Benzofuran compound or pharmaceutically acceptable salt thereof as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a benzofuran compound or pharmaceutically acceptable salt thereof as well as a preparation method and application thereof. The benzofuran compound can obviously inhibit the activity of phosphodiesterase 4, can be used for preparing drugs for treating inflammatory diseases, autoimmune diseases or neuropsychiatric diseases, and is especially used for treating cerebral apoplexy and ischemic dementia related diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and more specifically, relates to benzofuran compounds or pharmaceutically acceptable salts thereof, and preparation methods and applications thereof. Background Art

[0002] Cyclic nucleotide phosphodiesterases (PDEs) can specifically use cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) as substrates, catalyze the hydrolysis of cAMP and / or cGMP to generate the corresponding inactive AMP and / or GMP, control their intracellular concentrations, and thus affect a variety of physiological processes and metabolic functions. The PDEs family contains a total of 11 subtypes (PDE1–PDE11), which can be divided 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). Among them, PDE4 and PDE9 can activate protein kinase A (PKA) and protein kinase G (PKG) pathways by regulating cAMP and cGMP, thereby regulating many physiological activities such as energy metabolism, memory, immune response, vision, olfaction and the growth of various cell types.

[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. A large number of studies have confirmed that PDE4 is widely involved in various activities of brain nerves. PDE4 inhibitors can inhibit the enzymatic activity of PDE4, increase the concentration of cAMP, and then activate the cAMP / PKA / CREB pathway, regulate the concentration of BDNF, promote the growth of nerve cell synapses, increase synaptic plasticity and neuronal survival, and achieve the purpose of improving cognitive function; in addition, the increase in cAMP concentration can inhibit the nuclear transfer of NF-B, and then downregulate the level of intracellular inflammatory factors (such as TNF-α, IL-1 and IL-6, etc.), relieve neuroinflammation, and reduce inflammation-induced neuronal damage and apoptosis. PDE4 inhibitors have been used in the study of many diseases, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, psoriasis, Alzheimer's disease, schizophrenia, depression, etc.

[0004] At present, there are only three PDE4 inhibitors on the market: roflumilast, apremilast and crisaborole. In actual clinical applications, the three PDE4 inhibitors mentioned above all have adverse reactions to varying degrees. It can be seen that there are very few types of PDE4 inhibitors available for selection, and it is still necessary to continue researching and developing new PDE4 inhibitors. 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 pharmaceutically acceptable salts thereof.

[0006] The object of the present invention is to provide a method for preparing a benzofuran compound or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide the use of the benzofuran compound or a pharmaceutically acceptable salt thereof in the preparation of a phosphodiesterase 4 inhibitor.

[0008] Another object of the present invention is to provide the use of the benzofuran compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating phosphodiesterase 4-related diseases.

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

[0010] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0011] The present invention protects a benzofuran compound or a pharmaceutically acceptable salt thereof, wherein the benzofuran compound has a structure represented by formula (I) or formula (II):

[0012]

[0013] C 1-6 In the alkyl group, without R 1 Choose from or C 1-6 Alkyl or poly C 1 indivual -6 Alkyl C oxygen 1- 6, alkoxy 3- base 6 Cycloalkyl; 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 independently selected from H, hydroxyl, carbonyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzyl, C 5-9 Heterocyclic or C 5-9 heteroaryl;

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

[0018] Ar is a five-membered heterocyclic ring, which is unsubstituted or substituted with one or more carbonyl, 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, tetrahydropyrrolyl and hexahydropiperidinyl; C 1-3 The alkyl group is unsubstituted or substituted with one or more C 1-3 Alkoxy substitution;

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

[0021] Ar is a five-membered heterocyclic ring, which is unsubstituted or substituted with one or more carbonyl, C 1-4 The five-membered heterocyclic ring is substituted with an alkyl group, and the heteroatom in the five-membered heterocyclic ring is one or more of an oxygen atom and a nitrogen atom.

[0022] Preferably, when the benzofuran compound is of the structural formula (I), Select from any of the following structures:

[0023] Or, when the benzofuran compound is of the structural formula (II), Select from any of the following structures:

[0024] Preferably, R 1 is a cyclopropane group; when the benzofuran compound is of the structural formula (I), Select from any of the following structures: or

[0025] When the benzofuran compound is of the structural formula (II), The inventors found that when When selected from the above structures, the prepared compound has better phosphodiesterase 4 inhibitory activity.

[0026] More preferably, R 1is a cyclopropane group; when the benzofuran compound is of the structural formula (I), Select from any of the following structures: or

[0027] When the benzofuran compound is of the structural formula (II), The inventors found that when When selected from the above structures, the prepared compound has excellent phosphodiesterase 4 inhibitory activity, and its IC 50 Below 26.3nM.

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

[0029] S1. preparing a compound of formula (III) or a compound of formula (IV);

[0030] S2. A compound of formula (III) or a compound of formula (IV) is coupled with a compound of formula (VI) to obtain a compound of formula (I); or a compound of formula (IV) is coupled with a compound of formula (V) to obtain a compound of formula (II);

[0031]

[0032] Among them, benzene and furan are compound drugs. 2 , learn B (P can be in) 2 or Br; the preparation method of the salt is to obtain the compound represented by formula (I) or formula (II) and then perform a salt-forming reaction to obtain the compound.

[0033] Preferably, the coupling reaction is: mixing the compound of formula (III) or the compound of formula (IV) with the compound of formula (VI), a palladium catalyst and an alkaline reagent in a solvent, reacting at 85 to 95° C. under the protection of an inert gas, and post-treating to obtain the compound of formula (I); or mixing the compound of formula (IV) with the compound of formula (V), a palladium catalyst and an alkaline reagent in a solvent, reacting at 85 to 95° C. under the protection of an inert gas, and post-treating to obtain the compound of formula (II).

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

[0035] Preferably, the alkaline agent is an alkaline agent commonly used in the art; specifically, the alkaline agent includes but is not limited to potassium carbonate and the like.

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

[0038] Additionally, the present invention protects the use of the benzofuran compound or a pharmaceutically acceptable salt thereof in the preparation of a phosphodiesterase 4 inhibitor.

[0039] At the same time, the present invention also protects the use of the benzofuran compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating phosphodiesterase 4-related diseases.

[0040] Preferably, the phosphodiesterase 4-related disease is an allergic disease, an autoimmune disease, a central nervous system disease, or a disease of ischemic regurgitation caused by heart failure, shock, and cerebrovascular disease.

[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; the central nervous system disease is depression, amnesia or dementia.

[0042] The present invention also protects the use of the benzofuran compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating cerebral stroke and ischemic dementia-related diseases.

[0043] The present invention provides a phosphodiesterase 4 inhibitor, comprising any one of the benzofuran compounds of the present invention or a pharmaceutically acceptable salt thereof.

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

[0045] The benzofuran compounds provided by the present invention exhibit good inhibitory activity on PDE4 and can be used to treat related diseases mediated by abnormal expression of PDE4, such as allergic diseases, autoimmune diseases, central nervous system diseases, or local ischemic reflow diseases caused by heart failure, shock and cerebrovascular diseases. At the same time, the benzofuran compounds also have significant therapeutic effects on ischemic cerebral apoplexy (cerebral stroke). BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0048] Figure 3 This is a schematic diagram of the protective effect of the compound prepared in Example 20 on HT-22 cell injury in the oxygen glucose deprivation / reoxygenation model (OGD / R). DETAILED DESCRIPTION

[0049] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

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

[0051] In the present invention, C 1-6 Alkyl refers to a saturated alkyl group having 1 to 6 carbon atoms, including C 1-6 Straight chain alkyl, C 1-6 for example, a straight chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. 1-3 Alkyl groups have a similar explanation, except that the number of carbon atoms is different.

[0052] C 1-6 Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, including C 1-6 Straight chain alkoxy, C 1-6 for example, a straight chain alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a branched chain alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6. 1-3 Alkoxy groups have a similar interpretation, except that the number of carbon atoms is different.

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

[0054] C 3-6 A heterocyclic group refers to a group remaining after removing a hydrogen atom from a monocyclic or condensed ring having 3 to 6 ring atoms, wherein the group contains at least one N, O, or S ring atom, and the remaining ring atoms are C. Such a ring may be saturated or unsaturated (for example, having one or more double bonds), but does not have a completely conjugated π-electron system, such as ethylene oxide, tetrahydropyran ring, tetrahydrofuran ring, tetrahydropyrrole ring, hexahydropiperidine ring, etc. 5-9 A heterocyclic group has a similar interpretation, except that the number of ring atoms is different.

[0055] C 5-9 Heteroaryl refers to the remaining group after removing a hydrogen atom from a single ring or condensed ring with 5 to 9 ring atoms, which contains at least one N, O, or S ring atom, and the remaining ring atoms are C, and has a completely conjugated π-electron system, such as pyrrolyl, furanyl, thienyl, pyridyl, quinolyl, isoquinolyl, etc.

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

[0057] Example 1

[0058] Synthesis 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 (Compound 1-2, CAS No.: 35090-65-4):

[0061] Compound 1-1 6-bromo-2-hydroxy-3-methoxybenzaldehyde (22mmol, 1.0equiv.) was dissolved in methanol (100mL), and sodium borohydride (22mmol, 1.0equiv.) was slowly added in batches under an ice bath. After moving to room temperature and stirring for 6 hours, dilute hydrochloric acid (20mL) was added, and ethyl acetate was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography with ethyl acetate / petroleum ether = 1:5 (V / V) as the eluent to obtain intermediate 1-2 (yield 96%).

[0062] NMR data of intermediate 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 (Compound 1-3):

[0065] Compound 1-2 (20 mmol, 1.0 equiv.) was dissolved in acetonitrile (100 mL), and triphenylphosphonium hydrogen bromide (20 mmol, 1.0 equiv.) was added. The temperature was raised to 82°C and stirred for 3 hours, and the reaction process was monitored by thin layer chromatography (TLC). After the reaction was complete, most of the acetonitrile was evaporated under reduced pressure, an appropriate amount of ethyl acetate was added, and the intermediate 1-3 (white solid, yield 89%) was obtained by filtration.

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

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

[0068] NMR data of intermediate 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 (Compound 1-5):

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

[0072] NMR data of intermediate 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] Compound 1-5 (0.5mmol, 1.0equiv.), 5-bromobenzene-1,3-diol (0.6mmol, 1.2equiv.), Pd(dppf)Cl2 (0.025mmol, 0.05equiv.), potassium carbonate (1mmol, 2equiv.) were dissolved in a dioxane / water mixed solution (dioxane: water = 4:1, 5mL), stirred at 90°C under argon protection for 12 hours, cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography with ethyl acetate / petroleum ether = 1:3 (V / V) as the eluent to obtain compound 1 (white solid, yield 42%).

[0076] NMR data of 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 (101 MHz, 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] Synthesis route of 4-(2-cyclopropyl-7-methoxybenzofuran-4-yl)pyridine (Compound 2):

[0079]

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

[0081] NMR data of 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. The difference from Example 2 is that pyridine-4-boric acid in Example 2 was replaced with pyridine-3-boric acid to prepare compound 3, the structure of which is shown below:

[0086]

[0087] NMR data of 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. The difference from Example 2 is that the pyridine-4-boric acid in Example 2 was replaced with pyrimidine-5-boric acid to prepare compound 4, the structure of which is shown below:

[0092]

[0093] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-2-methylpyridine to prepare compound 5, the structure of which is shown below:

[0098]

[0099] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-2,6-dimethylpyridine to prepare compound 6, the structure of which is shown below:

[0104]

[0105] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 2-bromo-3,5-dimethylpyrazine to prepare compound 7, the structure of which is shown below:

[0110]

[0111] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-2,3-dimethylpyrazine to prepare compound 8, the structure of which is shown below:

[0116]

[0117] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 4-bromopyridine-2-ol to prepare compound 9, the structure of which is shown below:

[0122]

[0123] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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 of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-1-cyclopentylpyridin-2(1H)-one (intermediate 11-2) to prepare compound 11, the structure of which is shown below:

[0134]

[0135] NMR data of 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 (5mmol, 1.0equiv.) was dissolved in DMF (20mL), bromocyclopentane (10mmol, 2.0equiv.) and cesium carbonate (10mmol, 2.0equiv.) were added, and the mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography with 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 4-bromo-1-benzylpyridin-2(1H)-one (CAS No.: 1781092-40-7) to prepare compound 12, the structure of which is shown below:

[0145]

[0146] NMR data of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 13. The results are shown below:

[0151]

[0152] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-6-methylpyridin-2-ol to prepare compound 14, the structure of which is shown below:

[0157]

[0158] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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 of 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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 of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-1-cyclopentylpyridin-2(1H)-one (CAS No.: 1425045-03-9) to prepare compound 17, the structure of which is shown below:

[0175]

[0176] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-1-benzylpyridin-2(1H)-one (CAS No.: 217448-53-8) to prepare compound 18, the structure of which is shown below:

[0181]

[0182] NMR data of 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 (101 MHz, 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 6-bromoisobenzofuran-1(3H)-one to prepare compound 19, the structure of which is shown below:

[0186]

[0187] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromoisobenzofuran-1(3H)-one to prepare compound 20, the structure of which is shown below:

[0192]

[0193] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-3-methylisobenzofuran-1(3H)-one to prepare compound 21. The results are shown below:

[0198]

[0199] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo)-3-ethylisobenzofuran-1(3H)-one (intermediate 22-2) to prepare compound 22, the structure of which is shown below:

[0204]

[0205] NMR data of 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 (1mmol, 1.0equiv.) and ethylmagnesium bromide (1.1mmol, 1.1equiv.) were dissolved in anhydrous tetrahydrofuran (5mL), refluxed and stirred for 1 hour under argon protection, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography with ethyl acetate / petroleum ether = 1:20 (V / V) as the eluent to obtain intermediate 22-2 (white solid, yield 86%).

[0210] NMR data of 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 (101 MHz, 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo)-3-propylisobenzofuran-1(3H)-one (intermediate 23-1) to prepare compound 23, the structure of which is shown below:

[0214]

[0215] NMR data of 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 (1mmol, 1.0equiv.) and propylmagnesium bromide (1.1mmol, 1.1equiv.) were dissolved in anhydrous tetrahydrofuran (5mL), refluxed and stirred for 1 hour under argon protection, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography with ethyl acetate / petroleum ether = 1:20 (V / V) as the eluent to obtain 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-3-butylisobenzofuran-1(3H)-one (CAS No.: 950681-35-3) to prepare compound 24, the structure of which 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] Embodiment 25

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

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

[0230]

[0231] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromo-1H-indazole to prepare compound 27, the structure of which is shown below:

[0242]

[0243] NMR data of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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 of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 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 of 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] Embodiment 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. The difference from Example 1 is that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromoindol-2-one to prepare compound 30, the structure of which is shown below:

[0260]

[0261] NMR data of 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] Embodiment 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, which differed from Example 1 in that 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 6-bromoindol-2-one to prepare Compound 31:

[0266]

[0267] NMR data of 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 (101 MHz, 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] Synthesis route of 5-(2-isopropyl-7-methoxybenzofuran-4-yl)pyridine-2-ol (Compound 32):

[0270]

[0271] Compound 32 was synthesized according to the method described in Example 1, which differed from Example 1 in that cyclopropylcarbonyl chloride in step 3 of Example 1 was replaced with isobutyryl chloride to prepare intermediate 32-1, and intermediate 32-2 was obtained in sequence. 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 32.

[0272] NMR data of 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 of 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 of 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] Embodiment 33

[0276] Synthesis route of 5-(2-propyl-7-methoxybenzofuran-4-yl)pyridine-2-ol (Compound 33):

[0277]

[0278] Compound 33 was synthesized according to the method described in Example 1, which differed from Example 1 in that cyclopropylcarbonyl chloride in step 3 of Example 1 was replaced with butyryl chloride to prepare intermediate 33-1, and intermediate 33-2 was obtained in sequence. 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 33.

[0279] NMR data of 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 of 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 of 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] Embodiment 34

[0283] Synthesis 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, which differed from Example 1 in that cyclopropylcarbonyl chloride in step 3 of Example 1 was replaced with cyclobutylcarbonyl chloride to prepare intermediate 34-1, and intermediate 34-2 was obtained in sequence. 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 34.

[0286] NMR data of 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 of 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 of 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] Embodiment 35

[0290] Synthesis 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, which differed from Example 1 in that cyclopropylcarbonyl chloride in step 3 of Example 1 was replaced with cyclopentylcarbonyl chloride to prepare intermediate 35-1, and intermediate 35-2 was obtained in sequence. 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 35.

[0293] NMR data of 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 of 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 of 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] Embodiment 36

[0297] Synthesis route of 5-(7-methoxy-2-(methoxymethyl)benzofuran-4-yl)pyridine-2-ol (Compound 36):

[0298]

[0299] Compound 36 was synthesized according to the method described in Example 1, which differed from Example 1 in that cyclopropylcarbonyl chloride in step 3 of Example 1 was replaced with 2-methoxyacetyl chloride to prepare intermediate 36-1, and intermediate 36-2 was obtained in sequence. 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 36.

[0300] NMR data of 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 of 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 of 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] Embodiment 37

[0304] Synthesis route of 5-(7-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzofuran-4-yl)pyridine-2-ol (Compound 37):

[0305]

[0306] Compound 37 was synthesized according to the method described in Example 1. The difference from Example 1 is that the cyclopropylcarbonyl chloride in step 3 of Example 1 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), and 2-(7-methoxy-2-(tetrahydro-2H-pyran-4-yl)benzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate 37-2) was obtained in turn. Then, 5-bromobenzene-1,3-diol in step 5 of Example 1 was replaced with 5-bromopyridine-2-ol to prepare compound 37.

[0307] NMR data of 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 of 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 of 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 to 37 above are shown in the following table:

[0311] Table 1 Compound structures

[0312]

[0313]

[0314]

[0315]

[0316] Example 38 Phosphodiesterase 4 (PDE4D) Enzyme Inhibition Activity Test

[0317] (1) Establishment of an in vitro screening method and model for PDE4D enzyme activity inhibition: The inhibitory activity of PDE4D kinase was detected using the time-resolved fluorescence resonance energy transfer method, and Apremilast was used as a control drug to determine its half inhibition rate IC in this model. 50 The results are consistent with the IC values ​​reported in many literatures. 50 The values ​​are similar, indicating that the screening model was successfully constructed.

[0318] (2) Dissolve the compounds 1 to 37 of the present invention in DMSO to prepare a 10 mM stock solution, continue to dilute with DMSO in a gradient, and add it to the final reaction system to ensure that the concentration of DMSO should be lower than 1%. The reaction system consists of PDE4D enzyme, BSA (bovine serum albumin), PDE4D-specific fluorescent substrate FAM-cAMP, and reaction buffer. When all the components are mixed together, react at room temperature for 60 minutes. After the reaction is completed, add a specific phosphate-binding antibody and incubate at room temperature for another 60 minutes. Then use MD's SpectraMaxM5 multifunctional microplate reader to detect the fluorescence polarization signal, with an excitation wavelength of 485 nm and an emission wavelength of 528 nm. Substitute the values ​​into the following formula to calculate the activity percentage:

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

[0320] IC of the compound 50 The inhibition rate of different concentrations of compounds on the enzyme was tested by Prism GraphPad software, and the dose-effect curve was fitted by nonlinear regression and normalization method.

[0321] Table 2 Inhibitory activity of each example on PDE4D (IC 50 ,nM) a

[0322]

[0323]

[0324] a Note: All data are the average 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 by the present invention all have inhibitory activity against PDE4D. Among them, 9 compounds have IC 50 The value was less than 60.5 nM; 7 compounds showed satisfactory inhibitory activity against PDE4D (IC 50 <40 nM), such as compound 2 (IC 50 =6.0 nM), 5 (IC 50 =26.2nM), 9(IC 50 =32.6nM), 10(IC 50 =37.1 nM), 13 (IC 50 =6.3nM), 15(IC 50 =15.1nM) and 20(IC50 =23.8 nM)). Among them, the inhibitory activity of compounds 2 and 13 on PDE4D was significantly better than that of the positive control drug Apremilast (IC 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 expression of PDE4.

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

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

[0329] Preparation of culture medium containing different concentrations of compound 20: The compound 20 of the present invention was 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 was 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 was 0.1%.

[0330] Experimental method: Mouse hippocampal neuron cells (HT-22 cells) in the logarithmic growth phase were collected for digestion, centrifugation, resuspending, and adjusting the concentration of the cell suspension. The cell suspension was inoculated into a 96-well plate, with 20,000 cells per well. The culture medium was a culture medium containing 10% fetal bovine serum, and the edge of the 96-well plate was filled with sterile PBS; incubated in an incubator for 12 hours until the cells were completely attached to the wall; the original culture medium in the well was removed, and the culture medium containing different concentrations of compound 20 was added. The control group (C) wells were added with a culture medium containing 10% fetal bovine serum. The culture medium and DMSO were added to make the final concentration of the solution in the wells 0.1% DMSO; then placed in an incubator for 48 hours; the 96-well plate treated with the experiment was taken out of the incubator, 10% volume of thiazolyl blue solution (5 mg / mL) was added to each well, and placed in an incubator for 4 hours, the culture medium was carefully discarded, DMSO (150 μL) solution was added to each well, and the 96-well plate was shaken for 10 minutes using an ELISA reader, and the absorbance value of each well was measured at a wavelength of 570 nm using an ELISA reader, and then the cell survival rate of each group was calculated. Cell survival rate = (experimental well - blank well) / (control well - blank well) × 100%.

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

[0332] Example 40 Effect of Compound 20 on HT-22 Cell Viability in 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 consistent with that of Example 39, except that the prepared culture medium is serum-free pure culture medium;

[0335] Preparation of sugar-free culture medium containing different concentrations of Compound 20: The preparation method is consistent with that of Example 39, except that the prepared culture medium is a sugar-free culture medium.

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

[0337] Experimental methods:

[0338] The OGD / R model is a classic and well-recognized in vitro cell model for evaluating whether compounds have the ability to protect against 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 a 96-well plate and cultured overnight in an incubator, and then divided into the following groups: OGD / R group, drug administration group (three different concentrations of OGD / R + compound 20 groups) and control group. Then, HT-22 cells were subjected to serum deprivation treatment for 1 hour: the liquid in each group of wells was aspirated and replaced with serum-free pure culture medium (the drug administration group was replaced with serum-free pure culture medium containing different concentrations of compound 20); after the above treatment for 1 hour, the culture medium was aspirated, PBS was added and gently shaken for washing 3 times, and then aspirated and replaced with sugar-free culture medium (the drug administration group was replaced with sugar-free culture medium containing different concentrations of compound 20, and the control group was replaced with high-glucose culture medium), and then the 96-well plate was placed in an anoxic chamber for sealing (among which, the control group was placed in a normal incubator for 6 hours), and the ventilation tube was opened to pass gas (95% nitrogen and 5% carbon dioxide mixed gas) for 5 minutes, and the ventilation rate was 10L / min, and finally the ventilation tube was closed and placed in a 37°C incubator for 6 hours. After the above treatment, the 96-well plate was taken out, and the culture medium was replaced with normal culture medium (culture medium containing 10% fetal bovine serum). After incubation for 24 hours, the 96-well plate treated with the experiment was taken out from the incubator, and 10% volume of thiazolyl blue solution (5 mg / mL) was added to each well, and the plate was placed in the incubator for incubation for 4 hours. The culture medium was carefully discarded, and 150 μL of DMSO solution was added to each well. The 96-well plate was shaken for 10 minutes using an ELISA reader, and the absorbance value of each well was measured at a wavelength of 570 nm using an ELISA reader, and then the cell survival rate of each group was calculated. Cell survival rate = (experimental well - blank well) / (control well - blank well) × 100%.

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

[0341] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A benzofuran compound or a pharmaceutically acceptable salt thereof, characterized in that: The benzofuran compound has a structure shown in formula (I) or formula (II): Among them, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 One of the heterocyclic groups; C 1-6 The alkyl group is unsubstituted or substituted with one or more C 1-6 Alkoxy substitution; X, Y, Z, and A are each independently selected from C and N; R 2 Selected from H, hydroxyl or C 1-6 alkyl; R 3 , R 4 Each independently selected from H, hydroxyl, carbonyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzyl, C 5-9 Heterocyclic or C 5-9 heteroaryl; R 5 , R 6 Each independently selected from H or C 1-6 alkyl; Ar is a five-membered heterocyclic ring, which is unsubstituted or substituted with one or more carbonyl, C 1-6 Alkyl substitution.

2. The benzofuran compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R 1 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-5 One of cycloalkyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyrrolyl and hexahydropiperidinyl; C 1-3 The alkyl group is unsubstituted or substituted with one or more C 1-3 Alkoxy substitution; R 3 , R 4 Each independently selected from H, hydroxyl, carbonyl, C 1-3 Alkyl, C 3-5 Cycloalkyl, benzyl; Ar is a five-membered heterocyclic ring, which is unsubstituted or substituted with one or more carbonyl, C 1-4 The five-membered heterocyclic ring is substituted with an alkyl group, and the heteroatom in the five-membered heterocyclic ring is one or more of an oxygen atom and a nitrogen atom.

3. The benzofuran compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: When the benzofuran compound is of the structural formula (I), Select from any of the following structures: Or, when the benzofuran compound is of the structural formula (II), Select from any of the following structures:

4. The benzofuran compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The R 1 is cyclopropane; When the benzofuran compound is of the structural formula (I), Select from any of the following structures: When the benzofuran compound is of the structural formula (II), for 5. The benzofuran compound or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: The R 1 is cyclopropane; When the benzofuran compound is of the structural formula (I), Select from any of the following structures: When the benzofuran compound is of the structural formula (II), for 6. The method for preparing the benzofuran compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The steps include: S1. preparing a compound of formula (III) or a compound of formula (IV); S2. A compound of formula (III) or a compound of formula (IV) is reacted with a compound of formula (VI) to obtain a compound of formula (I); Or the compound represented by formula (II) is obtained by coupling reaction of the compound represented by formula (IV) and the compound represented by formula (V); Wherein, W is B(OH)2, B(Pin)2 or Br; The method for preparing the pharmaceutically acceptable salt of the benzofuran compound is to obtain the compound represented by formula (I) or formula (II) and then perform a salt-forming reaction to prepare the salt.

7. Use of the benzofuran compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a phosphodiesterase 4 inhibitor.

8. Use of the benzofuran compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a medicament for treating phosphodiesterase 4-related diseases.

9. The use according to claim 8, characterized in that: The phosphodiesterase 4-related diseases are allergic diseases, autoimmune diseases, central nervous system diseases, or ischemic reflow diseases caused by heart failure, shock and cerebrovascular disease.

10. A phosphodiesterase 4 inhibitor, characterized in that Containing the benzofuran compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

Images