Novel oxamide bridge chain-containing isoquinoline compound and application thereof in preparation of plant pathogenic fungus-resistant bactericide

Abstract

The invention relates to the fields of pesticides and plant protection. Specifically, the invention relates to a novel isoquinoline compound containing an oxamide bridge chain, including a stereoisomer, a prodrug molecule and a pharmaceutically acceptable salt thereof, and application of the molecule in preparation of a bactericide for resisting plant pathogenic fungi. The structure of the isoquinoline compound is shown as a formula (I). The isoquinoline compound disclosed by the invention has obvious inhibitory activity on various plant pathogenic fungi and can be used for preparing bactericides.

Description

Technical Field

[0001] This invention relates to the fields of pesticides and plant protection, and in particular to novel isoquinoline compounds containing oxalamide bridged chains and their application in the preparation of fungicides against plant pathogenic fungi. Background Technology

[0002] Plant pathogenic fungi are a major factor contributing to crop yield reduction and economic losses. Many plant pathogenic fungi produce mycotoxins, threatening not only food security but also posing a threat to mammals. Chemical fungicides remain the primary means of controlling fungal diseases in crops due to their low cost and high efficiency. However, with the long-term overuse of chemical fungicides, problems such as pesticide residues, resistance, and environmental hazards are increasingly serious. Therefore, there is an urgent need to develop new, highly efficient, and environmentally friendly fungicides to control plant fungal diseases and ensure food security.

[0003] Tetrahydroisoquinoline alkaloids are an important component of isoquinoline alkaloids, exhibiting diverse structures and a variety of biological activities, including antibacterial, anti-inflammatory, antitumor, antimalarial, and analgesic effects. Tetrahydroisoquinoline possesses unique structural advantages, offering ample room for structural modification, and its structure is found in numerous pharmaceuticals and agrochemicals. Based on previous research, the applicant employed a biomimetic synthesis strategy, using tetrahydroisoquinoline as the active core and employing a pharmacophore splicing strategy to design and synthesize a series of novel isoquinoline derivatives containing oxalamide-bridged chains. The results demonstrate that the novel isoquinoline compounds containing oxalamide-bridged chains involved in this invention possess antibacterial activity against various plant pathogenic fungi.

[0004] The novel isoquinoline compounds containing oxalamide bridged chains involved in this invention are all new compounds not previously reported in the literature. This patent is the applicant's first report on the antifungal activity of novel isoquinoline compounds containing oxalamide bridged chains. Summary of the Invention

[0005] The purpose of this invention is to provide novel isoquinoline compounds containing oxalamide bridged chains and their application in the preparation of fungicides against plant pathogenic fungi.

[0006] The novel isoquinoline compounds containing oxalamide bridged chains described in this invention have the general structural formula as shown in formula (I):

[0007] In formula (I), R1-R4 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy.

[0008] In formula (I), Ar is selected from aromatic groups such as benzene ring, biphenyl ring, N-phenylbenzamide ring, and pyridine ring, and the specific structure is shown in formula (II).

[0009] In formula (II), R5 is selected from hydrogen, halogen, ester group, nitro group, difluoromethyl, trifluoromethyl, C1-C6 straight-chain or branched alkyl and C1-C6 straight-chain or branched alkoxy; or aromatic heterocycle; or two adjacent R5 and the carbon atom on the aromatic ring connected thereto form a five- or six-membered aliphatic ring or alioxy heterocycle; n is an integer from 1 to 5.

[0010] This invention provides a general method for preparing the novel isoquinoline compound I containing oxalamide bridged chains, and its general synthetic route is as follows:

[0011]

[0012] Compound I was used in the preparation of drugs against plant pathogenic fungi. Bioactivity tests showed that the target compound exhibited significant inhibitory activity against *Bipolaris maydis* (corn leaf spot fungus), *Fusarium oxysporum* (cucumber wilt fungus), *Rhizotonia cerealis* (wheat sheath blight fungus), *Physalospora piricola* (apple ring rot fungus), and *Sclerotinia scleotiorum* (rapeseed sclerotium).

[0013] Compared with the prior art, the present invention has the following advantages and effects:

[0014] This invention uses the natural alkaloids berberine and norcodonine as lead compounds. Utilizing a biomimetic design strategy, and employing a pharmacophore splicing strategy, a series of novel isoquinoline compounds with oxalamide-bridged chains were designed and synthesized, with tetrahydroisoquinoline as the core and a pharmacophore splicing strategy. In vitro antibacterial activity tests demonstrated that these compounds exhibit significant activity against plant pathogenic fungi. Some target compounds showed comparable activity to commercial fungicides such as chlorothalonil and boscalid, providing fundamental data for the synthesis of isoquinoline derivatives with oxalamide-bridged chains and for broader bioactivity studies. Detailed Implementation

[0015] In this invention, the applicant designed and synthesized a novel isoquinoline compound I containing an oxalamide bridge chain, which has the following general structural formula:

[0016] In formula (I), R1-R4 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy.

[0017] In formula (I), Ar is selected from aromatic groups such as benzene ring, biphenyl ring, N-phenylbenzamide ring, and pyridine ring, and the specific structure is shown in formula (II).

[0018] In formula (II), R5 is selected from hydrogen, halogen, ester group, nitro group, difluoromethyl, trifluoromethyl, C1-C6 straight-chain or branched alkyl and C1-C6 straight-chain or branched alkoxy; or aromatic heterocycle; or two adjacent R5 and the carbon atom on the aromatic ring connected thereto form a five- or six-membered aliphatic ring or alioxy heterocycle; n is an integer from 1 to 5.

[0019] Novel isoquinoline compounds containing oxalamide bridged chains have been used in the preparation of fungicides against plant pathogenic fungi. These compounds exhibit significant inhibitory activity against common plant pathogenic fungi such as *Bipolaris maydis* (maize leaf spot), *Fusarium oxysporum* (cucumber wilt), *Rhizotonia cerealis* (wheat sheath blight), *Physalospora piricola* (apple ring rot), and *Sclerotinia scleotiorum* (rapeseed sclerotium).

[0020] The general synthetic method of the novel isoquinoline compound I containing oxalamide bridging chain described in this invention is shown in reaction formula 1, and is specifically illustrated using compound Is.

[0021]

[0022] Example 1: Synthesis of compound Is.

[0023] The synthetic route of compound Is is shown in reaction formula 2.

[0024]

[0025] Synthesis of intermediate 3S: 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.38 g, 2 mmol, 1.0 eq.) and triethylamine (0.30 g, 3 mmol, 1.5 eq.) were dissolved in 5 mL of dry dichloromethane and cooled in an ice bath. Oxaloyl chloride (0.28 g, 2.2 mmol, 1.1 eq.) was added dropwise, and the mixture was allowed to warm naturally to room temperature. The reaction was monitored by thin-layer chromatography (TLC) until complete. The reaction solution was concentrated under reduced pressure and then directly added to the next step of the reaction.

[0026] Synthesis of target compound Is: Intermediate 3s was dissolved in dry dichloromethane, and 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-amine (0.33 g, 2 mmol, 1.0 eq.) and triethylamine (0.30 g, 3 mmol, 1.5 eq.) were added. The mixture was stirred in an ice bath for 1 h, and the reaction was monitored by TLC until completion. Dichloromethane (40 mL) was added to the reaction solution, and the mixture was washed with saturated brine (15 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The target compound Is was obtained by column chromatography (PE:EA).

[0027] Compound Is: 86% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.54(s,1H),6.73(s,1H),6.65(d,J=3.1Hz,1H),6.61(d,J=3.7Hz,1H),5.27(s,1H),4.70(s,1H), 4.35(t,J=5.9Hz,1H),3.89(d,J=6.0Hz,1H),3.86(s,3H),3.86(s,3H),3.85(d,J=3.4Hz,3H),2.93(s,1H),2.87(s,1H). 13 C NMR(150MHz, CDCl3)δ158.96(158.70),158.00(157.85),148.22,148.11,148.09(141.53),135.63(135.60),125.93(125.61),124 .35,123.42,111.41(111.38),109.29(109.01),97.39,97.34,56.04,56.01,47.82(46.07),44.61(42.67),36.27,29.17(27.61).

[0028] The synthesis methods for the remaining target compound I are the same as those for Is.

[0029] According to the preparation method in Example 1, a series of target compounds Ia--It were obtained, and their structures are shown in Table 1.

[0030] Table 1. Structural formulas of target compounds Ia-It.

[0031]

[0032] Compound Ia: 93% yield, white solid. 1H NMR(600MHz, CDCl3)δ9.45(d,J=39.9Hz,1H),8.31(t,J=7.9Hz,1H),7.18–7.14(m, 1H),7.13(d,J=2.6Hz,1H),7.11–7.08(m,1H),6.64(s,1H),6.64(d,J=2.7Hz,1H),6 .61(s,1H),5.29(s,1H),4.74(s,1H),4.34(t,J=5.9Hz,1H),3.90(t,J=6.0Hz,1H) ,3.86(s,3H),3.85(d,J=10.5Hz,3H),2.93(t,J=5.9Hz,1H),2.88(t,J=6.0Hz,1H). 13 C NMR(150MHz, CDCl3)δ160.30(159.97),158.50(158.37),148.02(147.93),134.91,132.60,128.28,126.00,124.76(12 3.90),121.38(121.7),114.23,111.35,109.02(109.00),56.04,55.98,47.86(45.98),44.56(42.49),29.27(27.70).

[0033] Compound Ib: 87% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.36 (d, J=13.4Hz, 1H), 7.60 (dt, J=10.6, 2.1Hz, 1H), 7.34 –7.26(m,2H),7.23(t,J=6.3Hz,2H),6.92–6.82(m,1H),6.64(dd,J=6.4,4.0Hz, 2H),5.31(s,1H),4.74(s,1H),4.38(t,J=5.9Hz,1H),3.90(t,J=6.0Hz,4H),3.8 7(d,J=1.5Hz,7H),3.85(s,7H),2.94(t,J=5.8Hz,1H),2.88(t,J=6.0Hz,1H).13C NMR (150MHz, CDCl3)δ 162.19, 160.50 (160.20), 148.12, 148.04, 138.34, 130.25, 125.82, 123.83, 115.31, 111.90, 111.76, 111.48, 109.41, 107.45 (107.28), 56.03, 56.00, 47.91 (45.95), 44.61 (42.43), 29.68 (27.68).

[0034] Compound Ic: 88% yield, white solid. 1 H NMR(400MHz, CDCl3)δ9.27(d,J=15.4Hz,1H),7.58(ddd,J=9.3,4.8,2.7Hz,2H),7.10–7.02(m,2H),6.67–6.60(m,2H),5.31(s,1H),4.7 4(s,1H),4.38(t,J=5.9Hz,1H),3.90(t,J=6.0Hz,1H),3.87(s,3H),3.85(d,J=7.0Hz,3H),2.94(t,J=5.8Hz,1H),2.88(t,J=6.0Hz,1H). 13 CNMR(150MHz, CDCl3)δ166.81,160.91(160.48),159,42(159,34),158.79,157.17,147.94,136.31,126.14,124.80(12 4.11),122.06,121.42,117.49,111.38,109.39(109.00),55.97,52.85,47.74(45.70),44.38(42.17),29.26(27.69).

[0035] Compound Id: 96% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.84 (d, J=36.6Hz, 1H), 8.39 (dt, J=8.3, 1.8Hz, 1H), 7.41 (dt,1H),7.31(t,J=7.8Hz,1H),7.10(tt,J=7.6,1.6Hz,1H),6.65(s,1H),6.63( d,J=7.5Hz,1H),5.32(s,1H),4.76(s,1H),4.37(t,J=5.9Hz,1H),3.92(t,J=6.0 Hz,1H),3.87(s,3H),3.85(s,3H),2.94(t,J=5.9Hz,1H),2.90(t,J=6.0Hz,1H). 13C NMR (150MHz, CDCl3)δ 160.31(159.96),158.50(158.39),148.07,148.01,133.75,129.31,127.59,126.17,125.49,123.88,121.18,121.06,111.55(111.49),109.47(109.15),56.01,55.97,47.81(45.88),44.51(42.40),29.23(27.66).

[0036] Compound Ie: 94% yield, yellow solid. 1 H NMR (400MHz, CDCl3) δ9.50(s,1H),7.81(s,1H),7.44(t,J=9.9Hz,1H),7.30–7.21(m,1H),7.12(d,J=7.8Hz,1H),6.62(d,J=6.2Hz,2H),6.60(d,J= 5.1Hz,2H),5.26(s,1H),4.69(s,1H),4.31(t,J=5.9Hz,1H),3.86(d,J=8 .4Hz,8H),3.84(s,7H),3.83(d,J=4.3Hz,7H),2.92(s,1H),2.83(s,1H). 13 C NMR(150MHz, CDCl3)δ160.45(160.18),158.32,148.05,147.97,135.42(135.36),130.24(130.20),129.20,126.15 125.79),124.77(123.81),121.09(121.08),111.40,111.38,109.31,109 .02,56.03,56.01(56.00),47.92(45.99),44.62(42.46),29.27(27.69).

[0037] Compound If: 95% yield, white solid. 1H NMR (400MHz, CDCl3) δ9.41(d,J=9.1Hz,1H),7.59(d,J=2.9Hz,1H),7.57(d,J=2.9Hz,1H),7.32(d,J=1.2Hz,1H),7.30(d,J=1.2Hz,1H),6.64(d,J=4 .9Hz,1H),6.61(s,1H),5.28(s,1H),4.71(s,1H),4.34(t,J=5.9Hz,1H),3 .88(s,1H),3.85(s,3H),3.85(d,J=7.9Hz,3H),2.93(s,1H),2.85(s,1H). 13 C NMR (150MHz, CDCl3) δ160.44(160.17),158.49(158.31),148.08,147.99,135.42,130.24,129.20,126.16(125.80),124.79(123.8 3),121.09(121.07),111.41,109.34,109.05,56.04,56.00,47.92(46.00z),44.61(42.47),29.70(29.27),27.69.HRMS(ESI)calcd forC 19 H 19 ClN2O4[M+H] + 374.1033, found 374.1037.

[0038] Compound Ig: 93% yield, yellow solid. 1 H NMR (400MHz, CDCl3) δ9.87 (d, J = 38.8Hz, 1H), 8.37 (s, 1H), 7.58 (s, 1H), 7. 35(d,J=7.2Hz,1H),7.04(d,J=7.8Hz,1H),6.71–6.53(m,2H),5.33(d,J=5. 6Hz,1H),4.76(d,J=5.6Hz,1H),4.38(d,J=5.9Hz,1H),3.91(s,1H),3.88( s,3H),3.86(d,J=3.8Hz,3H),2.95(d,J=5.8Hz,1H),2.90(d,J=5.6Hz,1H). 13C NMR(150MHz, CDCl3)δ160.38(160.04),158.67(158.54),153.72,148.03,147.97,126.14,125.47,124.77,124.5 1,123.90,121.46,115.26,111.40,109.36(109.04),56.02,55.99,47.84(45.83),44.53(42.32),29.25(27.68).

[0039] Compound Ih: 89% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.31(d,J=15.5Hz,1H),7.55–7.52(m,1H),7.52–7.51(m,1H),7.49(s,1H),7.46(s,1H),6.64(dd,J=7.2,4.8Hz,2H),5.31(s, 1H),4.74(s,1H),4.40–4.36(m,1H),3.90(t,J=6.1Hz,1H),3.87–3.86(m ,3H),3.85(d,J=1.1Hz,3H),2.94(t,J=5.8Hz,1H),2.88(t,J=6.0Hz,1H). 13 C NMR (150MHz, CDCl3) δ166.84,160.91(160.48),159.35,158.79,157.17,147.96,136.33,126.01,124.80,124.11,122.06(121.93),121.42( 121.25),117.49(117.32),111.48(111.38),109.39(109.00),56.02,55.97,47.74(45.70),44.38(42.17),29.26(27.69).HRMS(ESI)calcd for C 19 H 19 BrN2O4[M+H] + 418.0528, found 418.0526.

[0040] Compound Ii: 92% yield, white solid. 1H NMR (400MHz, CDCl3) δ9.29(d,J=15.8Hz,1H),7.96(d,J=2.0Hz,1H),7.45(t,J=7.5Hz,1H),7.30(d,J=8.0Hz,1H),7.22(td,J=8.0,1.9Hz,1H),6.68 –6.61(m,2H),5.32(s,1H),4.74(s,1H),4.39(s,1H),3.91(s,1H),3.87(s ,3H),3.86(d,J=5.2Hz,3H),2.94(t,J=5.9Hz,1H),2.88(t,J=6.0Hz,1H). 13 C NMR(150MHz, CDCl3)δ160.40(160.10),158.57(158.41),148.07,147.99,138.14,138.07,132.13,130.37,128.11,12 8.09,122.82,121.43,118.37,111.40,109.34(109.04),56.04,56.00,47.91(45.98),44.62(42.46),29.26(27.68).

[0041] Compound Ij: 92% yield, white solid. 1 H NMR(400MHz, CDCl3)δ12.39(d,J=40.8Hz,1H),8.71(ddd,J=9.3,5.0,1.6Hz,1H),7.78–7.68(m,1H),7.27(s,1H),6.63(s,1H),6.60(s,1H),5.2 4(s,1H),4.74(s,1H),4.28(t,J=5.9Hz,1H),3.95(s,3H),3.91(s,1H), 3.85(s,3H),3.83(s,3H),2.91(t,J=5.8Hz,1H),2.86(t,J=6.1Hz,1H). 13C NMR(150MHz, CDCl3)δ160.48(160.20),158.53(158.37),148.07,147.99,135.95,135.89,132.14,126.14(125.79),124.76,123.80,12 1.41,117.88(117.84),115.14,111.42(111.40),109.32(109.04),56.03,56.01(55.99),47.91(45.97),44.61(42.45),29.26,27.68.

[0042] Compound Ik: 88% yield, white solid. 1 H NMR (400MHz, CDCl3) δ12.63(d,J=38.7Hz,1H),8.48(d,J=11.6Hz,1H),8.03(s,1H),6.80(s,1H),6.61(s,1H),6.59(s,1H), 5.20(s,1H),4.71(s,1H),4.24(s,1H),3.91–3.89(m,3H),3.87(s,1H),3.82(s,3H),3.81(s,3H),2.89(s,1H),2.83(s,1H). 13 C NMR (150MHz, CDCl3)δ 167.20 (167.15), 166.79 (165.11), 160.60 (160.17), 159.72 (159.63), 147.93, 147.90 (147.85), 142.06 (141.98), 133.41 (133.34), 126.11 (125.94), 124.72 (124.03), 112.53, 111.43 (111.39), 110.79 (110.65), 109.13 (108.95), 107.49 (107.30), 55.98, 55.92, 52.57, 47.68 (45.67), 44.34 (42.15), 29.32 (27.65).

[0043] Compound Il: 93% yield, white solid. 1H NMR (400MHz, CDCl3) δ12.48(d,J=40.2Hz,1H),8.70(d,J=9.0Hz,1H),8.04(t ,J=2.4Hz,1H),7.62–7.46(m,1H),6.66–6.60(m,2H),5.25(s,1H),4.76(s,1 H),4.29(t,J=5.9Hz,1H),3.96(d,J=2.4Hz,3H),3.93(t,J=6.0Hz,1H),3.86 (d,J=1.5Hz,3H),3.84(s,3H),2.93(t,J=5.9Hz,1H),2.88(t,J=6.0Hz,1H). 13 CNMR(150MHz, CDCl3)δ167.13,161.05(160.61),159.72,148.23,148.17,138.81,134.49,131.11,129.06,126.40,1 24.36,121.84,118.01,111.65,109.66(109.27),56.31,56.26,53.15,48.03(46.01),44.67(42.49),29.55(27.97).

[0044] Compound Im: 91% yield, white solid. 1 H NMR (400MHz, CDCl3) δ12.60(d,J=37.2Hz,1H),8.82(t,J=1.9Hz,1H),8.01(dd,J=8.6, 2.4Hz,1H),7.14(dt,J=8.6,1.8Hz,1H),6.64(d,J=3.3Hz,1H),6.63(d,J=2.5Hz,1H),5 .25(s,1H),4.76(s,1H),4.29(t,J=5.9Hz,1H),3.95(d,J=2.6Hz,3H),3.93(d,J=6.0Hz ,1H),3.86(s,3H),3.85(d,J=4.6Hz,3H),2.93(t,J=5.8Hz,1H),2.88(t,J=6.0Hz,1H). 13C NMR(150MHz, CDCl3)δ167.33(167.29),160.65(160.23),159.65(159.55),147.99(1 47.97),147.95(147.90),140.88(140.83),140.73(140.70),132.20,126.13(125.9 6), 124.72 (124.05), 123.82, 120.18 (120.12), 114.68 (114.65), 111.45 (111.36), 109.37 (108.97), 56.04, 55.99, 52.73, 46.75 (45.76), 44.40 (42.22), 29.28 (27.69).

[0045] Compound In: 91% yield, white solid. 1 H NMR (400MHz, CDCl3) δ10.04(d,J=38.5Hz,1H),7.84(d,J=7.9Hz,1H),7.63(d,J=8.0Hz,1H),7.27(t,J=8.0Hz,1H),6.64(s,1H),6.62(d,J=19.1H z,1H),5.22(s,1H),4.75(s,1H),4.28(t,J=5.9Hz,1H),3.93(s,1H),3. 91(d,J=5.1Hz,3H),3.86(s,3H),3.83(s,3H),2.92(s,1H),2.89(s,1H). 13 C NMR(150MHz, CDCl3)δ166.25(166.24),160.39(159.94),158.99(158.96),148.01(1 47.99),147.94(147.92),133.77(133.75),133.04(133.02),130.84(134.80),129. 31(129.28),127.49(126.88),126.19(125.95),124.84,123.98,111.45(111.42),109.35(109.06),56.04,55.98(52.75),52.73(47.63),45.55,44.38,29.24(27.71).

[0046] Compound Io: 92% yield, white solid. 1H NMR (400MHz, CDCl3) δ12.43 (s, 1H), 8.70 (d, J = 9.1Hz, 1H), 8.04 (t, J = 2.4Hz, 1 H),7.52(dd,J=9.0,1.8Hz,1H),6.64(s,1H),6.62(d,J=6.7Hz,1H),5.25(s,1 H),4.76(s,1H),4.28(t,J=5.9Hz,1H),3.96(d,J=2.4Hz,3H),3.93(s,1H),3. 86(d,J=1.5Hz,3H),3.84(s,3H),2.93(t,J=5.8Hz,1H),2.88(t,J=5.9Hz,1H). 13 C NMR (150MHz, CDCl3)δ 166.72 (166.70), 160.55 (160.34), 159.51 (159.47), 148.03, 147.96, 138.96 (138.94), 137.10 (137.09), 133.77, 126.09 (126.03), 124.45 (124.12), 121.80 (121.76), 118.05, 116.17, 111.51 (111.46), 109.29 (109.09), 56.05, 56.00, 52.84, 46.74 (45.74), 43.31 (42.22), 28.48 (27.70).

[0047] Compound Ip: 94% yield, white solid. 1 H NMR (400MHz, CDCl3) δ12.52(s,1H),8.95(s,1H),7.90(d,J=6.4Hz,1H),7.27(d,J=9.9Hz,1H),6.61(s,1H),5.24(s,1 H),4.74(s,1H),4.28(s,1H),3.94(s,3H),3.92(s,1H),3.85(s,3H),3.84(d,J=3.8Hz,3H),2.92(s,1H),2.87(s,1H). 13C NMR(150MHz, CDCl3)δ167.42(167.38),160.61(160.19),159.58(159.48),147.96,147. 94(147.89),140.80(140.75),132.21,129.30(129.28),126.79,126.13(125.95),124. 72(124.04),123.07(123.02),115.08(115.05),111.44(111.36),109.36(108.97),56.03,55.98(55.96),52.74,47.74(45.75),44.39(42.22),29.35(29.27),25.93(22.68).

[0048] Compound Iq: 91% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.92(d,J=34.4Hz,1H),7.88(dd,J=7.9,1.5Hz,1H),7.80(dt,J=8.0,1.4Hz,1H),7.21(t,J=7.9Hz,1H),6.66–6.59(m,2H),5.23( s,1H),4.76(s,1H),4.30(t,J=5.9Hz,1H),3.90(d,J=6.5Hz,3H),3.87(s,3 H),3.86(s,3H),3.83(s,1H),2.93(d,J=5.9Hz,1H),2.90(d,J=5.1Hz,1H). 13 C NMR (151MHz, CDCl3) δ166.21,160.33(159.88),158.95,148.00,147.95,136.81,134.07,129.96(129.93),128.01,127.31,126.19(125.9 5),123.98,120.88,111.45(111.43),109.36,109.06,56.04,56.01( 55.99),52.75(52.72),47.63(45.59),44.38(42.06),29.26(27.72).

[0049] Compound Ir: 89% yield, white solid. 1H NMR(600MHz, CDCl3)δ9.59(s,1H),6.65(s,1H),6.63(d,J=5.2Hz,1H),6.60(td,J=55.1,2.1Hz,1H),6.59(s,1H),5.24(s,1H),4.67(s,1H), 4.31(t,J=5.9Hz,1H),3.86(s,1H),3.85(d,J=1.5Hz,3H),3.83(s,3H),3.81(d,J=4.7Hz,3H),2.91(t,J=5.9Hz,1H),2.84(t,J=6.0Hz,1H). 13 C NMR (150MHz, CDCl3) δ157.82,148.20,148.08,126.00,125.64,124.45,123.52,111.41,111.3 8,111.07,109.32,109.03,56.05(56.03),56.02,47.82(46.09),44.60(42.65),35.96,29.20.

[0050] Compound Is: 86% yield, white solid. 1 H NMR (400MHz, CDCl3) δ9.54(s,1H),6.73(s,1H),6.65(d,J=3.1Hz,1H),6.61(d,J=3.7Hz,1H),5.27(s,1H),4.70(s,1H), 4.35(t,J=5.9Hz,1H),3.89(d,J=6.0Hz,1H),3.86(s,3H),3.86(s,3H),3.85(d,J=3.4Hz,3H),2.93(s,1H),2.87(s,1H). 13 C NMR(150MHz, CDCl3)δ158.96(158.70),158.00(157.85),148.22,148.11,148.09(141.53),135.63(135.60),125.93(125.61),124 .35,123.42,111.41(111.38),109.29(109.01),97.39,97.34,56.04,56.01,47.82(46.07),44.61(42.67),36.27,29.17(27.61).

[0051] Compound It: 89% yield, white solid. 1H NMR(400MHz, CDCl3) δ11.25(d,J=8.7Hz,1H),8.52(dd,J=4.6,1.3Hz,1H),8.02–7.9 6(m,1H),7.39–7.31(m,1H),7.14(s,1H),6.68(d,J=28.9Hz,1H),6.62(d,J=3.1Hz, 1H),6.59(d,J=8.0Hz,1H),5.28(s,1H),4.71(s,1H),4.37(t,J=5.9Hz,1H),3.88(d ,J=6.1Hz,1H),3.85(d,J=4.5Hz,6H),2.92(t,J=5.9Hz,1H),2.86(t,J=6.0Hz,1H). 13 C NMR(150MHz, CDCl3)δ159.21(158.98),157.22(157.00),148.13(148.10),1 48.01,147.67,147.51(147.48),146.15(146.14),141.92(141.91),138.18( 138.13),126.09(125.70),125.88,124.28,123.65,112.51,111.39,109.40( 109.32),94.88,56.04,55.99,47.76(45.98),44.47(42.50),29.22(27.62).

[0052] Example 2: Experimental methods and results of the antifungal activity of target compound I against plant pathogenic fungi.

[0053] This invention utilizes the mycelial growth rate method to test the in vitro activity of the target compound Ia-It against five common crop pathogens: *Bipolaris maydis* (corn leaf spot pathogen), *Fusarium oxysporum* (cucumber wilt pathogen), *Rhizotonia cerealis* (wheat sheath blight pathogen), *Physalospora piricola* (apple ring rot pathogen), and *Sclerotinia cleotiorum* (rapeseed sclerotinia cleotiorum). Chlorothalonil and boscalid were used as control agents. The compound was dissolved in dimethyl sulfoxide to prepare a 10 mg / mL solution, which was then diluted with 0.5% Tween 20 to a 1 mg / mL test solution. 0.75 mL of this test solution was added to a 45 mL centrifuge tube, and potato dextrose agar medium was added while hot to bring the volume to 15 mL. After mixing thoroughly, the mixture was poured into petri dishes, cooled and solidified, and then inoculated with the test bacteria. An equal volume of the test solution without the target compound was used as a blank control. Each group was tested in triplicate, and the cultures were inverted at 25±1℃. The average value was used for statistical analysis. Colony diameter was measured using the cross-crossing method. The results of the antifungal resistance test are shown in Table 2.

[0054] Table 2. Experimental data on the antifungal activity of target compounds Ia-It against plant pathogenic fungi.

[0055]

[0056] In summary, the novel isoquinoline compounds containing oxalamide bridged chains described in this invention exhibit broad-spectrum activity against plant pathogenic fungi and are promising candidate fungicide molecules. The target compounds are most sensitive to *Sclerotinia sclerotinia*, the causal agent of rapeseed disease; all compounds showed inhibition rates higher than 50.00%, with compound Is exhibiting the highest inhibition rate of 95.03%, comparable to the control samples chlorothalonil and cyazofamid.

[0057] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the essence and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A novel isoquinoline compound containing an oxalamide bridge chain, the structure of which is shown in formula (I):

2. According to claim 1, R1-R4 in formula (I) are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl and C1-C6 alkoxy.

3. According to claim 1, Ar in formula (I) is selected from aromatic groups such as benzene ring, biphenyl ring, N-phenylbenzamide ring, and pyridine ring, and the specific structure is shown in formula (II):

4. According to claim 3, R5 in formula (II) is selected from hydrogen, halogen, ester group, nitro group, difluoromethyl, trifluoromethyl, C1-C6 straight-chain or branched alkyl and C1-C6 straight-chain or branched alkoxy; or aromatic heterocycle; or two adjacent R5 and the carbon atom on the aromatic ring connected thereto form a five- or six-membered aliphatic ring or alioxy heterocycle; n is an integer from 1 to 5.

5. The application of the novel isoquinoline compound containing oxalamide bridged chains according to claim 1 in the preparation of fungicides against plant pathogenic fungi, wherein the plant pathogenic fungi are selected from *Bipolaris maydis* (corn leaf spot fungus), *Fusarium oxysporum* (cucumber wilt fungus), *Rhizotonia cerealis* (wheat sheath blight fungus), *Physalospora piricola* (apple ring rot fungus), and *Sclerotinia scleotiorum* (rapeseed sclerotium).

Images