Benzofuro [3, 2-d] pyrazolo [1, 5-a] pyrimidine compound as well as synthesis method and application thereof

Abstract

The invention discloses a benzofuro [3, 2-d] pyrazolo [1, 5-a] pyrimidine compound as well as a synthesis method and application thereof, and relates to the technical field of organic synthesis and medicinal chemistry, the synthesis method of the compound comprises the following steps: in the presence of a catalyst and alkali, mixing a salicylaldehyde compound, a terminal alkyne compound and an alpha-aminoazole compound in a solvent for reaction, and separating to obtain the benzofuro [3, 2-d] pyrazolo [1, 5-a] pyrimidine compound. The benzofuro [3, 2-d] pyrazolo [1, 5-a] pyrimidine compound is obtained through the reaction. The furo [3, 2-d] pyrimidine compound is prepared by taking a salicylaldehyde compound, a terminal alkyne compound and an alpha-aminoazole compound as initial raw materials through a one-pot method, the reaction condition is mild, the raw materials are cheap and easy to obtain, the operation is simple and convenient, the production cost can be greatly reduced, and the production efficiency is improved; the furo [3, 2-d] pyrimidine compound has remarkable antifungal activity on plant pathogenic fungi, and can be applied to inhibition of fungi such as apple black beetle fungus and rhizoctonia solani.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and medicinal chemistry, and particularly to benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds, their synthesis methods, and their applications. Background Technology

[0002] Fused heterocyclic compounds play an important role in drug and pesticide development due to their wide range of biological activities. Among them, benzofuran and pyrazolo[1,5-a]pyrimidine structural units are recognized as dominant pharmacophores and are widely found in a variety of marketed drugs and candidate compounds, such as the anti-psoriasis drug methoxsalen, the antidepressant vilazorone, the antiarrhythmic drug amiodarone, the antitumor candidate amuvatinib, and the hypnotic drug zaleplon.

[0003] Drug design strategies based on the principle of integration, which combine benzofuran and pyrazolo[1,5-a]pyrimidine into a single rigid polycyclic system (such as benzofuran[3,2-d]pyrazolo[1,5-a]pyrimidine), hold promise for generating novel chemical spaces and achieving synergistic optimization of target affinity and metabolic stability. However, currently, efficient synthetic methods for this core scaffold are extremely limited, severely restricting its structure-activity relationship and bioactivity studies.

[0004] In existing literature, the only method for constructing this framework relies on a copper-mediated tandem reaction of 3-chlorocryocystone and 1H-pyrazole-5-amine. While this method is instructive, it requires stoichiometric metal reagents and prefunctionalized substrates, is cumbersome, and has low atom economy, limiting its practical application.

[0005] Multicomponent reactions are an important tool for the rapid and efficient construction of complex molecules. Through retrosynthetic analysis of the target tetracyclic structure, we propose using salicylaldehyde, a terminal alkyne, and 3-aminopyrazole as starting materials. A³ coupling generates a key propyneamine intermediate, followed by oxidative activation to achieve 1,2-nitrogen-oxygen bifunctionalization of the alkyne, constructing two heterocycles—furan and pyrimidine—in one step, ultimately leading to the efficient synthesis of the target benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compound. This strategy successfully solves the challenges of nucleophilic polarity mismatch and regioselectivity control in traditional A³ coupling reactions. Summary of the Invention

[0006] Based on the technical problems existing in the background art, the present invention proposes benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds, their synthesis methods and applications. The compounds have novel structures and significant biological activities, and can be used to inhibit plant pathogenic fungi. Moreover, the synthesis method is simple and efficient.

[0007] This invention proposes a benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compound, the chemical structural formula of which is shown in formula (I):

[0008] (I)

[0009] Among them, R 1 It is one of hydrogen, methyl, halogen, methoxy, and naphthyl;

[0010] R 2 It is one of phenyl, halogenated phenyl, biphenyl, naphthyl, benzyl, benzoxy, pyridyl, and thiophene;

[0011] R 3 It is one of ethyl ester group, methyl ester group, phenyl and halogen-substituted phenyl.

[0012] This invention proposes a method for synthesizing benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds, the compounds of which are as described above. The method steps are as follows: in the presence of a catalyst and a base, a salicylaldehyde compound, a terminal alkyne compound, and an α-aminoazole compound are mixed and reacted in a solvent to obtain a benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compound.

[0013] Preferably, the chemical structural formula of the salicylaldehyde compound is shown in formula (II):

[0014] (II)

[0015] Among them, R 1 It is one of hydrogen, methyl, halogen, methoxy, and naphthyl.

[0016] Preferably, the chemical structural formula of the terminal alkyne compound is shown in formula (Ⅲ):

[0017] (III)

[0018] Among them, R 2 It is one of phenyl, halogenated phenyl, biphenyl, naphthyl, benzyl, benzoxy, pyridyl, and thiophene.

[0019] Preferably, the chemical structural formula of the α-aminoazole compound is shown in formula (IV):

[0020] (IV)

[0021] Among them, R 3 It is one of ethyl ester group, methyl ester group, phenyl and halogen-substituted phenyl.

[0022] Preferably, the catalyst is a monovalent copper salt or a divalent copper salt.

[0023] Preferably, the alkali is cesium carbonate or cesium fluoride.

[0024] Preferably, the solvent is 2-methyltetrahydrofuran or 1,4-dioxane.

[0025] Preferably, the molar ratio of the salicylaldehyde compound, the terminal alkyne compound, and the α-aminoazole compound is 1:1-3:1-3.

[0026] Preferably, the reaction conditions are: temperature 100-130℃, time 12-24h.

[0027] The present invention relates to the application of the above-mentioned benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds in the preparation of drugs or fungicides that inhibit plant pathogenic fungi.

[0028] Beneficial technical effects of the present invention:

[0029] (1) Excellent synthesis method: The one-pot multi-component series reaction is adopted. The raw materials are cheap and readily available, the reaction conditions are mild, the operation is simple, the atom economy is high, no intermediate separation is required, it is suitable for large-scale production, and the production cost can be greatly reduced.

[0030] (2) Novel compound structure: The provided benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds have novel polycyclic fused heteroaromatic structures, enriching the chemical library of heterocyclic compounds.

[0031] (3) Significant biological activity: These compounds exhibit significant in vitro inhibitory activity against a variety of plant pathogenic fungi, such as apple black rot fungus, staphylococcus aureus, rapeseed sclerotium rot fungus, and rice sheath blight fungus. Some compounds have better inhibitory effects than the commercial fungicide thifluzamide (TFZ), and have the potential to be developed into new agricultural fungicides. Detailed Implementation

[0032] The present invention will be further explained below with reference to specific embodiments.

[0033] This invention proposes a benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compound, the chemical structural formula of which is shown in formula (I):

[0034] (I)

[0035] Among them, R 1 It is one of hydrogen, methyl, halogen, methoxy, and naphthyl; R 2It is one of phenyl, halogenated phenyl, biphenyl, naphthyl, benzyl, benzoxy, pyridyl, and thiophene; R 3 It is one of ethyl ester group, methyl ester group, phenyl and halogen-substituted phenyl.

[0036] In embodiments of the present invention, the benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds are selected from the following compounds:

[0037]

[0038] Example 1

[0039] The reactant terminal alkyne compound (R) 2 4-Methylphenyl (0.5 mmol), CuTc (20 mol%), 4,4'-di-tert-butyl-2,2'-bipyridine (20 mol%), Cs2CO3 (0.3 mmol), α-aminoazoles (R 3 The compounds were ethyl 4-formate (0.5 mmol) and salicylaldehydes (R... 1 0.3 mmol of hydrogen was placed in an oven-dried 25 mL Schlenk tube, and 3 mL of 2-methyltetrahydrofuran was added. The system was evacuated and oxygen was purged. The reaction system was placed in an oil bath and stirred at room temperature for 10 minutes, followed by heating to 120 °C and reacting for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate, v / v ratio 4:1) to obtain the target product 10-p-tolylbenzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (compound designated I-1) in 70% yield.

[0040] (I-1)

[0041] 1 H NMR (600 MHz, CDCl3) δ 8.64 (s, 1H), 8.43 (d, J = 12.0 Hz, 1H), 8.17 (d, J = 6.0 Hz, 2H), 7.69 (t, J = 6.0 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.48 (t, J = 12.0 Hz, 3H), 4.48 (q, J = 6.0 Hz, 2H), 2.51 (s, 3H), 1.47 (t, J= 6.0 Hz, 3H).

[0042] 13C NMR (151 MHz, CDCl3) δ 162.92, 161.12, 150.09, 148.06, 147.48,142.34, 138.60, 132.71, 131.75, 130.67, 129.48, 124.26, 123.85, 123.00,121.57, 112.51, 101.49, 60.27, 21.79, 14.61.

[0043] HRMS (ESI): calcd for C 22 H 17 N3O3[M+H] + 372.1343, found 372.1341.

[0044] Example 2

[0045] In equimolar amounts of salicylaldehyde compounds (R 1 (replace 5-fluoro) with the salicylaldehyde derivative (R) in Example 1 1 (The reactants were hydrogen-containing), and all other raw materials and amounts, operating procedures, and reaction conditions were the same as in Example 1, yielding ethyl 6-fluoro-10-p-tolylbenzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-2), in a yield of 61%.

[0046] (I-2)

[0047] 1 H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 8.17 (d, J = 6.0 Hz, 2H), 8.10 (d, J = 6.0 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J = 12.0 Hz, 2H), 7.44 – 7.40 (m,1H), 4.49 (q, J = 6.0 Hz, 2H), 2.52 (s, 3H), 1.47 (t, J = 6.0 Hz, 3H).

[0048] 13C NMR (151 MHz, CDCl3) δ 162.97, 159.57 (d, JCF = 243.0 Hz), 157.19,148.12, 147.91, 142.71, 139.61, 132.30, 130.80, 129.67, 122.94, 122.81 (d,JCF = 9.0 Hz), 120.54 (d, JCF = 25.5 Hz), 113.71 (d, JCF = 9.0 Hz), 109.68 (d,JCF = 25.5 Hz), 101.85, 60.50, 21.95, 14.74.

[0049] HRMS (ESI): calcd for C 22 H 16 FN3O3[M+H] + 390.1248, found 390.1247.

[0050] Example 3

[0051] In equimolar amounts of salicylaldehyde compounds (R 1 (replace 5-methyl) in Example 1 with the salicylaldehyde derivative (R) 1 (The original text contains hydrogen), and other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 6-methyl-10-p-tolylbenzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-3), with a yield of 61%.

[0052] (I-3)

[0053] 1 H NMR (600 MHz, CDCl3) δ 8.63 (s, 1H), 8.22 (s, 1H), 8.17 (d, J = 6.0Hz, 2H), 7.48 (d, J = 6.0 Hz, 3H), 7.45 (d, J = 12.0 Hz, 1H), 4.48 (q, J =6.0 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 3H), 1.47 (t, J = 6.0 Hz, 3H).

[0054] 13C NMR (151 MHz, CDCl3) δ 162.94, 159.61, 150.14, 148.00, 147.40,142.24, 138.89, 134.10, 133.96, 131.57, 130.65, 129.46, 123.49, 123.09, 121.50, 112.00, 101.42, 60.23, 21.78, 21.23, 14.63.

[0055] HRMS (ESI): calcd for C 23 H 19 N3O3[M+H] + 386.1499, found 386.1499.

[0056] Example 4

[0057] In equimolar amounts of salicylaldehyde compounds (R 1 (replace 5-methoxy) in Example 1 with the salicylaldehyde derivative (R) 1 (The original text contains hydrogen), and other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 6-methoxy-10-(p-tolyl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-4), with a yield of 45%.

[0058] (I-4)

[0059] 1 H NMR (600 MHz, CDCl3) δ 8.62 (s, 1H), 8.16 (d, J = 6.0 Hz, 2H), 7.85(s, 1H), 7.50 – 7.43 (m, 3H), 7.28 (d, J = 6.0 Hz, 1H), 4.48 (q, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.51 (s, 3H), 1.46 (t, J = 6.0 Hz, 3H).

[0060] 13C NMR (151 MHz, CDCl3) δ 162.90, 156.73, 156.03, 150.22, 148.03,147.37, 142.31, 139.26, 131.77, 130.66, 129.47, 123.03, 122.54, 121.87,113.24, 104.50, 101.25, 60.24, 56.16, 21.79, 14.64.

[0061] HRMS (ESI): calcd for C 23 H 19 N3O4[M+H] + 402.1448, found 402.1447.

[0062] Example 5

[0063] In equimolar amounts of salicylaldehyde compounds (R 1 (replace phenylnaphthalene) with the salicylaldehyde derivative (R) in Example 1. 1 (The original text contains hydrogen), and other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 8-p-tolylnaphtho[1',2':4,5]furano[3,2-d]pyrazolo[1,5-a]pyrimidine-12-carboxylate (compound designated I-5), with a yield of 72%.

[0064] (I-5)

[0065] 1 H NMR (600 MHz, CDCl3) δ 9.40 (d, J = 6.0 Hz, 1H), 8.69 (s, 1H), 8.22 (d, J = 12.0 Hz, 2H), 8.12 (d, J = 6.0 Hz, 1H), 8.00 (d, J = 12.0 Hz, 1H),7.83 (t, J = 6.0 Hz, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.63 (t, J = 6.0 Hz, 1H),7.52 (d, J = 12.0 Hz, 2H), 4.53 (q, J = 6.0 Hz, 1H), 2.53 (s, 2H), 1.56 (t, J= 6.0 Hz, 2H).

[0066] 13C NMR (151 MHz, CDCl3) δ 163.22, 160.89, 150.72, 148.24, 147.61,142.29, 138.36, 134.56, 131.64, 130.75, 130.43, 129.50, 129.12, 128.75,128.66, 126.09, 125.09, 123.09, 114.89, 112.40, 101.28, 60.15, 21.80, 14.58.

[0067] HRMS (ESI): calcd for C 26 H 19 N3O3[M+H] + 422.1499, found 422.1498.

[0068] Example 6

[0069] Equimolar amounts of terminal alkyne compounds (R 2 (replace phenyl) in Example 1 with the terminal alkyne derivative (R) 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 10-phenylbenzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-6) in a yield of 64%.

[0070] (I-6)

[0071] 1 H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.44 (d, J = 12.0 Hz, 1H), 8.27 (d, J = 6.0 Hz, 2H), 7.73 – 7.64 (m, 4H), 7.59 (d, J = 6.0 Hz, 1H), 7.50 (t, J = 6.0 Hz, 1H), 4.49 (q, J = 6.0 Hz, 2H), 1.48 (t, J = 6.0 Hz, 3H).

[0072] 13C NMR (151 MHz, CDCl3) δ 162.89, 161.20, 150.26, 148.03, 147.51,138.69, 132.84, 131.65, 131.45, 130.74, 128.77, 125.96, 124.34, 123.90,121.52, 112.55, 101.65, 60.31, 14.61.

[0073] HRMS (ESI): calcd for C 21 H 15 N3O3[M+H] + 358.1186, found 358.1184.

[0074] Example 7

[0075] Equimolar amounts of terminal alkyne compounds (R 2 (4-Chlorophenyl) replaces the terminal alkyne derivative (R) in Example 1 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 10-(4-chlorophenyl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-7), with a yield of 60%.

[0076] (I-7)

[0077] 1 H NMR (600 MHz, CDCl3) δ 8.64 (s, 1H), 8.43 (d, J = 12.0 Hz, 1H), 8.28 (d, J = 6.0 Hz, 2H), 7.72 (t, J = 6.0 Hz, 1H), 7.66 (d, J = 12.0 Hz, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.50 (t, J = 6.0 Hz, 1H), 4.48 (q, J = 6.0 Hz, 2H), 1.47 (t, J = 6.0 Hz, 3H).

[0078] 13C NMR (151 MHz, CDCl3) δ 162.79, 161.14, 150.26, 147.98, 147.46,138.56, 137.87, 132.97, 132.18, 130.17, 129.13, 124.47, 124.36, 123.93,121.42, 112.53, 101.84, 60.36, 14.59.

[0079] HRMS (ESI): calcd for C 21 H 14 ClN3O3[M+H] + 392.0796, found 392.0794.

[0080] Example 8

[0081] Equimolar amounts of terminal alkyne compounds (R 2 (3-Chlorophenyl) replaces the terminal alkyne derivative (R) in Example 1 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 10-(3-chlorophenyl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-8), with a yield of 65%.

[0082] (I-8)

[0083] 1 H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.43 (d, J = 12.0 Hz, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.72 (t, J = 6.0 Hz, 1H), 7.65 – 7.59 (m, 3H), 7.51 (t, J = 12.0 Hz, 1H), 4.48 (q, J = 6.0 Hz, 2H), 1.47 (t, J = 6.0 Hz, 3H).

[0084] 13C NMR (151 MHz, CDCl3) δ 162.77, 161.20, 150.37, 147.92, 147.50,138.65, 134.82, 133.05, 131.68, 130.69, 130.01, 129.68, 128.94, 127.60,124.51, 123.92, 121.37, 112.61, 101.93, 60.37, 14.59.

[0085] HRMS (ESI): calcd for C 21 H 14 ClN3O3[M+H] + 392.0796, found 392.0796.

[0086] Example 9

[0087] Equimolar amounts of terminal alkyne compounds (R 2 (3-Bromophenyl) replaces the terminal alkyne derivative (R) in Example 1. 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 10-(3-bromophenyl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-9), with a yield of 62%.

[0088] (I-9)

[0089] 1 H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.45 – 8.41 (m, 2H), 8.23 ​​(d,J = 6.0 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.75 – 7.71 (m, 1H), 7.61 (d, J =6.0 Hz, 1H), 7.56 (t, J = 6.0 Hz, 1H), 7.53 – 7.48 (m, 1H), 4.48 (q, J = 6.0Hz, 2H), 1.47 (t, J = 6.0 Hz, 3H).

[0090] 13C NMR (151 MHz, CDCl3) δ 162.90, 161.33, 150.50, 148.04, 147.64,138.78, 134.71, 133.60, 133.18, 130.34, 129.69, 129.51, 127.97, 124.64,124.05, 122.86, 121.49, 112.75, 102.06, 60.51, 14.72.

[0091] HRMS (ESI): calcd for C 21 H 14 BrN3O3[M+H] + 436.0291, found 436.0287.

[0092] Example 10

[0093] Equimolar amounts of terminal alkyne compounds (R 2 (4-Biphenyl) replaces the phenylacetylene derivative (R) in Example 1. 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding 10-([1,1'-biphenyl]-4-yl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (compound designated I-10) in a yield of 81%.

[0094] (I-10)

[0095] 1 H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.39 (d, J = 6.0 Hz, 2H), 7.91 (d, J = 12.0 Hz, 2H), 7.74 – 7.70 (m, 3H), 7.62 (d,J = 6.0 Hz, 1H), 7.54 – 7.49 (m, 3H), 7.46 – 7.42 (m, 1H), 4.50 (q, J = 12.0Hz, 2H), 1.48 (t, J = 12.0 Hz, 3H).

[0096] 13C NMR (151 MHz, CDCl3) δ 162.90, 161.18, 150.21, 148.09, 147.52,144.48, 140.02, 138.72, 132.84, 131.25, 131.24, 129.04, 128.24, 127.43,127.32, 124.73, 124.37, 123.92, 121.55, 112.56, 101.67, 60.33, 14.62.

[0097] HRMS (ESI): calcd for C 27 H 19 N3O3[M+H] + 434.1499, found 434.1495.

[0098] Example 11

[0099] Equimolar amounts of terminal alkyne compounds (R 2 (replace the naphthyl group) in Example 1 with the terminal alkyne derivative (R). 2 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, yielding ethyl 10-(naphth-2-yl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-11), with a yield of 83%.

[0100] (I-11)

[0101] 1 H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H), 8.68 (s, 1H), 8.46 (d, J =12.0 Hz, 1H), 8.29 (d, J = 12.0 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 8.05 (d, J= 12.0 Hz, 1H), 7.97 (d, J = 12.0 Hz, 1H), 7.71 (t, J = 6.0 Hz, 1H), 7.65 (t,J = 6.0 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.51 (t, J = 6.0 Hz, 1H), 4.50 (q, J =6.0 Hz, 2H), 1.49 (t, J = 6.0 Hz, 3H).

[0102] 13C NMR (151 MHz, CDCl3) δ 163.04, 161.34, 150.36, 148.22, 147.68,139.03, 134.67, 132.94, 132.87, 132.11, 131.70, 129.26, 128.51, 128.45,128.03, 127.07, 126.48, 124.47, 124.04, 123.39, 121.70, 112.70, 101.81,60.44, 14.74.

[0103] HRMS (ESI): calcd for C 25 H 17 N3O3[M+H] + 408.1343, found 408.1340.

[0104] Example 12

[0105] The reactants included 3-pyridyne compounds (0.5 mmol), CuTc (20 mol%), 4,4'-di-tert-butyl-2,2'-bipyridine (20 mol%), Cs₂CO₃ (0.3 mmol), and 3-aminopyrazole compounds (R). 3 The compounds were ethyl 4-formate (0.5 mmol) and salicylaldehydes (R... 1 0.3 mmol of hydrogen was placed in an oven-dried 25 mL Schlenk tube, and 3 mL of 2-methyltetrahydrofuran was added. The system was evacuated and oxygen was purged. The reaction system was placed in an oil bath and stirred at room temperature for 10 minutes, followed by heating to 120 °C and reacting for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate, v / v) to give the target product ethyl 10-(pyridin-3-yl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-12) in 55% yield.

[0106] (I-12)

[0107] 1H NMR (600 MHz, CDCl3) δ 9.53 (s, 1H), 8.86 (s, 1H), 8.73 (d, J =12.0 Hz, 1H), 8.63 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.71 (d, J = 6.0 Hz,1H), 7.65 – 7.61 (m, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.50 (t, J = 6.0 Hz, 1H), 4.47 (q, J = 6.0 Hz, 2H), 1.47 (t, J = 6.0 Hz, 3H).

[0108] 13 C NMR (151 MHz, CDCl3) δ 162.69, 161.22, 151.98, 151.32, 150.36,147.86, 147.47, 138.75, 138.06, 133.17, 128.20, 124.61, 123.94, 123.42,121.28, 112.61, 102.09, 60.41, 14.59.

[0109] HRMS (ESI): calcd for C 20 H 14 N4O3[M+H] + 359.1139, found 359.1136.

[0110] Example 13

[0111] Equimolar amounts of terminal alkyne compounds (R 2 (replace the terminal alkyne derivative (R) in Example 1 with 2-thienyl) 2 The raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, and the target product 10-(thiophen-2-yl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (compound designated I-13) was obtained in a yield of 69%.

[0112] (I-13)

[0113] 1H NMR (600 MHz, CDCl3) δ 8.91 (s, 1H), 8.74 (s, 1H), 8.43 (d, J = 6.0Hz, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.73 – 7.70 (m, 1H), 7.67 (d, J = 6.0 Hz, 1H), 7.50 (t, J = 6.0 Hz, 1H), 7.44 – 7.41 (m, 1H), 4.49 (q, J = 6.0 Hz, 2H), 1.48 (t, J = 6.0 Hz, 3H).

[0114] 13 C NMR (151 MHz, CDCl3) δ 162.98, 160.39, 148.98, 147.56, 146.81,136.84, 135.77, 134.58, 132.37, 127.93, 127.00, 126.52, 124.45, 123.68,121.64, 112.46, 101.49, 60.34, 14.62.

[0115] HRMS (ESI): calcd for C 19 H 13 N3O3S [M+H] + 364.0750, found 364.0747.

[0116] Example 14

[0117] In equimolar amounts of α-aminoazole compounds (R 3 (replace 4-methyl formate group) with the α-aminoazole derivative (R) in Example 1. 3 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, to obtain methyl 10-p-tolylbenzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-14), with a yield of 63%.

[0118] (I-14)

[0119] 1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H), 8.44 (d, J = 12.0 Hz, 1H), 8.18 (d, J = 12.0 Hz, 2H), 7.73 – 7.68 (m, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.52 – 7.47 (m, 3H), 4.02 (s, 3H), 2.52 (s, 3H).

[0120] 13 C NMR (151 MHz, CDCl3) δ 163.39, 161.14, 150.16, 147.87, 147.75,142.40, 138.61, 132.78, 131.89, 130.69, 129.50, 124.28, 123.89, 122.95,121.51, 112.54, 101.26, 51.62, 21.80.

[0121] HRMS (ESI): calcd for C 21 H 15 N3O3[M+H] + 358.1186, found 358.1187.

[0122] Example 15

[0123] In equimolar amounts of α-aminoazole compounds (R 3 (replace 5-methyl-4-carboxyethyl ester group) with the α-aminoazole derivative (R) in Example 1. 3 The other raw materials and amounts, operating steps and reaction conditions were the same as in Example 1, to obtain 2-methyl-10-(p-tolyl)benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound designated I-15), with a yield of 71%.

[0124] (I-15)

[0125] 1H NMR (600 MHz, CDCl3) δ 8.40 (d, J = 6.0 Hz, 1H), 8.22 (d, J = 6.0Hz, 2H), 7.70 – 7.65 (m, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.47 (t, J = 6.0 Hz,3H), 4.50 (q, J = 12.0 Hz, 2H), 2.76 (s, 3H), 2.51 (s, 3H), 1.49 (t, J = 12.0Hz, 3H).

[0126] 13 C NMR (151 MHz, CDCl3) δ 163.88, 160.89, 158.17, 149.29, 142.23,138.42, 132.34, 131.10, 130.82, 129.41, 124.12, 123.66, 123.13, 121.82,112.46, 99.21, 60.06, 21.80, 15.94, 14.61.

[0127] HRMS (ESI): calcd for C 23 H 19 N3O3[M+H] + 386.1499, found 386.1497.

[0128] Example 16

[0129] In equimolar amounts of 3-aminoindazole compounds (R 3 (replace α-aminoazole derivative (R) in Example 1 with biphenyl) 3 (The formate is ethyl formate), and other raw materials and amounts, operating steps and reaction conditions are the same as in Example 1, to obtain 7-p-tolylbenzofurano[3',2':4,5]pyrimido[1,2-b]indazole (compound designated I-16), with a yield of 62%.

[0130] (I-16)

[0131] 1H NMR (600 MHz, CDCl3) δ 8.48 (dt, J = 12.0 Hz, 1H), 8.36 (d, J = 6.0Hz, 3H), 7.89 (d, J = 6.0 Hz, 1H), 7.68 – 7.59 (m, 3H), 7.56 – 7.48 (m, 3H), 7.36 – 7.31 (m, 1H), 2.54 (s, 3H).

[0132] 13 C NMR (151 MHz, CDCl3) δ 159.98, 151.42, 143.89, 143.09, 141.77,140.23, 131.13, 130.51, 129.49, 129.23, 129.19, 124.18, 123.98, 122.28,122.17, 120.81, 120.30, 116.21, 113.14, 112.46, 21.81.

[0133] HRMS (ESI): calcd for C 23 H 15 N3O [M+H] + 350.1288, found 350.1288.

[0134] Example 17

[0135] In equimolar amounts of 3-aminoindazole compounds (R 3 (2-Clphenyl) replaces the α-aminoazole derivative (R) in Example 1. 3 (The formate is ethyl formate), and other raw materials and amounts, operating steps and reaction conditions are the same as in Example 1, to obtain 2-chloro-7-(p-tolyl)benzofurano[3',2':4,5]pyrimido[1,2-b]indazole (compound designated as I-17), with a yield of 68%.

[0136] (I-17)

[0137] 1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 8.37 (d, J = 6.0 Hz, 1H), 8.33(d, J = 6.0 Hz, 2H), 7.81 (d, J = 12.0 Hz, 1H), 7.67 (t, J = 12.0 Hz, 1H), 7.62 (d, J = 12.0 Hz, 1H), 7.55 – 7.51 (m, 4H), 2.53 (s, 3H).

[0138] 13 C NMR (151 MHz, CDCl3) δ 160.22, 149.61, 142.02, 140.38, 131.51,130.52, 130.21, 129.68, 129.56, 129.54, 125.72, 124.39, 123.71, 122.42,122.00, 119.88, 117.68, 113.70, 112.55, 21.83.

[0139] HRMS (ESI): calcd for C 23 H 14 ClN3O [M+H] + 384.0898, found 384.0898.

[0140] Example 18

[0141] The synthetic routes for compounds I-18, I-19, and I-20 are shown below:

[0142]

[0143] A dried 50 mL round-bottom flask equipped with a reflux condenser was used to add compound I-1 (0.6 mmol), 5% sodium hydroxide aqueous solution (10 mL), and ethanol (5 mL) sequentially. The resulting mixture was stirred overnight in an oil bath at 75 °C. After the reaction was complete, the system was cooled to room temperature, the pH was adjusted to 2-3 with dilute hydrochloric acid solution, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give compound I-18 as a yellow solid (196 mg, 95% yield).

[0144]

[0145] In a dried 10 mL reaction tube, compound I-18 (0.1 mmol), tetramethylfluoromantaline hexafluorophosphate (TCFH, 0.125 mmol), N-methylimidazole (NMI, 0.365 mmol), and anhydrous acetonitrile (2 mL) were added sequentially. The resulting mixture was stirred at 40 °C for 40 min, followed by the addition of morpholine (0.1 mmol), and the reaction was stirred under a nitrogen atmosphere (nitrogen balloon) for 12 h. After the reaction was complete, the mixture was poured into ice water and extracted with dichloromethane. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give compound I-19 (36.4 mg, yield 88%).

[0146] 1 H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 6.0 Hz, 2H), 7.70 (t, J = 6.0 Hz, 1H), 7.58 (d, J = 12.0 Hz, 1H), 7.49 (t, J = 6.0 Hz, 3H), 3.94 – 3.78 (m, 8H), 2.53 (s, 3H).

[0147] 13 C NMR (151 MHz, CDCl3) δ 163.83, 161.04, 148.92, 146.98, 145.24,142.29, 138.32, 132.66, 131.37, 130.55, 129.50, 124.32, 123.15, 122.93,121.65, 112.72, 104.61, 21.80.

[0148] HRMS (ESI): calcd for C 24 H 20 N4O3[M+H] + 413.1608, found 413.1606.

[0149]

[0150] The experimental procedure was the same as that for compound I-19, except that morpholine was replaced with N-methylpiperazine, and the final compound was denoted as I-20 (36.2 mg, yield 85%).

[0151] 1 H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 12.0 Hz, 2H), 7.69 (t, J = 6.0 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.51–7.46 (m, 3H), 3.88 (s, 4H), 2.64 (s, 4H), 2.50 (s, 3H), 2.42 (s, 3H).

[0152] 13 C NMR (151 MHz, CDCl3) δ 163.67, 161.03, 148.87, 146.75, 145.36,142.22, 138.32, 132.58, 131.25, 130.54, 129.49, 124.28, 123.19, 122.99,121.71, 112.68, 104.88, 46.06, 21.79.

[0153] HRMS (ESI): calcd for C 25 H 23 N5O2[M+H] + 426.1925, found 426.1925.

[0154] In the examples, the synthesized benzofuran[3,2-d]pyrazolo[1,5-a]pyrimidine compounds were used as positive control drugs. The in vitro antiproliferative activity of the synthesized benzofuran[3,2-d]pyrazolo[1,5-a]pyrimidine compounds against six plant fungi was determined by the inhibition zone method. The results are shown in Table 1.

[0155] Table 1. In vitro antifungal activity

[0156]

[0157] As shown in Table 1, benzofuran[3,2-d]pyrazolo[1,5-a]pyrimidine compounds exhibit better inhibitory effects on *Valsa mali*, *Botryosphaeria dothidea*, *Gibberella zeae*, *Rhizoctonia cerealis*, *Sclerotonia sclerotiorum*, and *Rhizoctonia solani* compared to thifluzamide. In some cases, the inhibitory effects of these compounds on certain fungi are even significantly higher than those of the existing fungicide thifluzamide.

[0158] Although embodiments of this application have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of this application. The scope of this application is defined by the appended claims and their equivalents, all of which should be included within the protection scope of this application.

Claims

1. A benzofuro[3,2-d]pyrazolo[l,5-a]pyrimidine compound, characterized by, The chemical structural formula of the compound is shown as formula (I): （Ⅰ） Among them, R 1 It is one of hydrogen, methyl, halogen, methoxy, and naphthyl; R 2 is one of phenyl, halogen containing phenyl, biphenyl, binaphthyl, benzyl, benzyloxy, pyridyl and thienyl; R 3 is one of ethyl, methyl, phenyl and halogen-substituted phenyl.

2. A method for synthesizing a benzofuro[3,2-d]pyrazolo[l,5-a]pyrimidine compound, as claimed in claim 1, wherein, The method comprises the following steps: mixing and reacting a salicylaldehyde compound, a terminal alkyne compound and an α-aminoazole compound in a solvent in the presence of a catalyst and a base to obtain a benzofuro[3,2-d]pyrazolo[1,5-a]pyrimidine compound.

3. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines according to claim 2, characterized in that, The chemical structural formula of the salicylaldehyde compound is shown as formula (II): （Ⅱ） wherein R is one of hydrogen, methyl, halogen, methoxy and naphthyl. 1 is one of hydrogen, methyl, halogen, methoxy and naphthyl.

4. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines according to claim 2, characterized in that, The chemical structural formula of the terminal alkyne compound is shown as formula (III): （Ⅲ） wherein R 2 is one of phenyl, halogen containing phenyl, biphenyl, binaphthyl, benzyl, benzyloxy, pyridyl and thienyl.

5. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines according to claim 2, wherein, The chemical structural formula of the α-aminoazole compound is shown as formula (IV): (IV) wherein R is one of ethyl, methyl, phenyl, and halogen-substituted phenyl. 3 wherein R is one of ethyl, methyl, phenyl, and halogen-substituted phenyl.

6. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines according to claim 2, wherein, The catalyst is a monovalent copper salt or a divalent copper salt.

7. The method for synthesizing benzofurano[3,2-d]pyrazolo[1,5-a]pyrimidine compounds according to claim 2, characterized in that, The base is cesium carbonate or cesium fluoride. The solvent is 2-methyltetrahydrofuran or 1,4-dioxane.

8. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines as claimed in claim 2, wherein, ###0005### is synthesized by the reaction of ###0006### with ###0007### in presence of base and solvent. The molar ratio of the salicylaldehyde compound, the terminal alkyne compound and the α-aminoazole compound is 1:1-3:1-3.

9. The method of synthesis of benzo furano [3, 2-d] pyrazolo [1, 5-a] pyrimidines according to claim 2, characterized in that, The reaction condition is that the temperature is 100-130 ℃ and the time is 12-24 h.

10. Use of the benzofuro[3,2-d]pyrazolo[1,5-a]pyrimidine compound in claim 1 in the preparation of a medicine or a fungicide for inhibiting plant pathogenic fungi.

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