fungicidal arylamidines

Abstract

This disclosure relates to arylamidines of formula I and their use as fungicides. [Formula 1] JPEG2026520849000049.jpg30170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 501465, filed on 11 May 2023, the entire disclosure of which is expressly incorporated herein by reference. [Background technology]

[0002] Fungicides are naturally occurring or synthetic compounds that act to protect and / or treat plants from damage caused by agronomically relevant fungi. Generally, there is no single fungicide that is effective in all situations. Consequently, research is underway to develop fungicides that can have superior performance (e.g., higher efficacy with lower dosages), are easy to use, and are less expensive. [Overview of the project]

[0003] This disclosure relates to arylamidines and their use as fungicides. This disclosure also relates to methods for preparing these compounds, agricultural compositions containing them, and their use in the treatment and control of fungal diseases or disorders in agriculture.

[0004] International Publication No. 2020 / 237131A1 (hereinafter referred to as "Application 131") describes a series of fungicidal compounds. The three specific compounds disclosed in Application 131 are 3-(trifluoromethyl)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Example 25), 4-(trifluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Example 27), and 3-(trifluoromethyl)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Example 494). Their structures are shown below. [ka]

[0005] The compounds described in application 131 demonstrated activity against one or more agricultural fungi, including wheat septria leaf blight caused by Zymoseptoria tritici, wheat red rust caused by Puccinia triticina, Asian soybean rust caused by Phakopsora pachyrhizi, barley leaf blight caused by Rhynchosporium secalis, and barley leaf spot caused by Cochliobolus sativus.

[0006] Septoria leaf spot of wheat caused by Zymoseptoria tritici, net leaf spot of barley caused by Pyrenophora teres, Ramularia leaf spot of barley caused by Ramularia collo-cygni, leaf spot of barley caused by Rhynchosporium secalis, sugar beet brown spot caused by Cercospora beticola, anthracnose of cucurbits caused by Colletotrichum orbiculare, rice blast caused by Magnaporthe oryzae, and Puccinia fordei There is still a need for antifungal compounds that exhibit an improved fungicidal spectrum and increased fungicidal activity at lower doses, such as activity against barley rust disease caused by *Hordei*.

[0007] Therefore, an object of the present disclosure is to provide a compound that addresses one or more of the above needs.

[0008] In one embodiment, the present disclosure provides a compound of formula I:

Chemical formula

[0009] In another embodiment, the present disclosure provides a compound of formula I, and acceptable salts of formula I include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, formate, citrate, maleate, oxalate, tartrate, fumarate, benzenesulfonate, p-toluenesulfonate, succinate, methanesulfonate, L-malate, acetate, benzoate, or 4-hydroxybenzoate.

[0010] In another embodiment, the present disclosure provides a compound of formula I wherein the acceptable salt is a hydrochloride (formula I-B):

Chemical formula

[0011] In another embodiment, the present disclosure provides an agricultural composition comprising a compound of formula I as defined herein, or an acceptable salt, solvate, or hydrate thereof, and one or more botanically acceptable carrier materials.

[0012] In another embodiment, the present disclosure provides a compound of formula I as defined herein, or an acceptable salt, solvate, or hydrate thereof, or an agricultural composition as defined herein, for use in the treatment or prevention of fungal diseases or disorders in or on plants.

[0013] Yet another embodiment of the present disclosure is a method for controlling or preventing fungal attack on plants, which may include the step of applying one of the above compounds in a fungicidal effective amount to at least one fungus, seed, plant, and the area adjacent to the plant.

[0014] Another embodiment of the present disclosure is a method for suppressing or preventing fungal attack on plants, which may include the step of applying one of the above compounds in a fungicidal effective amount to a growth medium suitable for growing the plant or seed.

[0015] Another embodiment of the present disclosure is the use of a compound of formula I as defined herein, or an acceptable salt, solvate, or hydrate thereof, or a composition containing the compound, for protecting a plant from attack by phytopathogenic organisms or for treating a plant parasitized by phytopathogenic organisms, which comprises applying to soil, a plant, a part of a plant, leaves, and / or roots.

[0016] In addition, another embodiment of the present disclosure is a composition useful for protecting a plant from attack by phytopathogenic organisms and / or treating a plant parasitized by phytopathogenic organisms, which comprises a compound of formula I and a botanically acceptable carrier material.

[0017] The present disclosure further provides a method for synthesizing a compound of formula I as defined herein, or an acceptable salt, solvate, or hydrate thereof.

[0018] In another embodiment, the present disclosure provides a compound of formula I, or an acceptable salt, solvate, or hydrate thereof, which can be obtained, or is obtained, or is directly obtained by the synthetic method defined herein.

[0019] Similar to the compound in the '131 application, this compound is active against one or more agricultural fungi, including tomato ring spot caused by Alternaria solani, gray mold caused by Botrytis cinerea, cucumber powdery mildew caused by Podosphaera xanthii, Cercospora leaf spot caused by Cercospora kikuchii, soybean brown ring spot caused by Corynespora cassiicola, soybean spot caused by Septoria glycines, and wheat rust caused by Puccinia triticina.

[0020] The terms "ambient temperature" and "room temperature" refer to temperatures in the range of approximately 20°C to 24°C.

[0021] The terms "botanically acceptable carrier," "botanically acceptable carrier material," "agriculturally acceptable carrier," or "agriculturally acceptable carrier material" refer to carriers or excipients that are useful in the preparation of agricultural compositions and generally do not exhibit phytotoxicity to valuable crops.

[0022] The term "crystalline" refers to a solid state in which molecules are arranged to form a crystalline lattice containing recognizable unit cells. Specific crystalline states can be identified by specific diffraction peaks when irradiated with X-rays.

[0023] Throughout this disclosure, the ratio of solvent molecules to the compound of formula I or its acceptable salt in the solvate of formula I or its acceptable salt may be, but is not limited to, 1:2, 1:1, or 2:1.

[0024] Throughout this disclosure, the ratio of water molecules to the compound of formula I or its acceptable salt or solvate in the hydrate of formula I or its acceptable salt or solvate may be, but not limited to, 1:2 (hemihydrate), 1:1 (monohydrate), or 2:1 (dihydrate).

[0025] Throughout this disclosure, any reference to a compound of formula I or any compound of formula I shall be construed to include any acceptable salts, solvates, or hydrates thereof, unless otherwise indicated herein or unless clearly inconsistent with the context.

[0026] Throughout this disclosure, any reference to a compound or a compound of formula I is to include all positional isomers, structural isomers, geometric isomers, rotational isomers, tautomers, and stereoisomers, such as diastereomers, enantiomers, and mixtures thereof.

[0027] The compounds of this disclosure may also include bonds whose rotation is restricted around a particular bond, such as bonds restricted due to the presence of a ring or double bond (e.g., carbon-carbon bonds). Accordingly, all cis / trans and E / Z isomers are expressly included in this disclosure.

[0028] The compounds of this disclosure may exist in multiple tautomer forms. If one or more tautomers exist, this disclosure expressly includes all such tautomer forms of the compounds described herein, even if only a single tautomer form is shown.

[0029] The compounds of this disclosure may exist in the form of an amorphous solid or as an oil.

[0030] The compounds of this disclosure may exist in one or more crystalline or polymorphic forms. All crystalline and polymorphic forms of the compounds of this disclosure are expressly included in this disclosure.

[0031] In one embodiment, the present disclosure provides a crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula I).

[0032] In another embodiment, the crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula I) is an anhydrous and solvent-free crystalline polymorph.

[0033] In another embodiment, the crystalline form is crystalline polymorph A of formula I (hereinafter referred to as morph A).

[0034] In another embodiment, the present disclosure provides one or more crystalline forms of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB).

[0035] In another embodiment, one or more crystalline forms are crystalline polymorphs 1, 2, and 3 of formula IB (referred to herein as form 1, form 2, and form 3, respectively).

[0036] In another embodiment, crystalline polymorph 1 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) is a crystalline polymorph that is hemihydrate.

[0037] In another embodiment, crystalline polymorphs 2 and 3 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) are anhydrous and solvent-free crystalline polymorphs. [Brief explanation of the drawing]

[0038] [Figure 1]This graph summarizes the biological effectiveness of Zymoseptoria tritici against Septoria leaf blight in greenhouse experiments. [Figure 2] This graph shows the biological effectiveness against Septoria leaf blight caused by Zymoseptoria tritici in cross-test analysis of repeated field trials at three geographical locations. [Figure 3] This graph shows the biological effectiveness of Pyrenophora teres against barley net spot disease in cross-test analysis of repeated field trials at three geographical locations. [Figure 4] This graph shows the biological effectiveness of Ramularia collo-cygni against Ramularia leaf spot disease in barley in a cross-test analysis of repeated field trials at three geographical locations. [Figure 5] This graph shows the biological effectiveness of Rhynchosporium secalis against barley leaf blight in a cross-test analysis of repeated field trials at three geographical locations. [Figure 6] This graph shows the biological effectiveness of Puccinia hordei against barley rust disease in cross-sectional analysis of repeated field trials in three geographical regions. [Figure 7] The powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I), Form A (solvent-free, anhydrous) prepared in Example 12 of this disclosure is shown. [Figure 8] The powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), form 1 (hemihydrate) prepared in Example 17 of this disclosure is shown. [Figure 9] The powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), form 2 (solvent-free, anhydrous) prepared in Example 19 of this disclosure is shown. [Figure 10] The powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, solvent-free, anhydrous), form 3, prepared in Example 24 of this disclosure is shown. [Modes for carrying out the invention]

[0039] The compounds of this disclosure may be applied by any of the various known techniques, either as compounds or formulations containing the compounds. For example, the compounds may be applied to the roots or leaves of plants to control a variety of fungi without impairing the commercial value of the plants. The materials may be applied in any of the commonly used formulation forms, such as liquids, powders, wettable powders, flowables, or emulsions.

[0040] Preferably, the compounds of this disclosure are applied in the form of a formulation containing one compound of formula I together with a botanically acceptable carrier. The concentrated formulation may be dispersed in water or other liquid for application, or the formulation may be in the form of a powder or granules, which can then be applied by the end user or the like. The formulation can be prepared according to procedures commonly used in agrochemical technology.

[0041] This disclosure assumes all vehicles in which a single compound may be formulated for delivery and use as an antifungal agent. Typically, the formulation is administered as an aqueous suspension or emulsion. Such suspensions or emulsions may be prepared from water-soluble, water-suspended, or emulsifying formulations, which are solids commonly known as wettable powders; or from liquids commonly known as emulsions, aqueous suspensions, or suspensions. As is readily apparent, the compounds of this disclosure may be added to any material insofar as the desired utility is obtained without significantly impairing the antifungal activity of the compounds of this disclosure.

[0042] A wettable powder that can be compressed to form a water-dispersible granule comprises a well-mixed mixture of one compound of formula I, an inert carrier, and an optional additive such as a surfactant. The concentration of the compound of formula I in the wettable powder may be about 10% to about 90% by weight, more preferably about 25% to about 75% by weight, based on the total weight of the wettable powder. In the preparation of the wettable powder formulation, the compound of formula I may be mixed with any fine solid carrier such as pyrophyllite, talc, chalk, gypsum, fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clay, diatomaceous earth, or refined silicate. In such an operation, the fine carrier and other optional additives are typically blended with the compound of formula I and ground.

[0043] The emulsion contains an active ingredient, such as a compound of formula I dissolved in an inert carrier, the inert carrier being a water-miscible solvent or a mixture of a water-immiscible organic solvent and an emulsifier. The emulsion may contain a convenient concentration of the compound of formula I, such as about 1% to about 50% by weight, based on the total weight of the emulsion. The emulsion may be diluted with water to form a spray mixture in the form of an oil-in-water emulsion. Other components, including but not limited to surfactants, auxiliaries, oils, defoamers, and stabilizers, may be added to the emulsion or mixed with the emulsion during dilution to form a spray mixture.

[0044] Emulsifiers that can be advantageously used herein can be readily determined by those skilled in the art and include various nonionic emulsifiers, anionic emulsifiers, cationic emulsifiers, and amphoteric emulsifiers, or blends of two or more emulsifiers. Examples of nonionic emulsifiers useful for the preparation of emulsions include polyalkylene glycol ethers, alkyl and arylphenols, aliphatic alcohols, condensates of aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as ethoxylated alkylphenols, and carboxylic acid esters solubilized with polyols or polyoxyalkylenes. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include oil-soluble salts (e.g., calcium) or oil-soluble salts of alkylarylsulfonic acids, or sulfated polyglycol ethers and suitable salts of phosphorylated polyglycol ethers.

[0045] Typical organic liquids that can be used to prepare emulsions of the compounds of this disclosure include aromatic liquids such as xylene, propylbenzene fraction, or mixed naphthalene fraction; substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkylamides of various fatty acids, especially dimethylamides of fatty glycols, and glycol derivatives such as diethylene glycol n-butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, and triethylene glycol methyl ether; petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, and paraffin oil; terpene solvents including rosin derivatives; aliphatic ketones such as cyclohexanone; complex alcohols such as 2-ethoxyethanol; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, and tuni oil; and esters of the above vegetable oils. A mixture of two or more organic liquids may also be used to prepare the emulsion. Examples of organic liquids include xylene and propylbenzene fractions, with xylene being the most preferred in some cases. Surface-active dispersants are typically used in liquid formulations and are used in amounts of 0.1 to 20 weight percent, based on the combined weight of the dispersant with one or more compounds. The formulations may also contain other suitable additives, such as plant growth regulators and other biologically active compounds used in agriculture.

[0046] The aqueous suspension contains a fine solid or powder of a water-insoluble active ingredient, such as the compound of formula I, dispersed in an aqueous carrier at a concentration ranging from about 1 to about 50 weight percent, based on the total weight of the aqueous suspension. The suspension is prepared by finely grinding the compound and vigorously mixing the ground material in a carrier containing water and a surfactant selected from the same types as those previously considered. In addition, inorganic salts and other components such as synthetic rubber or natural rubber may be added to increase the density and viscosity of the aqueous carrier.

[0047] The compound of formula I can also be applied as a granular formulation, which is particularly useful for application to soil. The granular formulation generally contains, based on the total weight of the granular formulation, about 0.5 to about 10 weight percent of the active ingredient, dispersed in an inert solid carrier consisting entirely or largely of coarsely divided inert material such as attapulgite, bentonite, diatomaceous earth, clay, or similar inexpensive material. Such formulations can be prepared by dissolving the compound in a suitable solvent and applying it to a solid carrier pre-formed to a suitable particle size, for example, in the range of about 0.5 to about 3 millimeters (mm). A suitable solvent is one in which the compound is substantially or completely soluble. Alternatively, such formulations may be prepared by producing a lump or paste of the carrier and compound with the solvent, crushing and drying them to obtain the desired granular particles. Such formulations can also be prepared by producing a lump or paste of the carrier and compound with the solvent, and then extruding the lump or paste to form granules of the formulation.

[0048] A powder containing the compound of formula I can be prepared by thoroughly mixing one compound in powder form with a suitable powdered agricultural carrier, such as kaolin clay or crushed volcanic rock. The powder may appropriately contain about 1 to about 10 weight percent of the compound based on the total weight of the powder.

[0049] The formulation may contain additional auxiliary surfactants to enhance the deposition, wetting, and penetration of the compound onto target crops and organisms. These auxiliary surfactants may, in some cases, be used as components of the formulation or as part of the tank mix. The amount of auxiliary surfactant typically varies from 0.01 to 1.0 volume percent, preferably 0.05 to 0.5 volume percent, based on the amount of water sprayed. Suitable auxiliary surfactants include ethoxylated nonylphenol, ethoxylated synthetic or natural alcohols, salts or esters of sulfosuccinates, ethoxylated organosilicones, ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrates (mineral oil (85%) + emulsifier (15%)); nonylphenol ethoxylate; benzyl cocoalkyldimethyl quaternary ammonium salts; blends of petroleum hydrocarbons, alkyl esters, organic acids, and anionic surfactants; C9-C 11 Alkyl polyglycosides; phosphorylated alcohol ethoxylates; natural primary alcohols (C 12 ~C 16 Examples of formulations include, but are not limited to, ethoxylates; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap; nonylphenol ethoxylate + urea ammonium nitrate; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); tallow amine ethoxylate (15EO); and PEG(400) dioleate-99. Other formulations may include oil-in-water emulsions, such as those disclosed in U.S. Patent Application Publication No. 11 / 495,228, which are expressly incorporated herein by reference.

[0050] Another embodiment of the present disclosure is a method for controlling or preventing fungal attacks. This method comprises applying a fungicidal amount of one compound of formula I to soil, plants, roots, leaves, or the location where fungi are present or where their spread should be prevented (e.g., to cereal or grape plants). The compounds are suitable for treating various plants at fungicidal levels while exhibiting low phytotoxicity. The compounds may be useful in the form of both a protective agent and / or an eradicator.

[0051] Compounds of formula I have been found to have significant fungicidal effects, particularly for agricultural applications. Many of these compounds are especially effective for use on crops and horticultural plants.

[0052] The efficacy of the aforementioned compounds against fungi will be understood by those skilled in the art to establish the general usefulness of the compounds as fungicides.

[0053] Compounds of formula I exhibit broad activity against fungal pathogens. Exemplary pathogens include, but are not limited to, wheat septoria leaf spot (Zymoseptoria tritici), barley leaf spot (Cochliobolus sativus), wheat red rust (Puccinia triticina), wheat yellow rust (Puccinia striiformis), maize blister smut (Ustilago maydis), grape powdery mildew (Uncinula necator), barley leaf spot (Rhynchosporium secalis), and rice blast (Magnaporte oryzae). oryzae), Asian soybean rust (Phakopsora pachyrhizi), wheat blight (Parastagonospora nodorum), cucurbit anthracnose (Colletotrichum orbiculare), barley red rust (Puccinia hordei), sugar beet brown spot (Cercospora beticola), tomato ring spot (Alternaria solani), barley net spot (Pyrenophora teres), wheat powdery mildew (Blumeria graminis f.sp. tritisi) (f.sp. tritici), Barley Powdery Mildew (Blumeria graminis f.sp. hordei)Powdery mildew of cucurbitaceous plants (Erysiphe cichoracearum), cucumber powdery mildew (Podosphaera xanthii), neck rot or damping-off of seedlings (Rhizoctonia solani), gray mold (Botrytis cinerea), Ramularia leaf spot (Ramularia collo-cygni), wheat yellow spot (Pyrenophora tritici-repentis), maize sooty spot (Exserohilum turcicum), maize southern rust (Puccinia polysola) Examples of pathogens include polysora), white mold (Sclerotinia sclerotiorum), soybean powdery mildew (Erysiphe diffusa), apple powdery mildew (Podosphaera leucotricha), soybean anthracnose (Colletotrichum truncatum), Cercospora black leaf blight (Cercospora kikuchii), bell pepper spot disease (Cercospora sojina), soybean brown spot disease (Corynespora cassiicola), and soybean spot disease (Septoria glycines). The precise amount of active material applied depends not only on the specific active material being applied, but also on the desired action, the species of fungus being controlled, its growth stage, and the part of the plant or other product in contact with the active material. Therefore, compounds and formulations containing them may not all be equally effective at similar concentrations or against the same fungal species.

[0054] The compound of formula I is effective for use on plants in amounts that suppress disease and are botanically acceptable. The terms "disease-suppressing amount" or "botanically acceptable amount" refer to the amount of compound that kills or suppresses the disease of the plant to be controlled, but does not have significant toxicity to the plant. This amount is generally about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of the compound required will vary depending on the fungal disease to be controlled, the type of formulation used, the application method, the specific plant species, climatic conditions, etc. Appropriate application rates are typically about 0.10 to about 4 pounds / acre (about 0.01 to 0.45 grams per square meter, g / m²). 2 It is within the range of ).

[0055] The crystalline forms disclosed herein can be prepared using various solvents and solvent mixtures from the classification of solvents, such as alcohols, ketones, esters, ethers, hydrocarbons, polar aprotic solvents, and water. For example, crystalline form A of formula I can be prepared using ethyl acetate. For example, crystalline form 1 of formula IB can be prepared using various solvents, but are not limited to toluene, ethanol, isopropyl alcohol, dichloromethane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, heptane, chloroform, acetonitrile, acetone, methyl tert-butyl ether, and mixtures thereof. For example, crystalline form 2 of formula IB can be prepared using various solvents, but are not limited to toluene, methyl isobutyl ketone, methyl ethyl ketone, heptane, 2-methyltetrahydrofuran, methyl tert-butyl ether, and mixtures thereof. For example, crystalline form 3 of formula IB can be prepared using various solvents, but are not limited to ethyl acetate, tetrahydrofuran, methyl isobutyl ketone, acetone, methyl tert-butyl ether, and mixtures thereof.

[0056] Polymorph A, an intrinsic physical form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I), was prepared according to the method described herein. The powder X-ray diffraction (PXRD) pattern of polymorph A is shown in Figure 7, and the corresponding summarized data is shown in Table A.

[0057] [Table 1]

[0058] In some embodiments, the crystalline polymorph A of formula I is 5.5±0.2, 5.6±0.2, 11.1±0.2, 12.4±0.2, 14.2±0.2, 15.1±0.2, 15.2±0.2, 16.1±0.2, 16.7±0.2, 17.6±0.2, 18.3±0.2, 18.8±0.2, 19.2±0.2, 19.6±0.2, 20.6±0.2, 21.3±0.2, 21.6±0.2 The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of 21.9±0.2, 23.3±0.2, 23.3±0.2, 23.7±0.2, 24.3±0.2, 25.5±0.2, 25.9±0.2, 26.8±0.2, 27.1±0.2, 28.2±0.2, 28.9±0.2, 31.0±0.2, 31.3±0.2, 33.0±0.2, and 34.3±0.2. In some embodiments, the crystalline polymorph A of formula I is 5.5±0.1, 5.6±0.1, 11.1±0.1, 12.4±0.1, 14.2±0.1, 15.1±0.1, 15.2±0.1, 16.1±0.1, 16.7±0.1, 17.6±0.1, 18.3±0.1, 18.8±0.1, 19.2±0.1, 19.6±0.1, 20.6±0.1, 21.3±0.1, 21.6±0.1 It has a powder X-ray diffraction pattern including one or more peaks at diffraction angles (2θ) of 21.9±0.1, 23.3±0.1, 23.3±0.1, 23.7±0.1, 24.3±0.1, 25.5±0.1, 25.9±0.1, 26.8±0.1, 27.1±0.1, 28.2±0.1, 28.9±0.1, 31.0±0.1, 31.3±0.1, 33.0±0.1, and 34.3±0.1. In some embodiments, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including a combination of two or more peaks at diffraction angles (2θ) shown in the embodiments above. It will be understood that the diffraction angles (2θ) shown in Table A are within the experimental error of the values ​​shown above and referred to in this disclosure.

[0059] In a further embodiment, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including a diffraction angle (2θ) peak at 23.3±0.2. In a further embodiment, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 12.4±0.2 and 23.3±0.2. In a further embodiment, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 12.4±0.2, 23.3±0.2, and 27.1±0.2. In a further embodiment, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 12.4±0.2, 21.6±0.2, 23.3±0.2, and 27.1±0.2. In further embodiments, crystalline polymorph A of formula I has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 5.5±0.2, 12.4±0.2, 21.6±0.2, 23.3±0.2, and 27.1±0.2.

[0060] In a further embodiment, crystalline polymorph A of formula I has a powder X-ray diffraction pattern that includes a diffraction angle (2θ) peak essentially identical to that shown in Figure 7.

[0061] Polymorph 1, an intrinsic physical form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), was prepared according to the method described herein. The powder X-ray diffraction (PXRD) pattern of Polymorph 1 is shown in Figure 8, and the corresponding summarized data is shown in Table B.

[0062] [Table 2]

[0063] In some embodiments, the crystalline polymorph 1 of compound IB is 6.9±0.2, 9.4±0.2, 10.5±0.2, 12.1±0.2, 12.6±0.2, 13.8±0.2, 15.1±0.2, 15.8±0.2, 16.9±0.2, 18.0±0.2, 18.7±0.2, 20.6±0.2, 21.1±0.2, 21.9±0.2, 23 The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of 0.0±0.2, 23.6±0.2, 24.8±0.2, 25.3±0.2, 25.9±0.2, 26.7±0.2, 27.4±0.2, 28.9±0.2, 29.7±0.2, 30.3±0.2, 30.8±0.2, 31.6±0.2, and 33.8±0.2. In some embodiments, the crystalline polymorph 1 of compound IB is 6.9±0.1, 9.4±0.1, 10.5±0.1, 12.1±0.1, 12.6±0.1, 13.8±0.1, 15.1±0.1, 15.8±0.1, 16.9±0.1, 18.0±0.1, 18.7±0.1, 20.6±0.1, 21.1±0.1, 21.9±0.1, 23 The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of 0.0±0.1, 23.6±0.1, 24.8±0.1, 25.3±0.1, 25.9±0.1, 26.7±0.1, 27.4±0.1, 28.9±0.1, 29.7±0.1, 30.3±0.1, 30.8±0.1, 31.6±0.1, and 33.8±0.1. In some embodiments, crystalline polymorph 1 of compound IB has a powder X-ray diffraction pattern that has a combination of two or more peaks at diffraction angles (2θ) shown in the embodiments above. It will be understood that the diffraction angles (2θ) shown in Table B are within the experimental error of the values ​​shown above and referred to in this disclosure.

[0064] In a further embodiment, crystalline polymorph 1 of formula IB has a powder X-ray diffraction pattern including a diffraction angle (2θ) peak at 23.6±0.2. In a further embodiment, crystalline polymorph 1 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 12.1±0.2 and 23.6±0.2. In a further embodiment, crystalline polymorph B of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 12.1±0.2, 18.7±0.2, and 23.6±0.2. In a further embodiment, crystalline polymorph 1 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 10.5±0.2, 12.1±0.2, 18.7±0.2, and 23.6±0.2. In further embodiments, crystalline polymorph 1 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 10.5±0.2, 12.1±0.2, 18.7±0.2, 23.6±0.2, and 25.9±0.2.

[0065] In a further embodiment, crystalline polymorph 1 of formula IB has a powder X-ray diffraction pattern that includes a diffraction angle (2θ) peak essentially identical to that shown in Figure 8.

[0066] Polymorph 2, an intrinsic physical form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula IB), was prepared according to the method described herein. The powder X-ray diffraction (PXRD) pattern of polymorph 2 is shown in Figure 9, and the corresponding summarized data is shown in Table C.

[0067] [Table 3]

[0068] In some embodiments, the crystalline polymorph 2 of compound IB is 4.9±0.2, 9.6±0.2, 12.2±0.2, 12.8±0.2, 12.9±0.2, 13.4±0.2, 14.3±0.2, 14.9±0.2, 14.9±0.2, 16.1±0.2, 17.0±0.2, 17.5±0.2, 18.1±0.2, 19.0±0.2, 20.3±0.2, 20.9±0.2, 21.6±0. The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of 2, 21.6±0.2, 22.6±0.2, 23.3±0.2, 23.8±0.2, 24.5±0.2, 25.1±0.2, 25.9±0.2, 27.0±0.2, 27.4±0.2, 28.6±0.2, 29.4±0.2, 30.4±0.2, 31.6±0.2, 33.7±0.2, and 38.4±0.2. In some embodiments, the crystalline polymorph 2 of compound IB is 4.9±0.1, 9.6±0.1, 12.2±0.1, 12.8±0.1, 12.9±0.1, 13.4±0.1, 14.3±0.1, 14.9±0.1, 14.9±0.1, 16.1±0.1, 17.0±0.1, 17.5±0.1, 18.1±0.1, 19.0±0.1, 20.3±0.1, 20.9±0.1, 21.6±0. The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of 1, 21.6±0.1, 22.6±0.1, 23.3±0.1, 23.8±0.1, 24.5±0.1, 25.1±0.1, 25.9±0.1, 27.0±0.1, 27.4±0.1, 28.6±0.1, 29.4±0.1, 30.4±0.1, 31.6±0.1, 33.7±0.1, and 38.4±0.1. In some embodiments, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern having a combination of two or more peaks at diffraction angles (2θ) shown in the embodiments above. It will be understood that the diffraction angles (2θ) shown in Table C are within the experimental error of the values ​​shown above and referred to in this disclosure.

[0069] In a further embodiment, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern including a diffraction angle (2θ) peak at 9.6±0.2. In a further embodiment, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 9.6±0.2 and 21.6±0.2. In a further embodiment, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 4.9±0.2, 9.6±0.2, and 21.6±0.2. In a further embodiment, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 4.9±0.2, 9.6±0.2, 21.6±0.2, and 24.5±0.2. In further embodiments, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.9±0.2, 9.6±0.2, 16.1±0.2, 21.6±0.2, and 24.5±0.2.

[0070] In a further embodiment, crystalline polymorph 2 of compound IB has a powder X-ray diffraction pattern that includes a diffraction angle (2θ) peak essentially identical to that shown in Figure 9.

[0071] Polymorph 3, an intrinsic physical form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), was prepared according to the method described herein. The powder X-ray diffraction (PXRD) pattern of polymorph 3 is shown in Figure 10, and the corresponding summarized data is shown in Table D.

[0072] [Table 4]

[0073] In some embodiments, the crystalline polymorph 3 of formula IB is 4.7±0.2, 4.7±0.2, 9.4±0.2, 12.8±0.2, 12.9±0.2, 13.5±0.2, 14.1±0.2, 14.4±0.2, 15.8±0.2, 16.5±0.2, 17.2±0.2, 17.9±0.2, 19.0±0.2, 20.3±0.2, 21.1±0.2, 22.3±0.2, 22.7±0.2, 23.3 The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of ±0.2, 24.7±0.2, 25.1±0.2, 25.7±0.2, 26.9±0.2, 27.4±0.2, 28.0±0.2, 29.2±0.2, 29.8±0.2, 30.2±0.2, 30.8±0.2, 33.4±0.2, 34.4±0.2, 37.2±0.2, 38.1±0.2, and 38.4±0.2. In some embodiments, the crystalline polymorph 3 of formula IB is 4.7±0.1, 4.7±0.1, 9.4±0.1, 12.8±0.1, 12.9±0.1, 13.5±0.1, 14.1±0.1, 14.4±0.1, 15.8±0.1, 16.5±0.1, 17.2±0.1, 17.9±0.1, 19.0±0.1, 20.3±0.1, 21.1±0.1, 22.3±0.1, 22.7±0.1, 23.3 The powder X-ray diffraction pattern has one or more peaks at diffraction angles (2θ) of ±0.1, 24.7±0.1, 25.1±0.1, 25.7±0.1, 26.9±0.1, 27.4±0.1, 28.0±0.1, 29.2±0.1, 29.8±0.1, 30.2±0.1, 30.8±0.1, 33.4±0.1, 34.4±0.1, 37.2±0.1, 38.1±0.1, and 38.4±0.1. In some embodiments, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern that has a combination of two or more peaks at diffraction angles (2θ) shown in the embodiments above. It will be understood that the diffraction angles (2θ) shown in Table D are within the experimental error of the values ​​shown above and referred to in this disclosure.

[0074] In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern including a diffraction angle (2θ) peak at 9.4±0.2. In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 4.7±0.2 and 9.4±0.2. In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 4.7±0.2, 9.4±0.2, and 19.0±0.2. In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks at 4.7±0.2, 9.4±0.2, 19.0±0.2, and 24.7±0.2. In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.7±0.2, 9.4±0.2, 19.0±0.2, 21.1±0.2, and 24.7±0.2.

[0075] In a further embodiment, crystalline polymorph 3 of formula IB has a powder X-ray diffraction pattern that includes a diffraction angle (2θ) peak essentially identical to that shown in Figure 10.

[0076] Any range or desired value presented herein can be expanded or modified without loss of the effect sought, which will be obvious to those skilled in the art to understand the teachings herein.

[0077] Compounds of formula I can be prepared using well-known chemical procedures. Intermediates not specifically described herein are either commercially available, can be prepared by routes disclosed in the chemical literature, or can be readily synthesized from commercially available starting materials using standard procedures.

[0078] The following examples further illustrate the compounds of Formula I in this disclosure, but should not be construed as limiting their scope in any way.

[0079] Starting materials, reagents, and solvents obtained from commercial sources were used without further purification. The anhydrous solvent was purchased from Aldrich as Sure / Seal® and used as received. Melting points were obtained using the OptiMelt automated melting point measurement system from Stanford Research Systems. No corrections were made. Molecules were named according to the naming program in ChemDraw (version 22.2.0.3300). If a molecule could not be named using this program, it was named using conventional naming conventions. Unless otherwise specified, 1 1H NMR spectral data are in ppm(δ) units and were recorded at 396, 400, and 500 MHz. 19 The F NMR spectral data are in ppm(δ) units and were recorded at 376 or 471 MHz. 31 The P NMR spectral data is in ppm(δ) units and was recorded at 202 MHz. [Examples]

[0080] Examples and Methods Example 1: Preparation of 4-(difluoromethoxy)benzyl 4-amino-2,5-dimethylbenzoate [ka] In a 20 milliliter (mL) vial, (4-(difluoromethoxy)phenyl)methanol (253 milligrams (mg), 1.45 millimoles (mmol)), 4-amino-2,5-dimethylbenzoic acid (200 mg, 1.21 mmol), and 4-dimethylaminopyridine (DMAP, 14.8 mg, 0.121 mmol) were dissolved in dichloromethane (DCM, 6.05 mL), and the mixture was cooled to 0 °C in an ice / water bath. After about 5 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC, 279 mg, 1.45 mmol) was added in one portion, and the resulting pale yellow reaction mixture was stirred overnight, allowing it to slowly return to room temperature as the ice melted. After 18 hours, consumption of the starting materials was confirmed by thin layer chromatography (TLC). The reaction mixture was concentrated to give an oil. The resulting material was purified by flash column chromatography (silica gel (SiO2), 0%→100% ethyl acetate in hexane) to give the title compound as a colorless transparent oil (255 mg, 0.794 mmol, 66% yield): 1 H NMR(500MHz,CDCl3)δ 7.73(s,1H),7.43-7.38(m,2H),7.11-7.07(m,2H),6.49(t,J=73.9Hz,1H),6.42(s,1H),5.24(s,2H),3.94(s,2H),2.50(s,3H),2.08(s,3H); 19 F NMR(471MHz,CDCl3)δ -80.68(d,J=73.8Hz);ESIMS m / z 322([M+H] + ).

[0081] Example 2: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate

Chemical Structure

[0082] Example 3: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (230 mg, 0.589 mmol) in DCM (2.95 mL) was prepared in a 25 mL vial. Hydrochloric acid (147 microliters (μL), 0.589 mmol, in a 4.0 M solution in dioxane) was added all at once, and the resulting colorless, transparent solution was stirred at ambient temperature for 4 hours. Volatile components were removed under reduced pressure to obtain a colorless film. Tert-butyl methyl ether (5 mL) was added, and the resulting mixture was vigorously stirred. By vacuum filtration, the title compound was isolated as a mixture of isomers of a white solid (133 mg, 0.341 mmol, yield 58%). 1 H NMR(400MHz,DMSO-d6)δ 11.18-10.79(m,1H),8.54-8.27(m,1H),7.79(s,1H),7.55(d,J=8.2Hz,2H),7.38-7.33(m,1H),7.26(t,J=74.1Hz,1H),7.22(d,J=8.2H) z,2H),5.32(s,2H),3.75-3.61(m,2H),3.32-3.25(m,3H),2.52-2.49(m,3H),2.38-2.32(m,3H),1.30-1.23(m,3H) (E:Z isomers in a ratio of approximately 2:1); 19 F NMR(376MHz,DMSO-d6)δ -82.14;mp 95-100℃.

[0083] Example 4: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride [ka] The compound in the title can also be prepared as follows: A 500 mL jacketed reactor was fitted with a nitrogen inlet, a temperature probe, a stirrer, and an outlet connected to a scrubber. N-ethyl-N-methylformamide (8.83 g, 97.4 mmol, 96.0 wt%) and anhydrous DCM (130 mL) were added to the reaction. The jacket was set to 20°C and the mixture was stirred at 250 rpm per minute. Oxalyl chloride (8.17 mL, 93.4 mmol) was added over 30 minutes. After complete addition, the mixture was stirred for a further 1 hour. 4-(difluoromethoxy)benzyl 4-amino-2,5-dimethylbenzoate (25.0 g, 77.8 mmol) was added as a solution in DCM (64.8 mL) over 90 minutes. After complete addition, the mixture was stirred for a further 1 hour. After 1 hour, the reaction mixture was collected and analyzed by HPLC, which showed a high conversion rate of the starting materials. The reaction mixture was collected from the reactor and diluted with DCM (100 mL). The mixture was concentrated to approximately half its volume, and heptane (100 mL) was added to concentrate the mixture to dryness. By thoroughly drying it overnight under vacuum, the title compound (31.2 g, 73.1 mmol, 94% yield) was obtained as an off-white solid mixture of isomers.

[0084] Example 5: Preparation of 4-(difluoromethoxy)benzyl 4-amino-2,5-dimethylbenzoate [ka] A solution of 4-amino-2,5-dimethylbenzoic acid (0.750 g, 4.54 mmol) in anhydrous N,N-dimethylformamide (DMF, 5.00 mL) was prepared in a 20 mL vial magnetically stirred. Potassium carbonate (0.816 g, 5.90 mmol) was added in small amounts at ambient temperature. The mixture was stirred for about 10 minutes. 1-(chloromethyl)-4-(difluoromethoxy)benzene (0.874 g, 4.54 mmol) was added dropwise over about 5 minutes, and the resulting amber-colored mixture was stirred overnight at ambient temperature. Ultra-high performance liquid chromatography (UPLC) analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (25 mL) and extracted with diethyl ether (4 × 5 mL). The combined organic extract was washed with water (5 × 20 mL) and saturated saline (20 mL), dried over sodium sulfate, filtered, and concentrated to obtain a reddish-purple oil. The compound in question was obtained as an off-white solid by purification using flash column chromatography (C18 reversed phase, 20->100% acetonitrile aqueous solution) (1.05 g, 3.28 mmol, yield 72%).

[0085] Example 6: Preparation of 4-(difluoromethoxy)benzyl)-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate phosphate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (200 mg, 0.512 mmol) in dry acetonitrile (1 mL) was prepared in a 40 mL vial equipped with a magnetic stirring bar. In another 4 mL vial, phosphoric acid (55.2 mg, 0.563 mmol) was dissolved in dry acetonitrile (1 mL), and this solution was added dropwise to the starting material solution using a syringe. The resulting solution was stirred at ambient temperature for 15 minutes. The solvent was removed under reduced pressure to obtain a pale yellow solid. The solid was dried under high vacuum and triturated with dry diethyl ether (2 mL). Decantation of the solvent (×3) yielded the title compound as a mixture of isomers of a white solid (220 mg, 0.450 mmol, yield 88%). 1 H NMR(500MHz,acetone-d6)δ 8.10-7.87(m,1H),7.77(s,1H),7.61-7.53(m,2H),7.25-7.18(m,2H),7.17-6.80(m,2H),5.31(s,2H) ,3.73-3.57(m,2H),3.26(d,J=6.5Hz,3H),2.51(s,3H),2.29(d,J=11.5Hz,3H),1.29(q,J=8.4Hz,3H); 19 F NMR (471 MHz, acetone-d6) δ -82.72; 31 P NMR (202 MHz, acetone-6) δ 1.80.

[0086] Example 7: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate fumarate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (200 mg, 0.512 mmol) in methanol (2 mL) was prepared in a 20 mL vial equipped with a magnetic stirring bar. Fumaric acid (59.5 mg, 0.512 mmol) was added to this solution, and the resulting solution was stirred at ambient temperature for 15 minutes. The solvent was removed under reduced pressure, and the resulting oil was dried under high vacuum to obtain a foamy solid. This was triturated with dry diethyl ether (2 mL). By decanting the solvent (×3), the title compound was obtained as a mixture of isomers in a white solid (132 mg, 0.261 mmol, yield 51%). 1 H NMR(500MHz,CD3OD)δ 8.16-7.90(m,1H),7.81(s,1H),7.54-7.46(m,2H),7.20-7.12(m,2H),7.05(s,1H),6.99-6.64(m,3H),5.31 (s,2H),3.60(q,J=7.2Hz,2H),3.25-3.15(m,3H),2.54(s,3H),2.30(s,3H),1.31(dt,J=13.1,7.3Hz,3H),no COO(H); 19 F NMR (471 MHz, CD3OD) δ -83.43.

[0087] Example 8: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate oxalate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (215 mg, 0.551 mmol) in DCM (2.75 mL) was prepared in a 5 mL vial equipped with a magnetic stirring bar. Oxalic acid (49.6 mg, 0.551 mmol) was added to this colorless, transparent solution, and the resulting solution was stirred at ambient temperature for 3 hours. The solvent was removed under a stream of nitrogen. Dry diethyl ether (2 mL) was added, and the vial was shaken to obtain a white solid precipitate. This precipitate was recovered by vacuum filtration. The compound of the title was isolated as a mixture of white solid isomers (185 mg, 0.385 mmol, yield 70%): 1 H NMR(396MHz,DMSO-d6)δ 7.93(d,J=65.1Hz,1H),7.70(s,1H),7.62-7.39(m,2H),7.35-7.02(m,3H),6.90(d,J=24.7Hz,1H),5.27(s,2 H),3.47(dq,J=13.9,6.8Hz,2H),3.06(d,J=22.6Hz,3H),2.47(s,3H),2.20(m,3H),1.18(q,J=5.7Hz,3H),no COO(H); 19 F NMR(471MHz,DMSO- d6)δ -82.03(d,J=73.8Hz);mp 102-106℃.

[0088] Example 9: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate tartarate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (200 mg, 0.512 mmol) in methanol (2 mL) was prepared in a 20 mL vial equipped with a magnetic stirring bar. Tartaric acid (77.0 mg, 0.512 mmol) was added to this solution, and the resulting solution was stirred at ambient temperature for 15 minutes. The solvent was removed under reduced pressure, and the resulting oil was dried under high vacuum to obtain a brown foamy solid. This was triturated with dry diethyl ether (2 mL). By decanting the solvent (×3), the title compound was obtained as a mixture of isomers in a white solid (238 mg, 0.440 mmol, yield 86%). 1 H NMR(500MHz,CD3OD)δ 8.19-7.98(m,1H),7.82(s,1H),7.55-7.44(m,2H),7.20-7.13(m,2H),7.13-7.08(m,1H),6.83(t,J=74.1Hz,1H),5. 32(s,2H),4.42(s,2H),3.63(q,J=7.2Hz,2H),3.32-3.19(m,3H),2.55(s,3H),2.32(s,3H),1.34(t,J=7.1Hz,3H),no -O(H) or COO(H); 19 F NMR(471MHz,CD3OD)δ -83.44;mp 147℃.

[0089] Example 10: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate 4-hydroxybenzoate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (200 mg, 0.512 mmol) in methanol (2 mL) was prepared in a 20 mL vial equipped with a magnetic stirring bar. 4-hydroxybenzoic acid (70.8 mg, 0.512 mmol) was added to this solution, and the resulting solution was stirred at ambient temperature for 15 minutes. The solvent was removed under reduced pressure. The resulting brown oil was dried under high vacuum to obtain a brown foamy solid. This was triturated with dry diethyl ether (2 mL). By decanting the solvent (×3), the title compound was obtained as a mixture of light brown solid isomers (235 mg, 0.445 mmol, yield 87%). 1 H NMR(500MHz,CD3OD)δ 7.90-7.83(m,2H),7.74(s,2H),7.53-7.44(m,2H),7.19-7.12(m,2H),7.02-6.62(m,4H),5.2 8(s,2H),3.56-3.37(m,2H),3.05(s,3H),2.51(s,3H),2.22(s,3H),1.24(t,J=7.2Hz,3H),no -O(H) or COO(H); 19 F NMR(471MHz,CD3OD)δ -83.34;mp 64℃.

[0090] Example 11: Preparation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate succinate [ka] A solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (214 mg, 0.548 mmol) was prepared in a 20 mL vial equipped with a magnetic stirring bar, in a mixture of acetone (2.47 mL) and water (0.27 mL). Succinic acid (64.7 mg, 0.548 mmol) was added, and the resulting colorless, transparent solution was stirred at ambient temperature for 2 hours. Volatile substances were removed, and the residue was diluted in the following order: diethyl ether (approx. 2 mL), DCM (approx. 2 mL), and hexane (approx. 2 mL), and then evaporated to obtain a semi-solid foamy substance. The solid was isolated by suction filtration and washed with hexane. The compound of the title was isolated as a mixture of isomers of a white foamy substance (70 mg, 0.138 mmol, yield 25%): 1 H NMR(500MHz,CD3OD)δ 7.98-7.87(m,1H),7.80(s,1H),7.55-7.48(m,2H),7.22-7.14(m,2H),6.94(s,1H),6.84(t,J=74.1Hz,1H),5.31(s,2 H),3.63-3.47(m,2H),3.22-3.00(m,3H),2.56(d,J=0.8Hz,7H),2.28(d,J=5.8Hz,3H),1.31(td,J=7.2,3.8Hz,3H),no COO(H); 19 F NMR (471 MHz, CD3OD) δ -83.34.

[0091] Example 12: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I) as Form A - Evaporative crystallization from ethyl acetate One g of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula I), a colorless oil, was dissolved in ethyl acetate. The solution was concentrated under reduced pressure with stirring at 35°C for 5 hours. Upon cooling to room temperature, the oil crystallized into an off-white solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 1 and assigned morphology A.

[0092] Example 13: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (form IB) Form 1 - Evaporative crystallization from isopropyl alcohol A saturated solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) was prepared in isopropyl alcohol. The solution was evaporated to dryness at 50°C without stirring, and then a crystalline solid was obtained by placing it under reduced pressure at 50°C. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 1.

[0093] Example 14: Crystallization in another form as Form 1 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula IB) - Slow evaporation crystallization from acetone or from a combination of dichloromethane, ethyl acetate and / or heptane 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 15 mg) was dissolved in acetone or a combination of dichloromethane, ethyl acetate and / or heptane in a vial. A needle was inserted through the septum of the cap, and the mixture was slowly evaporated at room temperature to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 1 and assigned to Form 1.

[0094] Example 15: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form as Form 1 - Solvent / poor solvent crystallization from ethanol / methyl tert-butyl ether, acetonitrile / isopropyl acetate, chloroform / heptane, or chloroform / methyl isobutyl ketone 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was completely dissolved in a solvent (ethanol, acetonitrile, or chloroform) in a vial. A poor solvent (methyl tert-butyl ether, isopropyl acetate, heptane, or methyl isobutyl ketone) was added dropwise until the volume reached four times the initial solvent volume. The sample was stirred overnight at room temperature. If no precipitation occurred, the solution was then placed in a freezer at -20°C. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 1.

[0095] Example 16: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form - quenched crystallization from toluene / acetonitrile 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was dissolved in toluene-acetonitrile (70:30) at 50°C, and the solution was quickly placed in an ice bath without stirring. Stirring was started after 10 minutes. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 1.

[0096] Example 17: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form - slow cooling crystallization from methyl isobutyl ketone / acetone, ethanol / heptane, toluene / acetonitrile, ethyl acetate / heptane, or ethyl acetate / chloroform 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was placed in a 2 mL vial. A solvent mixture (methyl isobutyl ketone / acetone, ethanol / heptane, toluene / acetonitrile, ethyl acetate / heptane, or ethyl acetate / chloroform) was gradually added at 50°C until completely dissolved. The solution was slowly cooled to room temperature over approximately 12 hours. If no solid precipitate formed after reaching room temperature, the solution was further cooled to 0°C or -20°C by placing the vial in the freezer overnight. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to methods 1 and 2 and assigned to form 1.

[0097] Example 18: Crystallization in another form as Form 1 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula IB) - Stagnant cooling crystallization from methyl ethyl ketone or from a mixture of dichloromethane and heptane 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was dissolved at 50°C in a mixture of methyl ethyl ketone or dichloromethane and heptane. The solution was stored in a freezer. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 1.

[0098] Example 19: Evaporative crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) as Form 2 - 2-methyltetrahydrofuran or methyl isobutyl ketone A saturated solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in 2-methyltetrahydrofuran and an unsaturated solution of formula IB in methyl isobutyl ketone were prepared. Crystalline solids were obtained by evaporating these solutions to dryness at 50°C under reduced pressure without stirring. The samples were analyzed by powder X-ray diffraction (PXRD) according to methods 1 and 2 and assigned to form 2.

[0099] Example 20: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form as Form 2 - Solvent / poor solvent crystallization from isopropyl alcohol / methyl tert-butyl ether 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was completely dissolved in isopropyl alcohol in a vial. A poor solvent (methyl tert-butyl ether) was added dropwise until the volume reached four times the initial amount of solvent. The sample was stirred overnight at room temperature. If no precipitation occurred, the solution was placed in a freezer at -20°C. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 2.

[0100] Example 21: Crystallization in an alternative form as Form 2 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula IB) - Slow cooling crystallization from methyl isobutyl ketone or heptane / isopropyl alcohol 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was placed in a vial. Methyl isobutyl ketone, or a mixture of heptane and isopropyl alcohol, was gradually added at 50°C until the substance was completely dissolved. The solution was slowly cooled to room temperature over approximately 12 hours. If no solid precipitate formed after reaching room temperature, the solution was placed in the freezer overnight and further cooled to 0°C or -20°C. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 2.

[0101] Example 22: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) as form 3 - Evaporative crystallization from methyl isobutyl ketone A saturated solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) was prepared in methyl isobutyl ketone. The solution was evaporated to dryness at 50°C without stirring, and then a crystalline solid was obtained by placing it under reduced pressure at 50°C. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to Form 3.

[0102] Example 23: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form - quenched crystallization from methyl isobutyl ketone / acetone 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was dissolved in methyl isobutyl ketone / acetone (70:30) at 50°C, and the solution was quickly placed in an ice bath without stirring. Stirring was started after 10 minutes. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned to form 3.

[0103] Example 24: Crystallization of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB) in an alternative form - slow cooling crystallization from ethyl acetate or tetrahydrofuran / methyl tert-butyl ether 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB, 25 mg) was placed in a vial. Ethyl acetate, or a mixture of tetrahydrofuran and methyl tert-butyl ether, was gradually added at 50°C until the substance was completely dissolved. The solution was slowly cooled to room temperature over approximately 12 hours. If no solid precipitate formed after reaching room temperature, the solution was further cooled to 0°C or -20°C by placing it in a freezer overnight. After precipitation occurred, the sample was filtered to obtain a crystalline solid. The sample was analyzed by powder X-ray diffraction (PXRD) according to methods 1 and 2 and assigned to form 3.

[0104] Method 1: Powder X-ray diffraction (PXRD) of crystalline polymorphism A of formula I and forms 1-3 of formula IB. Samples were analyzed using a Bruker D2 Phaser with CuKα radiation (30 kilovolts (kV), 10 milliamperes (mA)) and a θ-θ goniometer. The incident beam passed through a 0.2 mm divergent slit. A 1 mm air scattering screen was placed above the sample, and the beam stop was removed. The diffracted beam passed through a 3 mm air scattering slit, a 2.5° solar slit, and a 0.5 Kβ filter, followed by a Lynxeye SSD160 detector with a 1.5° position detector (PSD) aperture. Samples were measured under ambient conditions as planar specimens using the as-received powder. Samples were prepared on polished zero-background (510) silicon wafers by lightly pressing them onto a flat surface or by filling cavities formed by cutting. Samples were rotated in-plane at 15 rpm. Data were collected in the 2θ range from 3° to 40° with a step size of 0.03°2θ and an acquisition time of 0.5 seconds.

[0105] Method 2: Powder X-ray diffraction (PXRD) of crystalline polymorphisms 1-3 of formula IB in different forms. The samples were analyzed using a Bruker D8 Advance X-ray diffraction system equipped with a LYNXEYE detector configured in a reflective Bragg-Brentano configuration. The parameters of the PXRD method used are listed in Table F.

[0106] [Table 5]

[0107] [Table 6]

[0108] [Table 7]

[0109] Details and examples of general biological experiments Example A: Evaluation of fungicidal activity using truck sprayer application: Septoria leaf blight in wheat (Zymoseptoria tritici; EPPO code SEPTTR) Industrial-grade materials of each test compound were formulated as 10% emulsions (EC) in a ratio of 1 part active ingredient to 9 parts mixtures of water-miscible and water-immiscible solvents and nonionic surfactants. Each emulsion was then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were sprayed onto wheat seedlings at a rate of 200 liters / hectare (L / ha) and a pressure of 220 kilopascals (kPa) (32 pounds / square inch (psi)) using an automated truck sprayer. All sprayed plants were air-dried before further handling.

[0110] [Table 8]

[0111] Wheat plants (variety "Yuma") were propagated in pots containing 7-10 plants each, using a soilless potting mix. The plants were used in the experiment when the first leaf had fully emerged. The test plants were inoculated with a spore suspension of Zymoseptoria tritici either 3 days before fungicide treatment (3-day curative agent; 3DC) or 1 day after fungicide treatment (1-day protective agent; 1DP). After inoculation, the plants were kept at 100% relative humidity for 3 days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. The infection level was visually assessed on a disease severity scale from 0 to 100 percent when disease symptoms fully manifested on the first leaf of an untreated plant. The percentage of disease control was calculated using the ratio of disease severity between treated and untreated plants. The data are shown in Figure 1.

[0112] Figure 1 shows the results of using formula I 3 days before fungicide treatment (3-day therapeutic agent; 3DC) or 1 day after fungicide treatment (1-day protective agent; 1DP). [ka] Example 25 [ka] Example 27 [ka] , Example 494 [ka] , and formula IB [ka] This shows the disease control rate for the test concentration.

[0113] Example B: Evaluation of fungicidal activity in a microplot field test: Septoria leaf blight of wheat (Zymoseptoria tritici; EPPO code SEPTTR) Industrial-grade materials of each test compound were prepared as 10% emulsions (EC) using a ratio of 1 part active ingredient to 9 parts of a mixture of water-miscible and water-immiscible solvents and a nonionic surfactant. These emulsions were then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were applied to 1m x 2m plots of wheat plants at a pressure of 220kPa and a rate of 200L / ha using a backpack sprayer and a flat fan nozzle.

[0114] Wheat plants (varieties 'Lancer', 'Barrel', and 'Tobak') were cultivated in 1m x 2m plots, and the material was applied at therapeutic application timings between growth stages 39–55, or protective application timings between growth stages 37–39, depending on the geographical location. Four replicate trials were used with a randomized block method. Disease severity was visually assessed on a 0–100% scale at multiple time points approximately 7–14 days apart, and the disease control rate was calculated based on the area under the disease progression curve. The trial was conducted at up to three geographical locations. The data are shown in Figure 2.

[0115] Figure 2 shows the cross-test analysis of repeated field trials. Equation I [ka] and Example 25 [ka] This shows the disease control rate for the test concentration.

[0116] Example C: Evaluation of fungicidal activity in small-plot field trials: Barley net spot disease (Pyrenophora teres; EPPO code PYRNTE) Industrial-grade materials of each test compound were prepared as 10% emulsions (EC) using a ratio of 1 part active ingredient to 9 parts mixtures of water-miscible and water-immiscible solvents and nonionic surfactants. These emulsions were then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were applied to 1m x 2m plots of barley plants at a pressure of 240-250kPa and a rate of 200L / ha using a backpack sprayer and flat fan nozzle.

[0117] Barley plants (varieties 'Snakebite', 'Planet', and 'LG Caspari') were cultivated in 1m x 2m plots, and the material was applied at protective application timings between growth stages 45 and 49, depending on the geographical region. Four replicate trials were used with a randomized block method. Disease severity was visually assessed on a scale of 0-100% at multiple time points approximately 7 days apart, and the disease control rate was calculated based on the area under the disease progression curve. The trial was conducted in up to three geographical locations. The data are shown in Figure 3.

[0118] Figure 3 shows the cross-test analysis of repeated field trials. Equation I [ka] and Example 25 [ka] This shows the disease control rate for the test concentration.

[0119] Example D: Evaluation of fungicidal activity in small-field trials: Ramularia collo-cygni (EPPO code RAMUCC) in barley Industrial-grade materials of each test compound were prepared as 10% emulsions (EC) using a ratio of 1 part active ingredient to 9 parts mixtures of water-miscible and water-immiscible solvents and nonionic surfactants. These emulsions were then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were applied to 1m x 2m plots of barley plants at a pressure of 250-300kPa and a rate of 200L / ha using a backpack sprayer and flat fan nozzle.

[0120] Barley plants (varieties 'Taverna', 'Lomerit', and 'LG Caspari') were cultivated in 1m x 2m plots, and the material was applied at protective application timings from growth stages 33 to 41, depending on the geographical region. Four replicate trials were used with a randomized block method. Disease severity was visually assessed on a scale of 0-100% at multiple time points approximately 7-14 days apart, and the disease control rate was calculated based on the area under the disease progression curve. The trial was conducted in up to three geographical locations. The data are shown in Figure 4.

[0121] Figure 4 shows the cross-test analysis of repeated field trials. Equation I [ka] and Example 25 [ka] This shows the disease control rate for the test concentration.

[0122] Example E: Evaluation of fungicidal activity in small-field trials: Barley leaf blight (Rhynchosporium secalis; EPPO code RHYNSE) Industrial-grade materials of each test compound were prepared as 10% emulsions (EC) using a ratio of 1 part active ingredient to 9 parts mixtures of water-miscible and water-immiscible solvents and nonionic surfactants. These emulsions were then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were applied to 1m x 2m plots of barley plants at a pressure of 250-300kPa and a rate of 200L / ha using a backpack sprayer and flat fan nozzle.

[0123] Barley plants (varieties 'Snakebite' and 'Pixel') were cultivated in 1m x 2m plots, and the material was applied at protective application timings from growth stages 33 to 41, depending on the geographical region. Four replicate trials were used with a randomized block method. Disease severity was visually assessed on a scale of 0-100% at multiple time points approximately 7-14 days apart, and the disease control rate was calculated based on the area under the disease progression curve. The trials were conducted in up to three geographical locations. The data are shown in Figure 5.

[0124] Figure 5 shows the cross-test analysis of repeated field trials. Equation I [ka] and Example 25 [ka] This shows the disease control rate for the test concentration.

[0125] Example F: Evaluation of fungicidal activity in small-plot field trials: Barley rust (Puccinia hordei; EPPO code PUCCHD) Industrial-grade materials of each test compound were prepared as 10% emulsions (EC) using a ratio of 1 part active ingredient to 9 parts of a mixture of water-miscible and water-immiscible solvents and a nonionic surfactant. These emulsions were then mixed with water (H2O) containing 0.1% Break Thru S233 and 0.3% Plurafac LF1300. Details of the EC formulations are shown in Table 1. The fungicide solutions were applied to 1m x 2m plots of barley plants at a pressure of 200-300kPa and a rate of 200L / ha using a backpack sprayer with a flat fan nozzle.

[0126] Barley plants (varieties 'Pixel' and 'Faro') were cultivated in 1m x 2m plots, and protective application timings were applied at growth stages 41–65, depending on the geographical location. Four replicate trials were used with a randomized block method. Disease severity was visually assessed on a 0–100% scale at multiple time points approximately 7–14 days apart, and disease control rates were calculated based on the area under the disease progression curve. The trials were conducted in up to three geographical locations. The data are shown in Figure 6.

[0127] Figure 6 shows the cross-test analysis of repeated field trials. Equation I [ka] and Example 25 [ka] This shows the disease control rate for the test concentration.

[0128] Example G: Evaluation of fungicidal activity: Sugar beet brown spot disease (Cercospora beticola; EPPO code CERCBE) Industrial-grade materials of each test compound were dissolved in acetone, and then mixed with nine times the volume of water (H2O) containing 110 ppm Triton X-100. The fungicide solution was applied to sugar beet seedlings using an automatic sprayer until it ran off. All sprayed plants were air-dried before further handling.

[0129] Sugar beet plants (variety "SV333") were propagated in pots containing one plant each, using a soilless potting mix. The plants were used for the experiment when the first leaf had fully emerged. One day after fungicide treatment (1-day protective agent; 1DP), the test plants were inoculated with a spore suspension of Cercospora beticola. After inoculation, the plants were kept in a fog chamber at 100% relative humidity for two days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. Disease evaluation was performed as described in Example A. The data are shown in Table 2.

[0130] Example H: Evaluation of fungicidal activity: Cucurbitaceae plant anthracnose (Colletotrichum orbiculare; EPPO code COLLLA) Cucumber seedlings (variety "BushPickle") were propagated in pots containing one plant each, using a soilless potting mix. The plants were used for the experiment when the first leaf had fully emerged. One day after fungicide treatment (1-day protective agent; 1DP), the test plants were inoculated with a spore suspension of Colletotrichum orbiculare. After inoculation, the plants were kept at 100% relative humidity for two days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 2.

[0131] Example I: Evaluation of fungicidal activity: Rice blast disease (Magnaporthe oryzae; EPPO code PYRIOR) Rice seedlings (variety "M202") were propagated in pots containing 8-10 plants each, using a soilless potting mix. The plants were used for the experiment when the first leaves had fully emerged. One day after fungicide treatment, the test plants were inoculated with a spore suspension of Magnaporthe oryzae (1DP). After inoculation, the plants were kept at 100% relative humidity for two days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 2.

[0132] [Table 9]

[0133] Example J: Evaluation of fungicidal activity: Asian soybean rust (Phakopsora pachyrhizi; EPPO code PHAKPA) Industrial-grade materials of each test compound were dissolved in acetone, and then mixed with nine times the volume of water (H2O) containing 0.011% Tween20. The fungicide solutions were applied to soybean seedlings using an automatic sprayer until runoff occurred. All sprayed plants were air-dried before further handling.

[0134] Soybean plants (variety "Williams 82") were propagated in pots containing one plant each, using a soilless potting mix. The plants were used for the experiment when the first leaf had fully emerged. The test plants were inoculated as described in Example A. After inoculation, the plants were kept at 100% relative humidity for 24 hours to allow the spores to germinate and infect the leaves. The plants were then moved to a growing chamber to induce disease. The application of fungicides and evaluation of disease were carried out as described in Example A. The data are shown in Table 3.

[0135] [Table 10]

[0136] Example K: Evaluation of fungicidal activity: Tomato ring spot disease (Alternaria solani; EPPO code ALTESO) Tomato plants (variety "Brandywine") were propagated in pots containing one plant each, using a soilless potting mix. The plants were used for the experiment when the first leaf had fully emerged. One day after fungicide treatment (1-day protective agent; 1DP), the test plants were inoculated with a spore suspension of Alternaria solani. After inoculation, the plants were kept in a fog chamber at 100% relative humidity for two days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 4.

[0137] [Table 11]

[0138] Example L: Evaluation of fungicidal activity: Gray mold (Botrytis cinerea; EPPO code BOTRCI) Grapevines (variety "Pinot noir") were propagated in pots containing one plant each, using a soilless potting mix, and pruned until the first fully emerged leaves appeared. The test plants were inoculated with a spore suspension of Botrytis cinerea one day after fungicide treatment (1-day protective agent; 1DP). After inoculation, the plants were kept in a fog chamber at 100% relative humidity for 4 days to allow the spores to germinate and infect the leaves. Next, the plants were moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 5.

[0139] [Table 12]

[0140] Example M: ​​Evaluation of fungicidal activity: Cucumber powdery mildew (Podosphaera xanthii; EPPO code PODOXA) Cucumber plants (variety "Straight eight") were propagated in pots containing one plant each, using a soilless potting mix. The plants were used in the experiment when the first leaf had fully emerged. One day after fungicide treatment (1-day protective agent; 1DP), the test plants were inoculated with a spore suspension of Podosphaera xanthii. After inoculation, the plants were moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 6.

[0141] [Table 13]

[0142] Example N: Evaluation of in vitro fungicidal activity: Cercospora kikuchii (EPPO code CERCKI); Corynespora cassiicola (EPPO code CORYCA); and Septoria glycines (EPPO code SEPTGL) The test compounds were serially diluted with dimethyl sulfoxide (DMSO) and placed in 2 microliters (μL) each into a 96-well flat-bottom microtiter plate (Falcon Products).

[0143] Fungal cultures of Cercospora kikuchii, Corynespora cassiicola, and Septoria glycines were cultured for 7–14 days until spore formation on potato dextrose agar (BDDIFCO® product 213400) or V-8 agar (200.0 ml (mL) of V8 juice, 3.0 g of calcium carbonate (CaCO3), 1 g of sucrose, 15.0 g / L (g / L) of agar, pH 7.2 ± 0.2). Spore suspensions were prepared in Difco YNB (6.7 g / L, amino acid-free nitrogen base for yeast culture, BD Diagnostic Systems) supplemented with 2 g of glucose and 3 g each of potassium dihydrogen phosphate and dipotassium hydrogen phosphate per liter (L). The total assay volume was 200 μL per well. The plates were kept at 22°C for 3–5 days, and growth inhibition was evaluated using a NepheloStar turbidimeter (BMG LABTECH). The growth inhibition rate was calculated relative to a control well containing growth medium supplemented with 1% DMSO and the inoculum. The data are shown in Table 7.

[0144] [Table 14]

[0145] Example O: Evaluation of fungicidal activity: Wheat rust (Puccinia triticina); Synonym: Puccinia recondita f.sp. tritici (Bayer code PUCCRT): Wheat plants (variety "Yuma") were grown in a greenhouse in a soilless potting mix, with 7-10 seedlings per pot, until the first leaves fully emerged from seed. These plants were inoculated with an aqueous spore suspension of Puccinia triticina after fungicide treatment. After inoculation, the plants were kept overnight in a fog chamber at 100% relative humidity to allow the spores to germinate and infect the leaves. The plants were then moved to a greenhouse to induce disease. The formulation and application of the fungicide were as described in Example G. Disease evaluation was as described in Example A. The data are shown in Table 8.

[0146] [Table 15]

[0147] Example P: Evaluation of in vitro fungicidal activity: Alternaria solani (EPPO code ALTESO); Botrytis cinerea (EPPO code BOTRCI); Colletotrichum orbiculare (EPPO code COLLLA); Corynespora cassiicola (EPPO code CORYCA); Magnaporthe oryzae (EPPO code PYRIOR); Zymoseptoria tritici (EPPO code SEPTTR); and Ustilago maydis (EPPO code USTIMA) The test compound was diluted with dimethyl sulfoxide (DMSO) and placed in 2 microliters (μL) portions in a 96-well flat-bottom microtiter plate (Falcon Products).

[0148] Spore suspensions were prepared in Difco YNB (6.7 g / L, amino acid-free nitrogen base for yeast culture, BD Diagnostic Systems) supplemented with 2 g of glucose and 3 g each of potassium dihydrogen phosphate and dipotassium hydrogen phosphate per liter (L). The total assay volume was 200 μL per well. Initial inoculum densities were adjusted to 100,000 spores / mL for BOTRCI, CORYCA, and SEPTTR; 250,000 spores / mL for COLLLA; 40,000 spores / mL for PYRIOR; 50,000 spores / mL for USTIMA; and 10,000–20,000 spores / mL for ALTESO.

[0149] Immediately after adding the spore suspension, initial cell density readings were determined using a NepheloStar turbidimeter (BMG LABTECH GmbH, Ortenberg, Germany). After incubation in a New Brunswick Innova 44 incubator (Eppendorf, Inc., Enfield, CT) at 22°C for 48 hours (ALTESO, BOTRCI, PYRIOR, USTIMA), 22°C for 72 hours (SEPTTR), 22°C for 96 hours (CORYCA), or 28°C for 96 hours (COLLLA), a second plate reading was performed using NepheloStar to evaluate growth. Growth inhibition rates were calculated relative to a control well containing growth medium supplemented with 1% DMSO and the inoculum. The data are shown in Table 9.

[0150] [Table 16]

[0151] From the foregoing, the compounds of this disclosure may be described as embodiments in any of the provisions listed below. It will be understood that any embodiment described herein may be used in connection with any other embodiment described herein to the extent that the embodiments are not inconsistent with each other. 1. Crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula I). 2. The crystalline form described in Embodiment 1, which is a crystalline polymorph of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I). 3. The crystalline form according to Embodiment 1 or 2, which is an anhydrous and solvent-free crystalline polymorph. 4. Crystalline polymorph A of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (formula I), having a powder X-ray diffraction pattern including a diffraction angle (2θ) peak of 23.3±0.2. 5. The crystalline polymorph according to Embodiment 4, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 12.4±0.2 and 23.3±0.2. 6. A crystalline polymorph according to Embodiment 4 or 5, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 12.4±0.2, 23.3±0.2, and 27.1±0.2. 7. A crystalline polymorph according to any one of embodiments 4 to 6, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 12.4±0.2, 21.6±0.2, 23.3±0.2, and 27.1±0.2. 8. A crystalline polymorph according to any one of embodiments 4 to 7, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 5.5±0.2, 12.4±0.2, 21.6±0.2, 23.3±0.2, and 27.1±0.2. 9. A crystalline polymorph according to any one of embodiments 4 to 8, having a powder X-ray diffraction pattern containing one or more peaks essentially identical to those shown in Figure 7. 10. Crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB). 11. The crystalline form according to Embodiment 10, which is a crystalline polymorph of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB). 12. The crystal form according to Embodiment 10 or 11, which is a hemihydrate crystal polymorph. 13. Crystalline polymorph 1 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), having a powder X-ray diffraction pattern including a diffraction angle (2θ) peak of 23.6±0.2. 14. The crystalline polymorph according to Embodiment 13, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 12.1±0.2 and 23.6±0.2. 15. A crystalline polymorph according to Embodiment 13 or 14, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 12.1±0.2, 18.7±0.2, and 23.6±0.2. 16. A crystalline polymorph according to any one of embodiments 13 to 15, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 10.5±0.2, 12.1±0.2, 18.7±0.2, and 23.6±0.2. 17. A crystalline polymorph according to any one of embodiments 13 to 16, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 10.5±0.2, 12.1±0.2, 18.7±0.2, 23.6±0.2, and 25.9±0.2. 18. A crystalline polymorph according to any one of embodiments 13 to 17, having a powder X-ray diffraction pattern containing one or more peaks essentially identical to those shown in Figure 8. 19. The crystalline polymorph according to Embodiment 10 or 11, which is an anhydrous and solvent-free crystalline polymorph. 20. Crystalline polymorph 2 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), having a powder X-ray diffraction pattern including a diffraction angle (2θ) peak of 9.6±0.2. 21. The crystalline polymorph according to Embodiment 20, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 9.6±0.2 and 21.6±0.2. 22. A crystalline polymorph according to Embodiment 20 or 21, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.9±0.2, 9.6±0.2, and 21.6±0.2. 23. A crystalline polymorph according to any one of embodiments 20 to 22, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.9±0.2, 9.6±0.2, 21.6±0.2, and 24.5±0.2. 24. A crystalline polymorph according to any one of embodiments 20 to 23, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.9±0.2, 9.6±0.2, 16.1±0.2, 21.6±0.2, and 24.5±0.2. 25. A crystalline polymorph according to any one of embodiments 20 to 24, having a powder X-ray diffraction pattern containing one or more peaks essentially identical to those shown in Figure 9. 26. Crystalline polymorph 3 of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula IB), having a powder X-ray diffraction pattern including a diffraction angle (2θ) peak of 9.4±0.2. 27. A crystalline polymorph according to Embodiment 26, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.7±0.2 and 9.4±0.2. 28. A crystalline polymorph according to Embodiment 26 or 27, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.7±0.2, 9.4±0.2, and 19.0±0.2. 29. A crystalline polymorph according to any one of embodiments 26 to 28, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.7±0.2, 9.4±0.2, 19.0±0.2, and 24.7±0.2. 30. A crystalline polymorph according to any one of embodiments 26 to 29, having a powder X-ray diffraction pattern including diffraction angle (2θ) peaks of 4.7±0.2, 9.4±0.2, 19.0±0.2, 21.1±0.2, and 24.7±0.2. 31. A crystalline polymorph according to any one of embodiments 26 to 30, having a powder X-ray diffraction pattern containing one or more peaks essentially identical to those shown in Figure 10.

[0152] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as they are incorporated herein by reference, with each reference being shown to be incorporated individually and specifically.

[0153] In the context of this disclosure (particularly in the context of the following claims), the use of the terms “a,” “an,” “the,” “at least one,” and similar demonstrative pronouns should be interpreted as encompassing both singular and plural forms, unless otherwise specifically indicated herein or unless clearly inconsistent with the context. The use of the term “at least one” followed by a list of one or more items (e.g., “at least one of A and B”) should be interpreted as meaning one item (A or B) selected from the enumerated items or any combination of two or more enumerated items (A and B), unless otherwise specifically indicated herein or unless clearly inconsistent with the context. The terms “contain,” “have,” “include,” and “contain” should be interpreted as non-restrictive terms (i.e., “contain, but not limited to”) unless otherwise specifically indicated. The descriptions of value ranges in this specification are intended solely as a convenient way to refer individually to each distinct value contained within the range, unless otherwise indicated herein, and each distinct value is incorporated herein as if it were individually described herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or unless it is clearly inconsistent with the context. Any use of any examples or illustrative language provided herein (e.g., "etc.") is intended solely to further clarify this disclosure and, unless specifically asserted, does not impose any limitation on the scope of this disclosure. Nothing in this specification should be construed as indicating that any unclaimed element is essential for the implementation of any embodiment herein.

Claims

1. Compound of formula I: 【Chemistry 1】 or any acceptable salt, solvate, or hydrate thereof.

2. The compound according to claim 1, wherein the acceptable salt is selected from the group consisting of hydrochloride, phosphate, oxalate, tartrate, fumarate, succinate, and 4-hydroxybenzoate.

3. The compound according to claim 1 or 2, wherein the acceptable salt is a hydrochloride salt.

4. The compound according to claim 3, wherein the compound is 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (formula I-B).

5. A compound according to any one of claims 1 to 4, for use in controlling fungal pathogens.

6. The aforementioned fungal pathogens include Zymoseptoria tritici, Cochliobolus sativus, Puccinia triticina, Puccinia striiformis, Ustilago maydis, Uncinula necator, Rhynchosporium secalis, Magnaporte oryzae, and Phakopsora pachyridi. pachyrhizi), Parastagonospora nodorum, Colletotrichum orbiculare, Puccinia hordei, Cercospora beticola, Alternaria solani, Pyrenophora teres, Blumeria graminis f. sp. tritici, Blumeria graminis f. sp. Hordei (Blumeria graminis f. sp. hordei), Erysiphe cichoracearum, Podosphaera xanthii, Rhizoctonia solani, Botrytis cinerea, Ramularia collo-cygni, Pyrenophora tritici-repentis, Exerohilum tulsicum turcicum, Puccinia polysora, Sclerotinia sclerotiorum, Erysiphe diffuserThe compound according to claim 5, which is one of the following: diffusa), Podosphaera leucotricha, Coletotrichum truncatam, Cercospora kikuchii, Cercospora sojina, Corynespora cassiicola, and Septoria glycinees.

7. The aforementioned fungal pathogens include Zymoseptoria tritici, Pyrenophora terres, Ramularia collo-cygni, Rhynchosporium secalis, Puccinia hordei, Cercospora beticola, Colletotrichum orbiculare, Magnaporte oryzae, and Phakopsora pachyridi. The compound according to claim 6, which is one of the following: pachyrhizi, Alternaria solani, Botrytis cinerea, Podosphaera xanthii, Cercospora kikuchii, Corynespora cassiicola, Septoria glycines, Ustilago maydis, and Puccinia triticina.

8. The compound according to claim 5, for treating one of the following diseases caused by the aforementioned fungal pathogen: wheat septor leaf blight (Zymoseptoria tritici), barley leaf spot (Cochliobolus sativus), wheat red rust (Puccinia triticina), wheat yellow rust (Puccinia striiformis), corn blister smut (Ustilago maydis), grape powdery mildew (Uncinula necatl) (necator), barley leaf blight (Rhynchosporium secalis), rice blast (Magnaporte oryzae), Asian soybean rust (Phacopsora pachyrhizi), wheat rot (Parasagonospora nodorum), cucurbit anthracnose (Coletotrichum orbiculare), barley red rust (Puccinia fordei) (hordei), sugar beet brown spot (Cercospora beticola), tomato ring spot (Alternaria solani), barley net spot (Pyrenophora teres), wheat powdery mildew (Blumeria graminis f.sp. tritici), barley powdery mildew (Blumeria graminis f.sp. hordei), cucurbitaceous plant powdery mildew (Erysiphe chicolaearum) (cichoraceaum), cucumber powdery mildew (Podosphaera xanthii), seedling neck rot or damping-off (Rhizoctonia solani), gray mold (Botrytis cinerea)(Cinerea), Ramularia spot disease (Ramularia collo-cygni), Wheat yellow spot disease (Pyrenophora tritici-repentis), Corn sooty spot disease (Exserohilum turcicum), Corn southern rust disease (Puccinia polysora), White mold disease (Sclerotinia sclerotiorum), Soybean powdery mildew (Erysiphe diffuser) (diffusa), apple powdery mildew (Podosphaera leucotricha), soybean anthracnose (Coletotrichum truncatam), Cercospora black leaf blight (Cercospora kikuchii), bell pepper spot disease (Cercospora sojina), soybean brown spot disease (Corynespora cassiicola), and soybean spot disease (Septoria glycines).

9. The compound according to claim 8, for treating one of the following diseases caused by the aforementioned fungal pathogen: wheat septoria leaf spot (Zymoseptoria tritici), barley net spot (Pyrenophora terres), Ramularia collo-cygni, barley leaf spot (Rhynchosporium secalis), barley red rust (Puccinia hordei), sugar beet brown spot (Cercospora beticola) (Beticola), Cucurbitaceae anthracnose (Coletotrichum orbiculae), Rice blast (Magnaporte oryzae), Asian soybean rust (Phacopsora pachyrhizi), Tomato ring spot (Alternaria solani), Gray mold (Botrytis cinerea), Cucumber powdery mildew (Podosphaera xanthii), Cercospora black leaf blight (Cercospora kikuchii) (kikuchii), soybean brown spot (Corynespora cassiicola), soybean spot (Septoria glycines), corn blister smut (Ustilago maydis), and wheat rust (Puccinia triticina).

10. A composition for use in the control of fungal pathogens, comprising a botanically acceptable amount of the compound and carrier described in any one of claims 1 to 4.

11. The aforementioned fungal pathogens include Zymoseptoria tritici, Cochliobolus sativus, Puccinia triticina, Puccinia striiformis, Ustilago maydis, Uncinula necator, Rhynchosporium secalis, Magnaporte oryzae, and Phakopsora pachyridi. pachyrhizi), Parastagonospora nodorum, Colletotrichum orbiculare, Puccinia hordei, Cercospora beticola, Alternaria solani, Pyrenophora teres, Blumeria graminis f. sp. tritici, Blumeria graminis f. sp. Hordei (Blumeria graminis f. sp. hordei), Erysiphe cichoracearum, Podosphaera xanthii, Rhizoctonia solani, Botrytis cinerea, Ramularia collo-cygni, Pyrenophora tritici-repentis, Exerohilum tulsicum turcicum, Puccinia polysora, Sclerotinia sclerotiorum, Erysiphe diffuserThe composition according to claim 10, which is one of the following: diffusa), Podosphaera leucotricha, Coletotrichum truncatam, Cercospora kikuchii, Cercospora sojina, Corynespora cassiicola, and Septoria glycinees.

12. The aforementioned fungal pathogens include Zymoseptoria tritici, Pyrenophora terres, Ramularia collo-cygni, Rhynchosporium secalis, Puccinia hordei, Cercospora beticola, Colletotrichum orbiculare, Magnaporte oryzae, and Phakopsora pachyridi. The composition according to claim 11, which is one of the following: pachyrhizi, Alternaria solani, Botrytis cinerea, Podosphaera xanthii, Cercospora kikuchii, Corynespora cassiicola, Septoria glycinees, Ustilago maydis, and Puccinia triticina.

13. The composition according to claim 10, for treating one of the following diseases caused by the aforementioned fungal pathogen: wheat septor leaf blight (Zymoseptoria tritici), barley leaf spot (Cochliobolus sativus), wheat red rust (Puccinia triticina), wheat yellow rust (Puccinia striiformis), corn blister smut (Ustilago maydis), and grape powdery mildew (Uncinula necatl) (necator), barley leaf blight (Rhynchosporium secalis), rice blast (Magnaporte oryzae), Asian soybean rust (Phacopsora pachyrhizi), wheat rot (Parasagonospora nodorum), cucurbit anthracnose (Coletotrichum orbiculare), barley red rust (Puccinia fordei) (hordei), sugar beet brown spot (Cercospora beticola), tomato ring spot (Alternaria solani), barley net spot (Pyrenophora teres), wheat powdery mildew (Blumeria graminis f.sp. tritici), barley powdery mildew (Blumeria graminis f.sp. hordei), cucurbitaceous plant powdery mildew (Erysiphe chicolaearum) (cichoraceaum), cucumber powdery mildew (Podosphaera xanthii), seedling neck rot or damping-off (Rhizoctonia solani), gray mold (Botrytis cinerea)(Cinerea), Ramularia spot disease (Ramularia collo-cygni), Wheat yellow spot disease (Pyrenophora tritici-repentis), Corn sooty spot disease (Exserohilum turcicum), Corn southern rust disease (Puccinia polysora), White mold disease (Sclerotinia sclerotiorum), Soybean powdery mildew (Erysiphe diffuser) (diffusa), apple powdery mildew (Podosphaera leucotricha), soybean anthracnose (Coletotrichum truncatam), Cercospora black leaf blight (Cercospora kikuchii), bell pepper spot disease (Cercospora sojina), soybean brown spot disease (Corynespora cassiicola), and soybean spot disease (Septoria glycines).

14. The composition according to claim 13 for treating one of the following diseases caused by the aforementioned fungal pathogen: wheat septoria leaf spot (Zymoseptoria tritici), barley net spot (Pyrenophora teres), Ramularia collo-cygni, barley leaf spot (Rhynchosporium secalis), barley rust (Puccinia hordei), sugar beet brown spot (Cercospora beticola) (Beticola), Cucurbitaceae anthracnose (Coletotrichum orbiculae), Rice blast (Magnaporte oryzae), Asian soybean rust (Phacopsora pachyrhizi), Tomato ring spot (Alternaria solani), Gray mold (Botrytis cinerea), Cucumber powdery mildew (Podosphaera xanthii), Cercospora black leaf blight (Cercospora kikuchii) (kikuchii), soybean brown spot (Corynespora cassiicola), soybean spot (Septoria glycines), corn blister smut (Ustilago maydis), and wheat rust (Puccinia triticina).

15. Seeds treated with a botanically acceptable amount of the compound according to any one of claims 1 to 4 or the composition according to claim 10.

16. A method for inhibiting fungal attack on a plant, comprising contacting a botanically acceptable amount of the compound according to any one of claims 1 to 4 or the composition according to claim 10 with an area adjacent to the plant, soil suitable for supporting the growth of the plant, the roots of the plant, the leaves of the plant, and a growing medium suitable for the growth of the plant or seeds.

17. 4-(difluoromethoxy)benzyl 4-amino-2,5-dimethylbenzoate compound 【Chemistry 2】 or its acceptable salts, solvates, isotopes, or tautomers.

18. Crystalline polymorph A of the compound of formula I according to claim 1, having a powder X-ray diffraction pattern that includes at least two peaks at diffraction angles (2θ) of 5.5±0.2, 12.4±0.2, 21.6±0.2, 23.3±0.2, and 27.1±0.

2.

19. Crystalline polymorph 1 of the compound according to claim 3 or 4, having a powder X-ray diffraction pattern including at least two peaks at diffraction angles (2θ) of 10.5±0.2, 12.1±0.2, 18.7±0.2, 23.6±0.2, and 25.9±0.

2.

20. Crystalline polymorph 2 of the compound according to claim 3 or 4, having a powder X-ray diffraction pattern including at least two peaks at diffraction angles (2θ) of 4.9±0.2, 9.6±0.2, 16.1±0.2, 21.6±0.2, and 24.5±0.

2.

21. Crystalline polymorph 3 of the compound according to claim 3 or 4, having a powder X-ray diffraction pattern that includes at least two peaks at diffraction angles (2θ) of 4.7±0.2, 9.4±0.2, 19.0±0.2, 21.1±0.2, and 24.7±0.2.

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