Oxime derivatives containing 3,4-dihydroisoquinoline structure, and preparation method and application thereof

Abstract

The present application belongs to the technical field of pesticides, and relates to an oxime derivative containing a 3,4-dihydroisoquinoline structure and a preparation method and application thereof. The present application synthesizes a kind of oxime derivative containing a 3,4-dihydroisoquinoline structure by introducing an oxime functional group into a 3,4-dihydroisoquinoline structure. The oxime derivative and hydrochloride thereof have inhibitory effects on various plant pathogenic fungi, and have excellent inhibitory activities on Ascomycota and Deuteromycota pathogenic fungi, such as Valsa mali, Physalospora piricola, Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum and Magnaporthe oryzae. Therefore, the oxime derivative containing a 3,4-dihydroisoquinoline structure is expected to be further developed into a high-efficiency, safe, economical and environment-friendly green fungicide.

Description

Technical Field

[0001] This invention belongs to the field of pesticide technology and relates to oxime derivatives containing a 3,4-dihydroisoquinoline structure, their preparation methods and applications. Background Technology

[0002] Pesticides are essential agricultural inputs, playing a crucial role in ensuring high and stable crop yields. Statistics show that pathogenic fungal infections cause a 20% annual reduction in global crop yields, with a further 10% loss after harvest, resulting in significant economic losses and a serious threat to global food security. Applying fungicides is currently the most effective measure for controlling pathogenic fungi, saving substantial losses annually. However, the irrational use of fungicides has led to increasingly serious fungal resistance. Therefore, developing new fungicides and addressing the resistance problem are crucial for sustainable agricultural development.

[0003] Isoquinolines and their derivatives are widely found in nature and possess a variety of excellent biological activities, including antibacterial, insecticidal, anti-inflammatory, and anticancer effects. In the field of medicinal chemistry, isoquinolines and their analogues have received widespread attention due to these activities, but their application in the pesticide field remains relatively limited, indicating significant potential for further research and development.

[0004] Oxime compounds are an important class of nitrogen-containing heterocyclic bioactive molecules with broad agricultural activities, including insecticidal, fungicidal, herbicidal, and antiviral properties against plant viruses. Many varieties also possess the advantages of low toxicity and low residue. Currently, several oxime fungicides, such as oximetrimer, azoxystrobin, and fenpropathrin, have been successfully commercialized. Due to their outstanding biological activity and good environmental compatibility, oxime derivatives remain a hot topic in the current research and development of agricultural fungicides. Summary of the Invention

[0005] To address the problems and deficiencies in the existing technology, this invention provides oxime derivatives containing a 3,4-dihydroisoquinoline structure, their preparation methods, and applications. This invention synthesizes a class of oxime derivatives containing a 3,4-dihydroisoquinoline structure by introducing an oxime functional group into the 3,4-dihydroisoquinoline structure. These compounds exhibit significant inhibitory effects against plant pathogenic fungi.

[0006] In a first aspect, the present invention provides an oxime derivative containing a 3,4-dihydroisoquinoline structure, having the structure shown in formula (I), or a pesticide-acceptable salt thereof.

[0007]

[0008] Equation (I); Among them, R 1Each of the following groups is independently selected from hydrogen, halogen, amino, amide, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamine, optionally substituted benzene ring, optionally substituted aromatic heterocycle and optionally substituted aryloxy. R 2 It is selected from any one of hydrogen, cyano, acyl, ester, aminoacyl, optionally substituted alkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted benzene ring and optionally substituted aromatic heterocycle; R 3 It is selected from any one of the optionally substituted acyl, ester, aminoacyl, optionally substituted alkyl, optionally substituted benzene ring and optionally substituted aromatic heterocycle; R 4 R 5 Each of the groups is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamine. R 6 R 7 Each of the groups is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamine. The aromatic heterocycle is a C1~C10 aromatic heterocycle containing nitrogen, sulfur or oxygen; The optional substitution is unsubstituted, or is selected from any one or more of halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, or aryl; m is an integer from 0 to 4; n is 0 or 1.

[0009] Furthermore, in the oxime derivatives containing a 3,4-dihydroisoquinoline structure provided by the present invention, the alkyl group has 1 to 8 carbon atoms; The alkyloxy group has 1 to 8 carbon atoms; The halogen is selected from any one of fluorine, chlorine, bromine, and iodine; The aromatic heterocycle is selected from any one of pyrrole, thiophene, furan, pyrazole, pyridine, pyran, imidazole, thiazole, benzothiazole, oxazole, isoxazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, indole, oxadiazole, thiadiazole, triazole, triadimefon, and tetrazolium.

[0010] Furthermore, among the oxime derivatives containing a 3,4-dihydroisoquinoline structure provided by this invention, those having the structure shown in formula (I-a), or a pesticide-acceptable salt thereof,

[0011] Equation (Ⅰ-a); R is independently selected from any one of hydrogen, halogen, amino, acylamino, hydroxyl, nitro, cyano, mercapto, acyl, ester, amide, aminoacyl, C1-C8 alkyl, C1-C8 haloalkane, C1-C8 alkyloxy, C1-C8 haloalkoxy, C1-C8 alkylthio, C1-C8 alkylamino, optionally substituted benzene ring, C1-C10 nitrogen-containing heterocycle, C1-C10 oxygen-containing heterocycle, C1-C10 sulfur-containing heterocycle, and C1-C10 aryloxy; or, R is fused with the parent nucleus to form a fused-ring aromatic hydrocarbon; R 2 It is selected from any one of hydrogen, cyano, acyl, ester, aminoacyl, optionally substituted alkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted benzene ring and optionally substituted aromatic heterocycle; R 4 R 5 Each of the following is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamine; The optional substitution is unsubstituted, or is selected from any one or more of halogen, alkyl, alkoxy, amino, amino, amide, hydroxy, haloalkyl, haloalkoxy, nitro, cyano, mercapto, acyl, ester, aminoacyl, or aryl; Y is selected from any one of hydrogen, oxygen, and C1~C8 alkyl groups; The halogen is selected from any one of fluorine, chlorine, bromine, and iodine; x is between 0 and 4.

[0012] Furthermore, the oxime derivatives containing a 3,4-dihydroisoquinoline structure provided by this invention are specifically selected from the following structures:

[0013]

[0014] .

[0015] Secondly, the present invention provides a method for preparing the above-mentioned oxime derivatives containing the 3,4-dihydroisoquinoline structure, comprising: ; Where X is chlorine, bromine, or iodine.

[0016] Furthermore, in the preparation method of the oxime derivative containing the 3,4-dihydroisoquinoline structure provided by the present invention, route 1 includes: using a ketone compound (II) containing the 3,4-dihydroisoquinoline structure as a raw material, reacting it with hydroxylamine to generate an oxime compound (III); and reacting the oxime compound (III) with a halogenated compound (IV) under alkaline conditions to undergo a nucleophilic substitution reaction to generate an oxime derivative (I) containing the 3,4-dihydroisoquinoline structure. Route 2 includes: using a ketone compound (II) containing a 3,4-dihydroisoquinoline structure as a starting material, and reacting it with R... 3 (CH2) n O-NH2(V) undergoes a condensation reaction to generate an oxime derivative containing a 3,4-dihydroisoquinoline structure corresponding to general formula (I), wherein R 3 (CH2) n O-NH2(V) is synthesized from a halogenated compound (IV) and hydroxylamine hydrochloride.

[0017] Furthermore, in the method for preparing oxime derivatives containing a 3,4-dihydroisoquinoline structure provided by the present invention, the method for synthesizing ketone compounds (II) containing a 3,4-dihydroisoquinoline structure includes: ; Where Z represents fluorine, chlorine, or bromine.

[0018] Furthermore, in the preparation method of the oxime derivative containing the 3,4-dihydroisoquinoline structure provided by the present invention, route 3 includes: using substituted phenylethanol (VI) as a raw material, reacting it with substituted acetonitrile (VII) under acidic conditions to undergo a nucleophilic addition and cyclization tandem reaction to generate a 3,4-dihydroisoquinoline compound (VIII); the 3,4-dihydroisoquinoline compound (VIII) undergoes an oxidation reaction to generate a ketone compound (II) containing the 3,4-dihydroisoquinoline structure; Route 4 includes: using formyl chloride (IX) as a raw material, reacting it with cyaniding reagents such as cuprous cyanide, sodium cyanide, or trimethylcyanosilane to generate formonitrile (X); then, under acidic conditions, formonitrile (X) reacts with substituted phenylethanol (VI) in a series of addition and cyclization reactions to generate ketone compounds (II) containing a 3,4-dihydroisoquinoline structure.

[0019] Thirdly, the present invention provides a bactericidal composition, wherein the active ingredient of the bactericidal composition includes the above-mentioned oxime derivatives containing a 3,4-dihydroisoquinoline structure.

[0020] Fourthly, the present invention provides the application of oxime derivatives or fungicidal compositions containing a 3,4-dihydroisoquinoline structure in the prevention and control of plant fungal diseases, wherein the plant pathogenic fungi are selected from one or more of the following phyla: clubroot, oomycetes, chytrid, zygomycetes, ascomycetes, basidiomycetes, and deuteromycetes. More preferably, the plant pathogenic fungus is selected from apple rot fungus, apple ring rot fungus, rapeseed sclerotium rot fungus, tomato gray mold fungus, wheat scab fungus and rice blast fungus.

[0021] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: This invention synthesizes a class of oxime derivatives containing a 3,4-dihydroisoquinoline structure by introducing an oxime functional group into the 3,4-dihydroisoquinoline structure. Results show that these compounds exhibit broad-spectrum antifungal activity against plant pathogens such as pathogenic fungi, particularly showing excellent antifungal activity against *Aureobasidium canis*, *Aureobasidium argentea*, *Sclerotinia sclerotiorum*, *Botrytis cinerea*, *Fusarium graminearum*, and *Bacillus thuringiensis*. Structure-activity relationship analysis indicates that introducing an aromatic heterocycle into the oxime functional group enhances the antifungal activity of these compounds. These compounds possess novel structures, are simple to synthesize, and are structurally completely different from existing commercial fungicides, making them promising candidates for development into highly efficient, safe, economical, and environmentally friendly new green fungicides. Detailed Implementation

[0022] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials can be purchased commercially.

[0023] The pesticide-acceptable salt refers to the salt obtained by reacting the oxime derivative containing the 3,4-dihydroisoquinoline structure of this invention with a chemically acceptable acid. The chemically acceptable acid can be an inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid) or an organic acid (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, or benzoic acid). The pesticide-acceptable salt can also be the salt obtained by reacting the oxime derivative containing the 3,4-dihydroisoquinoline structure of this invention with a chemically acceptable base, wherein the chemically acceptable base can be an inorganic base (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (such as trimethylamine, triethylamine, etc.). Further, the pesticide-acceptable salt can be a potassium salt, sodium salt, ammonium salt, calcium salt, pyridine salt, choline salt, hydrochloride salt, phosphate salt, acetate salt, benzenesulfonate salt, or oxalate salt.

[0024] The bactericide composition can be formulated by mixing the active components with a liquid carrier and / or a solid carrier, and by adding surfactants (such as emulsifiers, dispersants, stabilizers, and wetting agents), as well as other additives (such as adhesives, defoamers, and oxidants).

[0025] The oxime derivatives containing the 3,4-dihydroisoquinoline structure described in this invention can be used together with one or more other insecticides, fungicides, herbicides, plant growth regulators or fertilizers, etc., and the components can be applied simultaneously, sequentially or separately.

[0026] Example 1 The synthesis method of compound II-1 described in this embodiment is as follows: Route 3:

[0027] (1) Synthesis of compound VⅢ-1: Concentrated sulfuric acid (30 mL, 600 mmol) was slowly added dropwise to a solution of 2-methyl-1-phenyl-2-propanol (compound VI-1, 4.5 g, 30 mmol) and phenylacetonitrile (compound VII-1, 3.9 g, 30 mmol) dissolved in toluene (80 mL). The reaction temperature was controlled at 0–5 °C, and the mixture was stirred continuously for 15–20 minutes. The reaction was then stirred at room temperature, and the reaction progress was monitored by TLC (petroleum ether (PE) and ethyl acetate (EA) as the developing solvents, PE:EA = 5:1, v / v). After the reaction was completed, the organic phase was separated. The aqueous phase was adjusted to pH 8–9 with ammonia and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed successively with water (100 mL × 3) and saturated sodium chloride solution (100 mL × 3). After drying with anhydrous MgSO4, the mixture was filtered and concentrated under reduced pressure to obtain a white oily compound VⅢ-1. The product requires no further purification and can be used directly in the next reaction.

[0028] (2) Synthesis of compound II-1: Compound VIII-1 was dissolved in 80 mL of toluene, oxygen was bubbled through, and the mixture was heated to reflux and stirred overnight at 80 °C. After the reaction was completed by TLC (PE:EA=5:1, v / v), the reaction solution was concentrated under reduced pressure to obtain a yellow oily crude product, which was purified by silica gel column chromatography (eluent: PE:EA=5:1, v / v) to obtain a white solid compound II-1 (5.5 g, yield 69.6%).

[0029] Route 4:

[0030] Concentrated H₂SO₄ (30 mL, 600 mmol) was slowly added dropwise to a toluene (80 mL) solution of 2-methyl-1-phenyl-2-propanol (compound VI-1, 4.5 g, 30 mmol) and benzoyl nitrile (compound X-1, 3.9 g, 30 mmol). The reaction was carried out at 0–5°C with stirring for 15–20 minutes. The mixture was then stirred at room temperature, and the reaction progress was monitored by TLC (PE:EA = 5:1, v / v). After the reaction was complete, the organic phase was separated. The pH of the aqueous phase was adjusted to 8–9 with ammonia, followed by extraction three times with ethyl acetate (100 mL each time). The organic phases were combined and washed successively with water (100 mL × 3) and saturated sodium chloride solution (100 mL × 3), dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure to give a yellow oily crude product. Finally, the compound was purified by silica gel column chromatography (eluent: PE:EA = 5:1, v / v) to give a white solid compound II-1 (6.0 g, yield 75.9%).

[0031] The detection results for compound II-1 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.04 (d, J = 8.5 Hz, 2H), 7.63 – 7.59 (m, 1H), 7.49 – 7.45 (m, 2H), 7.43 – 7.39 (m, 1H), 7.28 – 7.21 (m, 3H), 2.89 (s, 2H), 1.38 (s, 6H).

[0032] Example 2 The compound I-1 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-pyridinyl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthetic method (route 1) for methyl (n=1) is as follows:

[0033] (1) Synthesis of compound III-1: In a 200 mL round-bottom flask, compound II-1 (5.5 g, 20 mmol) was dissolved in a mixed solvent of ethanol and water (4:1, v / v, 100 mL), and hydroxylamine hydrochloride (2.3 g, 33 mmol) and sodium acetate (3.4 g, 41 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC (PE:EA = 5:1, v / v). After the reaction was complete, the ethanol was removed by concentration under reduced pressure, the residue was diluted with water (30 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed sequentially with water (100 mL × 3) and saturated sodium chloride solution (100 mL × 3), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a pale yellow crude product. Finally, it was purified by silica gel column chromatography (eluent: PE:EA = 5:1, v / v) to give a white solid compound III-1 (4.0 g, yield 71.4%).

[0034] (2) Synthesis of compound I-1: Compound III-1 (0.10 g, 0.36 mmol), 2-chloromethylpyridine (compound IV-1, 0.92 g, 0.72 mmol), and anhydrous potassium carbonate (0.16 g, 1.17 mmol) were added sequentially to a 10 mL dry pressure-resistant tube and dissolved in anhydrous DMF (5 mL). The reaction mixture was stirred overnight at room temperature, and the reaction progress was monitored by TLC (PE:EA = 5:1, v / v). After the reaction was complete, water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed sequentially with water (10 mL × 3) and saturated sodium chloride solution (10 mL × 3), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a pale yellow oily crude product. Finally, the product was purified by silica gel column chromatography (eluent: PE:EA = 8:1, v / v) to give compound I-1 (0.90 g, yield 75.0%).

[0035] The detection results for compound III-1 are as follows: 1 H NMR (400 MHz, DMSO- d 6) d 11.32 (s, 1H), 7.58 – 7.55 (m, 2H), 7.40 –7.37 (m, 4H), 7.29 – 7.22 (m, 2H), 7.05 – 7.03 (m, 1H), 2.82 (s, 2H), 1.22(s, 6H).

[0036] The detection results for compound I-1 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.51 – 8.50 (m, 1H), 7.67 – 7.58 (m, 3H), 7.40– 7.13 (m, 9H), 5.39 (d, J = 14.6 Hz, 1H), 5.30 (d, J = 14.6 Hz, 1H). 2.94 – 2.85(m, 2H), 1.39 (s, 3H), 1.38 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.8, 158.6, 155.4, 148.8, 136.7, 136.0,133.4 (2C), 131.6, 130.0, 128.6 (2C), 128.5, 127.3, 126.9 (2C), 126.4, 122.3,121.5, 77.2, 55.5, 38.6, 28.3, 27.7; HRMS (ESI) m / z [M + H] + : calcd for C 24 H 23 N3O, 370.1914, found, 370.1922.

[0037] Example 3 The compound I-2 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-Fluoropyridin-6-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0038] The synthesis method of compound I-2 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-fluoro-6-chloromethylpyridine to obtain compound I-2 (yellow solid, 0.10 g, yield 73.8%).

[0039] The detection results for compound I-2 are as follows: mp = 85.1-88.0 ℃; 1 H NMR (400 MHz, CDCl3) d 7.71 – 7.64 (m, 3H), 7.40 – 7.29 (m, 4H), 7.23 – 7.12 (m, 4H), 6.78 – 6.75 (m, 1H), 5.29 (d, J = 15.1 Hz, 1H), 5.20 (d, J = 15.1Hz, 1H), 2.94 – 2.85 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 163.0 (d, J = 239.4 Hz), 160.7, 157.8 (d, J =12.4 Hz), 155.8, 141.6 (d, J = 7.6 Hz), 135.9, 133.3, 131.6, 130.1, 128.7 (2C),128.6, 127.3, 126.9 (2C), 126.4, 118.5, 118.4, 107.8 (d, J = 36.5 Hz), 76.3,55.5, 38.6, 28.4, 27.7; HRMS (ESI) m / z [M + H] + : calcd for C 24 H 22 FN3O, 388.1820, found, 388.1826.

[0040] Example 4 The compound I-3 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-Chloropyridin-6-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0041] The synthesis method of compound I-3 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-chloro-6-chloromethylpyridine to obtain compound I-3 (yellow solid, 0.12 g, yield 82.5%).

[0042] The detection results for compound I-3 are as follows: mp = 95.6-97.2 ℃; 1 H NMR (400 MHz, CDCl3) d 7.66 – 7.64 (m, 2H), 7.57 – 7.54 (m, 1H), 7.40 – 7.29 (m, 4H), 7.23 – 7.16 (m, 5H), 5.32 (d, J = 15.2 Hz, 1H), 5.23 (d, J = 15.2Hz, 1H), 2.94 – 2.84 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.7, 159.8, 155.8, 150.5, 139.2, 135.9,133.2, 131.6, 130.1, 128.64 (2C), 128.56, 127.3, 126.9 (2C), 126.35, 126.32,122.7, 119.8, 76.5, 55.5, 38.5, 28.4, 27.6; HRMS (ESI) m / z [M + H] + : calcd for C 24 H 23 ClN3O, 404.1524, found, 404.1534.

[0043] Example 5 The compound I-4 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-Bromopyridin-6-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0044] The synthesis method of compound I-4 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-bromo-6-bromomethylpyridine to obtain compound I-4 (yellow solid, 0.13 g, yield 80.5%).

[0045] The detection results for compound I-4 are as follows: mp = 114.6-115.8 ℃; 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.64 (m, 2H), 7.47 – 7.43 (m, 1H), 7.39 – 7.29 (m, 5H), 7.23 – 7.20 (m, 3H), 5.33 (d, J = 15.1 Hz, 1H), 5.24 (d, J = 15.1Hz, 1H), 2.94 – 2.85 (m, 2H), 1.39 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 160.7, 160.3, 155.7, 141.2, 138.9, 135.9,133.2, 131.6, 130.1, 128.6 (2C), 128.5, 127.3, 126.8 (2C), 126.5, 126.4,126.3, 120.1, 76.4, 55.4, 38.5, 28.4, 27.6.

[0046] Example 6 The compound I-5 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0047] The synthesis method of compound I-5 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-5 (yellow oil, 0.10 g, yield 72.4%).

[0048] The detection results for compound I-5 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.67 – 7.65 (m, 2H), 7.49 – 7.45 (m, 1H), 7.38 – 7.28 (m, 4H), 7.22 – 7.16 (m, 3H), 7.05 – 6.98 (m, 2H), 5.34 (d, J = 14.6 Hz, 1H), 5.26 (d, J = 14.5 Hz, 1H), 2.93 – 2.83 (m, 2H), 2.51 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.8, 157.9, 157.5, 155.3, 136.9, 135.9,133.5, 131.4, 129.9, 128.6 (2C), 128.5, 127.2, 126.8 (2C), 126.5, 126.4,121.9, 118.3, 77.3, 55.4, 38.6, 28.4, 27.7, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 25 N3O, 384.2070, found, 384.2079.

[0049] Example 7 The compound I-6 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-Methoxypyridin-6-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0050] The synthesis method of compound I-6 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-methoxy-6-chloromethylpyridine to obtain compound I-6 (yellow oil, 0.096 g, yield 66.8%).

[0051] The detection results for compound I-6 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.67 – 7.65 (m, 2H), 7.47 – 7.43 (m, 1H), 7.38 – 7.29 (m, 4H), 7.23 – 7.16 (m, 3H), 6.78 – 6.76 (m, 1H), 6.57 – 6.55 (m,1H), 5.24 (d, J = 14.4 Hz, 1H), 5.18 (d, J = 14.3 Hz, 1H), 3.85 (s, 3H), 2.95 –2.84 (m, 2H), 1.39 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 163.5, 160.8, 156.1, 155.1, 138.9, 135.9,133.5, 131.4, 129.9, 128.6 (2C), 128.5, 127.2, 126.8 (2C), 126.4, 126.4,113.8, 109.0, 77.1, 55.4, 53.3, 38.6, 28.3, 27.7.

[0052] Example 8 The compound I-7 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =2-Cyanopyridin-6-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0053] The synthesis method of compound I-7 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 6-chloromethyl-2-cyanopyridine to obtain compound I-7 (yellow solid, 0.094 g, yield 66.2%).

[0054] The detection results for compound I-7 are as follows: mp = 115.8-116.9℃; 1 H NMR (400 MHz, CDCl3) d 7.76 – 7.72 (m, 1H), 7.66 – 7.62 (m, 2H), 7.56 – 7.50 (m, 2H), 7.41 – 7.30 (m, 4H), 7.24 – 7.19 (m, 3H), 5.38 (d, J = 15.2 Hz, 1H), 5.28 (d, J = 15.3 Hz, 1H), 2.94 – 2.86 (m, 2H), 1.39 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 161.2, 160.6, 156.2, 137.6, 135.9, 133.1,133.0, 131.7, 130.3, 128.7 (2C), 128.6, 127.3, 127.0, 126.9 (2C), 126.3,124.9, 117.3, 76.3, 55.5, 38.5, 29.8, 28.4, 27.6; HRMS (ESI) m / z [M + H] + : calcd for C 24 H 23 N3O, 395.1866, found, 395.1874.

[0055] Example 9 The compound I-8 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =3,5-Dimethyl-4-methoxypyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0056] The synthesis method of compound I-8 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-chloromethyl-3,5-dimethyl-4-methoxypyridine to obtain compound I-8 (yellow oil, 0.12 g, yield 78.0%).

[0057] The detection results for compound I-8 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.16 (s, 1H), 7.65 – 7.62 (m, 2H), 7.33 – 7.28(m, 4H), 7.16 – 7.14 (m, 1H), 7.09 – 7.02 (m, 2H), 5.33 – 5.25 (m, 2H), 3.68(s, 3H), 2.81 (s, 2H), 2.22 (s, 3H), 2.03 (s, 3H), 1.30 (s, 3H), 1.30 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 164.3, 160.6, 155.0, 154.7, 148.6, 135.8,133.6, 131.2 (2C), 129.8, 128.5 (2C), 128.3, 127.2, 126.9 (2C), 126.5, 126.4,126.2, 77.5, 59.9, 55.3, 38.6, 28.2, 27.7, 13.4, 10.9.

[0058] Example 10 The compound I-9 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =3,4-Dimethoxypyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0059] The synthesis method of compound I-9 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride to obtain compound I-9 (yellow solid, 0.11 g, yield 68.6%).

[0060] The detection results for compound I-9 are as follows: mp = 129.2-132.1℃; 1 H NMR (400 MHz, CDCl3) d 8.22 – 8.21 (m, 1H), 7.64 – 7.62 (m, 2H), 7.33 – 7.27 (m, 4H), 7.14 – 7.12 (m, 1H), 7.09 – 7.06 (m, 2H), 6.79 – 6.78 (m,1H), 5.30 (s, 2H), 3.88 (s, 3H), 3.65 (s, 3H), 2.80 – 2.79 (m, 2H), 1.28 (s,6H); 13 C NMR (101 MHz, CDCl3) d 160.8, 159.0, 154.3, 151.0, 145.6, 145.1,135.8, 133.9, 131.2, 129.6, 128.5 (2C), 128.3, 127.1, 126.9 (2C), 126.6,126.4, 107.6, 73.6, 61.7, 55.8, 55.3, 38.5, 28.3, 27.6.

[0061] Example 11 The compound I-10 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0062] The synthesis method of compound I-10 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine to obtain compound I-10 (yellow oil, 0.11 g, yield 63.5%).

[0063] The detection results for compound I-10 are as follows: mp = 100.0-102.4℃; 1 H NMR (400 MHz, CDCl3) d 8.32 (s, 1H), 7.62 – 7.60 (m, 2H), 7.33 – 7.27(m, 4H), 7.18 – 7.16 (m, 1H), 7.06 – 6.97 (m, 2H), 6.64 (s, 1H), 5.32 (s,2H), 4.39 – 4.33 (m, 2H), 2.88 – 2.78 (m, 2H), 2.00 (s, 3H), 1.32 (s, 3H).1.31 (s,3H); 13 C NMR (101 MHz, CDCl3) d 161.9, 160.6, 156.6, 155.0, 147.3, 135.8,133.5, 131.4, 129.9, 128.5 (2C), 128.4, 127.1, 126.9 (2C), 126.4, 126.3,126.26 (q, J = 363.5 Hz), 123.4, 106.2, 76.9, 65.4 (q, J = 35.9 Hz), 55.4, 38.5, 28.3, 27.6, 10.3.

[0064] Example 12 The compound I-11 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =quinoline-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0065] The synthesis method of compound I-11 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with 2-(chloromethyl)quinoline to obtain compound I-11 (yellow oil, 0.12 g, yield 79.5%).

[0066] The detection results for compound I-11 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.08 – 8.04 (m, 2H), 7.79 – 7.77 (m, 1H), 7.72 – 7.65 (m, 3H), 7.53 – 7.49 (m, 1H), 7.41 – 7.28 (m, 5H), 7.23 – 7.16 (m,3H), 5.53 (d, J = 14.5 Hz, 1H), 5.46 (d, J = 14.4 Hz, 1H), 2.93 (d, J = 15.8 Hz, 1H), 2.87 (d, J = 15.9 Hz, 1H), 1.41 (s, 3H), 1.37 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.7, 159.3, 155.6, 147.5, 136.6, 136.0,133.4, 131.5, 130.0, 129.6, 129.0, 128.6 (2C), 128.5, 127.7, 127.6, 127.3,126.9 (2C), 126.5, 126.4, 126.3, 119.6, 77.9, 55.5, 38.6, 28.5, 27.6; HRMS (ESI) m / z [M + H] + : calcd for C 28 H 25 N3O, 420.2070, found, 420.2079.

[0067] Example 13 The compound I-12 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =( E2-(2-phenyl)-2-methoxyiminoacetic acid methyl ester, R 4 =R 5 =Hydrogen, R 6 =R 7 The structure of (=methyl, n=1) is as follows:

[0068] The synthesis method of compound I-12 in this embodiment is the same as that in Example 2, except that the 2-chloromethylpyridine used in Example 2 is replaced with (E)-2-(2-bromomethylphenyl)-2-methoxyiminoacetic acid methyl ester to obtain compound I-12 (yellow oil, 0.12 g, yield 68.4%).

[0069] The detection results for compound I-12 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.62 – 7.61 (m, 2H), 7.36 – 7.27 (m, 6H), 7.21 – 7.09 (m, 5H), 5.04 – 5.03 (m, 2H), 4.01 (s, 3H), 3.78 (s, 3H), 2.87 – 2.85(m, 2H), 1.35 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 163.3, 160.7, 155.0, 149.1, 136.2, 135.8,133.6, 131.3, 129.8, 129.3, 128.6, 128.5 (2C), 128.3, 127.93, 127.86, 127.2,127.1, 126.8 (2C), 126.4, 126.3, 74.0, 63.8, 55.3, 53.0, 38.5, 28.1, 27.6.

[0070] Example 14 The structure of compound I-13 (the hydrochloride salt of compound I-5) described in this embodiment is as follows:

[0071] Synthesis of compound I-13: Compound I-5 (0.050 g, 0.13 mmol) was dissolved in methanol, and excess concentrated hydrochloric acid (0.1 mL, 1.3 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed by TLC monitoring, the mixture was concentrated to dryness under reduced pressure. No further purification was required to obtain compound I-13 (pale yellow solid, 0.049 g, yield 89.7%).

[0072] The detection results for compound I-13 are as follows: mp = 142.1-144.3 ℃; 1 H NMR (400 MHz, DMSO- d 6) d 8.42 – 8.38 (m, 1H), 7.93 – 7.91 (m, 1H), 7.84 – 7.78 (m, 2H), 7.60 – 7.52 (m, 4H), 7.50 – 7.46 (m, 3H), 7.43 – 7.36(m, 2H), 5.65 (s, 2H), 3.46 – 3.29 (m, 2H), 2.75 (s, 3H), 1.59 (s, 3H), 1.46 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) d 166.3, 154.3, 150.6, 150.3, 145.7, 138.1,137.7, 131.9, 130.5, 130.0, 129.9, 129.5 (2C), 128.8, 127.3, 126.6 (2C),123.8, 122.0, 72.1, 57.4, 37.2, 25.7, 25.2, 19.2; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 26 ClN3O, 384.2076, found, 384.2109.

[0073] Example 15 The compound I-14 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =2-Fluorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0074] The synthesis method of compound I-14 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-14 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-14 (yellow oil, 0.10 g, yield 16.0%).

[0075] The detection results for compound I-14 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.86 – 7.81 (m, 1H), 7.48 – 7.44 (m, 1H), 7.38 – 7.30 (m, 3H), 7.23 – 7.18 (m, 2H), 7.14 – 7.11 (m, 1H), 7.01 – 6.94 (m,3H), 5.28 (s, 2H), 2.83 (s, 2H), 2.50 (s, 3H), 1.29 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 161.1, 160.7 (d, J = 253.54 Hz), 157.53,157.46, 152.6 (d, J = 2.56 Hz), 136.7, 135.9, 131.5 (d, J = 8.50 Hz), 131.0,129.7 (d, J = 2.73 Hz), 128.3, 126.9, 126.4 (d, J = 2.33 Hz), 126.2, 124.2 (d, J =3.42 Hz), 122.1 (d, J = 10.45 Hz), 121.9, 118.3, 116.4 (d, J = 21.93 Hz), 77.5,55.1, 38.5, 29.8 (2C), 24.4; HRMS (ESI) m / z [M + H] +: calcd for C 25 H 24 FN3O, 402.1976, found, 402.1985.

[0076] Example 16 The compound I-15 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =3-Fluorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0077] The synthesis method of compound I-15 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-15 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-15 (pale yellow oil, 0.13 g, yield 51.7%).

[0078] The detection results for compound I-15 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.50 – 7.46 (m, 1H), 7.41 – 7.35 (m, 3H), 7.29 – 7.27 (m, 1H), 7.22 – 7.15 (m, 3H), 7.06 – 6.99 (m, 3H), 5.34 (d, J = 14.63Hz, 1H), 5.27 (d, J = 14.63 Hz, 1H), 2.91 (d, J = 16.01 Hz, 1H), 2.85 (d, J = 15.88Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 162.8 (d, J = 245.7 Hz), 160.4, 157.7, 157.6,154.23, 154.20, 136.9, 135.9, 135.7 (d,J = 8.0 Hz), 131.6, 130.1 (d, J = 8.2Hz), 128.6, 127.3, 126.2, 122.7 (d, J = 3.0 Hz), 121.9, 118.3, 116.9 (d, J = 21.4Hz), 113.6 (d, J = 23.4 Hz), 77.5, 55.5, 38.5, 28.4, 27.6, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 FN3O, 402.1976, found, 402.1986.

[0079] Example 17 The compound I-16 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Fluorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0080] The synthesis method of compound I-16 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-16 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-16 (yellow oil, 0.66 g, yield 51.6%).

[0081] The detection results for compound I-16 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.67 – 7.62 (m, 2H), 7.50 – 7.46 (m, 1H), 7.39 – 7.35 (m, 1H), 7.22 – 7.15 (m, 3H), 7.02 – 6.97 (m, 4H), 5.32 (d, J = 14.62Hz, 1H), 5.24 (d, J= 14.56 Hz, 1H), 2.91 (d, J = 15.81 Hz, 1H), 2.84 (d, J = 15.89Hz, 1H), 2.51 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 163.9 (d, J = 250.18 Hz), 160.7, 157.7, 157.5,154.3, 137.1, 135.9, 131.6, 129.7 (d, J = 3.26 Hz, 2C), 128.8 (d, J = 8.47 Hz,2C), 128.6, 127.3, 126.3, 122.0, 118.4, 115.7 (d, J = 21.86 Hz, 2C), 77.2,55.5, 38.5, 28.4, 27.6, 24.3; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 FN3O, 402.1976, found, 402.1985.

[0082] Example 18 The compound I-17 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =2-Chlorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 =Methyl, n=1) is divided into cis-trans isomers.

[0083] (1) Compound ( E Synthesis of )-Ⅰ-17:

[0084] In this embodiment, the synthesis method of compound I-17 is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-17, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound ( E)-Ⅰ-17 (light yellow solid, 0.24 g, yield 72.5%).

[0085] compound ( E The test results for )-Ⅰ-17 are as follows: mp = 94.5-99.6 ℃; 1 H NMR (400 MHz, CDCl3) d 7.74 – 7.73 (m, 1H), 7.61 – 7.57 (m, 1H), 7.50 – 7.48 (m, 1H), 7.42 – 7.39 (m, 1H), 7.35 – 7.28 (m, 3H), 7.19 – 7.05 (m,4H), 5.32 (s, 2H), 2.66 (s, 2H), 2.54 (s, 3H), 1.09 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 159.0, 157.8, 157.6, 155.2, 137.4, 136.9,133.0, 131.9, 131.4, 130.6, 129.7, 129.3, 128.5, 128.1, 127.1, 126.4, 126.0,122.0, 118.7, 77.4, 55.0, 38.8, 27.1 (2C), 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 ClN3O, 418.1681, found, 418.1690.

[0086] (2) Compound ( Z Synthesis of )-Ⅰ-17:

[0087] In this embodiment, the compound ( Z The synthesis method of compound II-17 is the same as in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-17, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound ( Z )-Ⅰ-17 (yellow oil, 0.19g, yield 61.8%).

[0088] compound ( ZThe test results for )-Ⅰ-17 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.77 – 7.75 (m, 1H), 7.49 – 7.44 (m, 2H), 7.36 – 7.27 (m, 4H), 7.24 – 7.21 (m, 1H), 7.17 – 7.15 (m, 1H), 7.00 – 6.99 (m,1H), 6.89 – 6.87 (m, 1H), 5.26 (s, 2H), 2.78 (s, 2H), 2.51 (s, 3H), 1.26 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 160.8, 157.6, 157.3, 155.0, 136.8, 135.8, 133.5, 133.2, 131.9, 130.8, 130.6, 130.5, 128.2, 127.3, 126.85, 126.82, 126.7, 121.9, 118.4, 77.4, 55.3, 38.5, 30.5, 29.0, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 ClN3O, 418.1681, found, 418.1689.

[0089] Example 19 The compound I-18 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =3-Chlorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0090] The synthesis method of compound I-18 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-18 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-18 (pale yellow oil, 0.79 g, yield 47.6%).

[0091] The detection results for compound I-18 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.70 – 7.69 (m, 1H), 7.51 – 7.46 (m, 2H), 7.39 – 7.35 (m, 1H), 7.33 – 7.30 (m, 1H), 7.25 – 7.14 (m, 4H), 7.01 – 6.99 (m,2H), 5.34 (d, J = 14.56 Hz, 1H), 5.26 (d, J = 14.47 Hz, 1H), 2.91 (d, J = 15.88 Hz, 1H), 2.85 (d, J = 15.81 Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.3, 157.65, 157.60, 154.1, 136.9, 135.9, 135.3, 134.6, 131.6, 129.9, 129.8, 128.6, 127.3, 126.7, 126.22, 126.20, 125.1, 121.9, 118.3, 77.4, 55.5, 38.5, 28.5, 27.5, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 ClN3O, 418.1681, found, 418.1688.

[0092] Example 20 The compound I-19 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Chlorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0093] The synthesis method of compound I-19 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-19 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-19 (yellow solid, 1.2 g, yield 74.2%).

[0094] The detection results for compound I-19 are as follows: mp = 85.1-103.2 ℃; 1 H NMR (400 MHz, CDCl3) d 7.61 – 7.57 (m, 2H), 7.49 – 7.45 (m, 1H), 7.39 – 7.35 (m, 1H), 7.29 – 7.27 (m, 2H), 7.22 – 7.13 (m, 3H), 7.01 – 6.99 (m,2H), 5.33 (d, J = 14.49 Hz, 1H), 5.25 (d, J = 14.45 Hz, 1H), 2.91 (d, J = 15.88 Hz, 1H), 2.84 (d, J = 15.80 Hz, 1H), 2.51 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.5, 157.7, 157.5, 154.3, 137.0, 136.0,135.9, 132.0, 131.6, 128.8 (2C), 128.6, 128.1 (2C), 127.3, 126.24, 126.21,122.0, 118.3, 77.3, 55.5, 38.5, 28.4, 27.6, 24.3; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 ClN3O, 418.1681, found, 418.1689.

[0095] Example 21 The compound I-20 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =2-Bromophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 =Methyl, n=1) is divided into cis-trans isomers.

[0096] (1) Compound ( E Synthesis of )-Ⅰ-20:

[0097] In this embodiment, the compound ( E The synthesis method of compound II-I-20 is the same as in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-20, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound ( E )-Ⅰ-20 (light yellow solid, 0.56 g, based on intermediate ( E The yield of )-ⅠII-20 was 69.1%.

[0098] compound ( E The test results for )-Ⅰ-20 are as follows: mp = 105.9-107.9 ℃; 1 H NMR (400 MHz, CDCl3) d 7.77 – 7.75 (m, 1H), 7.62 – 7.58 (m, 2H), 7.45 – 7.36 (m, 2H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 2H), 7.13 – 7.06 (m,3H), 5.32 (s, 2H), 2.65 (s, 2H), 2.55 (s, 3H), 1.08 (s, 6H); 13 C NMR (101 MHz, CDCl3) d158.7, 157.8, 157.7, 156.5, 137.5, 137.0,135.2, 132.3, 131.6, 130.5, 129.8, 128.8, 128.0, 127.0, 126.6, 126.3, 122.1,121.2, 118.8, 77.3, 55.0, 38.9, 27.1 (2C), 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 BrN3O, 462.1176, found, 462.1185.

[0099] (2) Compound ( Z Synthesis of )-Ⅰ-20:

[0100] In this embodiment, the compound ( Z The synthesis method of compound II-I-20 is the same as in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-20, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound ( Z )-Ⅰ-20 (yellow solid, 0.42 g, based on intermediate ( Z The yield of )-ⅠII-20 was 78.1%.

[0101] compound ( Z The test results for )-Ⅰ-20 are as follows: mp = 84.5-90.1 ℃; 1 H NMR (400 MHz, CDCl3) d 7.73 – 7.71 (m, 1H), 7.57 – 7.53 (m, 2H), 7.49 – 7.45 (m, 1H), 7.35 – 7.28 (m, 2H), 7.23 – 7.15 (m, 3H), 7.01 – 6.99 (m,1H), 6.92 – 6.90 (m, 1H), 5.27 (s, 2H), 2.77 (s, 2H), 2.51 (s, 3H), 1.27 (s, 6H); 13 C NMR (101 MHz, CDCl3) d160.5, 157.5, 157.3, 155.6, 136.9, 135.9,135.2, 133.9, 132.2, 130.9, 130.6, 128.2, 127.6, 127.3, 126.9, 126.7, 122.3,122.0, 118.6, 77.3, 55.4, 38.6, 27.7 (2C), 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 BrN3O, 462.1176, found, 462.1184.

[0102] Example 22 The compound I-21 (R) described in this embodiment 1 ) m =Hydrogen, R 2 = 3-Bromophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0103] The synthesis method of compound I-21 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-21 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-21 (pale yellow oil, 0.68 g, yield 87.0%).

[0104] The detection results for compound I-21 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.86 – 7.85 (m, 1H), 7.55 – 7.45 (m, 3H), 7.40 – 7.36 (m, 1H), 7.23 – 7.19 (m, 2H), 7.18 – 7.14 (m, 2H), 7.02 – 7.00 (m, 2H), 5.35 (d, J = 14.73 Hz, 1H), 5.27 (d, J = 14.63 Hz, 1H), 2.92 (d, J= 15.87 Hz, 1H), 2.85 (d, J = 15.91 Hz, 1H), 2.53 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.3, 157.6, 154.0, 137.2, 135.9, 135.5,132.8, 131.6, 130.1, 129.6 (2C), 128.6, 127.3, 126.21, 126.17, 125.5, 122.8,122.1, 118.4, 77.1, 55.6, 38.5, 28.5, 27.5, 24.2; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 BrN3O, 462.1176, found, 462.1185.

[0105] Example 23 The compound I-22 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Bromophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0106] The synthesis method of compound I-22 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-22, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-22 (white solid, 0.65 g, yield 38.1%).

[0107] The detection results for compound I-22 are as follows: mp = 114.5-120.6 ℃; 1 H NMR (400 MHz, DMSO- d 6) d7.62 – 7.58 (m, 3H), 7.51 – 7.47 (m, 2H), 7.44 – 7.41 (m, 1H), 7.32 – 7.30 (m, 1H), 7.26 – 7.23 (m, 1H), 7.13 – 7.11(m, 1H), 7.06 – 7.05 (m, 1H), 6.98 – 6.96 (m, 1H), 5.18 (d, J = 2.65 Hz, 2H), 2.89 (d, J = 16.09 Hz, 1H), 2.81 (d, J = 16.09 Hz, 1H), 2.42 (s, 3H), 1.24 (s, 6H); 13 C NMR (101 MHz, DMSO- d 6) d 159.1, 157.3, 156.9, 153.9, 136.9, 135.6,132.3, 132.0 (2C), 131.7, 128.7, 128.3 (2C), 127.3, 125.5, 125.4, 123.7,122.0, 118.0, 76.9, 55.1, 37.4, 27.8, 27.4, 23.9; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 BrN3O, 462.1176, found, 462.1182.

[0108] Example 24 The compound I-23 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Iodophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0109] The synthesis method of compound I-23 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-23 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-23 (white solid, 1.6 g, yield 57.0%).

[0110] The detection results for compound I-23 are as follows: mp = 139.3-142.2 ℃; 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.63 (m, 2H), 7.48 – 7.45 (m, 1H), 7.39 – 7.34 (m, 3H), 7.21 – 7.12 (m, 3H), 7.00 – 6.98 (m, 2H), 5.32 (d, J = 14.40Hz, 1H), 5.25 (d, J = 14.43 Hz, 1H), 2.90 (d, J = 15.88 Hz, 1H), 2.83 (d, J = 15.87Hz, 1H), 2.51 (s, 3H), 1.37 (s, 3H), 1.33 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.3, 157.7, 157.5, 154.5, 137.7 (2C),136.8, 135.9, 133.1, 131.6, 128.6, 128.4 (2C), 127.3, 126.22, 126.16, 121.9,118.3, 96.3, 77.4, 55.5, 38.5, 28.4, 27.6, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 IN3O, 510.1037, found, 510.1046.

[0111] Example 25 The compound I-24 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =2-Methylphenyl, R3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 =Methyl, n=1) is divided into cis-trans isomers.

[0112] (1) Compound ( E Synthesis of )-Ⅰ-24:

[0113] In this embodiment, the compound ( E The synthesis method of compound II-I-24 is the same as in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-24, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound ( E )-Ⅰ-24 (yellow oil, 0.20g, based on intermediate ( E The yield of )-ⅠII-24 was 53.2%.

[0114] compound ( E The test results for )-Ⅰ-24 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.63 (m, 1H), 7.60 – 7.56 (m, 1H), 7.32 – 7.27 (m, 3H), 7.24 – 7.20 (m, 2H), 7.16 – 7.10 (m, 3H), 7.07 –7.05 (m, 1H), 5.31 (s, 2H), 2.67 (s, 2H), 2.55 (s, 3H), 2.29 (s, 3H), 1.11 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 159.4, 157.8 (2C), 157.3, 137.4, 136.9,136.1, 133.8, 130.6, 129.9, 128.5, 128.28, 128.26, 127.9, 127.3, 126.5,125.1, 122.0, 118.7, 77.2, 55.0, 38.9, 27.3 (2C), 24.4, 20.4; HRMS (ESI) m / z [M + H] + : calcd for C 26 H27 N3O, 398.2227, found, 398.2234.

[0115] (2) Compound ( Z Synthesis of )-Ⅰ-24:

[0116] In this embodiment, the compound ( Z The synthesis method of compound II-I-24 is the same as in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-24, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound ( Z )-Ⅰ-24 (yellow oil, 0.15g, based on intermediate ( Z The yield of )-ⅠII-24 was 70.6%.

[0117] compound ( Z The test results for )-Ⅰ-24 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.51 – 7.47 (m, 1H), 7.37 – 7.34 (m, 2H), 7.28(s, 1H), 7.23 – 7.18 (m, 4H), 7.13 – 7.09 (m, 1H), 7.06 – 6.99 (m, 2H), 5.28(s, 2H), 2.83 (s, 2H), 2.52 (s, 3H), 2.51 (s, 3H), 1.33 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 161.4, 157.9, 157.5, 156.6, 137.9, 136.8,136.1, 132.5, 131.8, 131.2, 129.6, 129.0, 128.5, 127.1, 126.6, 126.4, 125.7,121.8, 118.5, 77.2, 55.3, 38.6, 27.9 (2C), 24.4, 22.9; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 27 N3O, 398.2227, found, 398.2234.

[0118] Example 26 The compound I-25 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =3-Methylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0119] The synthesis method of compound I-25 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-25 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-25 (pale yellow oil, 0.27 g, yield 84.5%).

[0120] The detection results for compound I-25 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.52 – 7.47 (m, 2H), 7.41 – 7.34 (m, 2H), 7.22 – 7.14 (m, 5H), 7.07 – 6.99 (m, 2H), 5.35 (d, J = 14.69 Hz, 1H), 5.26 (d, J =14.73 Hz, 1H), 2.91 (d, J = 15.86 Hz, 1H), 2.85 (d, J = 15.93 Hz, 1H), 2.53 (s,3H), 2.31 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.9, 157.9, 157.4, 155.6, 138.3, 137.2,135.9, 133.4, 131.5, 130.8, 128.5 (2C), 127.29, 127.27, 126.49, 126.46,124.2, 122.0, 118.5, 77.2, 55.4, 38.6, 28.5, 27.6, 24.2, 21.6; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 27 N3O, 398.2227, found, 398.2236.

[0121] Example 27 The compound I-26 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Methylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0122] The synthesis method of compound I-26 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-26 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-26 (yellow solid, 0.59 g, yield 36.5%).

[0123] The detection results for compound I-26 are as follows: mp = 99.1-100.9 ℃; 1 H NMR (400 MHz, CDCl3) d 7.58 – 7.52 (m, 2H), 7.50 – 7.43 (m, 1H), 7.38 – 7.32 (m, 1H), 7.24 – 7.16 (m, 3H), 7.14 – 7.09 (m, 2H), 7.06 – 7.00 (m,1H), 7.00 – 6.95 (m, 1H), 5.32 (d, J = 14.59 Hz, 1H), 5.24 (d, J = 14.54 Hz, 1H), 2.91 (d, J = 15.83 Hz, 1H), 2.84 (d, J = 15.95 Hz, 1H), 2.51 (s, 3H), 2.32 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) d 160.8, 158.1, 157.4, 155.3, 140.0, 136.7,135.9, 131.3, 130.8, 129.3 (2C), 128.4, 127.2, 126.7 (2C), 126.5, 126.4,121.7, 118.2, 77.2, 55.3, 38.6, 28.4, 27.7, 24.4, 21.5; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 27 N3O, 398.2227, found, 398.2234.

[0124] Example 28 The compound I-27 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Methoxyphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows: Route 1:

[0125] The synthesis method of compound I-27 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-27 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-27 (yellow solid, 0.17 g, yield 21.7%).

[0126] Route 2:

[0127] In a 20 mL pressure-resistant tube, compound II-27 (0.050 g, 0.16 mmol) was dissolved in 2-propanol (5 mL), followed by the addition of p-toluenesulfonic acid monohydrate (0.030 g, 0.16 mmol) and compound V-27 (0.025 g, 0.18 mmol) (compound V-27 was prepared by reacting 2-chloromethylpyridine with hydroxylamine hydrochloride). The reaction mixture was stirred at 50 °C for 4 h and then at room temperature for 2 days. The reaction progress was monitored by TLC (PE:EA = 2:1, v / v). After the reaction was complete, the mixture was extracted with dichloromethane and saturated sodium bicarbonate (20 mL × 3). The combined organic phases were washed successively with water (20 mL × 3) and saturated sodium chloride solution (20 mL × 3), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a pale yellow crude product. Finally, the compound was purified by silica gel column chromatography (eluent: PE:EA = 5:1, v / v) to give a white solid compound I-27 (0.20 g, yield 30.2%).

[0128] The detection results for compound I-27 are as follows: mp = 115.6-118.5 ℃; 1 H NMR (400 MHz, CDCl3) d 7.60 – 7.58 (m, 2H), 7.48 – 7.44 (m, 1H), 7.37 – 7.33 (m, 1H), 7.21 – 7.16 (m, 3H), 7.04 – 6.97 (m, 2H), 6.84 – 6.82 (m, 2H), 5.30 (d, J = 14.62 Hz, 1H), 5.22 (d, J = 14.66 Hz, 1H), 3.78 (s, 3H), 2.91(d, J = 15.51 Hz, 1H), 2.84 (d, J = 15.96 Hz, 1H), 2.51 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d161.05, 160.97, 158.1, 157.4, 154.9, 137.0,135.9, 131.4, 128.5, 128.3 (2C), 127.2, 126.5, 126.4, 126.1, 121.8, 118.4,114.0 (2C), 77.0, 55.4, 55.3, 38.6, 28.4, 27.6, 24.3; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 27 N3O2, 414.2176, found, 414.2185.

[0129] Example 29 The compound I-28 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =3-Trifluoromethylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0130] The synthesis method of compound I-28 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-28 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-28 (pale yellow oil, 1.2 g, yield 73.9%).

[0131] The detection results for compound I-28 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.97 (s, 1H), 7.84 – 7.82 (m, 1H), 7.60 – 7.58(m, 1H), 7.50 – 7.36 (m, 3H), 7.23 – 7.14 (m, 3H), 7.01 – 6.98 (m, 2H), 5.35(d, J = 14.09 Hz, 1H), 5.28 (d, J = 14.47 Hz, 1H), 2.93 (d, J= 15.87 Hz, 1H), 2.85(d, J = 16.03 Hz, 1H), 2.52 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.3, 157.6, 157.5, 154.0, 136.9, 135.9,134.4, 131.7, 131.0 (q, J = 32.67 Hz), 130.0, 129.1, 128.6, 127.3, 126.4 (q, J =3.73 Hz), 126.2, 126.1, 124.0 (q, J = 272.45 Hz), 123.6 (q, J = 4.03 Hz), 122.0,118.3, 77.6, 55.6, 38.4, 28.6, 27.2, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 24 F3N3O, 452.1944, found, 452.1954.

[0132] Example 30 The compound I-29 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Trifluoromethylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0133] The synthesis method of compound I-29 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-29 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-29 (yellow solid, 0.65 g, yield 60.6%).

[0134] The detection results for compound I-29 are as follows: mp = 90.5-98.3 ℃; 1 H NMR (400 MHz, CDCl3) d 7.78 – 7.76 (m, 2H), 7.57 – 7.55 (m, 2H), 7.50 – 7.46 (m, 1H), 7.40 – 7.36 (m, 1H), 7.23 – 7.13 (m, 3H), 7.01 – 6.99 (m, 2H), 5.35 (d, J = 14.16 Hz, 1H), 5.29 (d, J = 14.19 Hz, 1H), 2.92 (d, J = 15.81 Hz, 1H), 2.85 (d, J = 15.81 Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.3, 157.6, 157.5, 154.1, 137.02, 136.96,136.0, 131.7, 131.5 (q, J = 32.46 Hz), 128.7, 127.3, 127.1 (2C), 126.2, 126.1,125.6 (q, J = 3.75 Hz, 2C), 124.1 (q, J = 272.49 Hz), 122.1, 118.4, 77.6, 55.6,38.5, 28.4, 27.6, 24.3; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 24 F3N3O, 452.1944, found, 452.1953.

[0135] Example 31 The compound I-30 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Trifluoromethoxyphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5=Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0136] The synthesis method of compound I-30 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-30 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-30 (yellow oil, 0.70 g, yield 46.0%).

[0137] The detection results for compound I-30 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.70 – 7.68 (m, 2H), 7.49 – 7.45 (m, 1H), 7.40 – 7.36 (m, 1H), 7.23 – 7.14 (m, 5H), 7.01 – 6.99 (m, 2H), 5.33 (d, J = 14.40Hz, 1H), 5.26 (d, J = 14.46 Hz, 1H), 2.92 (d, J = 15.93 Hz, 1H), 2.84 (d, J = 15.87Hz, 1H), 2.51 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.5, 157.7, 157.6, 154.0, 150.3 (q, J = 1.91Hz), 136.9, 135.9, 132.2, 131.6, 128.6, 128.4 (2C), 127.3, 126.25, 126.20,121.9, 120.9 (2C), 120.5 (q, J = 257.78 Hz), 118.3, 77.5, 55.5, 38.5, 28.4,27.6, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 26 H 24F3N3O2, 468.1893, found, 468.1902.

[0138] Example 32 The compound I-31 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-tert-butylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0139] The synthesis method of compound I-31 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-31 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-31 (yellow oil, 0.69 g, yield 86.0%).

[0140] The detection results for compound I-31 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.59 – 7.57 (m, 2H), 7.48 – 7.44 (m, 1H), 7.37 – 7.31 (m, 3H), 7.22 – 7.18 (m, 3H), 7.04 – 6.97 (m, 2H), 5.32 (d, J = 14.63Hz, 1H), 5.25 (d, J = 14.55 Hz, 1H), 2.91 (d, J = 15.92 Hz, 1H), 2.84 (d, J = 15.96Hz, 1H), 2.51 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.28 (s, 9H); 13 C NMR (101 MHz, CDCl3) d160.9, 158.1, 157.4, 155.2, 153.1, 136.8,135.9, 131.3, 130.7, 128.4, 127.2, 126.6 (3C), 126.4, 125.5 (2C), 121.7,118.3, 77.2, 55.3, 38.6, 34.8, 31.2 (3C), 28.4, 27.6, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 29 H 33 N3O, 440.2696, found, 440.2704.

[0141] Example 33 The compound I-32 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Methoxycarbonylphenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0142] The synthesis method of compound I-32 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-32, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-32 (white solid, 0.52 g, yield 38.1%).

[0143] The detection results for compound I-32 are as follows: mp = 134.1-139.1 ℃; 1 H NMR (400 MHz, CDCl3) d 8.00 – 7.95 (m, 2H), 7.75 – 7.70 (m, 2H), 7.50 – 7.44 (m, 1H), 7.39 – 7.34 (m, 1H), 7.23 – 7.13 (m, 3H), 7.03 – 6.97 (m,2H), 5.35 (d, J = 14.26 Hz, 1H), 5.28 (d, J= 14.27 Hz, 1H), 3.89 (s, 3H), 2.94 –2.83 (m, 2H), 2.51 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 166.6, 160.3, 157.6, 157.5, 154.4, 137.7,136.8, 135.9, 131.6, 131.0, 129.8 (2C), 128.6, 127.2, 126.7 (2C), 126.2,126.1, 121.9, 118.2, 77.6, 55.5, 52.2, 38.4, 28.4, 27.5, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 27 H 27 N3O3, 442.2125, found, 442.2133.

[0144] Example 34 The compound I-33 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-Nitrophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0145] The synthesis method of compound I-33 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-33, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine, to obtain compound I-33 (yellow oil, 0.52 g, yield 84.2%). Compound I-33 includes compound ( E )-Ⅰ-33 and compound ( Z )-Ⅰ-33, compound ( E )-Ⅰ-33: Compound ( Z )-Ⅰ-33=1:4.

[0146] The detection results for compound I-33 are as follows: (E )-I-33: 1 H NMR (400 MHz, CDCl3) d 8.22 (d, J = 8.9 Hz, 2H), 7.86 (d, J =8.9 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.36 – 7.31 (m,1H), 7.25 – 7.07 (m, 4H), 5.36 (s, 2H), 2.76 (s, 2H), 2.56 (s, 3H), 1.21 (s,6H); 13 C NMR (101 MHz, CDCl3) d 159.8, 158.2, 156.7, 152.8, 147.8, 138.4,137.0, 135.9, 131.4, 130.8, 128.5, 127.3, 126.9, 126.0 (2C), 123.2 (2C),122.4, 119.0, 77.9, 55.5, 38.6, 27.5 (2C), 24.5。

[0147] ( Z )-I-33: 1 H NMR (400 MHz, CDCl3) d 8.16 (d, J = 9.0 Hz, 2H), 7.82 (d, J =9.0 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.25 – 7.07 (m,3H), 7.06 – 6.97 (m, 2H), 5.38 (d, J = 14.0 Hz, 1H), 5.31 (d, J = 14.0 Hz, 1H),2.93 (d, J = 15.6 Hz, 1H), 2.86 (d, J = 15.8 Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H),1.36 (s, 3H); 13C NMR (101 MHz, CDCl3) d 160.0, 157.7, 157.2, 153.5, 148.4, 139.6,136.9, 135.9, 131.9, 130.8, 128.7, 127.6 (2C), 127.4, 126.0, 123.8 (2C),122.1, 118.3, 77.9, 55.7, 38.4, 28.3, 27.6, 24.4.

[0148] HRMS (ESI) m / z [M + H] + : calcd for C 25 H 24 N4O3, 429.1921, found, 429.1929.

[0149] Example 35 The compound I-34 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =3,4-Dichlorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0150] The synthesis method of compound I-34 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-34, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-34 (yellow oil, 0.72 g, yield 66.2%).

[0151] The detection results for compound I-34 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.77 (d, J = 2.10 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.40 – 7.36 (m, 2H), 7.23 – 7.18 (m, 2H), 7.12 – 7.11 (m, 1H), 7.02 – 6.97(m, 2H), 5.33 (d, J = 14.42 Hz, 1H), 5.26 (d,J = 14.36 Hz, 1H), 2.91 (d, J = 15.95Hz, 1H), 2.84 (d, J = 15.93 Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 160.1, 157.7, 157.5, 153.3, 136.9, 135.9, 134.0, 133.5, 132.9, 131.7, 130.6, 128.7, 128.5, 127.3, 126.08, 126.06, 126.0, 122.0, 118.3, 77.6, 55.6, 38.4, 28.5, 27.5, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 23 Cl2N3O, 452.1291, found, 452.1299.

[0152] Example 36 The compound I-35 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =3,5-Dichlorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0153] The synthesis method of compound I-35 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-35 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-35 (white solid, 0.37 g, yield 70.5%).

[0154] The detection results for compound I-35 are as follows: mp = 91.7-93.4 ℃; 1 H NMR (400 MHz, CDCl3) d 7.56 – 7.52 (m, 2H), 7.50 – 7.46 (m, 1H), 7.40 – 7.37 (m, 1H), 7.33 – 7.32 (m, 1H), 7.23 – 7.19 (m, 2H), 7.12 – 7.10 (m,1H), 7.02 – 6.96 (m, 2H), 5.33 (d, J = 14.66 Hz, 1H), 5.26 (d, J = 14.38 Hz, 1H), 2.91 (d, J = 15.89 Hz, 1H), 2.84 (d, J = 15.92 Hz, 1H), 2.52 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 159.9, 157.7, 157.4, 153.0, 136.9, 136.4,135.9, 135.3 (2C), 131.8, 129.7, 128.7, 127.4, 126.1, 126.0, 125.2 (2C),122.1, 118.3, 77.7, 55.7, 38.4, 28.5, 27.3, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 23 Cl2N3O, 452.1291, found, 452.1299.

[0155] Example 37 The compound I-36 (R) described in this embodiment 1 ) m =Hydrogen, R 2 =3,4,5-Trifluorophenyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0156] The synthesis method of compound I-36 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-36 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-36 (yellow solid, 0.49 g, yield 79.1%).

[0157] The detection results for compound I-36 are as follows: mp = 85.9-89.3 ℃; 1 H NMR (400 MHz, CDCl3) d 7.50 – 7.46 (m, 1H), 7.41 – 7.37 (m, 1H), 7.34 – 7.28 (m, 2H), 7.23 – 7.18 (m, 2H), 7.10 – 7.08 (m, 1H), 7.02 – 6.95 (m,2H), 5.32 (d, J = 14.34 Hz, 1H), 5.25 (d, J = 14.28 Hz, 1H), 2.91 (d, J = 15.94 Hz, 1H), 2.84 (d, J = 15.99 Hz, 1H), 2.52 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 159.8, 157.7, 157.3, 152.4, 151.3 (ddd, J =249.4, 10.3, 4.0 Hz, 2C), 140.9 (dt, J = 255.4, 15.5 Hz), 136.9, 135.9, 131.9,129.6 (m), 128.7, 127.3, 126.0, 125.9, 122.0, 118.3, 111.1 (m, 2C), 77.8,55.7, 38.4, 28.4, 27.5, 24.4; HRMS (ESI) m / z [M + H] + : calcd for C 25 H 22 F3N3O, 438.1788, found, 438.1796.

[0158] Example 38 The compound I-37 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =2-pyridinyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0159] The synthesis method of compound I-37 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-37 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-37 (white oil, 0.30 g, yield 41.3%).

[0160] The detection results for compound I-37 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.53 – 8.51 (m, 1H), 7.85 – 7.83 (m, 1H), 7.64 – 7.59 (m, 1H), 7.47 – 7.43 (m, 1H), 7.35 – 7.31 (m, 1H), 7.22 – 7.15 (m,4H), 7.04 – 7.02 (m, 1H), 6.98 – 6.96 (m, 1H), 5.37 (s, 1H), 5.33 (s, 1H), 2.87 (s, 2H), 2.49 (s, 3H), 1.34 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 160.6, 157.7, 157.5, 155.9, 152.8, 149.7, 136.8, 136.2, 135.9, 131.2, 128.3, 127.1, 126.8, 126.3, 123.9, 121.9, 121.8, 118.2, 77.7, 55.3, 38.6, 28.3, 27.7, 24.4.

[0161] Example 39 The compound I-38 (R) described in this embodiment 1 )m =Hydrogen, R 2 =3-pyridinyl, R 3 =6-Methylpyridin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0162] The synthesis method of compound I-38 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-38 and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-38 (yellow oil, 0.06 g, yield 32.8%).

[0163] The detection results for compound I-38 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.79 (s, 1H), 8.56 (s, 1H), 8.04 –8.01 (m,1H), 7.48 – 7.45 (m, 1H), 7.38 – 7.34 (m, 1H), 7.25 – 7.13 (m, 4H), 7.00 –6.89 (m, 2H), 5.36 – 5.25 (m, 2H), 2.87 (d, J = 9.04 Hz, 2H), 2.50 (s, 3H), 1.35 (d, J = 5.37 Hz, 6H); 13 C NMR (101 MHz, CDCl3) d 160.0, 157.7, 157.5, 153.0, 150.7, 148.3,136.8, 135.9, 133.8, 131.7, 128.6, 127.3, 126.11, 126.08, 123.5, 122.0 (2C),118.3, 77.7, 55.6, 38.5, 28.2, 27.7, 24.4.

[0164] Example 40 The compound I-39 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =4-pyridinyl, R 3 =6-Methylpyridin-2-yl, R4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0165] The synthesis method of compound I-39 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-39, and 2-chloromethylpyridine is replaced with 2-(bromomethyl)-6-methylpyridine to obtain compound I-39 (yellow oil, 0.07 g, yield 56.9%).

[0166] The detection results for compound I-39 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.56 – 8.55 (m, 2H), 7.51 – 7.44 (m, 3H), 7.39 – 7.35 (m, 1H), 7.22 – 7.16 (m, 2H), 7.10 – 7.07 (m, 1H), 7.00 – 6.95 (m,2H), 5.33 (s, 1H), 5.30 (s, 1H), 2.89 – 2.86 (m, 2H), 2.50 (s, 3H), 1.37 (s,3H), 1.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 159.7, 157.7, 157.2, 153.3, 150.1 (2C),141.0, 136.9, 135.9, 131.8, 128.7, 127.3, 126.0 (2C), 122.1, 120.8 (2C),118.3, 77.8, 55.6, 38.4, 28.3, 27.6, 24.3.

[0167] Example 41 The compound I-40 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =3,5-Dimethyl-4-isoxazolyl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0168] The synthesis method of compound I-40 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-40, and 2-chloromethylpyridine is replaced with 3,5-dimethyl-4-(chloromethyl)isoxazole, to obtain compound I-40 (white oil, 0.10 g, yield 70.8%).

[0169] The detection results for compound I-40 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.60 (m, 2H), 7.37 – 7.29 (m, 4H), 7.18 – 7.09 (m, 2H), 6.94 – 6.92 (m, 1H), 4.91 (d, J = 12.59 Hz, 1H), 4.83 (d, J =12.52 Hz, 1H), 2.87 – 2.78 (m, 2H), 2.27 (s, 3H), 1.98 (s, 3H), 1.32 (s, 3H), 1.29 (d, J = 4.58 Hz, 3H); 13 C NMR (101 MHz, CDCl3) d 168.2, 160.5, 160.0, 155.3, 135.8, 133.5,131.4, 130.0, 128.6 (2C), 128.4, 127.2, 126.7 (2C), 126.3, 125.9, 111.0,65.0, 55.4, 38.5, 28.4, 27.4, 11.1, 9.9.

[0170] Example 42 The compound I-41 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =1,3-Dimethyl-1H-pyrazole-5-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0171] The synthesis method of compound I-41 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-41 and 2-chloromethylpyridine is replaced with 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole to obtain compound I-41 (white oil, 0.09 g, yield 62.8%).

[0172] The detection results for compound I-41 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.65 – 7.62 (m, 2H), 7.37 – 7.29 (m, 4H), 7.18 – 7.15 (m, 1H), 7.13 – 7.08 (m, 1H), 6.94 (d, J = 7.65 Hz, 1H), 5.96 (s, 1H), 5.09 (d, J = 12.84 Hz, 1H), 5.03 (d, J = 12.75 Hz, 1H), 3.44 (s, 3H), 2.86 – 2.77(m, 2H), 2.20 (s, 3H), 1.30 (s, 6H); 13 C NMR (101 MHz, CDCl3) d 160.4, 155.5, 146.9, 138.8, 135.8, 133.4,131.4, 130.0, 128.6 (2C), 128.4, 127.3, 126.8 (2C), 126.3, 126.0, 106.9,66.6, 55.4, 38.5, 36.1, 28.3, 27.6, 13.5.

[0173] Example 43 The compound I-42 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =4-Methyl-quinazolin-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0174] The synthesis method of compound I-42 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-42 and 2-chloromethylpyridine is replaced with 2-chloromethyl-4-methylquinazoline to obtain compound I-42 (yellow oil, 0.12 g, yield 76.9%).

[0175] The detection results for compound I-42 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.98 – 7.90 (m, 2H), 7.79 – 7.75 (m, 1H), 7.53 – 7.49 (m, 3H), 7.44 – 7.42 (m, 1H), 7.24 – 7.16 (m, 4H), 7.10 – 7.05 (m,2H), 5.45 (d, J = 14.23 Hz, 1H), 5.34 (d, J = 14.21 Hz, 1H), 2.88 – 2.79 (m, 5H), 1.31 (s, 3H), 1.26 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 168.4, 162.5, 160.9, 154.7, 149.8, 136.0,133.8, 133.7, 131.3, 129.6, 129.0, 128.4 (2C), 128.3, 127.3, 127.15, 127.06,127.0 (2C), 126.4, 125.0, 123.3, 77.6, 55.4, 38.7, 28.6, 27.5, 21.8.

[0176] Example 44 The compound I-43 ((R) described in this embodiment 1 ) m =Hydrogen, R 2 =Phenyl, R 3 =benzothiazol-2-yl, R 4 =R 5 =Hydrogen, R 6 =R 7 The synthesis method of (=methyl, n=1) is as follows:

[0177] The synthesis method of compound I-43 in this embodiment is the same as that in Example 2, except that compound II-1 used in Example 2 is replaced with compound II-43 and 2-chloromethylpyridine is replaced with 2-(chloromethyl)benzothiazole to obtain compound I-43 (white oil, 0.09 g, yield 60.5%).

[0178] The detection results for compound I-43 are as follows: 1 H NMR (400 MHz, CDCl3) d 8.00 – 7.98 (m, 1H), 7.85 – 7.83 (m, 1H), 7.74 – 7.71 (m, 2H), 7.47 – 7.43 (m, 1H), 7.39 – 7.31 (m, 5H), 7.24 – 7.20 (m, 2H), 7.16 – 7.12 (m, 1H), 5.57 (s, 2H), 2.95 (d, J = 15.90 Hz, 1H), 2.86 (d, J =15.90 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 169.3, 160.1, 156.4, 152.9, 135.9, 135.4,133.1, 131.5, 130.2, 128.6 (2C), 128.5, 127.2, 127.0 (2C), 126.30, 126.28,126.0, 125.1, 123.0, 121.8, 74.1, 55.5, 38.5, 28.4, 27.6.

[0179] Example 45 This embodiment provides the inhibitory effect of compounds containing 3,4-dihydroisoquinoline oxime derivatives on plant pathogenic fungi.

[0180] The linear growth rate method of mycelium was used to determine the effects of compounds I-1 to I-36 on apple rot pathogens ( ). Waltz mali Apple ring rot fungus ( Physalospora piricola ), rapeseed sclerotinia pathogen ( Sclerotinia sclerotiorum ), tomato gray mold ( Botrytis cinerea ), wheat scab ( Fusarium graminearum ) and rice blast fungus ( Magnaporthe oryzae The in vitro inhibitory activity of six tested plant pathogens was studied. All fungi were provided by the College of Plant Protection, Northwest A&F University.

[0181] Using 20 mg / L Quinofumelin as a positive control and 5% DMSO aqueous solution as a blank control, compounds I-1 to I-13 were dissolved in 5% DMSO (v / v) aqueous solution to obtain the test solution (sample group). The test solution, Quinofumelin, and DMSO aqueous solution were rapidly mixed with 150 mL of sterile PDA medium (composed of potato extract, glucose, and agar) at 50 °C to obtain a drug-containing medium with a mass concentration of 20 μg / mL. Using 10 mg / L Quinofumelin as a positive control, compounds I-14 to I-36 were prepared into a drug-containing medium with a mass concentration of 10 μg / mL using the same method. The drug-containing medium was poured into sterilized petri dishes while still hot, 10 mL per dish, and cooled for later use. The tested plant pathogens (cup diameter = 5 mm) were inoculated into petri dishes, with 3 replicates for each test group; after incubation in a constant temperature incubator at 25℃ for 72 h, the colony diameter (mm) was measured using the cross-crossing method, and the mycelial growth inhibition rate (IR) was calculated according to formula (1):

[0182] In the formula, d0 is the diameter of the mushroom cake (5mm), d c The average diameter of colonies (mm) in the blank control group, d s The average diameter (mm) of the bacterial colonies in the sample group.

[0183] The inhibitory effects of compounds containing 3,4-dihydroisoquinoline oxime derivatives on plant pathogenic fungi are shown in Table 1: Table 1. Inhibition (%) of compounds containing 3,4-dihydroisoquinoline oxime derivatives on plant pathogenic fungi.

[0184] Note: The above data are the average of three repeated experiments.

[0185] As shown in Table 1, most compounds from I-1 to I-13 exhibited inhibition rates exceeding 60% against *Agromycetes rubra*, *Botrytis cinerea*, and *Agromycetes rubra* at a concentration of 20 μg / mL. For *Agromycetes rubra*, compounds I-1 to I-5, I-7, I-11, and I-13 (the hydrochloride salt of compound I-5) all showed inhibition rates higher than 70%. Among these, R... 3The inhibition rates of compounds I-5 and I-13, both 6-methylpyridin-2-yl groups, were 94.1% and 100%, respectively, which were close to the antibacterial activity of the positive control group (96.7%). For *Botrytis cinerea*, the order of inhibition activities above 60% was: compound I-13 (98.0%) > compound I-5 (92.5%) > compound I-1 (86.5%) > compound I-7 (81.3%) > compound I-2 (70.5%) > compound I-3 (67.9%), compound I-4 (67.9%) > compound I-6 (61.5%). For *Sclerotinia sclerotinia*, the inhibition rates of compounds I-1 to I-5, I-7, I-11, and I-13 all exceeded 70%, with compounds I-2, I-3, I-7, I-11, and I-13 achieving inhibition rates exceeding 90%. For *Rhizoctonia solani*, compounds I-1 to I-7, I-11, and I-13 all showed inhibition rates higher than 65%, with compounds I-5 and I-13 exhibiting the best antifungal effects, at 94.9% and 100%, respectively. For *Fusarium graminearum*, only compound I-5 showed high inhibitory activity, with an inhibition rate of 74.6%. For *Bacillus oryzae*, only compound I-1 showed high inhibitory activity, with an inhibition rate of 76.5%. These results indicate that compounds I-1 to I-13 prepared in this invention have the potential to become broad-spectrum antifungal agents. Preliminary structure-activity relationship studies revealed that the substituent R on the pyridine ring of compounds I-1 to I-13... 3 Substitution with halogen, methyl, or cyano groups can enhance antibacterial activity.

[0186] Compounds I-14 to I-36, at a concentration of 10 μg / mL, showed inhibition rates exceeding 80% against more than half of the pathogens causing apple rot, tomato gray mold, apple ring rot, rapeseed sclerotinia, and rice blast fungus. For apple rot, compounds I-16, I-18, I-19, I-21 to I-23, I-25, I-26, and I-28 to I-35 all showed inhibition rates exceeding 80%. For tomato gray mold, compounds I-14, I-15, I-18, I-22, I-28 to I-30, I-32, and I-34 to I-36 showed inhibition rates exceeding 80%, with compounds I-22 and I-34 to I-36 achieving inhibition rates exceeding 90%. For *Sclerotinia sclerotinia* causal agent of rapeseed, compounds I-14, I-15, I-18, I-19, I-21~I-23, I-27~I-32, I-34~I-36 showed inhibition rates above 80%, while compounds I-14, I-15, I-22, I-30, I-31, and I-34 showed inhibition rates above 90%. For *Rhizoctonia solani* var. *mongolica*, compounds I-15, I-16, I-18, I-19, and (…) showed inhibition rates above 90%. E Compounds I-20, I-21 to I-23, I-25 to I-33, and I-36 showed inhibition rates above 80%, while compounds I-15, I-18, I-19, I-21, I-23, I-25, I-26, I-27, I-29, I-30, and I-31 showed inhibition rates above 90%. For rice blast fungus, compounds I-15, I-21, I-23, I-25, I-28 to I-30, I-32, and I-33 showed inhibition rates above 80%, while compounds I-25, I-28, I-32, and I-33 showed inhibition rates above 90%. Overall, R... 2 Substituents on the benzene ring have a significant impact on antibacterial activity.

[0187] The above results indicate that compounds containing 3,4-dihydroisoquinoline oxime derivatives exhibit excellent broad-spectrum antifungal activity against pathogens such as apple rot fungus, tomato gray mold fungus, apple ring rot fungus, rapeseed sclerotinia rot fungus, and rice blast fungus, and are expected to be developed into broad-spectrum antifungal agents.

[0188] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art through related deductions and substitutions based on the inventive concept, without inventive effort, are within the scope of protection of the present invention.

Claims

1. An oxime derivative containing a 3,4-dihydroisoquinoline structure, characterized in that, Having a structure as shown in formula (I), or a salt acceptable for pesticide use, Equation (I); Among them, R 1 Each of the following is independently selected from hydrogen, halogen, amino, hydroxyl, nitro, cyano, C1-C8 alkyl and C1-C8 alkyloxy groups; R 2 Selected from any one of the optionally substituted benzene ring and pyridine; R 3 The aromatic heterocycle is optionally substituted; R 4 R 5 Each is independently selected from either hydrogen or halogen; R 6 R 7 Each is independently selected from hydrogen and any one of C1 to C8 alkyl groups; The aromatic heterocycle is selected from any one of pyrazole, pyridine, benzothiazole, isoxazole, quinoline, and quinazoline; The optional substitution is unsubstituted, or the substituent is selected from any one or more of halogen, C1-C8 alkyl, C1-C8 alkoxy, amino, hydroxyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, nitro, and cyano. m is an integer from 0 to 4; n is 1.

2. The oxime derivative containing a 3,4-dihydroisoquinoline structure according to claim 1, characterized in that, The halogen is selected from any one of fluorine, chlorine, bromine, and iodine.

3. An oxime derivative containing a 3,4-dihydroisoquinoline structure, characterized in that, Specifically selected from the following structure: 。 4. An oxime derivative containing a 3,4-dihydroisoquinoline structure, characterized in that, The specific structure is as follows: 。 5. A bactericidal composition, characterized in that, The active ingredient of the bactericidal composition includes any one of the oxime derivatives containing a 3,4-dihydroisoquinoline structure as described in claims 1 to 4.

6. The application of the oxime derivative containing the 3,4-dihydroisoquinoline structure according to any one of claims 1 to 4 or the fungicidal composition according to claim 5 in the control of plant fungal diseases, characterized in that, The fungi are selected from one or more of the following phyla: Plasmodiomycota, Oomycota, Chytridiomycota, Zygomycota, Basidiomycota, and Deuteromycota.

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