds include those shown in the following structural formulas:

2. The method for preparing the benzofuran compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: S1. Prepare compounds of formula (III) or formula (IV); S2. The compound shown in Formula 2 is obtained by coupling reaction of compound (III) and compound (VI); or the compound shown in Formula 13 is obtained by coupling reaction of compound (IV) and compound (V); or the compound shown in Formula 20 is obtained by coupling reaction of compound (IV) and compound (VI). The pharmaceutically acceptable salt of the benzofuran compound is prepared by obtaining the compound shown in Formula 2, 13 or 20 and then preparing it through a salt-forming reaction.

3. The use of the benzofuran compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of phosphodiesterase 4 inhibitors.

4. The use of the benzofuran compound of claim 1 or a pharmaceutically acceptable salt thereof as a phosphodiesterase 4 inhibitor in the preparation of a medicament for treating phosphodiesterase 4-related diseases.

5. The application according to claim 4, characterized in that, The phosphodiesterase 4-related diseases are allergic diseases, autoimmune diseases, central nervous system diseases, or diseases caused by local ischemic reflux due to heart failure, shock, and cerebrovascular diseases.

6. A phosphodiesterase 4 inhibitor, characterized in that, Contains the benzofuran compound of claim 1 or a pharmaceutically acceptable salt thereof.

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