Polysubstituted cyclobutanol compound as well as preparation method and application thereof

Abstract

The invention belongs to the field of organic synthesis, and relates to a polysubstituted cyclobutanol compound as well as preparation and application thereof. In a dry Schracker reaction tube, 2-alkynyl benzaldoxime and bicyclo [1.1. 0] butane are used as raw materials and react in a catalyst and a solvent to synthesize the compound. A silver (I) catalysis method is creatively applied, and the advantages are remarkable. The method has the advantages of mild reaction conditions, cheap catalyst, low energy consumption, small pollution and good functional group compatibility. The method provides an efficient and mild path for complex cyclobutanol synthesis, the substrate application is wide, the stereospecificity is high, and the tolerance to various functional groups is good. The product can also participate in the synthesis of other compounds, and the high efficiency and amplification experiment in reactants containing bioactive groups fully shows the wide application potential in the fields of synthetic chemistry and medicinal chemistry.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to multi-substituted cyclobutanol compounds, a preparation method thereof, and an application thereof. Background Art

[0002] From the perspectives of biological activity and chemical transformation, small-ring-containing molecules play an important role in the field of organic synthesis. Specifically, the strain energy of the four-membered ring is close to that of the three-membered ring, but much larger than that of cyclopentane and cyclohexane. It is a common structural unit in bioactive molecules and an important synthetic building block in organic chemistry. Among the molecules containing a four-membered ring, cyclobutanol shows important potential as a privileged precursor in various transformations involving the selective ring-opening of strained rings. In this context, transition-metal-catalyzed, organocatalyzed, and radical-mediated reactions have been widely studied. Therefore, it is of great significance to develop a simple method for synthesizing functionalized cyclobutanols. Small molecules play an important role in organic synthesis. The strain energy of the four-membered ring is comparable to that of the three-membered ring and much larger than that of cyclopentane and cyclohexane. The traditional synthesis of cyclobutanol mainly involves the nucleophilic addition reaction of organometallic reagents with cyclobutanone. However, this method is complex to operate and is limited by its intolerance to many base-sensitive functional groups. So far, only a limited number of methods for synthesizing multi-substituted cyclobutanols have been reported. Summary of the Invention

[0003] Aiming at the deficiencies of the above-mentioned existing technologies, the present invention provides multi-substituted cyclobutanol compounds, a preparation method thereof, and an application thereof. The present invention for the first time synthesizes multi-substituted cyclobutanol compounds by a method catalyzed by silver(I), and synthesizes cyclobutanediol compounds, cyclobutanecarboxylate compounds, and disubstituted cyclobutanol compounds using the cyclobutanol compounds as intermediates, which have broad application prospects in the fields of synthetic chemistry and medicinal chemistry.

[0004] To solve the above technical problems, the present invention adopts the following technical solutions:

[0005] Multi-substituted cyclobutanol compounds, the chemical structural formula thereof is:

[0006]

[0007] Wherein, Ar 1 is 7-methyl, 7-chloro, 7-fluoro, 6-methyl, 6-chloro, benzodioxole;

[0008] R 1 is 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, biphenyl, 2-thienyl, 3-methylphenyl, 3-chlorophenyl, 2-methylphenyl, 2-chlorophenyl, cyclopropyl, n-pentyl;

[0009] R2 phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, methyl;

[0010] R 3 selected from 1,3-dimethylimidazolyl, 2-naphthyl, n-butyl, 2-pyridyl, N-methylimidazolyl;

[0011] The present invention also protects a method for preparing a polysubstituted cyclobutanol compound, comprising the following steps:

[0012] The general reaction formula for the synthesis is:

[0013]

[0014] Using 2-alkynylbenzaldoxime and BCBs as raw materials, they are jointly added to a 25 mL Schlenk tube that is dry and equipped with a magnetic stirrer, and a catalyst and a solvent are added to the tube. Then the reaction mixture is stirred at room temperature for 8 h to obtain a reaction solution; the reaction solution is concentrated under reduced pressure and purified by column chromatography to obtain a polysubstituted cyclobutanol compound.

[0015] Preferably, the 2-alkynylbenzaldehyde oxime compound is selected from (E)-2-(phenylethynyl)benzaldehyde oxime, (E)-2-(p-tolylethynyl)benzaldehyde oxime, (E)-2-(4-methoxyphenylethynyl)benzaldehyde oxime, (E)-2-(4-fluorophenylethynyl)benzaldehyde oxime, (E)-2-(4-chlorophenylethynyl)benzaldehyde oxime, (E)-2-(4-trifluoromethylphenylethynyl)benzaldehyde oxime, (E)-2-(4-nitrophenylethynyl)benzaldehyde oxime, (E)-2-([1,1'-biphenyl]-4-ylethynyl)benzaldehyde oxime, (E)-2-(thiophen-2-ylethynyl)benzaldehyde oxime, (E)-2-(m-tolylethynyl)benzaldehyde oxime, (E)-2-(3-chlorophenylethynyl)benzaldehyde oxime, (E)-2-(o-tolylethynyl)benzaldehyde oxime, (E)-2-(2-chlorophenylethynyl)benzaldehyde oxime, (E)-2-(cyclopropylethynyl)benzaldehyde oxime, (E)-2-(hept-1-yn-1-yl)benzaldehyde oxime, (E)-5-methyl-2-phenylethynylbenzaldehyde oxime, (E)-5-chloro-2-phenylethynylbenzaldehyde oxime, (E)-5-fluoro-2-phenylethynylbenzaldehyde oxime, (E)-4-methyl-2-phenylethynylbenzaldehyde oxime, (E)-4-chloro-2-phenylethynylbenzaldehyde oxime, (E)-6-phenylethynylbenzo[d][1,3]dioxole-5-carboxaldehyde oxime, (2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, (E)-3,7-dimethylocta-2,6-dien-1-yl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, 3,7-dimethylocta-6-en-1-yl (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzoate, 2-isopropyl-5-methylphenyl (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzoate, ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzyl 2-(4-isobutylphenyl)propionate.

[0016] Preferably, the BCBs compounds are selected from (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone, (3-(4-chlorophenyl)bicyclo[1.1.0]butan-1-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butan-1-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-methoxyphenyl)bicyclo[1.1.0]butan-1-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone, (3-(3-chlorophenyl)bicyclo[1.1.0]butan-1-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone, phenyl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, (4-methoxyphenyl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, (4-fluorophenyl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, phenyl(3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)methanone, (3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)(phenyl)methanone, phenyl(3-(m-tolyl)bicyclo[1.1.0]butan-1-yl)methanone, naphthalen-2-yl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, 1-(3-phenylbicyclo[1.1.0]butan-1-yl)pentan-1-one, (3-phenylbicyclo[1.1.0]butan-1-yl)(pyridin-2-yl)methanone, (1-methyl-1H-imidazol-2-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone, bicyclo[1.1.0]butan-1-yl(naphthalen-2-yl)methanone, (3,5-dimethyl-1H-pyrazol-1-yl)(3-methylbicyclo[1.1.0]butan-1-yl)methanone.

[0017] Preferably, the molar ratio of the 2-alkynylbenzaldehyde oxime compound, the BCBs compound and the catalyst is 1.2:1:0.1.

[0018] Preferably, the catalyst is silver tetrafluoroborate. All silver salts have catalytic effects, but silver tetrafluoroborate has the best catalytic performance among silver salts.

[0019] Preferably, the solvent is selected from dichloromethane.

[0020] Preferably, the column chromatography conditions are a silica gel column of 200 - 300 mesh, and the eluent for column chromatography purification is composed of petroleum ether and ethyl acetate with a volume ratio of 30:1 - 15:1 or petroleum ether and dichloromethane with a volume ratio of 2:3.

[0021] The present invention also protects the use of the multi - substituted cyclobutanol compounds in the preparation of cyclobutanediol compounds, cyclobutanecarboxylate compounds, and cyclobutanol compounds with deacylated pyrazolyl groups.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] The reaction of the present invention is easy to occur, with simple steps, mild conditions, no need for oxidants, suitable catalyst prices, low energy consumption, little environmental pollution, and good functional group compatibility. The generated products can further be transformed into the required compounds, having broad application prospects in the fields of synthetic chemistry and medicinal chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the 1H - NMR spectrum of Compound 1 of the present invention;

[0025] Figure 2 is the 1H - NMR spectrum of Compound 4 of the present invention;

[0026] Figure 3 is the 13C - NMR spectrum of Compound 4 of the present invention;

[0027] Figure 4 is the 1H - NMR spectrum of Compound 5 of the present invention;

[0028] Figure 5 is the 13C - NMR spectrum of Compound 5 of the present invention;

[0029] Figure 6 is the 1H - NMR spectrum of Compound 6 of the present invention;

[0030] Figure 7 is the 13C - NMR spectrum of Compound 6 of the present invention;

[0031] Figure 8 is the 1H - NMR spectrum of Compound 7 of the present invention;

[0032] Figure 9 is the 13C - NMR spectrum of Compound 7 of the present invention; DETAILED DESCRIPTION OF THE INVENTION

[0033] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0034] Poly-substituted cyclobutanols are key synthetic intermediates for constructing complex molecular structures through ring-opening strategies. Developing efficient methods for synthesizing such important structural units has attracted extensive attention in the chemical community. Based on this, the present invention reports for the first time a silver(I)-catalyzed tandem cyclization-cycloaddition-isomerization reaction sequence, using bicyclobutane and 2-alkynylbenzaldoxime as starting materials, providing an effective route for the synthesis of poly-substituted cyclobutanols. This method has the advantages of mild reaction conditions, significant stereoselectivity, wide substrate scope, and excellent functional group tolerance.

[0035] Example 1

[0036] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3aa) comprises the following steps:

[0037] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3aa), and its chemical structural formula is:

[0038]

[0039] White solid (80 mg, 84%), mp 160.1 - 160.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 7.3 Hz, 2H), 8.10 - 7.95 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.57 (dt, J = 15.7, 7.9 Hz, 5H), 7.42 (dt, J = 22.5, 7.3 Hz, 4H), 7.26 (dd, J = 12.9, 5.5 Hz, 1H), 5.63 (s, 1H), 5.01 (s, 1H), 3.85 - 3.60 (m, 4H), 2.52 (s, 3H), 1.73 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 28 N3O2 + : 474.2176, found: 474.2178.

[0040] Example 2

[0041] A method for synthesizing ((3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(p-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3ba), comprising the following steps:

[0042] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(p-tolylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain ((3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(p-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3ba), and the chemical structural formula is:

[0043] White solid (76 mg, 78%), mp 173.9 - 174.5 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.52 - 7.38 (m, 5H), 7.31 (dd, J = 13.1, 5.7 Hz, 1H), 5.67 (s, 1H), 5.14 (s, 1H), 3.75 (t, J = 16.6 Hz, 4H), 2.57 (s, 3H), 2.49 (s, 3H), 1.77 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2328.

[0044] Example 3

[0045] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-(4-methoxyphenyl)isoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3ca), comprising the following steps:

[0046] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((4-methoxyphenyl)ethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (the eluent was PE / EA = 25:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-(4-methoxyphenyl)isoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3ca), and the chemical structural formula is:

[0047] White solid (79 mg, 79%), mp 182.3 - 182.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.50 - 7.44 (m, 1H), 7.31 (t, J = 7.6 Hz, 3H), 7.18 (dd, J = 12.3, 4.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.55 (s, 1H), 5.04 (s, 1H), 3.81 (s, 3H), 3.62 (t, J = 17.6 Hz, 4H), 2.44 (s, 3H), 1.65 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O3 + : 504.2282, found: 504.2284.

[0048] Example 4

[0049] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(1-(3-(4-fluorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)methanone (3da), comprising the following steps:

[0050] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((4-fluorophenyl)ethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(1-(3-(4-fluorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)methanone (3da), and its chemical structural formula is:

[0051] White solid (63 mg, 64%), mp 160.1 - 160.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.17 (dd, J = 8.6, 5.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.57 - 7.46 (m, 3H), 7.33 (dt, J = 15.5, 7.7 Hz, 3H), 7.23 - 7.10 (m, 3H), 5.55 (s, 1H), 4.80 (s, 1H), 3.79 - 3.48 (m, 4H), 2.43 (s, 3H), 1.65 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -113.6. HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 19F3O2 + : 492.2082, found: 492.2079.

[0052] Example 5

[0053] A method for synthesizing (1-(3-(4-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ea), comprising the following steps:

[0054] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((4-chlorophenyl)ethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(3-(4-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ea), and the chemical structural formula is:

[0055] White solid (87 mg, 85%), mp 148.1 - 148.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 8.4 Hz, 3H), 7.51 (d, J = 8.5 Hz, 2H), 7.48 - 7.42 (m, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.27 (dd, J = 13.4, 6.0 Hz, 1H), 5.64 (s, 1H), 4.79 (s, 1H), 3.74 (d, J = 13.2 Hz, 2H), 3.63 (d, J = 11.9 Hz, 2H), 2.52 (s, 3H), 1.73 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1778.

[0056] Example 6

[0057] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)cyclobutyl)methanone (3fa), comprising the following steps:

[0058] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((4-(trifluoromethyl)phenyl)ethynyl)benzaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)cyclobutyl)methanone (3fa), and the chemical structural formula is:

[0059] White solid (90 mg, 83%), mp 208.9 - 209.5 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 8.1 Hz, 2H), 7.99 - 7.91 (m, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 8.1 Hz, 3H), 7.44 - 7.37 (m, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.18 (dd, J = 14.1, 7.0 Hz, 1H), 5.56 (s, 1H), 4.59 (s, 1H), 3.67 (d, J = 13.2 Hz, 2H), 3.57 (d, J = 11.8 Hz, 2H), 2.43 (s, 3H), 1.65 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -62.4. HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 27 F3N3O2 + : 542.2050, found: 542.2049.

[0060] Example 7

[0061] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-(4-nitrophenyl)isoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3ga), comprising the following steps:

[0062] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((4-nitrophenyl)ethynyl)benzaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-(4-nitrophenyl)isoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3ga), and the chemical structural formula is:

[0063] White solid (79 mg, 76%), mp 180.1 - 180.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 8.9 Hz, 2H), 8.39 (d, J = 8.9 Hz, 2H), 8.15 - 8.03 (m, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.56 - 7.50 (m, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 5.66 (s, 1H), 4.33 (s, 1H), 3.78 (d, J = 13.4 Hz, 2H), 3.67 (d, J = 12.7 Hz, 2H), 2.51 (s, 3H), 1.75 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 N4O4 + : 519.2027, found: 519.2013.

[0064] Example 8

[0065] A method for synthesizing (3-([1,1'-biphenyl]-4-yl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ha) comprises the following steps:

[0066] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-([1,1'-biphenyl]-4-ylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3-([1,1'-biphenyl]-4-yl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ha), and its chemical structural formula is:

[0067] White solid (90 mg, 82%), mp 221.1 - 221.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 5.8 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.66 - 7.59 (m, 2H), 7.57 - 7.52 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.44 - 7.35 (m, 3H), 7.31 (q, J = 7.4 Hz, 3H), 7.19 (t, J = 7.3 Hz, 1H), 5.56 (s, 1H), 4.97 (s, 1H), 3.83 - 3.51 (m, 4H), 2.45 (s, 3H), 1.66 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 37 H 32 N3O2 + : 550.2489, found: 550.2487.

[0068] Example 9

[0069] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(thiophen-2-yl)isoquinolin-1-yl)cyclobutyl)methanone (3ia), comprising the following steps:

[0070] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, successively add (E)-2-(thiophen-2-ylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%), then add 2 mL of dichloromethane, and stir at room temperature in an air atmosphere for 8 h to obtain a reaction solution; concentrate the reaction solution under reduced pressure and purify it by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(thiophen-2-yl)isoquinolin-1-yl)cyclobutyl)methanone (3ia), and the chemical structural formula is:

[0071] White solid (52 mg, 54%), mp 190.1 - 190.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.81 - 7.74 (m, 2H), 7.68 - 7.60 (m, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.47 - 7.35 (m, 4H), 7.26 (dd, J = 13.7, 6.3 Hz, 1H), 7.21 - 7.15 (m, 1H), 5.63 (s, 1H), 4.92 (s, 1H), 3.71 (d, J = 13.1 Hz, 2H), 3.68 - 3.46 (m, 2H), 2.52 (s, 3H), 1.73 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 29 H 26 N3O2S + : 480.1740, found: 480.1736.

[0072] Example 10

[0073] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(m-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3ja), comprising the following steps:

[0074] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(m-tolylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(m-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3ja), and its chemical structural formula is:

[0075] White solid (83 mg, 86%), mp 145.2 - 145.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.15 - 8.04 (m, 2H), 8.03 - 7.95 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.59 - 7.53 (m, 1H), 7.51 - 7.36 (m, 4H), 7.33 - 7.22 (m, 2H), 5.63 (s, 1H), 5.01 (s, 1H), 3.71 (q, J = 15.8 Hz, 4H), 2.51 (d, J = 7.4 Hz, 6H), 1.73 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2329.

[0076] Example 11

[0077] A synthetic method of (1-(3-(3-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ka) comprises the following steps:

[0078] In a dry 25 mL Schlenk tube equipped with a magnetic stirrer, (E)-2-((3-chlorophenyl)ethynyl)benzaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(3-(3-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ka), and the chemical structural formula is:

[0079] White solid (79 mg, 78%), mp 170.5 - 171.3 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.31 - 8.23 (m, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.69 - 7.57 (m, 3H), 7.47 (tt, J = 7.2, 3.9 Hz, 2H), 7.43 - 7.35 (m, 3H), 7.26 (dd, J = 13.3, 6.0 Hz, 1H), 5.64 (s, 1H), 4.57 (s, 1H), 3.75 (d, J = 13.2 Hz, 2H), 3.66 (d, J = 12.3 Hz, 2H), 2.51 (s, 3H), 1.76 (s, 3H). HRMS (ESI, m / z): [M + H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1780.

[0080] Example 12

[0081] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(o-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3la), comprising the following steps:

[0082] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(o-tolylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-(o-tolyl)isoquinolin-1-yl)cyclobutyl)methanone (3la), and the chemical structural formula is:

[0083] White solid (92 mg, 94%), mp 182.8 - 183.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 7.64 - 7.52 (m, 4H), 7.51 - 7.43 (m, 1H), 7.34 (dt, J = 17.3, 6.9 Hz, 5H), 7.28 - 7.20 (m, 1H), 5.66 (s, 1H), 5.26 (s, 1H), 3.66 (d, J = 12.8 Hz, 2H), 3.62 - 3.40 (m, 2H), 2.67 (s, 3H), 2.54 (s, 3H), 1.79 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2335.

[0084] Example 13

[0085] A method for synthesizing (1-(3-(2-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ma), comprising the following steps:

[0086] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-((2-chlorophenyl)ethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(3-(2-chlorophenyl)isoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ma), and the chemical structural formula is:

[0087] White solid (91 mg, 90%), mp 142.5 - 143.1 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.87 - 7.78 (m, 2H), 7.63 - 7.54 (m, 4H), 7.52 - 7.47 (m, 1H), 7.47 - 7.42 (m, 1H), 7.42 - 7.35 (m, 3H), 7.29 - 7.22 (m, 1H), 5.63 (s, 1H), 5.12 (s, 1H), 3.69 (d, J = 12.9 Hz, 2H), 3.59 (d, J = 10.6 Hz, 2H), 2.52 (s, 3H), 1.77 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1789.

[0088] Example 14

[0089] A synthetic method of (1-(3-cyclopropylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3na) comprises the following steps:

[0090] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-cyclopropylethynylbenzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(3-cyclopropylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3na), and the chemical structural formula is:

[0091] White solid (69 mg, 79%), mp 133.1 - 133.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.39 (dd, J = 14.7, 7.2 Hz, 3H), 7.36 - 7.30 (m, 1H), 7.29 - 7.23 (m, 1H), 5.62 (s, 1H), 4.77 (s, 1H), 3.62 (d, J = 12.8 Hz, 2H), 3.56 - 3.32 (m, 2H), 2.48 (s, 3H), 2.24 (tt, J = 8.3, 4.8 Hz, 1H), 1.80 (s, 3H), 1.30 (dt, J = 6.0, 3.2 Hz, 2H), 1.09 (dq, J = 6.6, 4.0 Hz, 2H). HRMS (ESI, m / z): [M+H] + , calcd. For C 28 H 28 N3O2 + : 438.2176, found: 438.2175.

[0092] Example 15

[0093] A synthetic method of (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-pentylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3oa) comprises the following steps:

[0094] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-hept-1-yn-1-ylbenzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-pentylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3oa), and the chemical structural formula is:

[0095]

[0096] White solid (61 mg, 65%), mp 128.1 - 128.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.44 - 7.32 (m, 4H), 7.30 - 7.24 (m, 1H), 5.83 (s, 1H), 5.63 (s, 1H), 3.63 (d, J = 12.8 Hz, 2H), 3.49 (s, 2H), 3.01 (t, J = 7.5 Hz, 2H), 2.53 (s, 3H), 1.95 (p, J = 7.4 Hz, 2H), 1.73 (s, 3H), 1.45 (dq, J = 11.4, 7.9, 6.0 Hz, 4H), 0.93 (t, J = 7.0 Hz, 3H). HRMS (ESI, m / z): [M + H] + , calcd. For C 30 H 34 N3O2 + : 468.2646, found: 468.2651.

[0097] Example 16

[0098] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(7-methyl-3-phenylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3pa), comprising the following steps:

[0099] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-5-methyl-2-phenylethynylbenzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(7-methyl-3-phenylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3pa), and the chemical structural formula is:

[0100] White solid (79 mg, 81%), mp 155.0 - 155.4 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 7.9 Hz, 2H), 7.84 (s, 1H), 7.72 - 7.61 (m, 2H), 7.54 (d, J = 6.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.33 (dt, J = 13.6, 6.6 Hz, 4H), 7.18 (dd, J = 13.4, 5.7 Hz, 1H), 5.55 (s, 1H), 5.15 (s, 1H), 3.65 (d, J = 12.5 Hz, 2H), 3.55 (d, 2H), 2.45 (s, 3H), 2.37 (s, 3H), 1.64 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2332.

[0101] Example 17

[0102] A method for synthesizing (1-(7-chloro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3qa), comprising the following steps:

[0103] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-5-chloro-2-phenylethynylbenzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(7-chloro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3qa), and the chemical structural formula is:

[0104] White solid (89 mg, 88%), mp 111.8 - 112.2 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 7.4 Hz, 2H), 7.93 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.43 (dd, J = 8.8, 1.7 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.19 (dd, J = 13.6, 6.1 Hz, 1H), 5.58 (s, 1H), 4.79 (s, 1H), 3.67 (d, J = 13.5 Hz, 2H), 3.54 (d, J = 13.0 Hz, 2H), 2.47 (s, 3H), 1.65 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1783.

[0105] Example 18

[0106] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(1-(7-fluoro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)methanone (3ra), comprising the following steps:

[0107] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-5-fluoro-2-phenylethynylbenzaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(1-(7-fluoro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)methanone (3ra), and the chemical structural formula is:

[0108] White solid (74 mg, 75%), mp 150.8 - 151.2 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 7.4 Hz, 2H), 7.96 (s, 1H), 7.84 (dd, J = 8.8, 5.7 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.62 - 7.57 (m, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.26 (dd, J = 13.7, 6.4 Hz, 1H), 5.66 (s, 1H), 4.76 (s, 1H), 3.74 (d, J = 13.3 Hz, 2H), 3.64 (d, J = 12.4 Hz, 2H), 2.54 (s, 3H), 1.75 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -109.8 (dd, J = 7.2, 4.2 Hz). HRMS (ESI, m / z): [M + H] + , calcd. For C 31 H 27 19FN3O2 + : 492.2082, found: 492.2080.

[0109] Example 19

[0110] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(6-methyl-3-phenylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3sa), comprising the following steps:

[0111] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-4-methyl-2-phenylethynylbenzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(6-methyl-3-phenylisoquinolin-1-yl)-3-phenylcyclobutyl)methanone (3sa), and the chemical structural formula is:

[0112] White solid (74 mg, 76%), mp 214.4 - 214.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.18 (d, J = 7.4 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.4 Hz, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.22 - 7.14 (m, 2H), 5.55 (s, 1H), 5.10 (s, 1H), 3.62 (d, J = 12.8 Hz, 2H), 3.54 (d, 2H), 2.45 (s, 3H), 2.37 (s, 3H), 1.65 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2326.

[0113] Example 20

[0114] A method for synthesizing (1-(6-chloro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ta), comprising the following steps:

[0115] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-4-chloro-2-phenylethynylbenzaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(6-chloro-3-phenylisoquinolin-1-yl)-3-hydroxy-3-phenylcyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ta), and the chemical structural formula is:

[0116] White solid (83 mg, 82%), mp 202.6 - 203.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 7.6 Hz, 2H), 7.95 (d, J = 9.0 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.26 (dd, J = 13.7, 6.4 Hz, 1H), 5.66 (s, 1H), 4.83 (s, 1H), 3.72 (d, J = 13.2 Hz, 2H), 3.63 (d, J = 12.3 Hz, 2H), 2.52 (s, 3H), 1.74 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1781.

[0117] Example 21

[0118] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(7-phenyl-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)cyclobutyl)methanone (3ua), comprising the following steps:

[0119] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-6-phenylethynylbenzo[d][1,3]dioxole-5-carboxaldehyde oxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(7-phenyl-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)cyclobutyl)methanone (3ua), and the chemical structural formula is:

[0120]

[0121] White solid (80 mg, 77%), mp 193.1 - 193.5 °C. 11H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.4 Hz, 2H), 7.79 (s, 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.46 - 7.35 (m, 3H), 7.32 (s, 1H), 7.29 - 7.23 (m, 1H), 7.06 (s, 1H), 6.02 (s, 2H), 5.68 (s, 1H), 5.06 (s, 1H), 3.67 (d, J = 12.4 Hz, 3H), 2.54 (s, 3H), 1.78 (s, 3H). HRMS (ESI, m / z): [M + H] + , calcd. For C 32 H 28 N3O4 + : 518.2074, found: 518.2071.

[0122] Example 22

[0123] A method for synthesizing (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3va), comprising the following steps:

[0124] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, sequentially add (2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((2-((E)-(hydroxyimino)methyl)phenyl)ethynyl)benzoate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%), then add 2 mL of dichloromethane, and stir at room temperature in an air atmosphere for 8 h to obtain a reaction solution; concentrate the reaction solution under reduced pressure and purify it by column chromatography (the eluent is PE / EA = 25:1) to obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3va), and the chemical structural formula is:

[0125] White solid (102 mg, 78%), mp 162.1 - 162.5 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 8.3 Hz, 2H), 8.06 - 7.92 (m, 2H), 7.81 (d, J = 8.1 Hz, 1H), 7.63 - 7.50 (m, 3H), 7.46 - 7.38 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 - 7.17 (m, 1H), 5.57 (s, 1H), 4.91 (td, J = 10.8, 4.2 Hz, 1H), 4.67 (s, 1H), 3.86 - 3.46 (m, 4H), 2.45 (s, 3H), 2.11 (d, J = 11.6 Hz, 1H), 1.95 (dd, J = 13.6, 6.8 Hz, 1H), 1.67 (d, J = 10.0 Hz, 5H), 1.62 - 1.42 (m, 3H), 1.17 - 1.02 (m, 2H), 0.88 (d, J = 6.7 Hz, 6H), 0.76 (d, J = 6.9 Hz, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 42 H 46 N3O4 + : 656.3483, found: 656.3485.

[0126] Example 23

[0127] A method for synthesizing (E)-3,7-dimethylocta-2,6-dien-1-yl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3wa), comprising the following steps:

[0128] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-3,7-dimethylocta-2,6-dien-1-yl 4-((2-((E)-(hydroxyimino)methyl)phenyl)ethynyl)benzoate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 20:1) to obtain (E)-3,7-dimethylocta-2,6-dien-1-yl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3wa), and its chemical structural formula is:

[0129] White solid (101 mg, 77%), mp 116.1 - 116.6 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.1 Hz, 3H), 7.43 - 7.37 (m, 1H), 7.32 (t, J = 7.7 Hz, 2H), 7.24 - 7.16 (m, 1H), 5.56 (s, 1H), 5.52 - 5.40 (m, 1H), 5.11 - 5.00 (m, 1H), 4.82 (d, J = 7.0 Hz, 2H), 4.58 (s, 1H), 3.87 - 3.46 (m, 4H), 2.44 (s, 3H), 2.19 - 1.98 (m, 4H), 1.72 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H), 1.55 (d, J = 6.3 Hz, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 42 H 44 N3O4 + : 654.3326, found: 654.3329.

[0130] Example 24

[0131] A method for synthesizing 3,7-dimethyloct-6-en-1-yl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3xa), comprising the following steps:

[0132] In a dry 25 mL Schlenk tube equipped with a magnetic stirrer, successively add (E)-3,7-dimethyloct-6-en-1-yl 4-((2-((hydroxyimino)methyl)phenyl)ethynyl)benzoate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%), then add 2 mL of dichloromethane, and stir at room temperature in an air atmosphere for 8 h to obtain a reaction solution; concentrate the reaction solution under reduced pressure and purify it by column chromatography (the eluent is PE / EA = 20:1) to obtain 3,7-dimethyloct-6-en-1-yl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3xa), and the chemical structural formula is:

[0133]

[0134] White solid (108 mg, 82%), mp 126.1 - 126.5 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 8.3 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 10.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.5 Hz, 3H), 7.40 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.19 (dd, J = 12.6, 5.2 Hz, 1H), 5.56 (s, 1H), 5.05 (t, J = 7.0 Hz, 1H), 4.63 (s, 1H), 4.33 (tt, J = 10.9, 5.5 Hz, 2H), 3.74 - 3.46 (m, 4H), 2.44 (s, 3H), 1.96 (dhept, J = 14.2, 7.0 Hz, 2H), 1.79 (dq, J = 12.6, 6.9 Hz, 1H), 1.63 (d, J = 18.2 Hz, 7H), 1.55 (d, J = 7.9 Hz, 4H), 1.35 (ddd, J = 14.9, 8.3, 4.7 Hz, 1H), 1.25 - 1.13 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H). HRMS (ESI, m / z): [M + H] + , calcd. For C 42 H 46 N3O4 + : 656.3483, found: 656.3485.

[0135] Example 25

[0136] A method for synthesizing 2-isopropyl-5-methylphenyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3ya), comprising the following steps:

[0137] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, 2-isopropyl-5-methylphenyl (E)-4-((2-((hydroxyimino)methyl)phenyl)ethynyl)benzoate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added successively. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 20:1) to obtain 2-isopropyl-5-methylphenyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3ya), and its chemical structural formula is:

[0138]

[0139] White solid (94 mg, 72%), mp 187.0 - 187.6 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.57 - 8.42 (m, 4H), 8.19 - 8.07 (m, 2H), 7.94 (d, J = 8.1 Hz, 1H), 7.73 - 7.63 (m, 3H), 7.58 - 7.51 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.31 (q, J = 8.4, 7.4 Hz, 2H), 7.13 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 5.70 (s, 1H), 4.74 (s, 1H), 3.89 - 3.66 (m, 4H), 3.17 (hept, J = 6.8 Hz, 1H), 2.57 (s, 3H), 2.41 (s, 3H), 1.80 (s, 3H), 1.29 (s, 6H). HRMS (ESI, m / z): [M+H] + , calcd. For C 42 H 40 N3O4 + : 650.3013, found: 650.3015.

[0140] Example 26

[0141] Synthesis method of ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3za), comprising the following steps:

[0142] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-((2-((E)-(hydroxyimino)methyl)phenyl)ethynyl)benzoate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzoate (3za), and the chemical structural formula is:

[0143] White solid (129 mg, 85%), mp 165.7 - 166.2 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 10.4 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 - 7.17 (m, 1H), 5.57 (s, 1H), 5.52 (d, J = 4.9 Hz, 1H), 4.64 - 4.57 (m, 2H), 4.51 (dd, J = 11.4, 5.0 Hz, 1H), 4.41 (dd, J = 11.4, 7.5 Hz, 1H), 4.34 - 4.27 (m, 2H), 4.16 (t, J = 6.1 Hz, 1H), 3.65 (t, J = 17.9 Hz, 4H), 2.44 (s, 3H), 1.66 (s, 3H), 1.49 (s, 3H), 1.43 (s, 3H), 1.29 (d, J = 12.6 Hz, 6H). HRMS (ESI, m / z): [M+H] + , calcd. For C 44 H 46 N3O9 + : 760.3229, found: 760.3234.

[0144] Example 27

[0145] A method for synthesizing 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzyl 2-(4-isobutylphenyl)propionate (3αa), comprising the following steps:

[0146] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-4-((2-((hydroxyimino)methyl)phenyl)ethynyl)benzyl 2-(4-isobutylphenyl)propionate (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain 4-(1-(1-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-hydroxy-3-phenylcyclobutyl)isoquinolin-3-yl)benzyl 2-(4-isobutylphenyl)propionate (3αa), and the chemical structural formula is:

[0147] White solid (104 mg, 75%), mp 92.9 - 93.1 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 15.8, 7.8 Hz, 3H), 7.45 (dt, J = 11.9, 6.6 Hz, 5H), 7.35 - 7.27 (m, 3H), 7.17 (d, J = 7.8 Hz, 2H), 5.68 (s, 1H), 5.24 (q, J = 12.6 Hz, 2H), 5.03 (s, 1H), 3.85 (q, J = 7.1 Hz, 1H), 3.75 (q, 4H), 2.57 (s, 3H), 2.50 (d, J = 7.1 Hz, 2H), 1.91 (dq, J = 13.5, 6.6 Hz, 1H), 1.77 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H), 0.94 (d, J = 6.6 Hz, 6H). HRMS (ESI, m / z): [M+H] + , calcd. For C 45 H 46 N3O4 + : 692.3483, found: 692.3486.

[0148] Example 28

[0149] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(p-tolyl)cyclobutyl)methanone (3ab), comprising the following steps:

[0150] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(p-tolyl)cyclobutyl)methanone (3ab), and the chemical structural formula is:

[0151] White solid (75 mg, 77%), mp 188.5 - 189.1 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 8.23 - 8.16 (m, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.47 (q, J = 7.7, 6.8 Hz, 3H), 7.41 (d, J = 8.1 Hz, 2H), 7.38 - 7.31 (m, 2H), 7.16 - 7.08 (m, 2H), 5.54 (s, 1H), 4.86 (s, 1H), 3.71 - 3.44 (m, 4H), 2.43 (s, 3H), 2.26 (s, 3H), 1.64 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O2 + : 488.2333, found: 488.2334.

[0152] Example 29

[0153] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ac), comprising the following steps:

[0154] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ac), and the chemical structural formula is:

[0155] White solid (77 mg, 78%), mp 174.8 - 175.6 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 7.2 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.60 (dt, J = 10.9, 6.3 Hz, 5H), 7.48 (q, J = 7.3 Hz, 2H), 7.10 (t, J = 8.7 Hz, 2H), 5.68 (s, 1H), 5.12 (s, 1H), 3.70 (q, J = 12.7 Hz, 4H), 2.57 (s, 3H), 1.77 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -116.1. HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 19F3O2 + : 492.2082, found: 492.2085.

[0156] Example 30

[0157] A method for synthesizing (1-(4-chlorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ad), comprising the following steps:

[0158] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3-(4-chlorophenyl)bicyclo[1.1.0]butan-1-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(4-chlorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ad), and the chemical structural formula is:

[0159] White solid (80 mg, 79%), mp 189.8 - 190.3 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.35 - 8.24 (m, 2H), 7.97 (t, J = 4.0 Hz, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.63 - 7.51 (m, 5H), 7.44 (q, J = 7.4 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 5.63 (s, 1H), 5.09 (s, 1H), 3.64 (q, J = 12.7 Hz, 4H), 2.53 (s, 3H), 1.72 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1783.

[0160] Example 31

[0161] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(4-(trifluoromethyl)phenyl)cyclobutyl)methanone (3ae), comprising the following steps:

[0162] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(4-(trifluoromethyl)phenyl)cyclobutyl)methanone (3ae), and the chemical structural formula is:

[0163] White solid (88 mg, 81%), mp 179.4 - 180.1 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 7.4 Hz, 2H), 7.90 (d, J = 10.0 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.54 - 7.46 (m, 3H), 7.37 (q, J = 7.4 Hz, 2H), 5.57 (s, 1H), 5.16 (s, 1H), 3.61 (q, J = 12.7 Hz, 4H), 2.46 (s, 3H), 1.64 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -62.3. HRMS (ESI, m / z): [M + H] + , calcd. For C 32 H 27 F3N3O2 + : 542.2050, found: 542.2047.

[0164] Example 32

[0165] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-(3-methoxyphenyl)-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3af), comprising the following steps:

[0166] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-methoxyphenyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 20:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-(3-methoxyphenyl)-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3af), and the chemical structural formula is:

[0167] White solid (81 mg, 81%), mp 197.9 - 198.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.29 - 8.16 (m, 2H), 7.96 - 7.87 (m, 2H), 7.75 (d, J = 8.2 Hz, 1H), 7.48 (q, J = 7.5 Hz, 3H), 7.41 - 7.32 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.78 - 6.70 (m, 1H), 5.55 (s, 1H), 4.95 (s, 1H), 3.74 (s, 3H), 3.64 (d, J = 13.0 Hz, 2H), 3.56 (d, J = 11.3 Hz, 2H), 2.44 (s, 3H), 1.64 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 30 N3O3 + : 504.2282, found: 504.2283.

[0168] Example 33

[0169] A method for synthesizing (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ag), comprising the following steps:

[0170] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (3,5-dimethyl-1H-pyrazol-1-yl)(3-(3-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ag), and its chemical structural formula is:

[0171] White solid (75 mg, 76%), mp 156.5 - 157.2 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 7.7 Hz, 2H), 7.98 (d, J = 7.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.56 (q, J = 7.4 Hz, 3H), 7.44 (q, J = 7.7 Hz, 2H), 7.40 - 7.29 (m, 3H), 6.95 (t, J = 7.7 Hz, 1H), 5.64 (s, 1H), 5.12 (s, 1H), 3.66 (q, J = 12.5, 12.0 Hz, 4H), 2.53 (s, 3H), 1.72 (s, 3H). 19 19F NMR (376 MHz, Chloroform-d) δ -113.3. HRMS (ESI, m / z): [M + H] + , calcd. For C 31 H 27 19F3O2 + : 492.2082, found: 492.2087.

[0172] Example 34

[0173] A method for synthesizing (1-(3-chlorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ah), comprising the following steps:

[0174] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3-(3-chlorophenyl)bicyclo[1.1.0]butan-1-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-(3-chlorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3ah), and the chemical structural formula is:

[0175] White solid (80 mg, 78%), mp 171.4 - 171.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 7.7 Hz, 2H), 7.91 (d, J = 6.7 Hz, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.49 (q, J = 7.9 Hz, 3H), 7.37 (dt, J = 15.2, 7.6 Hz, 3H), 7.23 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 6.3 Hz, 1H), 5.56 (s, 1H), 5.06 (s, 1H), 3.57 (q, J = 12.4, 11.9 Hz, 4H), 2.45 (s, 3H), 1.64 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 27 ClN3O2 + : 508.1786, found: 508.1788.

[0176] Example 35

[0177] A method for synthesizing (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(phenyl)methanone (3ai) comprises the following steps:

[0178] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), phenyl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(phenyl)methanone (3ai), and the chemical structural formula is:

[0179] White solid (57 mg, 62%), mp 210.1 - 210.9 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 8.0 Hz, 2H), 8.01 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.94–7.90 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.61–7.54 (m, 5H), 7.50–7.42 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 12.9 Hz, 1H), 7.17 (t, J = 7.8 Hz, 2H), 3.87 (d, J = 12.9 Hz, 2H), 3.76 (s, 2H), 3.30 (s, 1H). HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 26 NO2 + : 456.1958, found: 456.1963.

[0180] Example 36

[0181] A method for synthesizing (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(4-methoxyphenyl)methanone (3aj), comprising the following steps:

[0182] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (4-methoxyphenyl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - 10:1) to obtain (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(4-methoxyphenyl)methanone (3aj), and its chemical structural formula is:

[0183]

[0184] White solid (53 mg, 55%), mp 201.3 - 201.9 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.34 (d, J = 7.8 Hz, 2H), 8.02 (d, J = 5.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.61–7.55 (m, 5H), 7.50–7.42 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.28–7.24 (m, 1H), 6.65 (d, J = 8.8 Hz, 2H), 3.82 (d, J = 15.3 Hz, 2H), 3.67 (s, 5H), 3.30 (s, 1H). HRMS (ESI, m / z): [M+H] + , calcd. For C 33 H 28 NO3 + : 486.2064, found: 486.2067.

[0185] Example 37

[0186] A method for synthesizing (4-fluorophenyl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ak), comprising the following steps:

[0187] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (4-fluorophenyl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - 10:1) to obtain (4-fluorophenyl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3ak), and the chemical structural formula is:

[0188] White solid (48 mg, 51%), mp 155.7 - 156.5 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.32 (d, J = 7.8 Hz, 2H), 8.02 (s, 1H), 7.97 (dd, J = 8.7, 5.5 Hz, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.61–7.53 (m, 5H), 7.46 (dt, J = 15.3, 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.26 (dd, J = 15.1, 7.8 Hz, 1H), 6.83 (t, J = 8.6 Hz, 2H), 3.99–3.60 (m, 4H), 3.17 (s, 1H). 19 19F NMR (376 MHz, Chloroform-d) δ -104.89. HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 25 FNO2 + : 474.1864, found: 474.1869.

[0189] Example 38

[0190] A method for synthesizing (3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(p-tolyl)cyclobutyl)(phenyl)methanone (3al), comprising the following steps:

[0191] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), phenyl(3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - 10:1) to obtain (3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(p-tolyl)cyclobutyl)(phenyl)methanone (3al), and the chemical structural formula is:

[0192] White solid (50 mg, 53%), mp 179.2 - 179.8 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.30–8.20 (m, 2H), 7.95–7.87 (m, 2H), 7.87–7.79 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.55–7.44 (m, 3H), 7.38 (ddd, J = 12.7, 7.9, 5.9 Hz, 4H), 7.23–7.14 (m, 1H), 7.09 (t, J = 7.9 Hz, 4H), 3.77 (d, J = 12.7 Hz, 2H), 3.67 (s, 2H), 3.16 (s, 1H), 2.26 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 33 H 28 NO2 + : 470.2115, found: 470.2120.

[0193] Example 39

[0194] A synthetic method of (3-(4-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(phenyl)methanone (3am) comprises the following steps:

[0195] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)(phenyl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - 10:1) to obtain (3-(4-fluorophenyl)-3-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(phenyl)methanone (3am), and the chemical structural formula is:

[0196] White solid (46 mg, 49%), mp 79.9 - 80.4 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.34 (d, J = 7.7 Hz, 2H), 8.03 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.60 (q, J = 8.0 Hz, 3H), 7.54 (dd, J = 8.1, 5.6 Hz, 2H), 7.52–7.44 (m, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 3.83 (d, J = 12.6 Hz, 2H), 3.75 (s, 2H), 3.40 (s, 1H). 19 19F NMR (471 MHz, Chloroform-d) δ -115.70. HRMS (ESI, m / z): [M+H] + , calcd. For C 32 H 25 FNO2 + : 474.1864, found: 474.1861.

[0197] Example 40

[0198] A method for synthesizing (3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(m-tolyl)cyclobutyl)(phenyl)methanone (3an), comprising the following steps:

[0199] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), phenyl(3-(m-tolyl)bicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - 10:1) to obtain (3-hydroxy-1-(3-phenylisoquinolin-1-yl)-3-(m-tolyl)cyclobutyl)(phenyl)methanone (3an), and the chemical structural formula is:

[0200] White solid (44 mg, 47%), mp 192.3 - 192.8 °C. 11H NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 7.1 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.64–7.57 (m, 3H), 7.49 (dt, J = 16.2, 7.6 Hz, 2H), 7.42–7.36 (m, 2H), 7.30 (td, J = 7.2, 3.6 Hz, 2H), 7.20 (t, J = 7.7 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 3.89 (d, J = 12.8 Hz, 2H), 3.78 (s, 2H), 3.32 (s, 1H), 2.39 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 33 H 28 NO2 + : 470.2115, found: 470.2119.

[0201] Example 41

[0202] A method for synthesizing (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(naphthalen-2-yl)methanone (3ao), comprising the following steps:

[0203] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), naphthalen-2-yl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence. Then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - PE / DCM = 2 / 3) to obtain (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(naphthalen-2-yl)methanone (3ao), and the chemical structural formula is:

[0204] White solid (40 mg, 40%), mp 218.4 - 218.9 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.43–8.35 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 8.00–7.94 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.66–7.58 (m, 5H), 7.58–7.54 (m, 2H), 7.51 (dt, J = 11.9, 7.7 Hz, 2H), 7.46–7.42 (m, 1H), 7.42–7.38 (m, 1H), 7.34 (dt, J = 12.4, 7.4 Hz, 3H), 7.23 (d, J = 9.6 Hz, 1H), 4.20–3.61 (m, 4H), 3.18 (s, 1H). HRMS (ESI, m / z): [M+H] + , calcd. For C 36 H 28 NO2 + : 506.2115, found: 506.2118.

[0205] Example 42

[0206] A method for synthesizing 1-(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)pentan-1-one (3ap), comprising the following steps:

[0207] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), 1-(3-phenylbicyclo[1.1.0]butan-1-yl)pentan-1-one (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain 1-(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)pentan-1-one (3ap), and the chemical structural formula is:

[0208] White solid (70 mg, 81%), mp 41.8 - 42.0 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 7.4 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 4H), 7.43 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.20 (dd, J = 15.0, 7.7 Hz, 1H), 3.51 (d, J = 12.6 Hz, 2H), 3.43 (d, J = 12.2 Hz, 2H), 2.66 (s, 1H), 2.00 (t, J = 7.2 Hz, 2H), 1.24 (p, J = 7.3 Hz, 2H), 0.89 (h, J = 7.4 Hz, 2H), 0.56 (t, J = 7.3 Hz, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 30 H 30 NO2 + : 436.2271, found: 436.2273.

[0209] Example 43

[0210] A method for synthesizing (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(pyridin-2-yl)methanone (3aq) comprises the following steps:

[0211] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3-phenylbicyclo[1.1.0]butan-1-yl)(pyridin-2-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added. Then, 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1 - PE / DCM = 2 / 3) to obtain (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(pyridin-2-yl)methanone (3aq), and the chemical structural formula is:

[0212] White solid (70 mg, 76%), mp 103.9 - 104.5 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.35–8.29 (m, 2H), 8.19–8.14 (m, 1H), 8.02–7.96 (m, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.63–7.54 (m, 5H), 7.54–7.49 (m, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.41–7.34 (m, 3H), 7.28–7.22 (m, 1H), 7.07 (ddd, J = 7.5, 4.7, 1.0 Hz, 1H), 4.74 (s, 1H), 3.75 (d, J = 13.5 Hz, 2H), 3.65 (d, J = 13.7 Hz, 2H). HRMS (ESI, m / z): [M+H] + , calcd. For C 31 H 25 N2O2 + : 457.1911, found: 457.1910.

[0213] Example 44

[0214] A method for synthesizing (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(1-methyl-1H-imidazol-2-yl)methanone (3ar), comprising the following steps:

[0215] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (1-methyl-1H-imidazol-2-yl)(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (0.2 mmol, 1.0 equiv), and silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were successively added, and then 2 mL of dichloromethane was added. The mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 15:1) to obtain (3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(1-methyl-1H-imidazol-2-yl)methanone (3ar), and the chemical structural formula is:

[0216]

[0217] White solid (45 mg, 49%), mp 213.1 - 213.9 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J = 7.4 Hz, 2H), 7.93 (s, 1H), 7.78 (dd, J = 17.7, 8.4 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.47 (q, J = 7.5 Hz, 3H), 7.38–7.34 (m, 1H), 7.34–7.26 (m, 3H), 7.21–7.16 (m, 1H), 6.64 (s, 2H), 4.66 (s, 1H), 3.86 (s, 3H), 3.72–3.51 (m, 4H). HRMS (ESI, m / z): [M+H] + , calcd. For C 30 H 26 N3O2 + : 460.2020, found: 460.2025.

[0218] Example 45

[0219] A method for synthesizing (1-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(naphthalen-2-yl)methanone (3as), comprising the following steps:

[0220] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), bicyclo[1.1.0]butan-1-yl(naphthalen-2-yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%) were added in sequence, then 2 mL of dichloromethane was added, and the mixture was stirred at room temperature in an air atmosphere for 8 h to obtain a reaction solution; the reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: PE / EA = 30:1) to obtain (1-hydroxy-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(naphthalen-2-yl)methanone (3as), and the chemical structural formula is:

[0221] White solid (30 mg, 35%). mp °C. 11H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.42 (d, J = 7.6 Hz, 2H), 8.05 (d, J = 8.6 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 12.3, 7.8 Hz, 5H), 7.51 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 4.66 - 4.46 (m, 1H), 3.72 (s, 2H), 3.33 (s, 2H), 2.18 (s, 1H). HRMS (ESI, m / z): [M + H] + , calcd. For C 30 H 24 NO2 + : 430.1802, found: 430.1801.

[0222] Example 46

[0223] A method for synthesizing (3,5 - dimethyl - 1H - pyrazol - 1 - yl)(3 - hydroxy - 3 - methyl - 1 - (3 - phenylisoquinolin - 1 - yl)cyclobutyl)methanone (3at), comprising the following steps:

[0224] In a dry 25 mL Schlenk tube equipped with a magnetic stir bar, successively add (E)-2-(phenylethynyl)benzaldoxime (0.24 mmol, 1.2 equiv), (3,5 - dimethyl - 1H - pyrazol - 1 - yl)(3 - methylbicyclo[1.1.0]butan - 1 - yl)methanone (0.2 mmol, 1.0 equiv), silver tetrafluoroborate (3.9 mg, 0.02 mmol, 10 mol%), then add 2 mL of dichloromethane, and stir at room temperature in an air atmosphere for 8 h to obtain a reaction solution; concentrate the reaction solution under reduced pressure and purify it by column chromatography (eluent: PE / EA = 20:1) to obtain (3,5 - dimethyl - 1H - pyrazol - 1 - yl)(3 - hydroxy - 3 - methyl - 1 - (3 - phenylisoquinolin - 1 - yl)cyclobutyl)methanone (3at), and the chemical structural formula is:

[0225]

[0226] White solid (54 mg, 65%), mp 112.3 - 113.2 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.57 (q, J = 7.2 Hz, 3H), 7.45 (q, J = 7.8 Hz, 2H), 5.65 (s, 1H), 3.97 (s, 1H), 3.41 (d, J = 12.9 Hz, 2H), 3.29 (d, J = 13.2 Hz, 2H), 2.55 (s, 3H), 1.75 (s, 3H), 1.51 (s, 3H). HRMS (ESI, m / z): [M+H] + , calcd. For C 26 H 26 N3O2 + : 412.2020, found: 412.2022.

[0227] The transformation applications of the multi-substituted cyclobutanol compounds of the present invention are as follows:

[0228] Transformation Application 1. Preparation of diol compounds:

[0229] (3,5-Dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3aa) is reduced, including the following steps:

[0230] At 0 °C, sodium borohydride (1 mmol) was added to a mixed solvent of 3aa (0.2 mmol) in tetrahydrofuran (4 mL) / water (1 mL). The reaction mixture was gradually warmed to room temperature and stirred for 24 hours to obtain a reaction solution; after quenching the reaction by adding 10 mL of saturated sodium bicarbonate solution to the reaction solution, the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure and then purified by column chromatography (eluent: PE / EA = 4 / 1) to obtain (1r,3r)-3-(hydroxymethyl)-1-phenyl-3-(3-phenylisoquinolin-1-yl)cyclobutan-1-ol (4), and the chemical structural formula is:

[0231] White solid (75 mg, 99%), mp 178.1 - 178.7 °C. 11H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.55 (dd, J = 18.4, 7.5 Hz, 3H), 7.42 (t, J = 7.5 Hz, 3H), 7.34 (t, J = 7.3 Hz, 3H), 7.24 (t, J = 7.3 Hz, 1H), 3.80 (d, J = 3.2 Hz, 2H), 3.31 (s, 4H), 2.05 (s, 1H), 1.78 (s, 1H). 13 13C{ 1 1H} NMR (101 MHz, Chloroform-d) δ 162.7, 147.7, 144.9, 138.3, 137.2, 128.8, 127.7, 127.5, 127.4, 126.6, 125.8, 125.3, 124.8, 124.6, 123.7, 114.5, 71.9, 68.4, 44.0, 41.9. HRMS (ESI, m / z): [M+H] + , calcd. For C 26 19 24 H + 17 Figure 1-2 NO2: 382.1802, found: 382.1801, as

[0232] Transformation Application 2. Preparation of diol compounds:

[0233] (3-Hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)(phenyl)methanone (3ai) is reduced, including the following steps:

[0234] At 0 °C, sodium borohydride (0.5 mmol) was added to a mixed solvent of 3ai (0.1 mmol) in tetrahydrofuran (2 mL) / water (0.5 mL). The reaction mixture was gradually warmed to room temperature and stirred for 24 hours to obtain a reaction solution; after quenching the reaction by adding 10 mL of saturated sodium bicarbonate solution to the reaction solution, the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure and then purified by column chromatography (eluent: PE / EA = 5 / 1) to obtain a 3-hydroxy(phenyl)methyl-1-phenyl-3-(3-phenylisoquinolin-1-yl)cyclobutan-1-ol (5), and the chemical structural formula is:

[0235]

[0236] White solid (45 mg, 98%), mp 84.8 - 85.6 °C. 1 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 7.4 Hz, 2H), 7.97 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 10.4 Hz, 2H), 7.53–7.46 (m, 3H), 7.42 (q, J = 6.9 Hz, 3H), 7.32 (t, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 8.8, 4.5 Hz, 1H), 7.05 (t, J = 7.0 Hz, 1H), 6.97 (t, J = 7.1 Hz, 2H), 6.71 (s, 2H), 5.07 (d, J = 4.4 Hz, 1H), 3.79 (d, J = 12.1 Hz, 1H), 3.59 (d, J = 11.7 Hz, 1H), 3.31 (dd, J = 25.7, 12.3 Hz, 2H), 1.99 (s, 1H), 1.26 (s, 1H). 13 13C{ 1 1H} NMR (101 MHz, Chloroform-d) δ 163.4, 148.5, 145.9, 140.9, 139.1, 138.0, 129.6, 128.8, 128.7, 128.1, 127.6, 127.6, 127.4, 127.0, 126.8, 126.4, 125.8, 125.7, 115.6, 77.9, 72.8, 47.1, 46.4. HRMS (ESI, m / z): [M+H] + , calcd. For C 32 27 28 H + 2 Figure 3-4 NO2

[0237] Transformation Application III. Preparation of Carboxylic Acid Ester Compounds:

[0238] (3,5-Dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3aa) undergoes nucleophilic substitution, including the following steps:

[0239] At room temperature, DBU (0.22 mmol) was added to a methanol (2 mL) solution of 3aa (0.2 mmol), and the mixture was stirred at room temperature for 16 h. After removing the solvent under reduced pressure, the product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain methyl (1r,3r)-3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutane-1-carboxylate (6), and the chemical structural formula is as follows:

[0240] White solid (78 mg, 95%), mp 146.1 - 146.6 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.35 - 8.26 (m, 2H), 8.11 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 - 7.65 (m, 3H), 7.57 (t, J = 7.7 Hz, 3H), 7.50 - 7.43 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 3.71 (d, J = 13.6 Hz, 2H), 3.66 - 3.60 (m, 2H), 3.59 (s, 3H), 3.18 (s, 1H). 13 C{ 1 H}NMR (101 MHz, Chloroform-d) δ 174.8, 158.6, 147.7, 144.4, 138.1, 137.0, 129.2, 127.8, 127.6, 127.3, 127.3, 126.3, 126.2, 125.9, 124.0, 124.0, 123.7, 115.3, 72.7, 51.7, 46.5, 45.1. HRMS (ESI, m / z): [M + H] + , calcd. For C 27 H 24 NO3 + : 410.1751, found: 410.1749, as Figure 5-6 shown.

[0241] Transformation Application IV. Preparation of cyclobutanol compounds:

[0242] (3,5-Dimethyl-1H-pyrazol-1-yl)(3-hydroxy-3-phenyl-1-(3-phenylisoquinolin-1-yl)cyclobutyl)methanone (3aa) transformation, including the following steps:

[0243] At room temperature, lithium hydroxide monohydrate (0.6 mmol) was added to a mixed solvent of 3aa (0.15 mmol) in tetrahydrofuran (1 mL) / water (1 mL). The mixture was stirred at 55 °C for 24 hours, then ethyl acetate was added to extract the reaction solution. The organic phases were combined and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then purified by column chromatography (eluent: PE / EA = 10 / 1) to obtain a (1S,3S)-1-phenyl-3-(3-phenylisoquinolin-1-yl)cyclobutan-1-ol (7) with the chemical structural formula as follows:

[0244] White solid (44 mg, 84%), mp 110.8 - 111.7 °C. 1 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.5 Hz, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.34 - 7.23 (m, 3H), 7.16 (dd, J = 12.4, 4.7 Hz, 1H), 5.06 - 4.43 (m, 1H), 3.21 (td, J = 9.5, 2.5 Hz, 2H), 2.95 - 2.65 (m, 2H), 2.21 (s, 1H). 13 13C{ 1 1H}NMR (101 MHz, CDCl3) δ 161.1, 148.1, 145.8, 138.6, 136.0, 128.9, 127.6, 127.3, 127.3, 126.8, 126.1, 125.8, 125.7, 124.6, 123.94, 123.87, 113.7, 74.5, 40.7, 31.5. HRMS (ESI, m / z): [M + H] + , calcd. For C 25 22 22 H + 19 Figure 7-8 NO

[0245] It should be noted that although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is limited by the appended claims and their equivalents.

Claims

1. A method for preparing the multi-substituted cyclobutanol compound according to claim 1, characterized in that, It includes the following steps: Take 2-alkynylbenzaldoxime and bicyclobutane as raw materials and add them to a dry Schlenk tube. Then add a catalyst and a solvent to the tube, and stir the reaction mixture at room temperature for 8 h to obtain a polysubstituted cyclobutanol compound; The general reaction formula for the synthesis is: Among them, Ar 1 is selected from 7-methyl, 7-chloro, 7-fluoro, 6-methyl, 6-chloro, benzodioxole; R 1 selected from 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, biphenyl, 2-thienyl, 3-methylphenyl, 3-chlorophenyl, 2-methylphenyl, 2-chlorophenyl, cyclopropyl, n-pentyl; R 2 selected from phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, methyl; R 3 Selected from 1,3-dimethylimidazolyl, 2-naphthyl, n-butyl, 2-pyridyl, 2-(1-methylimidazolyl).

2. The preparation method of the multi-substituted cyclobutanol compound according to claim 1, characterized in that, The molar ratio of the 2-alkynylbenzaldoxime compound, BCBs, and the catalyst is 1.2:1:0.

1.

3. The preparation method of the multi-substituted cyclobutanol compound according to claim 1, characterized in that, The 2-alkynylbenzaldoxime compound is selected from (E)-2-(phenylethynyl)benzaldoxime, (E)-2-(p-tolylethynyl)benzaldoxime, (E)-2-(4-methoxyphenylethynyl)benzaldoxime, (E)-2-(4-fluorophenylethynyl)benzaldoxime, (E)-2-(4-chlorophenylethynyl)benzaldoxime, (E)-2-(4-trifluoromethylphenylethynyl)benzaldoxime, (E)-2-(4-nitrophenylethynyl)benzaldoxime, (E)-2-([1,1'-biphenyl]-4-ylethynyl)benzaldoxime, (E)-2-(thiophen-2-ylethynyl)benzaldoxime, (E)-2-(m-tolylethynyl)benzaldoxime, (E)-2-(3-chlorophenylethynyl)benzaldoxime, (E)-2-(o-tolylethynyl)benzaldoxime, (E)-2-(2-chlorophenylethynyl)benzaldoxime, (E)-2-(cyclopropylethynyl)benzaldoxime, (E)-2-(hept-1-yn-1-yl)benzaldoxime, (E)-5-methyl-2-phenylethynylbenzaldoxime, (E)-5-chloro-2-phenylethynylbenzaldoxime, (E)-5-fluoro-2-phenylethynylbenzaldoxime, (E)-4-methyl-2-phenylethynylbenzaldoxime, (E)-4-chloro-2-phenylethynylbenzaldoxime, (E)-6-phenylethynylbenzo[d][1,3]dioxole-5-carboxaldoxime, (2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, (E)-3,7-dimethylocta-2,6-dien-1-yl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, 3,7-dimethylocta-6-en-1-yl (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzoate, 2-isopropyl-5-methylphenyl (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzoate, ((5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-((2-((E)-hydroxyiminomethyl)phenyl)ethynyl)benzoate, (E)-4-((2-(hydroxyiminomethyl)phenyl)ethynyl)benzyl 2-(4-isobutylphenyl)propionate.

4. The preparation method of the multi-substituted cyclobutanol compound according to claim 1, characterized in that The BCB compounds are selected from the known 1-(5-oxopyrrolidin-2-yl)-2-((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)ethane-1,2-dione, 1-(5-oxopyrrolidin-2-yl)-2-((1S,3R)-3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)ethane-1,2-dione, 1-((1S,3R)-3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione, 1-((1S,3R)-3-(4-chlorophenyl)bicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione, 1-(5-oxopyrrolidin-2-yl)-2-((1S,3R)-3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butan-1-yl)ethane-1,2-dione, 1-((1S,3R)-3-(3-methoxyphenyl)bicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione, 1-((1S,3R)-3-(3-fluorophenyl)bicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione, 1-((1S,3R)-3-(3-chlorophenyl)bicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione, phenyl((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)methanone, (4-methoxyphenyl)((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)methanone, (4-fluorophenyl)((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)methanone, phenyl((1S,3R)-3-(p-tolyl)bicyclo[1.1.0]butan-1-yl)methanone, ((1S,3R)-3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)(phenyl)methanone, phenyl((1S,3R)-3-(m-tolyl)bicyclo[1.1.0]butan-1-yl)methanone, naphthalen-2-yl((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)methanone, 1-((1s,3r)-3-phenylbicyclo[1.1.0]butan-1-yl)pentan-1-one, ((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)(pyridin-2-yl)methanone, (1-methyl-1H-imidazol-2-yl)((1S,3R)-3-phenylbicyclo[1.1.0]butan-1-yl)methanone, methyl (1S,3R)-3-phenylbicyclo[1.1.0]butane-1-carboxylate, (1s,3r)-N-methoxy-N-methyl-3-phenylbicyclo[1.1.0]butane-1-carboxamide, ((1R,3R)-bicyclo[1.1.0](butan-1-yl)(naphthalen-2-yl)methanone, 1-((1S,3R)-3-methylbicyclo[1.1.0]butan-1-yl)-2-(5-oxopyrrolidin-2-yl)ethane-1,2-dione.

5. The preparation method of the multi-substituted cyclobutanol compound according to claim 1, wherein, The catalyst is selected from silver tetrafluoroborate, silver nitrate, silver oxide, silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, lanthanum trifluoromethanesulfonate, scandium trifluoromethanesulfonate, triphenylphosphine gold chloride.

6. The preparation method of the multi-substituted cyclobutanol compound according to claim 1, characterized in that, The solvent is selected from dichloromethane, tetrahydrofuran, acetonitrile, toluene.

7. A polysubstituted cyclobutanol compound prepared by the preparation method according to claim 1, characterized in that, The structural formula of the poly-substituted cyclobutanol compounds is as follows: wherein Ar 1 is 7-methyl, 7-chloro, 7-fluoro, 6-methyl, 6-chloro, benz[1,3]dioxole; R 1 is 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, biphenyl, 2-thienyl, 3-methylphenyl, 3-chlorophenyl, 2-methylphenyl, 2-chlorophenyl, cyclopropyl, n-pentyl; R 2 phenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, methyl; R 3 Selected from 1,3-dimethylimidazolyl, 2-naphthyl, n-butyl, 2-pyridyl, 2-(1-methylimidazolyl).

8. Use of the cyclobutanol compound according to claim 7 in the preparation of cyclobutanediol compounds, cyclobutanecarboxylate compounds, and cyclobutanol compounds with a deacylated pyrazolyl group.

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