HK1114393A - Substituted isoxazoles as fungicides - Google Patents

Description

Substituted isoxazoles as fungicides

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application No. 60/608,589, filed on 9/10/2004, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to substituted isoxazoles, compositions thereof and methods of use thereof for controlling plant microbial pests, particularly fungal pests.

Background

The incidence of serious fungal infections (local or systemic) has been continuously increasing for plants, animals and humans. Many fungi are common in the environment, but are not harmful to plants or mammals. However, certain fungi can cause diseases in plants, humans and/or animals.

Fungicides are compounds of natural or synthetic origin which act to protect plants against damage caused by fungi, including Oomycetes. Current agricultural methods rely heavily on the application of fungicides. In fact, some crops do not grow efficiently without the use of fungicides. The use of fungicides allows growers to increase the yield of a crop and thus increase the value of the crop. A number of fungicides have been developed. However, the treatment of fungal infections and infestations has been a major problem. In addition, fungicide and antifungal resistance has become a serious problem, making these agents ineffective for certain agricultural and therapeutic applications. Thus, there remains a need to develop new fungicidal and antifungal compounds (see, for example, U.S. Pat. No. 6,673,827; see also U.S. Pat. No. 6,617,330 to Walter, which describes pyrimidin-4-enamines as fungicides).

Anderson et al, U.S. Pat. No. 5,627,137, describe the preparation of azinylisoprothiolane (azinylphthalamide) and related compounds as herbicides.

Friary et al, U.S. patent No. 5,679,692, describes the preparation of pyridylcarbonylpiperidine-4-methanol and analogs as antihistamines and platelet-activating factor antagonists.

Summary of The Invention

One aspect of the invention is a compound of formula I:

wherein:

R₁is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxyCyano-or nitro-substituted heteroaryl, especially 2-pyridyl, 3-pyridyl or 4-pyridyl; 5-pyrimidinyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group.

R₄Is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); a halogenated acyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; an alkylaminocarbonyl group; or a dialkylaminocarbonyl group.

The compounds and compositions of the present invention are useful as crop protection agents to combat or prevent fungal infestation, or to control other pests that are harmful to crops, such as weeds, insects, or mites.

A second aspect of the present invention is a composition for the control and prevention of phytopathogenic microorganisms comprising an active compound or a combination of compounds as described herein in association with a suitable carrier.

A third aspect of the present invention is a method of controlling or preventing infestation of cultivated plants by pathogenic microorganisms, which comprises applying to the plants, parts thereof or the locus thereof an active compound or combination of compounds as described herein in an amount effective to control said microorganisms.

Another aspect of the invention is a method of controlling or preventing infestation of industrial materials by pathogenic microorganisms, comprising applying to the industrial material, parts thereof or the locus thereof an active compound as described herein in an amount effective to control the microorganisms.

Another aspect of the invention is a method of treating a fungal infection in a subject in need thereof, comprising administering to the subject an active compound as described herein in an amount effective to treat the fungal infection.

A further aspect of the invention is the use of an active compound as described herein for the preparation of a composition (e.g. an agricultural formulation, a pharmaceutical formulation) for the consumption of a method as described herein (e.g. an agricultural treatment as described herein, an industrial material treatment as described herein, a treatment of a fungal infection in a subject as described herein).

The foregoing and other objects and aspects of the invention are described in detail below.

Detailed description of the preferred embodiments

As used herein, "alkyl" refers to a saturated hydrocarbon radical, which may be straight or branched chain (e.g., ethyl, isopropyl, t-amyl, or 2, 5-dimethylhexyl) or cyclic (e.g., cyclobutyl, cyclopropyl, or cyclopentyl), containing from 1 to 24 carbon atoms. Both of these definitions apply when the term is used alone and when it is used as part of a compound term (e.g., "haloalkyl" and similar terms). In certain embodiments, preferred alkyl groups are those containing 1 to 4 carbon atoms, also referred to as "lower alkyl". In certain embodiments, preferred alkyl groups are those containing 5 or 6 to 24 carbon atoms, which may also be referred to as "higher alkyl groups".

"alkenyl" as used herein refers to a straight or branched chain hydrocarbon containing from 2 to 24 carbons, which contains at least one carbon-carbon double bond formed by the removal of 2 hydrogens. Representative examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and the like. As used herein, "lower alkenyl" is a subset of alkenyl and refers to straight or branched chain hydrocarbon radicals containing from 1 to 4 carbon atoms.

"alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 24 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like. As used herein, "lower alkynyl" is a subset of alkyls and refers to straight or branched chain hydrocarbon radicals containing from 1 to 4 carbon atoms.

"alkoxy" refers to an alkyl group as described above which also has an oxygen substituent capable of covalently attaching another hydrocarbyl group (e.g., methoxy, ethoxy, and t-butoxy).

As used herein, "alkylthio" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

"aryl" or "aromatic ring moiety" refers to an aromatic substituent which may be monocyclic or polycyclic, said polycyclic rings being fused together, covalently linked, or linked to a common group, such as an ethylene moiety or a methylene moiety. The aromatic rings may each contain heteroatoms, and thus "aryl" includes "heteroaryl" as used herein. Representative examples of aryl groups include azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, biphenyl, diphenylmethyl, 2-diphenyl-1-ethyl, thienyl, pyridyl and quinoxalinyl. "aryl" means substituted or unsubstituted aryl unless otherwise specified, and thus the aryl moiety may be optionally substituted with a halogen atom or other groups such as nitro, carboxyl, alkoxy, phenoxy, and the like. In addition, the aryl group can be attached to other moieties at any position on the aryl group, which in other instances can be occupied by a hydrogen atom (e.g., 2-pyridyl, 3-pyridyl, and 4-pyridyl).

"heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms are replaced by heteroatoms. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuryl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, 2, 3-naphthyridinyl, 1, 5-naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo [ b ] thienyl. Preferred heteroaryl groups are 5 and 6 membered rings containing 1 to 3 heteroatoms independently selected from O, N and S. Heteroaryl groups, including each heteroatom, may be unsubstituted or, if chemically feasible, substituted with 1 to 4 substituents. For example, the heteroatom S may be substituted with 1 or 2 oxo groups (which may be represented as ═ O).

By "agriculturally acceptable salt" is meant a salt whose cation is known and accepted in the art for forming salts for agricultural or horticultural use. Preferably the salts are soluble in water.

As used herein, "cyano" refers to a-CN group.

As used herein, "halo" or "halogen" refers to-Cl, -Br, -I or-F.

"haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative haloalkyl examples include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

As used herein, "hydroxy" refers to an-OH group.

As used herein, "nitro" refers to-NO₂A group.

As used herein, "oxy" refers to the moiety-O-.

As used herein, "thio or thio" refers to the moiety-S-.

As used herein, "organic base" includes, but is not limited to, triethylamine, triisobutylamine, triisooctylamine, triisodecylamine, diethanolamine, triethanolamine, pyridine, morpholine, and mixtures thereof. Preferred classes of organic bases are organic amines.

As used herein, "inorganic base" includes, but is not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and mixtures thereof.

As used herein, "inert solvent" includes any suitable inert solvent such as tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, toluene, dimethyl ether, methyl tert-butyl ether and dioxane, dichloromethane, chloroform, 1, 2-dichloroethane and mixtures thereof.

As used herein, a "protic solvent" may be any suitable protic solvent, including, but not limited to, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, methyl cellosolve, ethyl cellosolve, cyclohexanol, glycerol, diethylene glycol, triethanolamine, polyethylene glycol, sec-butanol, n-propanol, and tert-butanol.

The contents of all U.S. patent references cited herein are hereby incorporated by reference in their entirety as if fully set forth.

2. Compounds the compounds of the present invention are represented by structural formula I:

wherein:

R₁is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or optionally halogen, alkyl, alkenyl, alkynyl, haloalkaneHeteroaryl substituted with alkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro;

R₂is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; heteroaryl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro, especially 2-pyridyl, 3-pyridyl or 4-pyridyl; 5-pyrimidinyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group.

R₄Is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); a halogenated acyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; an alkylaminocarbonyl group; or a dialkylaminocarbonyl group.

The preparation method has the general structure I (wherein R)₄H) can be prepared by reacting imidoyl chloride (carboximidoyl chloride) II with [3+2] of acetylene-type methanol (acetylcarboxylic) III]-cycloaddition reaction to prepare:

the reaction is carried out in the presence of an organic base such as triethylamine in an inert solvent such as DCE (1, 2-dichloroethane) or an inorganic base such as sodium bicarbonate in an protic solvent such as isopropanol. The reaction time and temperature are not critical but can be carried out at a temperature in the range of 20 to 60 ℃ for 1 to 24 hours.

Imidoyl chloride II is prepared from the corresponding oxime using a chlorinating agent such as N-chlorosuccinimide or sodium hypochlorite (bleach), or is obtained from commercial sources.

By adding organometallic acetylenes IV (M ═ Li, MgX ═ Cl, Br) to the aldehydes R₂Cho (v) to obtain acetylenic methyl III, as follows:

in some cases, when the corresponding ketone (VI) of the acetylene form of methanol III is used, the [3+2] -cycloaddition proceeds faster and in higher yields:

the compound of formula VII may be used to prepare compounds of formula I as described below, wherein isoxazole VII is reduced (e.g., with sodium borohydride) to provide I.

In some cases, together with I, a regioisomer of I is formed in a [3+2] -cycloaddition. This regioisomer VIII is generally less active than I in biological evaluation.

The alkynone VI can be prepared from III by oxidation, for example, with IBX (iodosobenzoic acid) in an inert solvent such as DMSO (dimethyl sulfoxide), at any suitable time and temperature (e.g., 20 ℃ for 1-2 hours). Reduction of isoxazole VII with sodium borohydride in alcoholic solvent (e.g. ethanol) at 0 deg.C for 0.3-2 hours to yield isoxazole I (R)₄＝H)。

From I (R) using standard acylation or carbamylation conditions₄H) preparation of isoxazoles, where R₄Not equal to H. For example, the acetic acid derivative of I (R ═ H) is synthesized from alcohol I (R ═ H) by reaction with acetic anhydride and pyridine in an ether solvent at room temperature overnight₄＝COCH₃). Acylation can be carried out with an acid anhydride (e.g., acetic anhydride, propionic anhydride) or an acid chloride (e.g., benzoyl chloride) in the presence of an organic base in an inert solvent (e.g., diethyl ether, dichloromethane). Carbamylation can be achieved by treating alcohol I with a strong base such as sodium hydride followed by carbamoyl chloride (e.g., N-dimethylcarbamoyl chloride) in an inert solvent such as DMF (dimethylformamide).

Exemplary compounds are provided. Compounds of the invention which are particularly useful for controlling fungal pathogens are those in which:

R₁alkyl; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or heteroaryl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro,

R₂heteroaryl optionally substituted with halo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitroAryl, especially 2-pyridyl, 3-pyridyl or 4-pyridyl; or 5-pyrimidinyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₃alkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or an alkylsilyl group; and

R₄＝H。

examples of compounds of the invention include, but are not limited to, the following:

salts the compounds described herein and optionally all isomers thereof may be obtained in the form of their salts. Since certain compounds I have a basic center, they can, for example, form acid addition salts. For example, the acid addition salts are formed with the following acids: inorganic acids, typically sulfuric acid, phosphoric acid or hydrogen halides; organic carboxylic acids, typically acetic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, or phthalic acid; hydroxycarboxylic acids, typically ascorbic, lactic, malic, tartaric or citric acid; or benzoic acid or an organic sulfonic acid, typically methanesulfonic acid or p-toluenesulfonic acid. The compounds of the formula I having at least one acidic group can also form salts together with bases. Suitable salts with bases are, for example, metal salts, usually alkali metal salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or organic amines, for example morpholine, piperidine, pyrrolidine, monoalkylamine, dialkylamine or trialkylamine, usually ethylamine, diethylamine, triethylamine or dimethylpropylamine or monohydroxyalkylamine, dihydroxyalkylamine or trihydroxyalkylamine, usually monoethanolamine, diethanolamine or triethanolamine. If appropriate, corresponding internal salts may also be formed. Within the scope of the present invention, an agrochemically acceptable salt or a pharmaceutically acceptable salt is preferred.

3. Agrochemical compositions and uses the active compounds according to the invention can be used for the preparation of agrochemical compositions for controlling fungi in a similar manner to other antifungal compounds. See, e.g., U.S. Pat. nos. 6,617,330; see also U.S. patent No. 6,616,952; 6,569,875 No; 6,541,500, and 6,506,794.

The active compounds described herein are useful for protecting plants against diseases caused by fungi. For the purposes of this document, oomycetes shall be regarded as fungi. The active compounds can be used as active components for controlling plant diseases and insect pests in the agricultural sector and in the related fields. The active compounds can be used to inhibit or eliminate pests which occur on plants or plant parts (fruits, flowers, leaves, stems, tubers, roots) of useful plants in different seasons, optionally while also protecting later-growing parts of the plants from, for example, phytopathogenic microorganisms.

The active compounds can be used as seed dressings (dressing agents) for the treatment of plant propagation material, in particular of seeds (fruits, tubers, grains) and plant cuttings (e.g. rice), for protecting against fungal infections and against phytopathogenic fungi present in the soil.

For example, the active compounds can be used against phytopathogenic fungi of the following classes: fungi imperfecti (Fungi) (e.g. Botryis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria) and Basidiomycetes (e.g. Rhizoctonia, Camellia, Puccinia). In addition, they can also be used against Ascomycetes (Ascomycetes) (for example, Venturia (Venturia) and Erysiphe (Erysiphe), Sphaerotheca (Podosphaera), Sclerotinia (Monilinia), Uncinula (Uncinula)) and Oomycetes (Oomyycetes) (for example, Phytophthora (Phytophthora), Pythium (Pythium), Plasmopara). Specific examples of fungi that can be treated include, but are not limited to, Septoria tritici, Stagonospora nodorum, phytophthora infestans, Botrytis cinerea, sclerotina homoocarpa, and Puccinia recondita.

The target crops to be protected with the active compounds and compositions according to the invention generally include the following plant species: cereals (wheat, barley, rye, oats, rice, maize, sorghum and related species); sugar beet (sugar beet and fodder beet); pomes, stone fruits and berries (apples, pears, plums, peaches, apricots, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olive, sunflower, coconut, castor oil plants, cocoa beans, groundnuts); cucurbits (squash, cucumber, melon); fiber plants (cotton, flax, hemp, jute); citrus fruits (oranges, lemons, grapefruits, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cinnamon, camphor) or plants such as tobacco, nuts, coffee, eggplant, sugar cane, tea, pepper, vine and natural rubber plants including grapes, hops, bananas, grass roots, and ornamentals (flowers, shrubs, broad-leaved trees and evergreens, for example conifers). This list is not intended to be limiting in any way.

The active compounds can be used in the form of compositions which can be applied to the crop area or plant to be treated simultaneously or sequentially with further compounds. These additional compounds may be, for example, fertilizers or micronutrient donors or other preparations that affect plant growth. They may also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides, plant growth regulators, plant catalysts or mixtures of several of these preparations, if desired together with further carriers, surfactants or adjuvants conventionally employed in the formulation art to facilitate application.

The active compounds can be mixed with other fungicides, in some cases giving unexpected synergistic activity.

Particularly preferred mixing components are the following: azoles, such as azaconazole, bitertanol, propiconazole, difenoconazole, diniconazole, cyproconazole, epoxiconazole (epoxyconazole), fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, tebuconazole, tetraconazole, fenbuconazole, metconazole, myclobutanil, perfurazole, penconazole, bromuconazole, pyriproxyfen, prochloraz, triadimefon, triadimenol, triflumizole or triticonazole; pyrimidinylmethanols, such as pyrimidinol, isocitritol or fluoropyrimidinol; 2-amino-pyrimidines, such as sulfopyrimethanil, metrafidine or ethidium; morpholines, such as moroxydine, fenpropidin, fenpropimorph, spiroxamine or tridemorph; anilinopyrimidines, for example cyprodinil, pyrimethanil or mepanipyrim; azoles, such as fenpiclonil or fluxapyroxas; benzamides, for example benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, furalamide or oxadixyl; benzimidazoles, such as benomyl, carbendazim, imibencarb, fuberidazole or thiabendazole; dicarboximides such as ethidium, sclerotium, iprodione (iprodine), myclozolium, procymidone or vinclozolin; carboxamides, such as carboxin, furanilide, flutolanil, mefenamide, carboxin oxide or fludioxonil; guanidines, such as diguanidine, dodekuanidine or diguanidine; imines (strobilurines), such as azoxystrobin, kresoxim-methyl, dichlofluanid, pyraclostrobin, picoxystrobin, SSF-129, 2[ (2-trifluoromethyl) -pyridin-6-yloxymethyl ] -3-methoxy-acrylic acid methyl ester or 2- [ { α [ (α -methyl-3-trifluoromethyl-benzyl) imino ] -oxy } -O-tolyl ] -glyoxylic acid methyl ester-O-methyloxime (trifloxystrobin); dithiocarbamates, such as ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb or ziram; n-halomethylthio-dicarboximides, such as captafol, captan, dichlofluanid, folpet or meflosulfan; copper compounds such as bordeaux mixture, copper hydroxide, copper oxychloride, copper sulfate, cuprous oxide, mancopper or oxine-copper; nitrophenol derivatives, such as dinocap or ipratropium; organophosphorus derivatives such as blasticidin, iprobenfos, isoprothiolane, dichlofenphos, fenamiphos or tolclofos-methyl; and other compounds having different structures, such as benzothiadiazole, an allelopathic protein, benomyl, blasticidin, chlorfenapyr, dimethomorph, chlorothalonil, cymoxanil, dichloronaphthoquinone, pyridaben, niclosamide, diethofencarb, dimethomorph, dithianon, hymexazol, famoxadone, fenamidone, fentin, ferimzone, fluazinam, sulfvalicarb, fenamidol, hymexazol, kasugamycin, sulbencarb, pencycuron, isoprothiolane, polyoxin, probenazole, propamocarb, prazole, quintozene, thioben, triazoxide, tricyclazole, triforine, fluazinam, validamycin, (S) -5-methyl-2-methylthio-5-phenyl-3-phenylamino-3, 5-dihydroimidazol-4-one (RPA 407213), 3, 5-dichloro-N- (3-chloro-1-ethyl-1-methyl-2-oxopropyl) -4-methylbenzamide (RH-7281), N-allyl-4, 5-dimethyl-2-trimethylsilylthiophene-3-carboxamide (MON 65500), 4-chloro-4-cyano-N, N-dimethyl-5-p-tolylimidazole-1-sulfonamide (IKF-916), N- (1-cyano-1, 2-dimethylpropyl) -2- (2, 4-dichlorophenoxy) -propionamide (AC 382042) or propineb (SZX 722).

The active compounds may be mixed with one or more systemic acquired resistance inducers ("SAR" inducers), alone or in combination with the above fungicides. SAR inducers are known and described, for example, in U.S. patent No. 6,919,298. Generally, a SAR inducer is any compound that has the ability to initiate resistance of a plant to a pathogenic agent (including but not limited to viruses, bacteria, fungi, or a combination of these factors). In addition, SAR inducers may induce plants to feed against insects as described by Enyedi et al (1992; Cell 70: 879-886). Exemplary SAR inducers include a variety ofA family of compounds, but are linked together by their ability to induce resistance to plant disease and/or feeding by pests. One class of SAR inducers is salicylates. Commercial SAR inducers benzothiadiazole (available as Actigard ® from Syngenta), allergenic pathogenic proteins (available as Messenger)^TMObtained from Eden Biosciences), yeast extract hydrolysate (available as Keyplex) from Saccharomyces cerevisiae (Saccharomyces cerevisiae)^®350-DP^®Available from Morse Enterprises Limited, inc. of miam, Florida), probenazole may be used in the present invention. Elicitors, including the product of goeman, are another class of SAR inducers that may also be used. In addition, ethylene, its biosynthetic precursors or ethylene-releasing compounds such as ethephon are considered useful SAR inducers in this regard. See also U.S. patent No. 6,919,298.

Suitable carriers and auxiliaries can be solid or liquid, which are substances used in formulation technology, for example natural or regenerated mineral substances, solvents, dispersants, wetting agents, adhesives, thickeners, binders or fertilizers.

A preferred method of applying the active compounds according to the invention or agrochemical compositions containing at least one of the compounds is foliar application. The frequency and rate of application will depend on the risk of infestation by the respective pathogen. However, the active compound can also penetrate the plant through the roots via the soil by wetting through the plant locus with a liquid preparation (systemic action), or by applying the compound to the soil in solid form (for example in granular form) (soil application). In water-requiring crops such as rice, these granules can be applied to flooded rice fields. The active compounds can also be applied to the seed (wrapping) by impregnating the seed or tuber with a liquid formulation of the fungicide or by wrapping the seed or tuber with a solid formulation.

The term locus as used herein is intended to include a field in which the crop to be treated is growing, or a field in which the seeds of cultivated plants are sown, or a locus of seeds to be placed in soil. The term seed is intended to encompass plant propagation material, such as cuttings, seedlings, seeds, germinated seeds or soaked seeds.

The active compounds are used in unmodified form or, preferably, together with the auxiliaries conventionally used in the art of formulation. For this purpose, they are expediently formulated in known manner as emulsifiable concentrates, coatable pastes, directly sprayable or dilute solutions, dilute emulsions, wettable powders, soluble powders, dusting powders, granules, or else encapsulated with, for example, polymeric substances. As with the compositions of the type in question, the method of application is chosen according to the intended purpose and prevailing circumstances, for example spraying, atomising, dusting, spreading, coating or pouring.

Advantageous application rates are generally 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably 10g to 1kg a.i./ha, most preferably 20g to 600g a.i./ha. When used as a seed wetting agent (seeddrenching agent), it is convenient to use an amount of 10mg to 1g of active substance per kg of seed.

The formulations are generally prepared by known methods, i.e. compositions comprising a compound of the formula I and, if desired, solid or liquid auxiliaries, by homogeneously mixing and/or milling the compounds with extenders, for example solvents, solid carriers and optionally surface-active compounds (surfactants).

Suitable carriers and auxiliaries can be in the solid or liquid state and correspond to the substances customarily employed in formulation technology, for example natural or regenerated mineral substances, solvents, dispersants, wetting agents, adhesives, thickeners, binders or fertilizers. Such vectors are described, for example, in WO 97/33890.

Other surfactants commonly used in the formulation art are known to the expert or can be found in the literature.

The agrochemical formulations generally comprise from 0.1 to 99% by weight (preferably from 0.1 to 95% by weight) of a compound of the formula I, from 99.9 to 1% by weight (preferably from 99.8 to 5% by weight) of a solid or liquid adjuvant, from 0 to 25% by weight (preferably from 0.1 to 25% by weight) of a surfactant.

However, it is preferred to formulate commercial products as concentrates, with the end user typically using dilute formulations.

The composition may also contain other adjuvants such as stabilizers, antifoams, viscosity regulators, binders or adhesives as well as fertilizers, micronutrient donors or other agents in order to obtain a specific effect.

4. Industrial materials the compounds and combinations of the present invention are also useful in the field of controlling fungal infections (especially caused by molds) of industrial materials, including the protection of industrial materials from fungal attack and the reduction or eradication of fungal infections of industrial materials after such infections have occurred. Industrial materials include, but are not limited to, organic and inorganic materials such as wood, paper, leather, natural and synthetic fibers, composites thereof such as particle board, plywood, wallboard, and the like, woven and non-woven fabrics, building surfaces and materials, cooling and heating system surfaces and materials, ventilation and air conditioning system surfaces and materials, and the like. The compounds and combinations of the present invention can be applied to such materials or surfaces in an amount effective to inhibit or prevent adverse effects such as decay, discoloration, or mildew in the same manner as described above. Structures and dwellings constructed with or mixed with industrial materials to which such compounds or combinations have been applied are likewise protected against fungal attack.

5. Pharmaceutical use in addition to the foregoing, the active compounds of the present invention may be used for medical and veterinary purposes, for the treatment of fungal infections in human and animal subjects (including but not limited to horses, cattle, sheep, dogs, cats and the like). Examples of such infections include, but are not limited to, fungal infections of diseases such as onychomycosis, sporotrichosis, footrot, jungle disease (jungle rot), pseudomycosis boydii (pseudoallomyces boydii), scopularia (scopulariopsis) or tinea pedis (sometimes commonly referred to as white scratch disease) as well as immunodeficient patients such as AIDS patients and transplant patients. Thus, fungal infections may be skin or keratin materials (e.g. hair, hooves or nails) as well as systemic infections, such as those caused by Candida (Candida spp.), Cryptococcus neoformans (cryptococci neoformans), Aspergillus (Aspergillus spp), for example as in pulmonary aspergillosis and Pneumocystis carinii (Pneumocystis carinii) pneumonia. The active compounds described herein can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition according to, for example, U.S. patent No. 6,680,073; 6,673,842 No; 6,664,292 No; 6,613,738 No; 6,423,519 No; 6,413,444 No; 6,403,063 No; and 6,042,845 (the contents of which are expressly set forth herein by reference in their entirety), are administered or administered to such patients or to such infections (e.g., topically, parenterally).

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that carries or transports the subject peptidomimetic drug from one organ or part of the body to another organ or part of the body. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient in question. Examples of certain materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc powder; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. Such formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to form a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to form a single dosage form will generally be that amount of active ingredient which produces a therapeutic effect. Generally, it should be in the range of about 1% to about 99% active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%, by 100%.

The method of preparing these formulations or compositions comprises the step of bringing into association the compound of the invention with the carrier and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the peptides or peptidomimetics of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Ointments, pastes, creams and gels may contain, in addition to the active ingredient, excipients, for example, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain conventional propellants, for example chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

Formulations suitable for oral administration may be presented as discrete units, for example in the form of: capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; powder or granules; solutions or aqueous or non-aqueous liquid suspensions; or an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy including the step of bringing into association the active compound and a suitable carrier which may contain one or more accessory ingredients as described above. In general, the formulations of the invention are prepared by uniformly and intimately bringing into association the active compound with liquid or finely divided solid carriers or both, and then, if necessary, shaping the resulting mixture. For example, tablets may be prepared by compressing or molding a powder or granules containing the active compound and optionally one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, for example as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent. Molded tablets may be made by molding in a suitable machine a powdered compound moistened with an inert liquid binder.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more active compounds of the invention together with one or more of the following pharmaceutically acceptable substances: sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into injectable solutions or dispersions just prior to use; they may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. For example, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersants, and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and other antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

When the compound of the present invention is administered as a medicament to humans and animals, it may be administered as it is, or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of an active ingredient together with a pharmaceutically acceptable carrier.

The formulations of the present invention may be administered by any suitable mode of administration, including oral, parenteral, topical, transdermal, rectal, and the like. The formulations of the invention are of course administered in a form suitable for the respective route of administration. For example, it is administered in the form of tablets or capsules, by injection, inhalation, eye lotion (eye deposition), ointment, suppository, and the like, by injection, infusion, or inhalation; topically administered by lotion or ointment; and rectal administration by suppository. Topical or parenteral administration is preferred.

"parenteral administration" and "parenterally administered" as used herein means modes of administration other than enteral and topical administration, typically by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intracameral, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Actual dosage levels of the active ingredient in the pharmaceutical compositions of the invention may vary in order to obtain an amount of the active ingredient which is effective for a particular patient, composition, mode of administration to achieve a desired therapeutic response (e.g., antifungal activity) without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the specific active compound employed, the route of administration, the time of administration, the rate of excretion of the specific active compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the specific inhibitor employed, the age, sex, body weight, condition, general health and past medical history of the patient to be treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and administer an effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can initially administer to a pharmaceutical composition a dose of a compound of the invention which is lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. It is generally recommended that a dose of about 0.01 or 0.1 to about 50, 100 or 200mg/kg will have therapeutic efficacy, with all weights calculated based on the weight of the active compound, including the case where a salt is employed.

The invention is explained in more detail in the following non-limiting examples.

Example 1

3- (2, 6-dichlorophenyl) -4- [ (3-pyridyl)

Hydroxymethyl ] -5-trimethylsilylisoxazole (Compound 1)

And 3- (2, 6-dichlorophenyl) -5- [ (3-pyridyl)

Hydroxymethyl ] -4-trimethylsilylisoxazole (Compound 2)

A mixture of 55mg (0.24mmol) of 2, 6-dichloro-N-hydroxyphenylimidoyl chloride (hydroxybenzenecarboximidamidoyl chloride), 50mg (0.24mmol) of 1- (3-pyridyl) -3-trimethylsilyl-2-propyn-1-ol and 20mg (0.24mmol) of sodium hydrogen carbonate in 2mL of isopropanol is heated at 55 ℃ for 24 hours. The reaction mixture was diluted with ether. The ether layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The crude product was purified by preparative thin layer chromatography (prep TLC) to isolate 2 products. The less polar product (10mg, 0.025mmol) was identified as 3- (2, 6-dichlorophenyl) -4- [ (3-pyridyl) hydroxy-methyl]-5-trimethylsilylisoxazole.¹H NMR(CDCl₃): δ 0.45(br s, 9), 5.82(s, 1) and 7.40ppm (d, 1). MS m/z: 393.0(M + H).

The product with stronger polarity is 3- (2, 6-dichlorophenyl) -5- [ (3-pyridyl) hydroxymethyl]-4-trimethylsilylisoxazole.¹H NMR(CDCl₃): δ 0.20(m, 9), 6.12(s, 1), 7.80(d, 1) and 7.87ppm (d, 1). MS m/z: 393.0(M + H).

Example 2

5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4-

[ (3-pyridyl) hydroxymethyl ] isoxazole (compound 4)

A mixture of 53mg (0.24mmol) of 2, 4-dichloro-N-hydroxyphenylimidoyl chloride, 50mg (0.21mmol) of 1- (3-pyridyl) -3- (3-chlorophenyl) -2-propyn-1-ol, 26mg (0.31mmol) of sodium bicarbonate in 2.5mL of isopropanol is heated at 55 ℃ on a bench top rotary shaker equipped with a hot sand bath. After 20 hours, an additional 20mg of 2, 4-dichloro-N-hydroxyphenylimidoyl chloride and 10mg of sodium hydrogencarbonate were added, and the reaction mixture was stirred and heated for a further 16 hours. The mixture was then diluted with ether, and the solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The crude product was purified by prep TLC to give 15mg (0.035mmol) of 5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl]Isoxazoles.¹H NMR(CDCl₃): δ 5.92(br s, 1), 7.04(d of d, 1), 7.12(d, 1), 7.72(m, 1), 8.86(br s, 1) and 8.29ppm (br s, 2). MS m/z: 430.9(M + H).

Example 3

5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) acetoxymethyl ] isoxazole

Azole

To a solution of 43mg (0.10mmol) of 5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] isoxazole in 2mL of pyridine was added 19. mu.L (0.20mmol) of acetic anhydride. The reaction was stirred at room temperature overnight, then pyridine was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride, and the ethyl acetate fraction was dried over magnesium sulfate. The drying agent was removed by filtration and the ethyl acetate was removed by rotary evaporation. The crude product is purified by preparative thin layer chromatography (prep TLC) to yield 35mg (0.074mmol) of 5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) acetoxymethyl ] isoxazole.

Example 4

3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl) -4- [ (3-pyridinyl) carbonyl ] isoxazole

To 200mg (1.06mmol) of 4, 4-dimethyl-1-pyridinyl-2-pentyn-1-ol solution in 2.5mL of dimethyl sulfoxide (DMSO) was added 443mg (1.58mmol) of iodosobenzoic acid (IBX). The reaction mixture was stirred at room temperature overnight and then filtered to remove the solids. The filtrate was diluted with ether and washed with saturated sodium chloride solution. The organic portion was separated and dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The ketone product, 4-dimethyl-1- (3-pyridyl) -2-pentyn-1-one (182mg), was used without any purification.

A mixture of 72mg (0.32mmol) of 2, 4-dichloro-N-hydroxyphenylimidoyl chloride, 60mg (0.32mmol) of 4, 4-dimethyl-1- (3-pyridyl) -2-pentyn-1-one and 32mg (0.38mmol, 1.2 eq) of sodium hydrogen carbonate in 2.5mL of isopropanol is heated at 55 ℃ for 16 hours on a bench top rotary shaker. A second addition of 25mg of imidoyl chloride and 10mg of sodium bicarbonate was followed by another 20 hours heating at 55 ℃. The reaction mixture was cooled, diluted with ether and washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The crude product was purified by prep TLC to give 92mg of 3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl) -4- [ (3-pyridyl) carbonyl as an oily product]Isoxazoles.¹H NMR(CDCl₃): δ 1.47(s, 9), 7.90(m, 1), 7.60(br s, 1) and 8.72ppm (br s, 1). MS m/z: 375.0(M + H).

Example 5

3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl)

-4- [ (3-pyridinyl) hydroxymethyl ] -isoxazole (compound 7)

To 92mg (0.24mmol) of 3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl) -4- [ (3-pyridinyl) carbonyl in 5mL of ethanol at 0 deg.C]To the isoxazole solution was added 20mg (0.53mmol) of sodium borohydride. After 2 hours, the reaction mixture was poured into water and the product was extracted several times with ethyl acetate. The combined ethyl acetate fractions were washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the ethyl acetate was removed by rotary evaporation. The crude product was purified by prepTLC to give 68mg (0.18mmol) of 3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl) -4- [ (3-pyridyl) hydroxy-methyl]Isoxazoles.¹H NMR(CDCl₃): δ 1.52(s, 9), 6.14(br s, 1), 6.86(d, 1), 7.38(m, 1), 8.27(br s, 1) and 8.33ppm (m, 1). MS m/z: 377.0(M + H).

Example 6

5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl)

-4- [ (3-pyridinyl) hydroxymethyl ] isoxazole (compound 14)

To a solution of 655mg (4.8mmol) of 2-chlorophenylacetylene cooled to-78 deg.C in 10mL of Tetrahydrofuran (THF) under nitrogen was added 3.0mL (4.8mmol) of 1.6M n-butyllithium in hexane. The solution was stirred at-78 ℃ for 2 hours, then a solution of 514mg (4.8mmol) of 3-pyridinecarboxaldehyde in 2.5mL of Tetrahydrofuran (THF) was added. After 3.5 hours, the reaction mixture was poured into water. The organic product was extracted several times with diethyl ether. The combined ether extracts were washed with saturated sodium bicarbonate and dried over magnesium sulfate. The drying agent was removed by filtration and the ether removed by rotary evaporation to give 3- (2-chlorophenyl) -1- (3-pyridyl) -2-propyn-1-ol as an oil.

A mixture of 52mg (0.23mmol) of 2, 4-dichloro-N-hydroxyphenylimidoyl chloride, 50mg (0.21mmol) of 3- (2-chlorophenyl) -1- (3-pyridyl) -2-propyn-1-ol and 30mg (0.36mmol) of sodium hydrogencarbonate in 3mL of isopropanol was heated at 55 ℃ with shaking overnight. The reaction mixture was cooled, diluted with ether and washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The crude product was purified by prep TLC to give 15mg (0.035mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl]Isoxazoles.¹H NMR(CDCl₃)：δ5.80(br s，1).MS m/z：431.0(M+H)。

Example 7

5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl)

-4- [ (3-pyridinyl) hydroxymethyl ] isoxazole (compound 14)

A mixture of 56mg (0.25mmol) of 2, 4-dichloro-N-hydroxyphenylimidoyl chloride, 60mg (0.25mmol) of 3- (2-chlorophenyl) -1- (3-pyridyl) -2-propyn-1-one and 30mg (0.36mmol) of sodium hydrogencarbonate in 2.5mL of isopropanol was heated at 55 ℃ with shaking overnight. An additional 30mg of imidoyl chloride and 15mg of sodium bicarbonate were then added and the mixture was heated for an additional 20 hours. The reaction mixture was cooled, diluted with ether and washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was removed by filtration and the ether was removed by rotary evaporation. The crude product was purified by prep TLC to give 90mg (0.21mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) carbonyl]Isoxazoles.¹H NMR(CDCl₃): δ 7.16(m, 1), 7.60(m, 2), 7.92(m, 1), 8.53(br d, 1) and 8.74ppm (br s, 1). MS m/z: 428.9(M + H).

To 80mg (0.19mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) carbonyl in 3mL of ethanol at 0 deg.C]To the isoxazole solution was added 40mg (1.06mmol) of sodium borohydride. The mixture was stirred for 2 hoursThen diluted with ethyl acetate. The ethyl acetate solution was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was removed by filtration and the ethyl acetate was removed by rotary evaporation. The crude product was purified by prep TLC to give 65mg (0.15mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl]-isoxazole.¹H NMR(CDCl₃): δ 5.80(br s, 1), 6.97(m, 1), 8.23(br s, 1) and 8.28ppm (br s, 1). MS m/z: 431.0(M + H).

Example 8

5- (2-chlorophenyl) -3- (2, 4-dichlorobenzyl)

-4- [ (3-pyridinyl) hydroxymethyl ] isoxazole (compound 15)

A solution of 59mg (0.25mmol) of 2, 4-dichlorobenzyl imidoyl chloride (prepared as G.Kumaran and G.H.Kulkarni, J.Org.Chem.1997, 62, 1516), 50mg (0.21mmol) of 3- (2-chlorophenyl) -1- (3-pyridyl) -2-propyn-1-one, 43. mu.L (0.31mmol) of triethylamine in mL of dichloromethane was heated in a sealed tube vial at 55 ℃ overnight. The reaction mixture was cooled, diluted with ether, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified by prep TLC to give 50mg (0.11mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorobenzyl) -4- [ (3-pyridyl) carbonyl]Isoxazoles.¹H NMR(CDCl₃): δ 4.23(s, 2), 7.48(d, 1), 7.88(d of d, 1), 8.66(br d, 1) and 8.70ppm (br s, 1). MS m/z: 442.9(M + H).

To 50mg (0.11mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorobenzyl) -4- [ (3-pyridyl) carbonyl in 15mL of THF at room temperature]To the isoxazole solution was added 21mg (0.56mmol) of sodium borohydride. After 2 hours, the solution was diluted with ethyl acetate, washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified by prep TLC to give 39mg (0.088mmol) of 5- (2-chlorophenyl) -3- (2, 4-dichlorobenzyl) -4- [ (3-pyridyl) hydroxymethyl]Different oxygenAnd (3) azole.¹H NMR(CDCl₃)：δ3.91(d，1)，4.00(d，1)，6.97(br s，1)，7.64(d，1)，8.42ppm(brm，2).MS m/z：445.0(M+H)。

Example 9

5- (3-chlorophenyl) -3- (2-fluoro-5-trifluoromethylphenyl)

-4- [ (3-pyridinyl) hydroxy-methyl ] isoxazole (compound 29)

To a solution of 643mg (3.10mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde oxime in 5mL of Dimethylformamide (DMF) was added 456mg (3.41mmol) of N-chlorosuccinimide (see K. -C.Liu., B.R.Shelton and R.K.Howe, J.org.chem.1980, 45, 3916). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was removed by rotary evaporation to give 675mg (2.79mmol) of crystalline 2-fluoro-5-trifluoromethyl-N-hydroxyphenylimidoyl chloride as a pure white color.

A mixture of 60mg (0.25mmol) of 2-fluoro-5-trifluoromethyl-N-hydroxyphenylimidoyl chloride, 50mg (0.21mmol) of 3- (3-chlorophenyl) 1- (3-pyridyl) -2-propyn-1-one (prepared by a procedure analogous to the above-described oxidation of lithium 3-chlorophenylethynyl and 3-pyridinecarboxaldehyde followed by IBX) and 26mg (0.36mmol) of sodium bicarbonate in 2.5mL of isopropanol was shaken with heating at 55 ℃ overnight. An additional 30mg of imidoyl chloride and 15mg of sodium bicarbonate were added and the reaction was heated for an additional 24 hours. The mixture was cooled and diluted with ether. The ether fraction was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by prep TLC to give 56mg (0.13mmol) of 5- (3-chlorophenyl) -3- (2-fluoro-5-trifluoromethylphenyl) -4- [ (3-pyridyl) carbonyl]Isoxazoles.¹H NMR(CDCl₃): δ 7.10(t, 1), 7.41(m, 1), 7.52(m, 1), 8.65(br s, 1) and 8.86ppm (br s, 1). MS m/z: 447.0(M + H).

To a solution of 56mg (0.13mmol) of 5- (3-chlorophenyl) -3- (2-fluoro-5-tris (tert-butyl) chloride in 2mL of ethanolFluoromethyl-phenyl) -4- [ (3-pyridyl) carbonyl]To the isoxazole solution was added 24mg (0.63mmol) of sodium borohydride. After 2 hours at room temperature, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by prep TLC to give 44mg (0.098mmol) of 5- (3-chlorophenyl) -3- (2-fluoro-5-trifluoromethylphenyl) -4- [ (3-pyridyl) hydroxymethyl]Isoxazoles.¹H NMR(CDCl₃): δ 6.01(s, 1), 7.01(m, 1), 7.83(m, 1), 8.27(m, 1) and 8.35ppm (br s, 1). MS m/z: 449.0(M + H).

Example 10

Biological screening

The fungicidal activity of the compounds of the invention was determined using microwell plates. In the primary screening, test compounds in 1 μ L of Dimethylsulfoxide (DMSO) were placed in each well of a 96-well microplate. Then, 100. mu.L of minimal medium consisting of 1.5% agar was added to each well and allowed to cool. Finally, inoculation was performed by adding 10. mu.L of an aqueous suspension of fungal spores to the surface of solid agar. Cover the plate and culture in 20 deg.c controlled environment. After 3-5 days (varied depending on the pathogen), the fungicidal activity was determined by visual and photometric analysis of the fungal growth. Commercial standards (azoxystrobin, benomyl, captan, chlorothalonil, oxazolinone, flusilazole, propiconazole) were included in all assays. The pathogens tested included Septoria tritici (Septoria tritici), Stagonospora nodorum, Phytophthora infestans (Phytophthora infestans) and Botrytis cinerea (Botrytis cinerea). Dose response data for compounds found to be fungicidal were obtained in a preliminary screen by 3-fold serial dilutions of the test compounds. Fungicidal activity the fungicidal activity of certain compounds encompassed by the present invention is expressed as IC50 values in μ M concentration and is included in table 1 below. The coefficient of variance (ratio of standard deviation to mean) in percent is shown in parentheses.

Table 1.
					Number of Compounds	Botrytis cinerea (B.cinerea)	Phytophthora infestans (P.infestans)	S.nodorum	Wheat septoria (S.tritici)
1	E	E	E	C(b)
					3	B(b)	E	B(d)	A(b)
4	B(d)	E	A(b)	A(c)
					7	B(c)	E	E	E
12	B(c)	E	B(d)	A(b)
					13	B(b)	E	B(d)	A(b)

IC50(μM)：A＝0-0.1；B＝0.11-1.0；C＝1.1-10；D＝11-100；E＝＞100

C.V.(％)：(a)＝0-5；(b)＝6-15；(c)＝16-30 (d)＝＞30

Example 11

Turf test of Compound 4

Fungicide tests were performed in spring on 15-age stoloniferous glume cultivar Penncross turf. Turf is maintained in the southern united states with breeding practices similar to the maintenance of clipgrass golf grass. Treatment was performed in divided cells (0.5X 1.0m), randomized complete block design, 4 replicates. Compound 4 was applied as a 25% active ingredient (weight/weight) air milled (air milled) wettable powder. The application rate of compound 4 was as follows (grams active ingredient/1000 square feet): 2.2, 4.4 and 8.8. All other fungicides were applied as indicated (Banner MAXX 1.3ME and Insignia 20 WG). 6 hours after application of the initial prophylactic treatment, turf was inoculated with Sclerotinia homoocarpa (common name: silver spot) infested autoclaved fescue seeds. The cells received approximately 0.24 inches of irrigation water at 1700 f a day to ensure that the leaves were wet for infection overnight. Disease severity was assessed visually using a Horsfall-Barratt rating scale approximately every 7 days from the initial day of administration. Turf quality was evaluated on a scale of 0-9, where 0 is a necrotic, sparse leaf curtain and 9 is a dark green, dense leaf curtain. Disease and mass values were analyzed for variance, and the mean values were statistically separated using the Scott-Knott cluster analysis program.

The silver spot was severe in untreated plots, reaching a peak of > 50% disease. During the study, disease was significantly inhibited (α ≦ 0.05) for all treatment groups compared to untreated controls. For glume-cut golf greens, an average disease rating of < 3.0% was considered acceptable. According to the acceptance criteria, only Banner MAXX and Compound 4 are treatments that provide effective control for the majority of the experimental period.

All treatments significantly (α < 0.05) improved turf quality compared to untreated controls. For a grass-cutting golf green, a quality rating of > 6.0 was considered acceptable. The highest quality grade was associated with the cells treated with Banner MAXX or Compound 4. No appreciable phytotoxicity was observed on any of the cells. Turf quality degradation is mainly caused by coin dome.

Example 12

Cereal test for Compound 4

The field trial of compound 4 was performed with the soft red grain winter wheat cultivar Sisson. Very dry weather results in a low natural incidence of late leaf rust (Puccinia recondita): PUCCRT) in the test. Compound 4 was applied as a 9.5% active ingredient (weight/weight) emulsifiable concentrate (each weight/weight) having the following formulation: 9.5% Compound 4, 9.5% m-Pyrol, 65% Surfadone LP-100, 6% Surfadone LP-300, 5% Toximul 3463F, and 5% Toximul 3464F. The application rate of compound 4 was as follows (grams active ingredient/hectare: g a.i./ha): 140. 280 and 421. Compound 4 showed good control of rust, statistically similar to the commercial standards used in the test [ Stratego (91 and 183g a.i./ha), Absolute (91 and 182g a.i./ha), Quilt (101 and 160g a.i./ha), Tilt (126g a.i./ha), Quadris (170g a.i./ha), headset (82 and 110g a.i./ha) ]. The highest ratio of compound 4 was observed to improve yield compared to the commercial standard.

The foregoing description is intended to be illustrative of the invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims (33)

1. A compound of formula I:

wherein:

R₁is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyAryl substituted with alkyl, alkyl thio, halogen alkoxy, cyano or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; 5-pyrimidinyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group;

R₄is H; an acyl group; a halogenated acyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; an alkylaminocarbonyl group; or a dialkylaminocarbonyl group.

2. The compound of claim 1, or a salt thereof, wherein R₁Is aryl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro.

3. The compound of claim 1, wherein R₁Is 2-chlorphenyl, 4-chlorphenyl, 2, 4-dichlorophenyl, 2-fluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl or 2-thienyl.

4. The compound of claim 1, wherein R₁Is alkyl or aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

5. The compound of claim 1, wherein R₁Is n-pentyl, tert-butyl, benzyl or 4-chlorophenylmethyl.

6. The compound of claim 1, wherein R₂Is heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

7. The compound of claim 1, wherein R₂Is 2-pyridyl, 3-pyridyl or 4-pyridyl or 5-pyrimidinyl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

8. The compound of claim 1, wherein R₃Is an alkyl group; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitroAryl substituted with a substituent; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or an alkylsilyl group.

9. The compound of claim 1, wherein R₃Is phenyl, 3-chlorophenyl, 4-fluorophenyl, 3, 5-difluorophenyl, 4-methylphenyl, 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, tert-butyl or trimethylsilyl.

10. The compound of claim 1, or a salt thereof, wherein R₄Is H.

11. The compound of claim 1, or a salt thereof, wherein:

R₁is aryl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂is heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro;

R₃is an alkyl group; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; or an alkylsilyl group; and

R₄is H.

12. The compound of claim 9, wherein R₁Is 2-chlorphenyl, 4-chlorphenyl, 2, 4-dichlorophenyl, 2-fluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyPhenyl or 2-thienyl.

13. The compound of claim 9, wherein R₂Is 2-pyridyl, 3-pyridyl or 4-pyridyl or 5-pyrimidinyl optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

14. The compound of claim 9, wherein R₃Is phenyl, 3-chlorophenyl, 4-fluorophenyl, 3, 5-difluorophenyl, 4-methylphenyl, 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, tert-butyl or trimethylsilyl.

15. A compound of claim 1 and salts thereof selected from the group consisting of:

3- (2, 6-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5-trimethylsilylisoxazole (compound 1);

3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5-trimethylsilylisoxazole (compound 3);

5- (3-chlorophenyl) -3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] isoxazole (compound 4);

3- (2, 4-dichlorophenyl) -5- (1, 1-dimethylethyl) -4- [ (3-pyridinyl) hydroxymethyl ] -isoxazole (compound 7);

3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5- (2-thienyl) isoxazole (compound 12);

3- (2, 4-dichlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5- (3-thienyl) isoxazole (compound 13);

3- (4-chlorophenyl) -5- (3-chlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] isoxazole (compound 70);

3- (4-chlorophenyl) -5- (4-fluorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] isoxazole (compound 88)

3- (4-chlorophenyl) -5- (4-chlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] isoxazole (compound 91);

3- (4-chlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5- (3-thienyl) isoxazole (compound 94);

5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 96);

3- (4-chlorophenyl) -5- (3, 5-difluorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 105);

3- (4-chlorophenyl) -5- (3-chlorophenyl) -4- [ (5-pyrimidinyl) hydroxymethyl ] -isoxazole (compound 107);

5- (3-chlorophenyl) -3- (5-chloro-2-thienyl) -4- [ (5-pyrimidinyl) hydroxymethyl ] -isoxazole (compound 108);

3- (5-bromo-2-thienyl) -5- (4-chlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 109);

3- (4-chlorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -5- (2-thienyl) isoxazole (compound 116);

5- (4-chlorophenyl) -3- (2, 4-difluorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 121);

3- (4-chlorophenyl) -5- (5-chloro-2-thienyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 122);

3- (5-chloro-2-thienyl) -5- (5-chloro-2-thienyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 123);

5- (4-chlorophenyl) -3- (3, 5-difluorophenyl) -4- [ (3-pyridyl) hydroxymethyl ] -isoxazole (compound 124).

16. A composition for the control and prevention of phytopathogenic microorganisms, comprising a compound according to claim 1 in combination with an acceptable carrier.

17. The composition of claim 14, further comprising at least one additional fungicide or systemic acquired resistance inducer.

18. A method of controlling or preventing infestation of a cultivated plant by pathogenic microorganisms, the method comprising:

applying a compound of claim 1 to said plant, part thereof or locus thereof in an amount effective to control said microorganism.

19. The method of claim 16, wherein the microorganism is a fungal organism.

20. The method of claim 17, wherein the fungal organism is selected from the group consisting of Septoria tritici (Septoria tritici), Stagonospora nodorum, Phytophthora infestans (Phytophthorainfestans), Botrytis cinerea (Botrytis cinerea), Sclerotinia homoeocarpa, and Puccinia recondita (Puccinia).

21. A method of controlling or preventing infestation of plant propagation material by pathogenic microorganisms, the method comprising:

applying a compound of claim 1 to said plant propagation material in an amount effective to control said microorganism.

22. The method of claim 19, wherein the plant propagation material comprises seeds.

23. The method of claim 19, wherein the microorganism is a fungal organism.

24. A method of controlling or preventing infestation of industrial materials by pathogenic microorganisms, the method comprising:

applying a compound of claim 1 to said industrial material in an amount effective to control said microorganisms.

25. A method of treating a fungal infection in a subject in need of treatment, the method comprising:

administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the fungal infection.

26. A composition for treating a fungal infection in a subject in need of treatment, the composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

27. A process for preparing a compound of formula I:

wherein:

R₁is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; 5-pyrimidinyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkylOxy, alkylthio, haloalkoxy, cyano or nitro substituted arylthioalkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group; and

R₄is H;

the method comprises the following steps:

reacting imidoyl chloride of formula II

Wherein R is₁In order to be given as above, it is,

with acetylene type methanol of formula III:

wherein R is₂And R₃In order to be given as above, it is,

in the presence of a base in an inert or protic solvent to give the compounds of formula I.

28. The process of claim 25, wherein the solvent is an inert solvent and the base is an organic base.

29. The process of claim 25, wherein the solvent is a protic solvent and the base is an inorganic base.

30. A process for preparing a compound of formula I:

wherein:

R₁is an alkyl group; an alkoxyalkyl group; a haloalkyl group; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkylAlkoxy, alkylthio, haloalkoxy, cyano or nitro substituted aralkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group; and

R₄is H;

the method comprises the following steps:

reacting imidoyl chloride of formula II

Wherein R is₁In order to be given the above, it is,

with an alkynone of formula VI:

wherein R is₂And R₃In order to be given as above, it is,

reaction in an inert or protic solvent in the presence of a base, followed by reduction with sodium borohydride in an alcoholic solvent, yields the compound of formula I.

31. A process for preparing a compound of formula VI:

wherein

R₂Is an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or 2-thiazolyl or 5-thiazolyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, cyano or nitro;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxyCyano-or nitro-substituted arylthioalkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or an alkylsilyl group;

the method comprises the following steps:

oxidizing an acetylene type alcohol of formula III with an oxidizing agent in the presence of an inert solvent,

to produce the compound of formula VI.

32. The method of claim 29, wherein the oxidizing agent is iodosobenzoic acid.

33. A compound of formula VI

Wherein:

R₂is 3-pyridyl or 5-pyrimidinyl;

R₃is H; an alkyl group; an alkoxyalkyl group; a haloalkyl group; aralkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro; optionally substituted by halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitroThe heteroaryl group of (a); or an alkylsilyl group.