DHODH inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a plant DHODH inhibitor as well as a preparation method and application thereof. The DHODH inhibitor is a compound as shown in a formula I or an isomer, a salt or a solvate or a crystal form thereof: # imgabs 0 #, wherein R1 is selected from substituted tetrahydronaphthyl, C3-C8 cycloalkyl, phenyl, biphenyl, tetrahydronaphthyl, benzocycloheptyl, benzocyclopentyl, substituted C3-C8 cycloalkyl and # imgabs 1 # cyclohexylpyridyl; r2 is selected from C1-C8 straight-chain and branched-chain alkylene or isomers thereof, and C3-C8 cycloalkyl; and R3 is selected from a substituted phenyl group, a biphenyl group, a benzocyclohexyl group, a tetrahydronaphthyl group, a benzocyclopentyl group and a benzopiperidyl group. The compound provided by the invention is novel in structure, has better DHODH inhibition activity than most of known structures in the market, and is expected to be used as a novel weed control drug to be applied to rice planting.

Description

Technical Field

[0001] The present invention belongs to the field of pesticide science, and in particular relates to a plant DHODH inhibitor, a preparation method and an application thereof. Background Art

[0002] Weeds infest over 930 million hectares of farmland in my country annually, resulting in economic losses totaling 220 billion yuan. Herbicide use mitigates these losses significantly. However, the long-term use of a single herbicide type has led to the rapid development of resistant weeds, posing a serious threat to agricultural sustainability. Rotating between different herbicides, particularly those with novel mechanisms of action, is considered one of the most effective strategies for managing herbicide-resistant weeds.

[0003] Pyrimidine biosynthesis plays a key role in the synthesis of DNA, RNA, glycoproteins and phospholipids. Dihydroorotate dehydrogenase (DHODH) is responsible for catalyzing the fourth step of pyrimidine synthesis, oxidizing dihydroorotate (DHO) to orotate (OR), and is a key protein in pyrimidine biosynthesis. In plants, inhibition of DHODH can lead to pyrimidine deficiency, cell cycle arrest and ultimately cell death, thereby preventing weed growth. In recent years, DHODH inhibitors have received widespread attention in the agricultural field due to their unique mechanism of action and are regarded as a new weed control strategy. Currently, Tetflupyrolimet is the only DHODH inhibitor approved for marketing and has been successfully used in rice cultivation.

[0004] This patent invents a series of compounds containing tetralin and provides a preparation method. This series of compounds shows significant inhibitory activity against the DHODH recombinant protein of barnyard grass. They are DHODH inhibitors with a novel skeleton structure and have broad application prospects in agricultural production fields such as weed control and plant protection. Summary of the Invention

[0005] The purpose of the present invention is to provide a DHODH inhibitor with good herbicidal activity, a preparation method and an application thereof.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A DHODH inhibitor, which is a compound represented by formula I or its isomer, salt, solvate or crystal form:

[0008]

[0009] Wherein, R1 is selected from substituted tetrahydronaphthyl, C3-C8 cycloalkyl, phenyl, biphenyl, tetrahydronaphthyl, benzocycloheptyl, benzocyclopentyl, substituted C3-C8 cycloalkyl, Cyclohexylpyridinyl;

[0010] R2 is selected from C1-C8 straight chain, branched chain alkylene or its isomers, C3-C8 cycloalkyl;

[0011] R3 is selected from substituted phenyl, biphenyl, benzocyclohexyl, tetrahydronaphthyl, benzocyclopentyl, benzopiperidinyl;

[0012] The substituents on the substituted phenyl group are selected from halogenated C1-C6 alkoxy, substituted C1-C8 straight or branched alkylene, substituted C1-C8 straight or branched alkyl, halogen, C1-C8 straight or branched alkylene, C1-C8 straight or branched alkyl;

[0013] The substituent on the substituted C1-C8 straight chain branched alkylene, or substituted C1-C8 straight chain or branched alkyl is halogen;

[0014] The substituent on the substituted C3-C8 cycloalkyl group is a C1-C8 straight or branched chain alkylene group;

[0015] The substituent on the substituted tetrahydronaphthyl group is halogen.

[0016] In a preferred embodiment, the substituents on the substituted phenyl group are selected from substituted C1-C6 straight chain or branched alkylene, substituted C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkylene, and C1-C6 straight chain or branched alkyl.

[0017] In a preferred embodiment, the substituents on the substituted phenyl group are selected from substituted C1-C4 straight or branched alkylene groups, substituted C1-C4 straight or branched alkyl groups, C1-C4 straight or branched alkylene groups, and C1-C4 straight or branched alkyl groups.

[0018] In a preferred embodiment, R2 is selected from C1-C5 straight or branched chain alkylene.

[0019] In a preferred embodiment, the number of substituents on the substituted phenyl group is 1-5.

[0020] In a preferred embodiment, the halogenated C1-C6 alkoxy group includes trihalogenated C1-C6 alkoxy group, dihalogenated C1-C6 alkoxy group, and halogenated C1-C6 alkoxy group, and the halogen includes fluorine, chlorine, bromine, and iodine.

[0021] In a preferred embodiment, the substituted halogen elements in the trihalogenated C1-C6 alkoxy group and the dihalogenated C1-C6 alkoxy group may be the same or different.

[0022] In a preferred embodiment, the halogenated C1-C6 alkoxy group includes trihalogenated C1-C4 alkoxy group, dihalogenated C1-C4 alkoxy group, and halogenated C1-C4 alkoxy group, and the halogen includes fluorine, chlorine, bromine, and iodine.

[0023] In a preferred embodiment, the halogenated C1-C6 alkyl group includes a trihalogenated C1-C6 alkyl group, a dihalogenated C1-C6 alkyl group, and a halogenated C1-C6 alkyl group, and the halogen includes fluorine, chlorine, bromine, and iodine.

[0024] In a preferred embodiment, the substituted halogen elements in the trihalogenated C1-C6 alkyl group and the dihalogenated C1-C6 alkyl group may be the same or different.

[0025] In a preferred embodiment, R1 is selected from Cyclohexyl,

[0026] In a preferred embodiment, R2 is selected from

[0027] In a preferred embodiment, R3 is selected from

[0028] In a preferred embodiment, the DHODH inhibitor is the following compound or its isomer, salt, solvate or crystal form:

[0029]

[0030] Wherein, R4 and R5 are independently selected from hydrogen, C1-C8 straight or branched chain alkyl, and halogen;

[0031] R6 is selected from C1-C8 straight or branched alkylene,

[0032] X is selected from -NHCO-, -CONH-;

[0033] R7 is selected from the group consisting of: halogenated C1-C6 alkoxy, substituted C1-C8 straight or branched chain alkyl, halogen, C1-C8 straight or branched chain alkyl;

[0034] The substituent on the substituted C1-C8 linear or branched alkyl group is halogen.

[0035] In a preferred embodiment, R6 is selected from ethylene, isopropylene, n-butylene, sec-butylene, isobutylene, and tert-butylene.

[0036] In a preferred embodiment, R4 and R5 are independently selected from C1-C6 straight chain or branched alkyl groups.

[0037] In a preferred embodiment, R4 and R5 are independently selected from C1-C4 straight chain or branched alkyl groups.

[0038] In a preferred embodiment, R7 is selected from: substituted C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkyl.

[0039] In a preferred embodiment, R7 is selected from: substituted C1-C4 straight chain or branched alkyl, C1-C4 straight chain or branched alkyl.

[0040] In a preferred embodiment, the DHODH inhibitor is the following compound or its isomer, salt, solvate or crystal form:

[0041]

[0042]

[0043]

[0044] Based on the same inventive concept, the present invention also claims a method for preparing the DHODH inhibitor, comprising the following steps:

[0045] S1, raw material 1 is prepared to obtain intermediate 1;

[0046]

[0047] S2, intermediate 1 and carboxylic acid react to obtain the DHODH inhibitor;

[0048]

[0049] Based on the same inventive concept, the present invention also claims to protect the use of the DHODH inhibitor, which is used for preparing a herbicide.

[0050] Based on the same inventive concept, the present invention also claims protection for a herbicide comprising the DHODH inhibitor.

[0051] In a preferred embodiment, the herbicide further comprises other applicable surfactants, solvents, stabilizers, synergists, adhesives, penetrants, defoaming agents and antifreeze agents.

[0052] In a preferred embodiment, the herbicide is directed against one or more of Echinochloa crusgalli, Leptochloa chinensis, Portulaca oleracea, Solanum nigrum, and Digitaria sanguinalis.

[0053] The compound of the present invention has a novel structure and is more effective in inhibiting DHODH than most structures known on the market. It is expected to be used as a new weed control drug in rice cultivation.

[0054] The present invention provides a series of tetralinyl-containing compounds and a preparation method. The series of compounds exhibit significant inhibitory activity against barnyardgrass DHODH recombinant protein and are DHODH inhibitors with a novel skeleton structure. They have broad application prospects in agricultural production fields such as weed control and plant protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 The figure shows the results of using the compound of the present invention and tetrafluthion for weed control. DETAILED DESCRIPTION

[0056] The present invention is not limited to the following specific embodiments. Based on the disclosure of the present invention, a person skilled in the art may adopt a variety of other specific embodiments to implement the present invention. Any simple changes or modifications made to the design structure and concept of the present invention fall within the scope of protection of the present invention. It should be noted that the embodiments and features of the embodiments of the present invention may be combined with each other unless they conflict.

[0057] The present inventors, through extensive and in-depth research, unexpectedly discovered for the first time a class of DHODH inhibitors with novel structure and excellent performance, and completed the present invention on this basis.

[0058] the term

[0059] The term "C1-C6 alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0060] The term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.

[0061] As used herein, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

[0062] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0063] The term "C haloalkane" refers to a straight or branched alkane having 1 to 6 carbon atoms substituted by one or more halogen atoms as described above, which may be the same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.

[0064] The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, fluorenyl, tetrahydronaphthyl, indanyl, etc. As used herein, the aryl group may be optionally substituted with one or more substituents described herein.

[0065] The groups described in the present invention, whether specifically stated as "unsubstituted or optionally substituted" or not specifically stated as "unsubstituted or optionally substituted", can be substituted by 0 to multiple (usually 0, 1, 2 or 3) substituents selected from the following groups: halogen, cyano, nitro, amino, carboxyl, mercapto, hydroxyl, hydroxymethyl, C1-6 alkyl, C1-6 haloalkyl (such as trifluoromethyl), halogen-substituted alkoxy (such as trifluoromethoxy), C3-8 cycloalkyl, C1-6 alkoxy (such as methoxy), optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted aryloxy (such as optionally substituted phenoxy), optionally substituted benzyloxy, optionally substituted arylcarboxamido and optionally substituted arylaminocarboxylic acid.

[0066] Example 1 Preparation of (1R, 2R)-2-amino-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)cyclopentane-1-carboxamide (Intermediate 1)

[0067]

[0068] The first step is to prepare tert-butyl ((1R,2R)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)cyclopentyl)carbamate:

[0069] (R)-1,2,3,4-Tetrahydronaphthalen-1-amine (1 g, 6.8 mmol, 1.0 eq) was placed in a flask, 20 mL of DCM (1,2-dichloromethane) was added and stirred to dissolve. Then, (1R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1.56 g, 6.8 mmol, 1.0 eq) and HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (3.1 g, 8.16 mmol, 1.2 eq) were added in sequence. TEA (triethylamine) (2.1 g, 20.4 mmol, 3.0 eq) was added with stirring at room temperature. The reaction was continued at room temperature and monitored by TLC. The reaction was complete after 4 h. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was isolated by column chromatography as a yellow solid (2.1 g, yield 86.1%). 1H NMR (600 MHz, CDCl3) δ 7.31–7.27 (m, 2H), 7.17–7.11 (m, 2H), 7.10–7.05 (m, 1H), 5.25–5.10 (m, 1H), 4.05–3.95 (m, 1H), 2.87–2.71 (m, 2H), 2.67–2.59 (m, 1H), 2.08–1.66 (m, 10H), 1.49–1.43 (m, 1H), 1.39 (s, 9H).

[0070] The second step is to prepare (1R,2R)-2-amino-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)cyclopentane-1-carboxamide:

[0071] To a flask, tert-butyl ((1R,2R)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)cyclopentyl)carbamate (0.5 g, 1.4 mmol, 1.0 eq) was added 10 mL of DCM. With stirring at room temperature, 4 mL of TFA (trifluoroacetic acid) was added. The reaction was continued at this temperature and monitored by TLC. The reaction was complete after 2 h. Aqueous NaHCO₃ solution was slowly added to adjust the pH to 7-8. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was isolated by column chromatography as a pale yellow solid (0.21 g, 58.3% yield). 1H NMR (600MHz, DMSO-d6) δ7.28–7.23(m,1H),7.17–7.11(m,2H),7.09–7.06(m,2H),5.23–5.08(m,1H),3.41–3. 29(m,1H),2.85–2.69(m,2H),2.34–2.23(m,1H),2.07–1.89(m,4H),1.86–1.61(m,5H),1.43–1.33(m,1H).MS m / z(ESI):259.2[M+H].

[0072] Example 2 Preparation of Intermediates 2 to 12

[0073] Different carboxylic acids were reacted with (R)-1,2,3,4-tetrahydronaphthalene-1-amine, (R)-3,4-dihydro-2H-1-benzopyran-4-amine, or (R)-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-amine, and raw materials such as HATU, TEA, and TFA were added to obtain the following intermediates 2 to 12 by a method similar to that described for the preparation of intermediate 1.

[0074] Table 1 Structural formulas of intermediates 2 to 12

[0075]

[0076]

[0077] Example 3 Preparation of (1R, 2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylic acid (Intermediate 13)

[0078]

[0079] The first step is to prepare methyl (1R, 2R)-2-(tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate:

[0080] (1R,2R)-2-(tert-Butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1.0 g, 4.4 mmol, 1.0 eq), iodomethane (0.35 mL, 5.3 mmol, 1.2 eq), and KCO (1.5 g, 11 mmol, 2.5 eq) were dissolved in 20 mL of DMF, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, saturated brine was added, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined and evaporated to dryness to obtain the product as a white solid (1.0 g, 94.3% yield). 1H NMR (600MHz, DMSO-d6) δ6.96 (d, J=8.2Hz, 1H), 3.97–3.81 (m, 1H), 3.56 (s, 3H), 2.56–2. 51(m,1H),1.92–1.81(m,2H),1.69–1.55(m,3H),1.49–1.42(m,1H),1.37–1.35(m,9H).

[0081] The second step is to prepare methyl (1R, 2R)-2-aminocyclopentane-1-carboxylate:

[0082] Methyl (1R,2R)-2-(tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate (1 g, 4.1 mmol, 1.0 eq) was added to a flask, 15 mL of DCM was added, and 5 mL of TFA (trifluoroacetic acid) was added with stirring at room temperature. The reaction was continued at this temperature and monitored by TLC. The reaction was complete after 2 h. Aqueous NaHCO₃ solution was slowly added to adjust the pH to 7-8. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness to obtain the crude product, which was a white solid (0.4 g, 68.0% yield) without further purification. MS m / z (ESI): 144.1 [M+H].

[0083] Step 3: Preparation of methyl (1R,2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylate: 5,6,7,8-Tetrahydronaphthalene-2-carboxylic acid (0.4 g, 2.3 mmol, 1.0 eq) was added to a flask and dissolved in 10 mL of DCM. Methyl (1R,2R)-2-aminocyclopentane-1-carboxylate (0.33 g, 2.3 mmol, 1.0 eq) and HATU (1.0 g, 2.76 mmol, 1.2 eq) were then added sequentially. TEA (0.7 g, 6.9 mmol, 3.0 eq) was then added with stirring at room temperature. The reaction was continued at room temperature and monitored by TLC. The reaction was complete after 4 hours. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was isolated by column chromatography as a white solid (0.6 g, 86.3% yield). 1H NMR(600MHz,Chloroform-d)δ7.45(s,1H),7.43(d,J=7.7,2.0Hz,1H),7.09(d,J=7.8Hz,1H),6.14(d,J=7.1Hz,1H),4.58–4.48(m,1H ),3.70(s,3H),2.74(q,J=8.3Hz,1H),2.30–2.23(m,1H),2.10–2.02(m,1H),1.98–1.92(m,1H),1.85–1.74(m,7H),1.68–1.56(m,3H).

[0084] The fourth step is to prepare (1R, 2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylic acid:

[0085] Methyl (1R,2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylate (0.5 g, 1.7 mmol, 1.0 eq) was dissolved in 5 mL of THF (tetrahydrofuran) and 5 mL of water. LiOH (122.4 mg, 5.1 mmol, 3.0 eq) was added and stirred at room temperature. The reaction was complete after 4 h, monitored by TLC. The reaction was stopped, the pH was adjusted to 6-7 with dilute hydrochloric acid, and DCM was added. The aqueous phase was extracted three times. The combined DCM layers were evaporated to dryness to afford Intermediate 13 as a white solid (323.5 mg, 67.8% yield). 1H NMR(600MHz,DMSO-d6)δ12.18(s,1H),8.35(d,J=7.6Hz,1H),7.59–7.49(m,2H),7.11(d,J=7.8Hz,1 H),4.49–4.36(m,1H),2.80–2.64(m,5H),2.00–1.92(m,2H),1.77–1.66(m,6H),1.66–1.50(m,2H). MSm / z(ESI):288.2[M+H].

[0086] Example 4 Preparation of (R)-4-oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butanoic acid (Intermediate 14)

[0087]

[0088] The first step is to prepare (R)-4-oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butanoic acid methyl ester:

[0089] (R)-1,2,3,4-Tetrahydronaphthalen-1-amine (1 g, 6.8 mmol, 1.0 eq) was added to a flask, 20 mL of DCM was added, and the mixture was stirred to dissolve. 4-Methoxy-4-oxobutanoic acid (0.9 g, 6.8 mmol, 1.0 eq) and HATU (3.1 g, 8.16 mmol, 1.2 eq) were then added sequentially. TEA (triethylamine) (2.1 g, 20.4 mmol, 3.0 eq) was then added with stirring at room temperature. The reaction was continued at room temperature and monitored by TLC. After 4 hours, the reaction was complete. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was isolated by column chromatography as a white solid (1.5 g, 84.3% yield). 1H NMR (600 MHz, DMSO-d6) δ 8.24 (d, J = 8.6 Hz, 1H), 7.17–7.11 (m, 3H), 7.10–7.05 (m, 1H), 4.95 (q, J = 8.1, 4.4 Hz, 1H), 3.59 (s, 3H), 2.77–2.65 (m, 2H), 2.59–2.53 (m, 2H), 2.48–2.33 (m, 2H), 1.88–1.84 (m, 2H), 1.75–1.55 (m, 2H). Step 2: Preparation of (R)-4-oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butanoic acid:

[0090] To a solution of methyl (R)-4-oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butanoate (1.0 g, 3.8 mmol, 1.0 eq) in 10 mL of THF (tetrahydrofuran) and 10 mL of water, was added LiOH (273.6 mg, 5.1 mmol, 3.0 eq). The mixture was stirred at room temperature and monitored by TLC. The reaction was complete after 4 h. The reaction was stopped, the pH was adjusted to 6-7 with dilute hydrochloric acid, and DCM was added. The aqueous phase was extracted three times. The combined DCM layers were evaporated to dryness to afford Intermediate 14 as a white solid (810.2 mg, 85.6% yield). MS m / z (ESI): 248.1 [M+H].

[0091] Example 5 Preparation of (R)-N-(2-methyl-4-oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butan-2-yl)-4-(trifluoromethoxy)benzamide (Compound 1)

[0092]

[0093] (R)-3-Amino-3-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)butanamide (Intermediate 6) (50 mg, 0.2 mmol, 1.0 eq) was added to a flask, 5 mL of DCM was added, and the mixture was stirred to dissolve. 4-(Trifluoromethoxy)benzoic acid (41 mg, 0.2 mmol, 1.0 eq) and HATU (91 mg, 0.24 mmol, 1.2 eq) were then added sequentially. With stirring at room temperature, TEA (triethylamine) (61 mg, 0.6 mmol, 3.0 eq) was added. The reaction was continued at room temperature and monitored by TLC. After 4 h, the reaction was complete. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was purified by evaporation with EA to obtain a white solid (53 mg, 60.0% yield). 1H NMR (600MHz, CDCl3) δ7.91(s,1H),7.81(d,J=8.0Hz,2H),7.23(d,J=8.3Hz,2H),7.21–7.12(m,2H),7.09–7.02(m,2H),6.23(d,J=8.5Hz ,1H),5.17(q,J=7.3Hz,1H),2.76–2.69(m,2H),2.62–2.47(m,2H),1.83–1.73(m,4H),1.57(d,J=8.7Hz,6H).MSm / z(ESI):436.2[M+H].

[0094] Example 6 Preparation of Compound 2-31

[0095] Compound 2-31 was obtained using alkylamines containing different substituents and carboxylic acids as raw materials using a method similar to that described in Example 5.

[0096] Table 2 Structural formula of compound 2-31

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104] Example 7 Preparation of N-((1R,2R)-2-(cyclohexylcarbamoyl)cyclopentyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 32)

[0105]

[0106] (1R,2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylic acid (Intermediate 13) (60 mg, 0.21 mmol, 1.0 eq) was added to a flask, 5 mL of DCM was added, and the mixture was stirred to dissolve. Cyclohexylamine (21 mg, 0.21 mmol, 1.0 eq) and HATU (95 mg, 0.25 mmol, 1.2 eq) were then added in sequence. TEA (triethylamine) (64 mg, 0.63 mmol, 3.0 eq) was then added while stirring at room temperature. The reaction was continued at room temperature and monitored by TLC. The reaction was complete after 4 h. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the target product was purified by slurrying with EA to obtain a white solid (57 mg, 74% yield). NMR (600MHz, DMSO-d6) δ8.14(d,J=7.6Hz,1H),7.63(d,J=8.0Hz,1H),7.53(d,J=7.6H z,2H),7.11(d,J=8.2Hz,1H),4.29(p,J=7.6Hz,1H),3.50(q,J=14.3,5.2,4.0Hz,1H) ,2.74(d,J=6.0Hz,4H),2.60(q,J=7.8Hz,1H),1.99–1.90(m,1H),1.87–1.78(m,1H), 1.77–1.47(m,13H),1.27–1.17(m,2H),1.15–1.04(m,3H).MSm / z(ESI):369.3[M+H].

[0107] Example 8 Preparation of Compounds 33-39

[0108] Compounds 33-39 were obtained using amines containing different substituents and (1R, 2R)-2-(5,6,7,8-tetrahydronaphthalene-2-carboxamido)cyclopentane-1-carboxylic acid as starting materials using a method similar to that described in Example 7.

[0109] Table 3 Structural formulas of compounds 33-39

[0110]

[0111]

[0112]

[0113] Example 9 Preparation of (1R,2R)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(3-(4-(trifluoromethyl)phenyl)ureido)cyclopentane-1-carboxamide (Compound 40)

[0114]

[0115] (1R,2R)-2-amino-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)cyclopentane-1-carboxamide (Intermediate 1) (300 mg, 1.16 mmol, 1.0 eq) was placed in a flask, 10 mL of DCM was added, stirred and dissolved, cooled to 0 degrees, and 1-isocyanato-4-(trifluoromethyl)benzene (230 mg, 1.27 mmol, 1.1 eq) was slowly added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and the reaction continued. TLC monitoring showed that the reaction was complete after 4 hours. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The DCM layers were combined and evaporated to dryness. The target product was slurried with EA to obtain a white solid (376 mg, yield 73%). NMR(400MHz, DMSO-d6)δ8.76(s,1H),8.17(d,J=8.6Hz,1H),7.66–7.53(m,4H),7.1 9(d,J=7.9Hz,1H),7.03(d,J=4.0Hz,2H),6.81(s,1H),6.33(d,J=8.2Hz,1H),4.95 (q,J=6.8,5.9Hz,1H),4.31–4.16(m,1H),2.78–2.61(m,2H),2.50(t,J=4.3,2.3Hz ,1H),2.03–1.93(m,1H),1.90–1.82(m,3H),1.78–1.60(m,5H),1.52–1.39(m,1H). MSm / z(ESI):248.1[M+H]. MSm / z(ESI):446.2[M+H].

[0116] Example 10 Preparation of N-((1R,2R)-2-(cyclohexylcarbamoyl)cyclopentyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound 41)

[0117]

[0118] (R)-4-Oxo-4-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)butanoic acid (Intermediate 14) (50 mg, 0.2 mmol, 1.0 eq) was added to a flask, 5 mL of DCM was added, and the mixture was stirred to dissolve. 4-(Trifluoromethoxy)aniline (36 mg, 0.2 mmol, 1.0 eq) and HATU (91 mg, 0.24 mmol, 1.2 eq) were then added sequentially. TEA (triethylamine) (61 mg, 0.6 mmol, 3.0 eq) was then added with stirring at room temperature. The reaction was continued at room temperature and monitored by TLC. After 4 h, the reaction was complete. The reaction was stopped and quenched with water. The aqueous layer was extracted three times with DCM. The combined DCM layers were evaporated to dryness, and the desired product was purified by evaporation with EA to obtain a white solid (52 mg, 63% yield). 1HNMR (600MHz, DMSO-d6) δ10.17(s,1H),8.26(d,J=8.8Hz,1H),7.71(d,J=9.0Hz,2H),7.31(d,J=8.9Hz,2H),7.16–7.10(m,2H),7. 09–7.05(m,2H),5.03–4.89(m,1H),2.77–2.69(m,2H),2.65–2.57(m,2H),2.49–2.41(m,2H),1.92–1.81(m,2H),1.75–1.59(m,2H). MSm / z(ESI):407.2[M+H].

[0119] Example 11

[0120] DHODH enzyme activity inhibition assay

[0121] The activity of the compounds was tested using a recombinant DHODH protein from barnyardgrass, the amino acid sequence of which is as follows:

[0122] PKKVPPPPRKGRLLTGALIGLAIGGGAYVSTADEARFCFSHYLAVKAAAHGFVPREKRPDPAVLGLEIWGRKFANPIGLAAGFDKNAEAVEGLLGMGFGFVEVGSVTPLPQEGNPKPRVFRLREHGAVINRYGFNSEGIVVVAKRLGAQHGKRKMEETSSSTPPSTSDVKQGGKAGPGILGVNLGKNKTSEDAAADYVQGV HTLSQYADYLVINISSPNTPGLRKLQGRKQLKDLVKKVQAARDEMQWAEDGPPPLLVKIAPDLSKQDLEDIAAVALALRLDGLIISNTTVSRPPPADTHPLAQETGGLSGKPLFDLSTNILREMYILTRGKIPLIGCGGVSSGEDAYKKIRSGATLVQLYTALAYGGPALIPRIKAELAECLERDGFKSVQEAVGADFSFV.

[0123] The 2,6-dichlorophenol blue (DCIP) colorimetric method is used to test the inhibitory activity of compounds against DHODH. The specific principle is that the oxidation of dihydroguanine (DHO, the reaction substrate) is proportional to the reduction of coenzyme Q10 and DCIP. The change in absorbance at 600nm reflects the degree of DCIP reduction, which is correlated with the enzyme activity of DHODH. The specific experimental method is as follows:

[0124] Reagent preparation:

[0125] Coenzyme Q10 was dissolved in DMF to a stock solution concentration of 10 mM and stored at -20°C in the dark.

[0126] DCIP was dissolved in distilled water to a stock concentration of 10 mM and stored at 4°C.

[0127] DHO was dissolved in distilled water to a stock concentration of 10 mM and stored at 4°C.

[0128] Tris buffer: The enzyme activity test buffer system is 100 mM Tris with 0.1% Triton X-100 (pH 8.0). The concentration of Tris stock solution is 1 M, and the concentration of Triton X-100 stock solution is 1%. Store at 4°C.

[0129] Experimental steps:

[0130] Take out Tris buffer, DCIP, DHO and coenzyme Q10 from 4℃ and -20℃ in advance (Q10 has extremely low solubility at low temperatures and needs to be completely dissolved at 26℃ in the dark before use), and add different components in sequence according to the following system:

[0131] Table 4 Reaction system

[0132]

[0133] 10 μL of inhibitor (compound) was added to the above 180 μL solution and incubated for 10 min. Then 10 μL of DHO reaction substrate was added to a final volume of 200 μL. The reaction started and the activity of the compound was determined using a microplate reader.

[0134] Table 5 Activity data of each compound

[0135]

[0136] It can be seen that the compound of the present invention has good DHODH inhibitory activity and can be well utilized in weed control.

[0137] Example 12

[0138] Herbicidal activity

[0139] DHODH herbicides are systemic herbicides that can be added to the barrel where plants are grown to inhibit plant growth.

[0140] 25 mg of the compound was dissolved in 6 mL of water to prepare a herbicide solution. The field application rate of tetrafluthrin was 125 g / ha, i.e. 12.5 mg / m 2 , the herbicide solution and the tetrafluthion solution were applied to the soil in the bucket where the plants were cultured, respectively.

[0141] The structure of tetrafluthion is as follows:

[0142]

[0143] Each experimental group took the seeds of wild hexaploid barnyard grass in the field that had sprouted and grown young shoots and moved them into a small white bucket with a diameter of 9 cm. 15 germinated seeds were transplanted into each bucket, and watering was done regularly every day to keep the soil moist. The seeds were placed in a 26°C plant incubator. When the barnyard grass grew to about 1 week old, barnyard grass with basically the same growth height and morphology were selected for the experiment, and 190 μL of herbicide solution was added to each of them. The seeds were cultured in a 26°C plant incubator for 7-14 days, and watering was done regularly every day to keep the soil moist. The results of the 7-day culture are as follows: Figure 1As shown. Compared with the control, tetrafluthria inhibits the growth of barnyard grass relative to the control, so its growth height is significantly lower than that of other groups. The compound of the present invention accelerates the withering and yellowing of barnyard grass and promotes the death of barnyard grass. And with the increase of concentration, the withering effect becomes more obvious. The figure only provides the results of compound 31 cultured for 7 days. When cultured for 14 days, 70-90% of the stems and leaves of barnyard grass have turned yellow. At the same time, experiments have shown that the effects of compounds 3, 8, 15, 18-19, 21-30, 35-36, and 39 of the present invention are also close to the results of compound 31, and can effectively promote the death of barnyard grass.

[0144] It should be noted that the above embodiments are merely examples for the purpose of clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. A person skilled in the art would be able to make other variations or modifications based on the above description. It is not possible to enumerate all embodiments here. Any obvious variations or modifications arising from the technical solution of the present invention remain within the scope of protection of the present invention.

Claims

1. A DHODH inhibitor, characterized in that It is a compound represented by formula I or its isomer, salt, solvate or crystal form: Wherein, R1 is selected from substituted tetrahydronaphthyl, C3-C8 cycloalkyl, phenyl, biphenyl, tetrahydronaphthyl, benzocycloheptyl, benzocyclopentyl, substituted C3-C8 cycloalkyl, Cyclohexylpyridinyl; R2 is selected from C1-C8 straight chain, branched chain alkylene or its isomers, C3-C8 cycloalkyl; R3 is selected from substituted phenyl, biphenyl, benzocyclohexyl, tetrahydronaphthyl, benzocyclopentyl, benzopiperidinyl; The substituents on the substituted phenyl group are selected from halogenated C1-C6 alkoxy, substituted C1-C8 straight or branched alkylene, substituted C1-C8 straight or branched alkyl, halogen, C1-C8 straight or branched alkylene, C1-C8 straight or branched alkyl; The substituent on the substituted C1-C8 straight chain branched alkylene, or substituted C1-C8 straight chain or branched alkyl is halogen; The substituent on the substituted C3-C8 cycloalkyl group is a C1-C8 straight or branched chain alkylene group; The substituent on the substituted tetrahydronaphthyl group is halogen.

2. The DHODH inhibitor according to claim 1, characterized in that R2 is selected from C1-C5 straight or branched alkylene groups; the number of substituents on the substituted phenyl group is 1-5.

3. The DHODH inhibitor according to claim 1, characterized in that R1 is selected from Cyclohexyl, R2 is selected from 4. The DHODH inhibitor according to claim 1, characterized in that R3 is selected from 5. The DHODH inhibitor according to claim 1, characterized in that It is a compound represented by formula II or its isomer, salt, solvate or crystal form: Wherein, R4 and R5 are independently selected from hydrogen, C1-C8 straight or branched chain alkyl, halogen; R6 is selected from C1-C8 straight or branched alkylene, X is selected from -NHCO-, -CONH-; R7 is selected from the group consisting of: halogenated C1-C6 alkoxy, substituted C1-C8 straight or branched chain alkyl, halogen, C1-C8 straight or branched chain alkyl; The substituent on the substituted C1-C8 linear or branched alkyl group is halogen.

6. The DHODH inhibitor according to claim 1, characterized in that R6 is selected from ethylene, isopropylene, n-butylene, sec-butylene, isobutylene and tert-butylene.

7. The DHODH inhibitor according to any one of claims 1 to 6, characterized in that The DHODH inhibitor is the following compound or its isomer, salt, solvate or crystal form:

8. The method for preparing a DHODH inhibitor according to claim 1, wherein: The following steps are involved: S1, raw material 1 is prepared to obtain intermediate 1; S2, intermediate 1 and carboxylic acid react to obtain the DHODH inhibitor; 9. The use of the DHODH inhibitor according to claim 1, characterized in that The DHODH inhibitor is used for preparing herbicides.

10. A herbicide, characterized in that The herbicide comprises the DHODH inhibitor according to claim 1.

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