Apyrase inhibitors

Abstract

Disclosed herein are apyrase inhibitors of formula (I). Disclosed herein are methods of using the disclosed inhibitors, including methods for protecting crops from pests. In one aspect, apyrase inhibitors are useful for enhancing the activity of pesticides to protect crops from pathogens and supporting crop yield. In a further embodiment, the apyrase inhibitors described herein are used in combination with one or more pesticides to treat at-risk crops. JPEG2025529184000148.jpg24161

Description

[Technical Field]

[0001] The present disclosure relates to inhibitors of apyrase and methods of their use, particularly in the treatment of pathogen-susceptible crops. [Background technology]

[0002] Crops are plagued by a variety of pathogens worldwide. Pathogens, including insects, mites, nematodes, bacteria, weeds, and fungi, have developed a series of mechanisms to survive by sequestering, excreting, or detoxifying pesticides. The present inventors have discovered molecules and methods for enhancing the efficacy of pesticides by blocking specific resistance mechanisms. Summary of the Invention [Means for solving the problem]

[0003] Disclosed herein are molecules and methods for their use in supporting crop survival and yield, for example, by protecting crops from pests. In one embodiment, disclosed herein is a method for inhibiting the apyrase enzyme, comprising inhibiting apyrase by reacting a compound of the formula [ka] wherein Ar 1 is selected from aryl and heteroaryl; R 1 is hydrogen, C 3-6 Cycloalkyl, C 1-6 Alkyl, aralkyl, and C 1-3 haloalkyl; R 2 is selected from alkyl, aryl, and heteroaryl.

[0004] In further embodiments, the apyrase inhibitors described herein are used in combination with one or more pesticides to treat at-risk crops.

[0005] The foregoing and other objects, features, and advantages of the present invention will become apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0006] I. Terminology The following explanations of terms and methods are provided to more fully describe the present disclosure and to guide those skilled in the art in practicing the present disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to any single element of listed alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "including A or B" means "including A, B, or A and B," excluding additional elements. All references cited herein, including patents and patent applications, are incorporated by reference in their entirety unless otherwise specified.

[0007] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, and the like used in the specification or claims should be understood to be modified by the term "about." Thus, unless implicitly or explicitly indicated otherwise, the numerical parameters given are approximations and may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. When directly and explicitly distinguishing an embodiment from the prior art discussed, the numbers of the embodiments are not approximations unless the word "about" is explicitly recited.

[0008] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0009] "Administering" refers to any suitable mode of administration for controlling fungal pathogens, including treatment of existing crops, seeds, soil, or combinations thereof.

[0010] "Control," with respect to fungal pathogens, means blocking, inhibiting, and / or eradicating the fungal pathogen and / or preventing the fungal pathogen from damaging the crop. In one embodiment, control refers to reducing one or more fungi to undetectable levels, or reducing or suppressing fungi to an acceptable level as determined by one skilled in the art (e.g., a crop grower). Determining an acceptable level of fungal reduction is based on numerous factors, including the crop, the pathogen, pathogen severity, use limitations, economic thresholds, and other factors known to those skilled in the art.

[0011] As used herein, the terms "accelerator" and "potentiator" refer to a compound(s) disclosed herein that enhances the effectiveness of a pesticide. Without being limited by theory, the accelerator compounds disclosed herein may function by blocking one or more pathways by which pathogens, such as fungal pathogens, avoid toxicity by detoxifying, sequestering, or excreting the pesticide. In certain embodiments, the compounds inhibit the activity of the enzyme apyrase, which leads to the enhancement, emphasis, or potentiation of pesticides, such as acaricides, antimicrobials, fungicides, herbicides, insecticides, molluscicides, and / or nematicides. For example, when an accelerator or potentiator is used in conjunction with a fungicide, the combination of the potentiator and fungicide enhances the fungicidal effect of the fungicide, and / or as a result of the activity of the potentiator, fungi that have previously been resistant to the fungicide become susceptible to the fungicide. In most cases, these promoters or enhancers do not themselves inhibit the fungus itself and do not have any deleterious effects on organisms infected (or potentially infected) with the fungus.

[0012] As used herein, the term "inoculation" refers to a method used to administer or apply an effective amount of a disclosed compound or formulation thereof to a target area of ​​a field and / or plant. Inoculation methods can include, but are not limited to, aerosol spray, pressure spray, direct watering, and immersion. Target areas of a plant can include, but are not limited to, leaves, roots, stems, buds, flowers, fruits, plant seeds, and plant bulbs, including bulbs, corms, rhizomes, tubers, root nodules, and rhizophores. Inoculation can include methods in which a plant is treated in one area (e.g., the root zone or foliage) and another area of ​​the plant is protected (e.g., the foliage is inoculated when the disclosed compound is applied to the shoots when applied to the root zone or foliage).

[0013] As used herein, the terms "water-dispersible granules," "water-dispersible granules," and "dispersible granules" refer to solid granule formulations prepared by a granulation process, optionally containing polymer-associated active ingredient microparticles or agglomerates thereof, wetting agents and / or dispersing agents, and optionally inert fillers. The water-dispersible granules can be stored as a formulation and provided to the market and / or end users without further processing. In some embodiments, they are packaged in water-soluble bags for end-user ease of use. In actual applications, the water-dispersible granules are prepared for application by the end user. The water-dispersible granules are mixed with water in the end user's spray tank to the appropriate dilution for the particular application. The dilution may vary depending on the crop, fungal pathogen, time of year, geography, local regulations, and the degree of infestation, among other factors. Once appropriately diluted, the solution can be applied for spraying.

[0014] As used herein, the terms "wettable powder," "water-dispersible powder," and "dispersible powder" refer to a solid powder formulation containing an active ingredient, optionally associated with a polymer or aggregates thereof, and optionally one or more dispersing agents, wetting agents, and inert fillers. Wettable powders can be stored as a formulation and provided to markets and / or end users without further processing. In some embodiments, they are packaged in water-soluble bags for end-user ease of use. In actual applications, the wettable powders are prepared for application by the end user. The wettable powder is mixed with water in the end user's spray tank to the appropriate dilution for the particular application. The dilution may vary depending on the crop, target pathogen, time of year, geography, local regulations, and degree of infestation or pathogen load, among other factors. Once appropriately diluted, the solution can be applied for spraying.

[0015] As used herein, the term "high solids liquid suspension" refers to a liquid formulation containing microparticles of an active ingredient or polymer microparticles associated with the active ingredient, or aggregates thereof, a wetting agent and / or dispersant, an antifreeze, optionally an antisettling or thickening agent, optionally a preservative, and water or oil as a carrier. The high solids liquid suspension can be stored as a formulation and provided to the market and / or end user without further processing. In actual use, the high solids liquid suspension is prepared for application by the end user. The high solids liquid suspension is mixed with water or oil in the end user's spray tank to the appropriate dilution for the specific application. The dilution may vary depending on the crop, target pathogen, time of year, geography, local regulations, and the degree of infection or pathogen load, among other factors. Once appropriately diluted, the solution or suspension can be applied for spraying.

[0016] As used herein, the term "physiologically acceptable" refers to compositions, diluents, excipients, and / or carriers that are generally applicable for use on any part of a plant during any part of the plant's life cycle, including, but not limited to, seeds, seedlings, plant cells, plants, or flowers. Compositions can be prepared according to procedures, methods, and formulas known to those skilled in the agricultural arts. Armed with the teachings of the present disclosure, those skilled in the agricultural and / or chemical arts can readily prepare desired compositions. Most generally, the compounds of the present invention can be formulated for storage and / or application as neat or as aqueous or non-aqueous suspensions or emulsions prepared from concentrated formulations of the compositions. Alternatively, the compounds of the present invention can be formulated for use in an aerosol-generating device for application to produce stored in a sealed chamber, an application method known as spraying. Water-soluble, water-suspendable, or emulsifiable formulations containing the presently disclosed compounds can also be converted to or formulated as solids (e.g., wettable powders), which can then be diluted into the final formulation. In certain formulations, the compositions of the present disclosure may also be provided to growth media such as in vitro media for the growth of plants or other types of cells, laboratory plant growth media, soil, or for spraying onto seeds, seedlings, roots, trunks, stems, leaves, flowers, or whole plants.

[0017] The compounds herein may include all stereoisomers, including E and Z isomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.

[0018] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azide groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, haloalkyl groups, alkenyl groups, haloalkenyl groups, alkynyl groups, haloalkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclylalkyl groups, heteroaryl groups, cycloalkyl groups, acyl groups, acyloxy groups, carbamate groups, amido groups, ureido groups, epoxy groups, and ester groups.

[0019] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon. Non-limiting examples of alkyl groups include straight-chain, branched, and cyclic alkyl and alkylene groups. Alkyl groups include, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C77, C88, C99, C78, ​​C89, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C109, C111, C121, C131, C142, C151, C152, C162, C173, C184, C195, C196, C197, C198, C199, C199, C200, C210, C221, C231, C242, C253, C263, C274, C285, C298, C3 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C45 , C 46 , C 47 , C 48 , C 49 , or C 50 In some cases, alkyl refers to a group having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms, and the sp of the alkyl residue 3 The -hybridized carbon is attached to the rest of the molecule by a single bond. Whenever a numerical range such as "Ci_6 alkyl" appears herein, it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a Ci_ 10 alkyl, C1-9 alkyl, C1-8 alkyl, C1-7 alkyl, C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, or C1 alkyl.

[0020] Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl.

[0021] Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0022] Branched alkyl groups include any straight chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0023] Unless otherwise stated herein, alkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0024] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon double bonds. The olefin(s) of the alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. The alkyl group can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26, C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Non-limiting examples of substituted alkenyl and alkenylene groups include ethenyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl, 2-chloroethenyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methyloct-3,5-dien-2-yl.

[0025] Whenever a numerical range appears herein, such as "C2-C6 alkenyl," means that the alkenyl group consists of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl refers to any of the C2-C6 alkenyl groups. 10Alkenyl is C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0026] "Alkynyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon. The triple bond of an alkynyl group can be internal or terminal. An alkynyl or alkynylene group can be, for example, a substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C78, ​​C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C91, C92, C93, C94, C95, C96, C97, C98, C99, C99, C99, C101, C102, C103, C104, C105, C106, C107, C108, C109, C111, C112, C113, C114 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 Non-limiting examples of alkynyl groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5-ethylhept-3-yn-1-yl.

[0027] Whenever a numerical range appears herein, such as "C2-C6 alkynyl," means that the alkynyl group consists of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. In some embodiments, alkynyl refers to any of the C2-C6 alkynyl groups. 10 alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with, as the case may be, halogen.

[0028] A haloalkyl group can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. A haloalkenyl group can be any alkenyl group substituted with any number of halogen atoms. A haloalkynyl group can be any alkyl group substituted with any number of halogen atoms.

[0029] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. Ether or ether groups include alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0030] The term "acyl" refers to the groups HC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclyl-C(O)-, where alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are as defined herein. Exemplary acyl groups include acetyl and benzoyl groups.

[0031] "Alkoxy" means a group of the formula -OR a (wherein R a is an alkyl radical as defined above). Unless stated otherwise in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0032] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0033] "Aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to a cycloalkyl or heterocyclylalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise in the specification, an aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0034] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3-C4). 15 cycloalkyl), 3 to 10 carbon atoms (C3-C 10Cycloalkyl groups include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl), 3 to 6 carbon atoms (C-C cycloalkyl), 3 to 5 carbon atoms (C-C cycloalkyl), or 3 to 4 carbon atoms (C-C cycloalkyl). In some embodiments, cycloalkyls are 3 to 6-membered cycloalkyls. In some embodiments, cycloalkyls are 5 to 6-membered cycloalkyls. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include fused bicyclic, bridged bicyclic, and spiro bicyclic rings, as well as higher fused, bridged, and spiro systems. Cycloalkyl groups can be substituted with any number of linear, branched, or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-1-yl, Examples include 3,5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptatanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0035] Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0036] Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.

[0037] Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, cycloalkyls can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, cycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyls are optionally substituted with halogen.

[0038] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0039] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

[0040] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0041] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl is an atom other than carbon, for example, oxygen, nitrogen (e.g., The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, or -CH(CH)OCH. Unless stated otherwise in the specification, the heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0042] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0043] "Heterocyclyl" refers to a stable 3- to 24-membered heterocycle. A heterocycle can be any ring containing a ring atom that is not carbon, such as N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, such as alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0044] Non-limiting examples of heterocycles include heterocyclic units having a single ring containing one or more heteroatoms, including, but not limited to, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4, 5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii) heterocyclic units having two or more rings, one of which is a heterocycle, non-limiting examples of which include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

[0045] "Heterocyclylalkyl" refers to a stable 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Unless stated otherwise in the specification, a heterocyclylalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocyclylalkyl is attached through a non-aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclylalkyl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized.

[0046] Representative heterocyclylalkyls include those containing 2 to 15 carbon atoms (C2-C 15 heterocyclylalkyl), 2 to 10 carbon atoms (C2-C 10Heterocyclylalkyl includes, but is not limited to, heterocyclylalkyl having 2 to 8 carbon atoms (C2-C8 heterocyclylalkyl), 2 to 6 carbon atoms (C2-C6 heterocyclylalkyl), 2 to 5 carbon atoms (C2-C5 heterocyclylalkyl), or 2 to 4 carbon atoms (C2-C4 heterocyclylalkyl). In some embodiments, heterocyclylalkyl is a 3- to 6-membered heterocyclylalkyl. In some embodiments, cycloalkyl is a 5- to 6-membered heterocyclylalkyl. Examples of such heterocyclylalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperazinyl, and 4-piperazinyl. Examples of heterocyclylalkyl include lydonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocyclylalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms of a heterocyclylalkyl, it is understood that the number of carbon atoms of the heterocyclylalkyl is not the same as the total number of atoms (including heteroatoms) constituting the heterocyclylalkyl (i.e., the skeletal atoms of the heterocyclylalkyl ring).Unless stated otherwise in the specification, a heterocyclylalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocyclylalkyl is optionally substituted with halogen.

[0047] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. Unless otherwise specified herein, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems (when fused to a cycloalkyl or heterocyclylalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, isoindolyl, indolinyl, iso Examples include, but are not limited to, indolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0048] II. Compounds In one embodiment, the pesticidal enhancers disclosed herein include those having the formula (I): [ka] In the formula, Ar 1 is selected from aryl and heteroaryl; R 1 is hydrogen, C 3-6 selected from cycloalkyl, C alkyl, aralkyl, and C haloalkyl; R 2 is selected from alkyl, aryl, and heteroaryl; provided that the compound does not have the formula: [ka]

[0049] With respect to formula (I), the bond [ka] indicates that the carbon-nitrogen double bond may be cis or trans, and the compound may be an E or Z isomer. Thus, in one embodiment of a compound according to formula (I), a compound of formula (Ia) is provided: [ka] In the formula, Ar 1 is selected from aryl and heteroaryl; R 1 is hydrogen, C 3-6 selected from cycloalkyl, C alkyl, aralkyl, and C haloalkyl; R 2 is selected from alkyl, aryl, and heteroaryl; provided that the compound does not have the formula [ka]

[0050] In another embodiment, the compound of formula (I) has the formula (Ib) [ka] In the formula, Ar 1 is selected from aryl and heteroaryl; R 1 is hydrogen, C 3-6 selected from cycloalkyl, C alkyl, aralkyl, and C haloalkyl; R 2 is selected from alkyl, aryl, and heteroaryl.

[0051] In certain embodiments, compounds of formula (I), (Ia) and (Ib) have the formula [ka] wherein X, at each occurrence, is independently selected from the group consisting of R a , R b , the same or different R b R substituted with one or more of a , the same or different R b or R d -OR replaced by one or more of a ,or -(CH2) m -R b ,-(CHR a ) m -R b ,-O-(CH2) m -R b ,-S-(CH2) m -R b ,-O-CHR a R b ,-O-CR a (R b )2, -O-(CHR a ) m -R b ,-O-(CH2) m -CH[(CH2)m R b ]R b ,-S-(CHR a ) m -R b ,-C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b ,-O-(CH2) m -C(O)NH-(CH2) m -R b ,-S-(CH2) m -C(O)NH-(CH2) m -R b , -O-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-S-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-NH-(CH2) m -R b , -NH-(CHR a ) m -R b ,-NH[(CH2) m R b ],-N[(CH2) m R b ]2,-NH-C(O)-NH-(CH2) m -R b ,-NH-C(O)-(CH2) m -CHR b R b Selected from; or two X substituents, together with the atoms to which they are attached, form a 5- to 8-membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be joined by the same or different R b may be substituted with one or more of the groups; Each R a independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, C 6-16 selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R b are independently =O, -OR d , C 1-3 Haloalkyloxy, -OCF2H, -OCH2F, -OCF3, =S, -SR d , -SCF3, -SF5, =NR d , =NOR d , -NR c R c , halogen, -CF3, -CN, -NO2, -S(O)R d , -S(O)2R d , -S(O)2CF3, -S(O)2OR d , -S(O)NR c R c , -S(O)2NR c R c , -OS(O)R d , -OS(O)2R d , -OS(O)2OR d , -OS(O)2NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c , -C(NH)NR c R c , -C(NR a )NR c R c , -C(NOH)R a , -C(NOH)NR c R c , -OC(O)R d , -OC(O)OR d , -OC(O)NR c Rc , -OC(NH)NR c R c , -OC(NR a )NR c R c , -[NHC(O)] n R d , -[NR a C(O)] n R d , -[NHC(O)] n OR d , -[NR a C(O)] n OR d , -[NHC(O)] n NR c R c , -[NR a C(O)] n NR c R c , -[NHC(NH)] n NR c R c and -[NR a C(NR a )] n NR c R c is a group selected from the group consisting of: Each R c are independently a or alternatively two R cは Together with the nitrogen atom to which they are attached, they form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally contain the same or different R b may be substituted with one or more of the groups; Each R d are independently hydrogen or C 1-6 is alkyl; each m is independently an integer from 1 to 3; Each n is independently an integer from 0 to 3.

[0052] In certain embodiments, compounds of formula (I), (Ia), and (Ib) are 1-6 Alkyl, -ORa , -S(O)NR c R c and X is selected from halogen.

[0053] In certain embodiments disclosed herein, including compounds of formula (I), (Ia), (Ib), and (II), Ar 1 is optionally substituted aryl, such as optionally substituted phenyl. In particular examples of such compounds, X is the same or different R b or R d -OR replaced by one or more of a Ar 1 is phenyl, in one such embodiment, n is 2 and X is -OR a and each R a is C 1-6 In certain embodiments, the inhibitor compound has the formula (IIa): [ka]

[0054] In certain embodiments of formulas (I), (Ia), (Ib), (II), and (IIa), R 1 is hydrogen and R 2 is selected from hydrogen, alkyl, aryl, and heteroaryl. In one embodiment of the above formula, R 1 is hydrogen and R 2 is selected from hydrogen and methyl (e.g., in the formula R 1 and R 2 is hydrogen).

[0055] In certain embodiments described herein, including embodiments of Formulas (I), (Ia), and (Ib), Ar 1 is heteroaryl, for example, Ar 1 is a monocyclic heteroaryl or a bicyclic heteroaryl.

[0056] In certain embodiments of Formulas (I), (Ia), and (Ib), Ar 1is a monocyclic heteroaryl, for example, Ar 1 is optionally substituted pyridyl. In one embodiment, the compounds of formula (I), (Ia) and (Ib) are of formula (III) [ka] wherein X, at each occurrence, is independently selected from the group consisting of R a , R b , the same or different R b R substituted with one or more of a , the same or different R b or R d -OR replaced by one or more of a ,or -(CH2) m -R b ,-(CHR a ) m -R b ,-O-(CH2) m -R b ,-S-(CH2) m -R b ,-O-CHR a R b ,-O-CR a (R b )2, -O-(CHR a ) m -R b ,-O-(CH2) m -CH[(CH2) m R b ]R b ,-S-(CHR a ) m -R b ,-C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b ,-O-(CH2) m -C(O)NH-(CH2) m -R b ,-S-(CH2) m -C(O)NH-(CH2) m -R b , -O-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-S-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-NH-(CH2) m -R b , -NH-(CHR a ) m -R b ,-NH[(CH2) m R b ],-N[(CH2) m R b ]2,-NH-C(O)-NH-(CH2) m -R b ,-NH-C(O)-(CH2) m -CHR b R b Selected from; or two X substituents, together with the atoms to which they are attached, form a 5- to 8-membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be joined by the same or different R b may be substituted with one or more of the groups; Each R a independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, C 6-16 selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R b are independently =O, -OR d , C 1-3 Haloalkyloxy, -OCF2H, -OCH2F, -OCF3, =S, -SRd 、-SCF3、-SF5、=NR d 、=NOR d 、-NR c R c 、ハロゲン、-CF3、-CN、-NO2、-S(O)R d 、-S(O)2R d 、-S(O)2CF3、-S(O)2OR d 、-S(O)NR c R c 、-S(O)2NR c R c , -OS(O)R d 、-OS(O)2R d 、-OS(O)2OR d 、-OS(O)2NR c R c 、-C(O)R d 、-C(O)OR d 、-C(O)NR c R c 、-C(NH)NR c R c 、-C(NR a )NR c R c 、-C(NOH)R a 、-C(NOH)NR c R c 、-OC(O)R d 、-OC(O)OR d 、 -OC(O)NR c R c 、-OC(NH)NR c R c 、-OC(NR a )NR c R c 、-[NHC(O)] n R d 、-[NR a C(O)] n R d 、-[NHC(O)] n OR d 、-[NR a C(O)] n OR d 、-[NHC(O)] n NR c R c 、-[NRa C(O)] n NR c R c , -[NHC(NH)] n NR c R c and -[NR a C(NR a )] n NR c R c and each R c are independently a or alternatively two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally contain the same or different R b may be substituted with one or more of the groups; Each R d are independently hydrogen or C 1-6 is alkyl; each m is independently an integer from 1 to 3; Each n is independently an integer from 0 to 3.

[0057] In one embodiment, the compounds of formula (I), (Ia), (Ib) and (III) have the formula (IIIa) [ka] It has.

[0058] In another embodiment of Formulas (I), (Ia), and (Ib), Ar 1 is a monocyclic heteroaryl and the compound has the formula (IV) [ka]

[0059] In one embodiment of Formulas (I), (Ia), and (Ib), Ar 1 is a bicyclic heteroaryl and the compound has the formula (V) [ka]

[0060] In another embodiment of Formulas (I), (Ia), and (Ib), Ar 1 is a bicyclic heteroaryl and the compound has the formula [ka] It has.

[0061] In certain embodiments of formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), and (VI), R 2 is alkyl, such as methyl. In other embodiments of Formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), and (VI), R 2 is heteroaryl or aryl. In one such embodiment, R 2 is aryl, and in certain embodiments of such compounds, R 2 is an optionally substituted phenyl, such as in compounds of formula (VII) [ka] wherein Y is independently for each occurrence R a , R b , the same or different R b R substituted with one or more of a , the same or different R b or R d -OR replaced by one or more of a ,or -(CH2) m -R b ,-(CHR a ) m -R b ,-O-(CH2) m -R b ,-S-(CH2) m -R b ,-O-CHR a Rb ,-O-CR a (R b )2, -O-(CHR a ) m -R b ,-O-(CH2) m -CH[(CH2) m R b ]R b ,-S-(CHR a ) m -R b ,-C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b ,-O-(CH2) m -C(O)NH-(CH2) m -R b ,-S-(CH2) m -C(O)NH-(CH2) m -R b , -O-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-S-(CHR a ) m -C(O)NH-(CHR a ) m -R b ,-NH-(CH2) m -R b , -NH-(CHR a ) m -R b ,-NH[(CH2) m R b ],-N[(CH2) m R b ]2,-NH-C(O)-NH-(CH2) m -R b ,-NH-C(O)-(CH2) m -CHR b R b Selected from; or two X substituents together with the atom to which they are attached form a 5-8 membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be alkyl, cycloalkyl, and R b may be substituted with one or more of the same or different containing groups; Each R a independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, C 6-16 selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R b are independently =O, -OR d , C 1-3 Haloalkyloxy, -OCF2H, -OCH2F, -OCF3, =S, -SR d , -SCF3, -SF5, =NR d , =NOR d , -NR c R c , halogen, -CF3, -CN, -NO2, -S(O)R d , -S(O)2R d , -S(O)2CF3, -S(O)2OR d , -S(O)NR c R c , -S(O)NR c R c , -OS(O)R d , -OS(O)2R d , -OS(O)2OR d , -OS(O)2NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c , -C(NH)NR c R c, -C(NR a )NR c R c , -C(NOH)R a , -C(NOH)NR c R c , -OC(O)R d , -OC(O)OR d , -OC(O)NR c R c , -OC(NH)NR c R c , -OC(NR a )NR c R c , -[NHC(O)] n R d , -[NR a C(O)] n R d , -[NHC(O)] n OR d , -[NR a C(O)] n OR d , -[NHC(O)] n NR c R c , -[NR a C(O)] n NR c R c , -[NHC(NH)] n NR c R c and -[NR a C(NR a )] n NR c R c and each R c are independently a or alternatively two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be the same or different R b may be substituted with one or more of the groups; Each R d are independently hydrogen or C 1-6is alkyl; each m is independently an integer from 1 to 3; Each n is independently an integer from 0 to 3.

[0062] In further embodiments of Formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), and (VI), the compounds disclosed herein include compounds of Formula (VIII): [ka]

[0063] Specific examples of apyrase inhibitors and compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and / or (VIII) according to the present disclosure for use in enhancing the activity of the agricultural or horticultural pesticides described herein are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

[0064] III. Methods for producing compounds The compounds disclosed herein, including compounds of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII), can be prepared as will be understood by one of ordinary skill in the art upon review of this disclosure. For example, such compounds can be prepared by condensation of an acyl hydrazide with an aldehyde or ketone. In one embodiment, compounds of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII) are prepared according to Scheme (I), as illustrated below: [ka] In the formula, Ar 1 , R 1 , and R 2is selected from those described in Section II above. Continuing to refer to Scheme (I), appropriate conditions can be determined by one skilled in the art and may include, but are not limited to, mildly acidic conditions. Exemplary conditions that may be suitable for the preparation of compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and / or (VIII) are described in G Vantomme, S Jiang & JM Lehn, J. Am. Chem. Soc., 2014, 136, 9509-9518, and K Jasiak & A Kudelko, Tetrahedron Lett., 2015, 56, 5878-5881. Similarly, suitable starting materials, such as acyl hydrazides, can be prepared from compounds of formula Ar, as known to those skilled in the art, for example, 1 It can be prepared from esters of COR, where R is alkyl. Ketones and aldehydes suitable for condensation with acyl hydrazides can also be prepared as known to those skilled in the art.

[0065] IV. Target Crops and Their Pathogens The present disclosure provides formulations and methods for use in treating crops for pathogens. In one embodiment, one or more of the presently disclosed compounds, e.g., compounds of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII), are administered in combination with an agricultural or horticultural pesticide, such as an acaricide, antimicrobial, fungicide, herbicide, insecticide, molluscicide, and / or nematicide. Crops that can be treated include those affected by various pathogens, including, but not limited to, bacterial, viral, fungal pathogens, mites, nematodes, molluscs, weeds, or other pests, as known to those skilled in the agricultural arts. By way of example, such agricultural and horticultural crops that can be treated in accordance with the present disclosure include plants, including their crops, whether genetically modified or not, such as, for example, grains; vegetables; root vegetables; potatoes; fruit trees, such as trees, e.g., banana trees, tea trees, coffee trees, or cocoa trees; grasses; turf; or cotton.

[0066] Lu and coworkers discovered the compound [ka] (referred to herein as "Lu Compound 15") has been described as enhancing the ability of certain fungicides to inhibit the growth of different plant pathogenic fungi (Molecular Plant Pathology, 2017, 18(7), 1012-1023; and WO 2016 / 123191). The compounds of the present invention surprisingly enhance the ability of various fungicides against a wide variety of pathogens, including fungal pathogens. Furthermore, exemplary compounds currently disclosed exhibit superior promoter activity to that of Lu Compound 15.

[0067] The agricultural or horticultural enhancers disclosed herein can be applied to various parts of plants, such as leaves, stems, stems, flowers, buds, fruits, seeds, shoots, roots, tubers, tuberous roots, shoots, or cuttings. The agricultural or horticultural enhancers according to the present disclosure can also be applied to improved varieties / varieties, cultivars, and mutant, hybrid, and genetically modified embodiments of these plants. The agricultural or horticultural treatments described herein can be used to perform seed treatments, foliage applications, soil applications, or water applications to control a variety of diseases occurring in agricultural or horticultural crops, including flowers, turf, and pasture grasses.

[0068] The compounds of the present invention are useful for enhancing the effectiveness of antibacterial agents, for example, the compounds can be used in combination with antibacterial agents to combat bacterial and viral infections. The compounds of the present invention are useful for enhancing the effectiveness of herbicides, for example, the compounds can be used in combination with one or more herbicides to control weeds or other unwanted vegetation.

[0069] The compounds of the present invention are useful for enhancing the effectiveness of insecticides, for example, the compounds can be used in combination with one or more insecticides to control insect infestations.

[0070] The compounds of the present invention are useful for enhancing the effectiveness of acaricides or acaricides. For example, the compounds can be used in combination with one or more acaricides to control mites.

[0071] The compounds of the present invention are useful for enhancing the effectiveness of molluscicides. For example, the compounds can be used in combination with one or more molluscicides to prevent slugs or snails from damaging crops.

[0072] The compounds of the present invention are useful for enhancing the effectiveness of nematicides. For example, the compounds can be used in combination with one or more nematicides to prevent nematodes from damaging crops.

[0073] The compounds of the present invention are particularly useful for enhancing the effectiveness of fungicides against fungal pathogens of plants. Examples of pathogens that may be treated according to the present disclosure include, but are not limited to, Botrytis cinerea, Colletotrichum graminicola, Fusarium oxysporum, Sclerotiana sclerotiorum, Verticillium dahlia, Mycospharella gramincola, and Sphacelotheca reliana.

[0074] Botrytis cinerea is an airborne plant pathogen whose necrotrophic lifestyle affects over 200 crop hosts worldwide. The fungus primarily attacks dicotyledonous plant species, including important protein, oil, fiber, and horticultural crops, grapes, and strawberries; Botrytis also causes soft rot of fruits and vegetables during storage, transport, and marketing. Many classes of fungicides have failed to control Botrytis cinerea due to its genetic plasticity.

[0075] The genus Colletotrichum consists of approximately 600 species that infect over 3,200 species of monocotyledonous and dicotyledonous plants. Colletotrichum graminicola primarily infects corn (Zea mays), causing losses of approximately $1 billion annually in the United States alone (Connell et al., 2012).

[0076] Banana wilt disease, caused by the soil-borne pathogen Fusarium oxysporum f.sp. cubense, is a major threat to banana production worldwide. Currently, no fungicides are available to effectively control the disease once plants are infected (Peng J et al., 2014).

[0077] The mildew fungus Sclerotinia sclerotiorum is known to infect over 400 host species and is considered one of the most prolific plant pathogens. The majority of crop species affected are dicotyledons, as well as several agriculturally important monocotyledons. Some important crops affected by S. sclerotiorum include legumes (soybeans), most vegetables, stone fruits, and tobacco.

[0078] The ascomycete Verticillium dahliae is a soil-borne fungal plant pathogen that causes vascular wilt disease in a wide range of dicotyledonous host species. V. dahliae can cause severe yield and quality losses in cotton and other important crops, such as vegetables, fiber, fruit, nuts, trees, and ornamentals.

[0079] The ascomycete fungus Mycospharella grammingola (anamorph: Septoria tritici) is one of the most important foliar diseases of wheat leaves and occurs wherever wheat is grown. Yield losses due to this disease range from 25% to 50%, and are particularly high in Europe, the Mediterranean region, and East Africa. Infection by M. gramincola is initiated by airborne ascospores produced in residues from the previous year's crop. Primary infection usually occurs after seedling emergence in spring or autumn. Mature disease is characterized by necrotic lesions on the leaves and stems of infected plants.

[0080] The basidiomycete fungus Sphacelotheca reliana infects maize (Zea mays) systemically and causes head smut. Yield losses due to the disease are variable and directly depend on the incidence of the disease. The fungus overwinters as diploid teliospores in crop debris or soil. Floral structures transform into sporangia containing powdery teliospore masses, similar to the galls of common smut.

[0081] Examples of crops that may be treated and plant diseases (pathogens) that may be controlled using the presently disclosed compounds and compositions include, but are not limited to, the following: Sugar beet: brown spot disease (Cercospora beticola), black root disease (Aphanomyces cochlioides), root rot disease (Thanaphorus cucumeris), Thanatephorus cuumeris disease (Thanaphorus cuumeris), leaf rot disease (Thanaphorus cucumeris), etc. Peanut: Brown spot (Mycosphaerella arachidis), leaf mold (Ascochyta sp.), rust (Puccinia arachidis), damping-off (Pythium debaryanum), rust spot (Alternaria alternata), stem rot (Sclerotium rolfsii), black rust (Mycosphaerella berkeleyi), etc. Cucumber: Powdery mildew (Sphaerotheca fuliginea), downy mildew (Pseudoperonospora cubensis), vine blight (Mycosphaerella melonis), wilt (Fusarium oxysporum), sclerotinia sclerotiorum, gray mold (Botrytis cinerea), anthracnose (Colletotrichum orbiculare), black spot (Cladosporium cucumerinum), brown spot (Corynespora cassiicola), damping-off (Pythium debaryanum, Rhizoctonia solani Kuhn), Phomopsis root rot (Phomopsis sp.), bacterial spot (Pseudomonas syringae pv. Lechrymans), etc. Tomatoes: Gray mold (Botrytis cinerea), leaf mold (Cladosporium fulvum), leaf blight (Phytophthora infestans), verticillium wilt (Verticillium albo-atrum, Verticillium dahliae), powdery mildew (Oidium neolycopersici), summer blight (Alternaria solani), leaf mold (Pseudocercospora fuligena), etc. Eggplant: Gray mold (Botrytis cinerea), black rot (Corynespora melongenae), powdery mildew (Erysiphe cichoracearum), leaf mold (Mycovellosiella nattrassii), sclerotinia rot (Sclerotinia sclerotiorum), verticillium wilt (Verticillium dahlia), brown spot (Phomopsis vexans), etc. Strawberries: Gray mold (Botrytis cinerea), powdery mildew (Sphaerotheca humuli), anthracnose (Colletotrichum acutatum, Colletotrichum fragariae), Phytophthora rot (Phytophthora cactorum), soft rot (Rhizopus stolonifer), Fusarium wilt (Fusarium oxysporum), and Verticillium dahlia wilt, etc. Onion: Neck dwarf disease (Botrytis allii), gray mold (Botrytis cinerea), leaf blight (Botrytis squamosa), downy mildew (Peronospora destructor), Phytophthora porn, etc. Cabbage: Clubroot (Plasmodiophora brassicae), soft rot (Erwinia carotovora), black rot (Xanthomonas campestris pv. campestris), bacterial black spot (Pseudomonas syringae pv. Maculicola, Pspv. alisalensis), dew fungus (Peronospora parasitica), sclerotinia rot (Sclerotinia sclerotiorum), black spot (Alternaria brassicicola), gray mold (Botrytis cinerea), etc. Common beans: Sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum lindemuthianum), angular spot disease (Phaeoisariopsis griseola), etc. Apples: Powdery mildew (Podosphaera leucotricha), black spot (Venturia inaequalis), monilinia (Monilinia mali), black spot (Mycosphaerella pomi), canker (Valsa mali), leaf spot (Alternaria mali), rust (Gymnosporangium yamadae), ring rot (Botryosphaeria berengeriana), anthracnose (Glomerella cingulata, Colletotrichum acutatum), leaf rot (Diplocarpon mali), fly speck disease (Zygophiala jamaicensis), sooty blotch (Gloeodes pomigena), purple root rot (Helicobasidium mompa), gray mold (Botrytis cinerea), etc. Plum: Black spot (Cladosporium carpophilum), gray mold (Botrytis cinerea), brown spot (Monilinia mumecola), etc. Persimmon: Powdery mildew (Phyllactinia kakicola), anthracnose (Gloeosporium kaki), angular leaf spot (Cercosporakaki), etc. Peaches: Brown rot (Monilinia fructicola), black spot (Cladosporium carpophilum), Phomopsis root rot (Phomopsis sp.), bacterial bore (Xanthomonas campestris pv.pruni), etc. Almonds: Monilinia taxa, Stigmina carpophila, Cladosporium carpophilum, Polystigma rubrum, Alternaria alternata, Colletotrichum gloeospoides, etc. Yellow peach: Monilinia fructicola, anthracnose (Colletotrichum acutatum), black spot (Alternaria sp.), young fruit fungus (Monilinia kusanoi), etc. Grapes: Gray mold (Botrytis cinerea), powdery mildew (Uncinula necator), late rot (Glomerella cingulata, Colletotrichum acutatum), downy mildew (Plasmopara viticola), anthracnose (Elsinoe ampelina), brown spot (Pseudocercospora vitis), black rot (Guignardia bidwellii), white rot (Coniella castaneicola), rust (Phakopsora ampelopsidis), etc. Pear: Common scab (Venturia nashicola), rust (Gymnosporangium asiaticum), black spot (Alternaria kikuchiana), ring rot (Botryosphaeria berengeriana), powdery mildew (Phyllactinia mali), chitospora blight (Phomopsis fukushii), brown spot blotch disease (Stempphylium vesicarium), anthracnose (Glomerella cingulata), etc. Tea: Ring spot (Pestalotiopsis longiseta, P. theae), anthracnose (Colletotrichum theae-sinensis), net blight (Exobasidium reticulatum), etc. Citrus fruits: Common scab (Elsinoe fawcettii), blue mold (Penicillium italicum), green mold (Penicillium digitatum), gray mold (Botrytis cinerea), black spot (Diaporthe citri), canker (Xanthomonas campestris pv. Citri), powdery mildew (Oidium sp.), etc. Wheat: Powdery mildew (Blumeria graminis f.sp. tritici), Fusarium head blight (Gibberella zeae), Brown rust (Puccinia recondita), Brown snow rot (Pythium iwayamai), Pink snow rot (Monographella nivalis), Eyespot (Pseudocercosporella herpotrichoides), Leaf scorch (Septoria tritici), Leaf blight (Leptosphaeria nodorum), Small snow rot (Typhula incarnata), Large snow rot (Myriosclerotinia borealis), Damping-off (Gaeumannomyces graminis), Ergot (Claviceps purpurea), Smut (Tilletia caries), Pungent slump (Telletia caries), Naked smut (Ustilago nuda), etc. Barley: leaf spot disease (Pyrenophora graminea), web spot disease (Pyrenophora teres), leaf blight (Rhynchosporium secalis), naked smut disease (Ustilago tritici, U. nuda), etc. Rice: Blight (Pyricularia oryzae), Sheath blight (Rhizoctonia solani), Bakanae disease (Gibberella fujikuroi), Brown spot disease (Cochliobolus miyabeanus), Damping-off disease (Pythium graminicola), Bacterial leaf blight (Xanthomonas oryzae), Bacterial seedling blight (Burkholderia plantarii), Brown stripe disease (Acidovorax avenae), Bacterial grain rot (Burkholderia glumae), Brown spot disease (Cercospora oryzae), Rice smut (Ustilaginoidea virens), Brown spot disease of rice (Alternaria alternata, Curvularia intermedia), Black rice (Alternaria padwickii), Pink rice grain disease (Epicoccum purpurascens), etc. Tobacco: Sclerotinia rot (Sclerotinia sclerotiorum), powdery mildew (Erysiphe cichoracearum), Phytophthora rot (Phytophthora nicotianae), etc. Tulips: Gray mold (Botrytis cinerea), etc. Sunflower: Dew fungus (Plasmopara halstedii), Sclerotinia rot (Sclerotinia sclerotiorum), etc. Bentgrass: Snow mold (Sclerotinia borealis), large patch (Rhizoctonia solani), brown patch (Rhizoctonia solani), dollar spot (Sclerotinia homoeocarpa), blight (Pyricularia sp.), Pythium wilt (Pythium aphanidermatum), anthracnose (Colletotrichum graminicola), etc. Orchardgrass: Powdery mildew (Erysiphe graminis), etc. Soybean: Purple spot (Cercospora kikuchii), dew fungus (Peronospora manshurica), Phytophthora rot (Phytophthora sojae), rust (Phakopsora pachyrhizi), Sclerotinia rot (Sclerotinia sclerotiorum), anthracnose (Colletotrichum truncatum), gray mold (Botrytis cinerea), black rot (Elsinoe glycines), black spot (Diaporthe phaseolorum var. sojae), etc. Potatoes: Phytophthora infestans, Alternaria solani, Thanatephorus cucumeris, Verticillium albo-atrum, V. dahlia, V. nigrescens, etc. Banana: Panama disease (Fusarium oxysporum), Sigatoka disease (Mycosphaerella fijiensis, M. musicola), etc. Rapeseed: Sclerotinia rot (Sclerotinia sclerotiorum), root rot (Phoma lingam), black leaf spot (Alternaria brassicae), etc. Coffee: Rust (Hemileia vastatrix), anthracnose (Colletotrichum coffeanum), leaf spot (Cercospora coffeicola), etc. Sugarcane: Brown rust (Puccinia melanocephala), etc. Corn: Ring spot (Gloeocercospora sorghi), rust (Puccinia sorghi), southern rust (Puccinia polysora), ear smut (Ustilago maydis), brown spot (Cochliobolus heterostrophus), sooty leaf spot (Setosphaeria turcica), etc. Cotton: Seedling damping-off (Pythium sp.), rust (Phakopsora gossypii), white mold (Mycosphaerella areola), anthracnose (Glomerella gossypii), etc.

[0082] V. Pesticides The presently disclosed compounds, including compounds according to Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), are useful for enhancing the effectiveness of various pesticides, including fungicides, antivirals, antibacterials, herbicides, insecticides / acaricides, molluscicides, nematicides, soil pesticides, plant control agents, plant regulators, synergists, fertilizers, and soil conditioners.

[0083] In one embodiment, the presently disclosed compounds are useful for enhancing the fungicidal effect of various fungicides. Fungicides for use in combination with the accelerators disclosed herein are well known to those of skill in the art and include, but are not limited to, those listed by class in Table 2: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0084] Fungicides are more broadly classified by the Fungicide Resistance Task Force (FRAC) in the FRAC Code List 2022, reproduced in Appendix 1, which is incorporated herein by reference in its entirety.

[0085] In one embodiment, the presently disclosed accelerator compounds are used in combination with one or more compounds from a family or group set forth in Table 2, Appendix 1, or both. In certain embodiments, the presently disclosed accelerators are used in combination with one or more fungicides listed in column 1 of Table 2. By way of example, the use of an accelerator compound of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII) in combination with a fungicide can include administration at the same time or at different times. In one embodiment, the accelerator compound is administered before the fungicide. In one embodiment, the accelerator compound is administered after the fungicide.

[0086] In certain embodiments, the disclosed enhancers are cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, morpholine, cyflufenamid, metrafenone, pyriophenone, strobilurin, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbons, phthalimide, gluconamide, methylparaben ... In some embodiments, the fungicides may be used in combination with one or more of the fungicides selected from benzimidazoles, including imidazoles and triazoles such as anidines, polyoxins, furadinams, and thiazolidines, dicarboximides, phenylpyrroles, anilinopyrimidines, hydroxyanilides, carboxamides, phenylamides, phosphonates, cinnamic acids, oxysterol binding protein inhibitors (OSBPIs), triazole carboxamides, cymoxanil, carbamates, benzamides, demethylation-inhibiting piperazines, demethylation-inhibiting pyrimidines, and demethylation-inhibiting azoles.

[0087] Specific fungicides that may be potentiated by administration of an apyrase inhibitor when used in combination with an accelerator according to the methods herein include copper, such as copper octoate, copper hydroxide, myclobutanil, propiconazole, tebuconazole, epoxiconazole, difenoconazole, triticonazole, and prothioconazole.

[0088] In one embodiment, a combination treatment of a selected fungicide and an enhancer according to the present disclosure provides synergistic fungicidal activity against plant pathogenic filamentous fungi.

[0089] In one embodiment, the present disclosure provides compositions and methods for treating plants or plant seeds infected with or at risk of infection by fungal pathogens. In one embodiment, the composition of the present disclosure includes a fungicide formulation, an accelerator, and a phytologically acceptable carrier. In another embodiment, the fungicide and accelerator are administered in separate compositions. In a further embodiment, agricultural or horticultural fungicides are used in combination with other compounds in addition to the presently disclosed apyrase inhibitors. Like the apyrase inhibitor, such other compounds can be administered in the same or separate compositions as the fungicide. Examples of other ingredients include known carriers used to formulate the formulation. Additional examples include conventional herbicides, insecticides / acaricides, nematicides, soil pesticides, plant control agents, synergists, fertilizers, soil conditioners, and animal feeds. In one embodiment, the inclusion of such other ingredients provides a synergistic effect on crop growth.

[0090] In one embodiment, the presently disclosed compounds, including compounds according to Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), are used to enhance the effectiveness of herbicides. Exemplary herbicides for use in combination with the present compounds will be known to those of skill in the art and include, but are not limited to, those listed in Appendix 2. By way of example, suitable herbicides for use in combination with the present compounds include inhibitors of acetyl-CoA synthetase, inhibitors of acetolactate synthesis, inhibitors of microtubule polymerization, inhibitors of microtubule organization, auxin mimetics, photosynthesis inhibitors, deoxy-D-xylulose phosphate synthase inhibitors, enolpyruvyl phosphate synthase inhibitors, phytoene desaturase inhibitors, glutamine synthetase inhibitors, dihydropteroate synthesis inhibitors, protoporphyrinogen oxidase inhibitors, cellulose synthesis inhibitors, uncouplers, hydroxyphenylpyruvate dioxygenase inhibitors, fatty acid thioesterase inhibitors, serine-threonine protein phosphatase inhibitors, solanesyl diphosphate synthase inhibitors, inhibitors of very long chain fatty acid synthesis, homogentisate solanesyltransferase inhibitors, and lycopene cyclase inhibitors.

[0091] In one embodiment, the presently disclosed compounds, including compounds according to Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), are used to enhance the effectiveness of insecticides. Exemplary insecticides for use in combination with the present compounds will be known to those of skill in the art and include, without limitation, those listed in Appendix 3.

[0092] VI. Formulations The present disclosure provides specific apyrase inhibitors, including compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), for enhancing the efficacy of pesticides and effectively limiting the growth of plant pathogenic species. In certain non-limiting embodiments, the apyrase inhibitor can be provided in about 0.01 to about 80% by weight, or about 25% to about 55%, e.g., about 30% to about 50%, about 35% to about 45%, e.g., about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 20, 30, 40, 50, 55, 60, or 80% by weight of the final composition. In one embodiment, the apyrase inhibitor is provided in a liquid form that is about 0.01 to about 50% volume to volume in the final diluted composition, e.g., about 15% to about 50%, about 20% to about 45%, or about 25% to about 40%, e.g., about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 15, 20, 30, 40, or 50%. Those skilled in the art will recognize that formulations of pesticides, apyrase inhibitors, or combinations thereof, can be provided in concentrates that can be diluted before use, or in ready-to-use diluted forms.

[0093] The accelerator, the pesticide, and their combinations are not particularly limited by the dosage form. Examples of dosage forms include wettable powders, emulsions, emulsifiable concentrates, oil dispersions, powders, granules, water-soluble agents, suspensions, water-dispersible granules, and tablets. The method for preparing the formulation is not particularly limited, and conventionally known methods can be used depending on the dosage form. [Example]

[0094] Some formulation examples are described below. The preparation formulations shown below are merely examples and may be modified within the scope consistent with the essence of the present disclosure. For example, additional active and inactive ingredients may be added to the formulations described below.

[0095] "Parts" means "parts by weight" unless otherwise specified.

[0096] Formulation Example 1: Wettable powder 40 parts of an accelerator disclosed herein, 53 parts of diatomaceous earth, 4 parts of an ethoxylated higher alcohol sulfate, and 3 parts of an alkyl naphthalene sulfonate in combination with a suitable solid carrier such as magnesium sulfate are uniformly mixed and then pulverized to obtain a wettable powder containing 40 parts by weight of the accelerator. Formulation Example 2: Emulsion Three parts of an accelerator disclosed herein, 60 parts mixed petroleum distillates, 27 parts dimethyl lactamide, and 10 parts tristyrylphenol ethoxylate are mixed and dissolved to provide an emulsion containing 3% by weight of the accelerator. Formulation Example 3: Granules Five parts of an accelerator disclosed herein, 10 parts of talc, 38 parts of clay, 10 parts of bentonite, 30 parts of sodium lignosulfonate, and 7 parts of sodium alkyl sulfate are uniformly mixed and pulverized, and then fluidized bed granulation is performed to obtain granules containing 5% by mass of an accelerator disclosed herein on a dry weight basis, with a median particle size of 0.2 to 2.0 mm. Formulation Example 4: Granules Five parts of the accelerator disclosed herein, 73 parts of clay, 20 parts of bentonite, 1 part of dioctyl sodium sulfosuccinate, and 1 part of potassium phosphate are mixed and milled, water is added, and the mixture is kneaded. Extrusion granulation is then carried out, and the resultant is dried to obtain granules containing 5% by weight of the accelerator on a dry weight basis. Formulation Example 5: Suspension 10 parts of an accelerator disclosed herein, 4 parts of polyoxyethylene alkyl ether, 2 parts of a 3 kDa sodium polycarboxylate as a dispersant, 10 parts of glycerin, 0.2 parts of xanthan gum, 0.1 parts of a biocide as a stabilizer, 0.1 parts of an organosilicon antifoam emulsion, and 73.6 parts of water are mixed and then wet-milled to a particle size of 3 microns or less to obtain a suspension containing 10% by weight of the accelerator. Formulation Example 6: Oil Dispersible Concentrate 40 parts of an accelerator disclosed herein, 5 parts of Atlox 4914, 5 parts of organically modified bentonite, and 50 parts of methylated rapeseed oil as a carrier are homogeneously mixed and then wet-milled to a median particle size of 3 microns or less to obtain an oil-dispersible concentrate containing 40% by weight of the accelerator.

[0097] Those skilled in the art will recognize that various compositions are commercially available in a variety of concentrations and formulations. For example, disinfectants are commonly formulated commercially as liquids at concentrations of 10-40%. In one embodiment, the presently disclosed accelerators allow for the use of lower amounts of a given disinfectant due to the enhanced efficacy of the disinfectant when combined with the accelerators disclosed herein.

[0098] VII. Methods for assessing promoter activity The presently disclosed compounds exhibit activity against a variety of pathogens. Their activity is assessed, in part, according to the following assays:

[0099] Method 1: In vitro apyrase assay: Apyrase inhibitors useful as enhancers of insecticidal activity are evaluated using an in vitro assay. The method of Windsor, BioTechniques 33:1024-1030 (November 2002) was used as follows: Screening of apyrase inhibitors A 96-well plate was used for the assay: (Greiner bio-one: REF-655901-96 well, PS, F-bottom, clear, non-binding) Buffer: Reaction buffer: 60 mM Hepes, 3 mM MgCl, 3 mM CaCl, and 3 mM ATP (pH 6.5) Developing buffer A: 2% ammonium molybdate aqueous solution Developing buffer B: 11% ascorbic acid in 37.5% TCA aqueous solution Stop buffer C: 2% trisodium citrate in 2% aqueous acetic acid Add 100ul of reaction buffer to each well. Add 10ul of DMSO (control) or inhibitor / compound or compounds such as N1915 or orthovanadate to each well (inhibitor concentration 1mM; use 2mM orthovanadate and 1mM N1915). Add 10 ul of apyrase (concentration based on optimization - dilute 1 U / ul enzyme to different concentrations such as 0.1 U, 0.05 U, 0.0025, 0.001 U, 0.0005 U to find a good range). Incubate the plate at room temperature for 1 hour. Mix developing buffer A and B in a ratio of 1:1.5 (just before use). Add 50ul of A:B mix to each well (incubate for 2 minutes) Add 50ul of C to each well. ●Measure / read the plate absorbance at 630nm For selected compounds, inhibition data for the above apyrase assay are shown in Table 3: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] Referring to Table 3, percent inhibition of apyrase is reported as the rounded mean of two assay results. Blank cells indicate either observed inhibition of less than 10% or large differences between replicates. In certain instances, the lack of observed inhibition is due to a lack of compound solubility under the assay conditions, rather than a lack of apyrase inhibitory activity. Compound 15 inhibited apyrase by approximately 60% in this assay.

[0100] Method 2: In vitro assessment of combination activity Selected compounds were evaluated in combination with fungicides against a range of commercially important plant pathogenic filamentous fungi.

[0101] The tests were performed as follows: the fungicide was applied to the fungal plant pathogen in combination with an appropriate dose of the test compound at a rate slightly lower than that which gave any control. If control of the pathogen was observed, the test compound was recorded as active.

[0102] More specifically, the test was performed as follows: For each combination of fungicide, pathogen, and test compound, the following wells were used: Well 1 contained a fungal pathogen growing on agar and a fungicide at a rate slightly below the rate that controlled the pathogen. Well 2 was identical to Well 1, except that the test compound was also added at Rate 1. Well 3 was identical to Well 2, except that the test compound was added at Rate 2, which was higher than Rate 1. Finally, as a baseline, Well 4 was identical to Well 1, except that it contained a higher rate of fungicide, but partially controlled the pathogen. Each of Wells 1–4 was performed in duplicate, giving a total of eight wells for each combination of fungicide, pathogen, and test compound. After the appropriate incubation period, each well was visually evaluated for percent pathogen control by the fungicide. Test compounds were scored as inactive, active, or highly active.

[0103] The following fungicides were used in this assay: azoxystrobin, fluxapyroxad, and desthioprothioconazole. The following fungal pathogens were also used in this assay: first, a Zymoseptoria tritici strain with reduced susceptibility to strobilurin fungicides; second, a Zymoseptoria tritici strain with reduced susceptibility to SDHI fungicides (i.e., those that inhibit succinate dehydrogenase); and third, Microdochium nivale. Compound 15 showed no activity in this assay. In contrast, compound I-4, which inhibited only 24% of apyrase activity in Method 1 and was highly effective in the combination assay, showed significant activity against all three fungal pathogens in combination with each of the three fungicides.

[0104] Compound I-223, which inhibited only 10% of apyrase activity in Method 1, showed significant activity in combination with fluxapyroxad against Microdochium nivale and in combination with desthioprothioconazole against Zymoseptoria tritici, which has reduced susceptibility to strobilurin fungicides.

[0105] Compound I-214, which showed 55% inhibition in Method 1, showed significant activity against Microdochium nivale in combination with fluxapyroxad and against Zymoseptoriatritici with reduced susceptibility to strobilurin fungicides and Zymoseptoria tritici with reduced susceptibility to SDHI fungicides in combination with desthioprothioconazole.

[0106] Compound I-9, which showed 19% inhibition in Method 1, showed significant activity in combination with azoxystrobin against Microdochium nivale and in combination with desthioprothioconazole against Zymoseptoria tritici, which has reduced susceptibility to SDHI fungicides.

[0107] Compound I-215, which showed 46% inhibition in Method 1, showed significant activity against Microdochium nivale in combination with fluxapyroxad.

[0108] Surprisingly, exemplary compounds, including compounds that showed lower activity than Lu Compound 15 in the in vitro inhibition assay of Method 1 above, showed significant activity in the combination assay where Lu Compound 15 showed zero activity.

[0109] Method 3: Greenhouse crop testing In this method, exemplary compounds were evaluated for their ability to control Zymoseptoria tritici on wheat, Botrytis cinerea on tomato, Asian soybean rust (Phakopsora pachyrhizi) on soybean, and brown rust (Puccinia recondita) on wheat in a controlled greenhouse environment in combination with one of four fungicides (Amistar, Intrex, Proline, or Balaya). These studies used soybean cultivar Siverka, tomato (Money maker), and wheat plants (JB Diego). Seeds were sown 1-2 cm deep in 9 cm diameter pots using Petersfield horticultural compost (75% medium peat, 12% sieved sterilized loam, 3% medium vermiculite, 10% granular (sieved to 5 mm, lime-free), 1.5 kg PG mix per m³, lime added to pH 5.5-6.0, and a wetting agent (Vitax Ultrawet, 200 ml per m³). Germinated and grown at 23°C under 16 hours of light per day and 8 hours of light overnight. Plants were treated 2-3 weeks after sowing, when they were at the BBCH11 growth stage (the first pair of true leaves (single leaves) had developed). Using a track sprayer, plants were treated with a mixture of commercial fungicide and test compound at a water volume of 200 L / ha. 24 hours after treatment, plants were inoculated with the appropriate fungus (pathogen). The fungal pathogen was Botrytis The fungicides tested were P. cinerea (gray mold on tomato plants), Zymoseptoria tritici (Septoria leaf blight on wheat plants), Puccinia triticina (brown rust on wheat plants), and Phakopsora pachyrhyzi (Asian soybean rust on soybean plants). Four replicates were used for each combination of fungicide, pathogen, and test compound. When disease symptoms were fully developed, 7–20 days (depending on the pathogen), each plant was evaluated for percent disease control. Appropriate controls, including "inoculation checks," were used in all experiments; plants were inoculated with specific pathogens and assessed for disease levels. Each commercial fungicide was also tested alone as part of each treatment; this served as the basis for evaluating experimental compounds.Exemplary compounds showed enhanced disease control in combination with fungicides compared to the disease control observed with the fungicide alone, i.e., the compounds are not fungicidal by themselves, but enhance the activity of the fungicide.

[0110] In these studies, fungicides were applied at the following rates: [Table 4] In this method, Amister or Balaya in combination with compound I-214 applied at 20 ppm provided significantly better control of Zymoseptoria tritici than Amister or Balaya alone, or in combination with Lou Compound 15 applied at 30 ppm. Intrex or Proline in combination with compound I-214 at 20 ppm provided similar control of Zymoseptoria tritici as Intrex or Proline in combination with Lou Compound 15 applied at 15 and 30 ppm, and provided better control than Intrex or Proline alone. Intrex and Balaya in combination with compound I-214 applied at 20 ppm provided significantly better control of Botrytis than Intrex or Balaya alone, or in combination with Lou Compound 15 applied at 30 ppm. The activity of Intrex against brown rust and the activity of Amister, Proline, and Balaya against Asian soybean rust were all substantially enhanced by the addition of compound I-214 at 20 ppm.

[0111] Proline and balaya supplemented with compound I-223 applied at 20 ppm showed significantly better results in controlling Zymoseptoria tritici than proline or balaya alone or in combination with Lou compound 15 applied at 30 ppm.

[0112] Amistar in combination with compound I-4 provided the same level of control of Botrytis as Amistar in combination with Lou Compound 15 at the same rate. In both cases, control was significantly greater than Amistar alone. In contrast, Amistar in combination with compound I-4 at 15 ppm provided a much higher level of control of Botrytis than Amistar in combination with Lou Compound 15 at a similarly low rate. Again, control was significantly greater than Amistar alone. Proline in combination with compound I-4 at 30 ppm provided the same level of control of Botrytis as proline in combination with Lou Compound 15 at a similar rate. In both cases, activity was significantly greater than proline alone. Intrex in combination with compound I-4 at 30 ppm provided significantly better control of Botrytis than Intrex alone or in combination with Lou Compound 15 at the same rate. Finally, balaya in combination with compound I-4 applied at 15 ppm was significantly more active against Botrytis than balaya alone or in the same ratio with Lou Compound 15. In fact, balaya in combination with 15 ppm of Lou Compound 15 was less active against Botrytis than balaya alone.

[0113] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. The inventors therefore claim as their invention all that comes within the spirit and scope of these claims. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

Table 5-20

Table 5-21

Table 5-22

Table 5-23

Table 5-24

Table 5-25

Table 5-26

Table 5-27

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 6-19

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Claims

1. 1. A method for inhibiting apyrase, comprising: 【Chemistry 19】 wherein Ar １ is selected from aryl and heteroaryl; R １ is hydrogen, C ３－６ Cycloalkyl, C １ - ６ Alkyl, aralkyl, and C １ - ３ haloalkyl; R ２ is selected from alkyl, aryl, and heteroaryl; provided that said compound has the formula 【Chemistry 20】 The method, wherein the method does not have

2. The compound has the formula 【Chemical 21】 wherein X is independently at each occurrence R ａ , R ｂ , the same or different R ｂ R substituted with one or more of ａ , the same or different R ｂ or R ｄ -OR substituted with one or more of ａ ,or -(CH ２ ) ｍ -R ｂ 、-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -R ｂ 、-S-(CH ２ ) ｍ -R ｂ 、-O-CHR ａ R ｂ 、-O-CR ａ (R ｂ ) ２ 、-O-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -CH[(CH ２ ) ｍ R ｂ ]R ｂ 、-S-(CHR ａ ) ｍ -R ｂ 、-C(O)NH-(CH ２ ) ｍ -R ｂ 、-C(O)NH-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ 、-S-(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ 、-O-(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ 、-S-(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ 、-NH-(CH ２ ) ｍ -R ｂ 、-NH-(CHR ａ ) ｍ -R ｂ , -NH[(CH ２ ) ｍ R ｂ ], -N[(CH ２ ) ｍ R ｂ ] ２ , -NH-C(O)-NH-(CH ２ ) ｍ -R ｂ , -NH-C(O)-(CH ２ ) ｍ -CHR ｂ R ｂ Selected from: or two X substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be joined by the same or different R ｂ may be substituted with one or more of the groups; Each R ａ are independently １－６ Alkyl, C ３－８ Cycloalkyl, C ６－１０ Aryl, C ５－１０ Heteroaryl, C ６－１６ selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R ｂ are independently ═O, —OR ｄ , C １－３ Haloalkyloxy, -OCF ２ H, -OCH ２ F, -OCF ３ , =S, -SR ｄ , -SCF ３ , -SF ５ , =NR ｄ , = NOR ｄ , -NR ｃ R ｃ , halogen, -CF ３ , -CN, -NO ２ , -S(O)R ｄ , -S(O) ２ R ｄ , -S(O) ２ CF ３ , -S(O) ２ OR ｄ , -S(O)NR ｃ R ｃ , -S(O) ２ NR ｃ R ｃ , -OS(O)R ｄ , -OS(O) ２ R ｄ , -OS(O) ２ OR ｄ , -OS(O) ２ NR ｃ R ｃ , -C(O)R ｄ , -C(O)OR ｄ , —C(O)NR ｃ R ｃ , —C(NH)NR ｃ R ｃ , -C(NR ａ ) NR ｃ R ｃ , —C(NOH)R ａ , -C(NOH)NR ｃ R ｃ , -OC(O)R ｄ , -OC(O)OR ｄ , —OC(O)NR ｃ R ｃ , -OC(NH)NR ｃ R ｃ , -OC(NR ａ ) NR ｃ R ｃ , -[NHC(O)] ｎ R ｄ , -[NR ａ C(O)] ｎ R ｄ , -[NHC(O)] ｎ OR ｄ , -[NR ａ C(O)] ｎ OR ｄ , -[NHC(O)] ｎ NR ｃ R ｃ , -[NR ａ C(O)] ｎ NR ｃ R ｃ , -[NHC(NH)] ｎ NR ｃ R ｃ and -[NR ａ C (NR ａ )] ｎ NR ｃ R ｃ is a group selected from the group consisting of: Each R ｃ are independently R ａ or alternatively, two R ｃは Together with the nitrogen atom to which they are attached, they form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally contain the same or different R ｂ may be substituted with one or more of the groups; Each R ｄ are independently hydrogen or C １－６ is alkyl; each m is independently an integer from 1 to 3; 2. The method of claim 1, wherein each n is independently an integer from 0 to 3.

3. X is C １－６ Alkyl, -OR ａ , -S(O) ２ NR ｃ R ｃ and halogen.

4. Ar １ The method of claim 1 , wherein is heteroaryl.

5. Ar １ The method of claim 1 , wherein is a monocyclic heteroaryl.

6. Ar １ The method of claim 1 , wherein is a bicyclic heteroaryl.

7. The compound has the formula 【Chemical 22】 wherein X is independently at each occurrence R ａ , R ｂ , the same or different R ｂ R substituted with one or more of ａ , the same or different R ｂ or R ｄ -OR substituted with one or more of ａ ,or -(CH ２ ) ｍ -R ｂ 、-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -R ｂ 、-S-(CH ２ ) ｍ -R ｂ 、-O-CHR ａ R ｂ 、-O-CR ａ (R ｂ ) ２ 、-O-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -CH[(CH ２ ) ｍ R ｂ ]R ｂ 、-S-(CHR ａ ) ｍ -R ｂ 、-C(O)NH-(CH ２ ) ｍ -R ｂ 、-C(O)NH-(CHR ａ ) ｍ -R ｂ 、-O-(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ 、-S-(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ 、-O-(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ 、-S-(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ 、-NH-(CH ２ ) ｍ -R ｂ 、-NH-(CHR ａ ) ｍ -R ｂ , -NH[(CH ２ ) ｍ R ｂ ], -N[(CH ２ ) ｍ R ｂ ] ２ , -NH-C(O)-NH-(CH ２ ) ｍ -R ｂ , -NH-C(O)-(CH ２ ) ｍ -CHR ｂ R ｂ Selected from: or two X substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be joined by the same or different R ｂ may be substituted with one or more of the groups; Each R ａ are independently １－６ Alkyl, C ３－８ Cycloalkyl, C ６－１０ Aryl, C ５－１０ Heteroaryl, C ６－１６ selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R ｂ are independently ═O, —OR ｄ , C １－３ Haloalkyloxy, -OCF ２ H, -OCH ２ F, -OCF ３ , =S, -SR ｄ , -SCF ３ , -SF ５ , =NR ｄ , = NOR ｄ , -NR ｃ R ｃ , halogen, -CF ３ , -CN, -NO ２ , -S(O)R ｄ , -S(O) ２ R ｄ , -S(O) ２ CF ３ , -S(O) ２ OR ｄ , -S(O)NR ｃ R ｃ , -S(O) ２ NR ｃ R ｃ , -OS(O)R ｄ , -OS(O) ２ R ｄ , -OS(O) ２ OR ｄ , -OS(O) ２ NR ｃ R ｃ , -C(O)R ｄ , -C(O)OR ｄ , —C(O)NR ｃ R ｃ , —C(NH)NR ｃ R ｃ , -C(NR ａ ) NR ｃ R ｃ , —C(NOH)R ａ , -C(NOH)NR ｃ R ｃ , -OC(O)R ｄ , -OC(O)OR ｄ , —OC(O)NR ｃ R ｃ , -OC(NH)NR ｃ R ｃ , -OC(NR ａ ) NR ｃ R ｃ , -[NHC(O)] ｎ R ｄ , -[NR ａ C(O)] ｎ R ｄ , -[NHC(O)] ｎ OR ｄ , -[NR ａ C(O)] ｎ OR ｄ , -[NHC(O)] ｎ NR ｃ R ｃ , -[NR ａ C(O)] ｎ NR ｃ R ｃ , -[NHC(NH)] ｎ NR ｃ R ｃ and -[NR ａ C (NR ａ )] ｎ NR ｃ R ｃ is a group selected from the group consisting of: Each R ｃ are independently R ａ or alternatively, two R ｃ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, and optionally R ｂ may be substituted with one or more of the groups; Each R ｄ are independently hydrogen or C １－６ is alkyl; each m is independently an integer from 1 to 3; 2. The method of claim 1, wherein each n is independently an integer from 0 to 3.

8. The compound has the formula 【Chemical 23】 2. The method of claim 1, comprising:

9. The compound has the formula 【Chemistry 24】 2. The method of claim 1, comprising:

10. The compound has the formula 【Chemistry 25】 2. The method of claim 1, comprising:

11. The compound has the formula 【Chemical 26】 2. The method of claim 1, comprising:

12. The compound has the formula 【Chemical 27】 2. The method of claim 1, comprising:

13. R ２ The method of any one of claims 1 to 12, wherein is hydrogen.

14. R ２ The method of any one of claims 1 to 12, wherein is methyl.

15. R ２ The method of claim 1 , wherein is heteroaryl.

16. R ２ The method of claim 1 , wherein is alkyl.

17. R ２ The method of claim 1 , wherein is aryl.

18. The compound has the formula 【Chemical Formula 28】 and wherein Y is independently at each occurrence R ａ , R ｂ , the same or different R ｂ R substituted with one or more of ａ , the same or different R ｂ or R ｄ -OR substituted with one or more of ａ , or -(CH ２ ) ｍ -R ｂ , -(CHR ａ ) ｍ -R ｂ , —O—(CH ２ ) ｍ -R ｂ , -S-(CH ２ ) ｍ -R ｂ , —O—CHR ａ R ｂ , -O-CR ａ (R ｂ ) ２ , —O—(CHR ａ ) ｍ -R ｂ , —O—(CH ２ ) ｍ -CH[(CH ２ ) ｍ R ｂ ]R ｂ , -S-(CHR ａ ) ｍ -R ｂ , -C(O)NH-(CH ２ ) ｍ -R ｂ , -C(O)NH-(CHR ａ ) ｍ -R ｂ , —O—(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ , -S-(CH ２ ) ｍ -C(O)NH-(CH ２ ) ｍ -R ｂ , —O—(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ , -S-(CHR ａ ) ｍ -C(O)NH-(CHR ａ ) ｍ -R ｂ , —NH—(CH ２ ) ｍ -R ｂ , —NH—(CHR ａ ) ｍ -R ｂ , -NH[(CH ２ ) ｍ R ｂ ], -N[(CH ２ ) ｍ R ｂ ] ２ , -NH-C(O)-NH-(CH ２ ) ｍ -R ｂ , -NH-C(O)-(CH ２ ) ｍ -CHR ｂ R ｂ Selected from: or two Y substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocyclylalkyl, or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally contain one or more of the same or different alkyl, cycloalkyl, and R ｂ may be substituted with one or more containing groups; Each R ａ are independently １－６ Alkyl, C ３－８ Cycloalkyl, C ６－１０ Aryl, C ５－１０ Heteroaryl, C ６－１６ selected from the group consisting of arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocyclylalkyl, 4- to 11-membered heterocyclylalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl; R ｂ are independently ═O, —OR ｄ , C １－３ Haloalkyloxy, -OCF ２ H, -OCH ２ F, -OCF ３ , =S, -SR ｄ , -SCF ３ , -SF ５ , =NR ｄ , = NOR ｄ , -NR ｃ R ｃ , halogen, -CF ３ , -CN, -NO ２ , -S(O)R ｄ , -S(O) ２ R ｄ , -S(O) ２ CF ３ , -S(O) ２ OR ｄ , -S(O)NR ｃ R ｃ , -S(O) ２ NR ｃ R ｃ , -OS(O)R ｄ , -OS(O) ２ R ｄ , -OS(O) ２ OR ｄ , -OS(O) ２ NR ｃ R ｃ , -C(O)R ｄ , -C(O)OR ｄ , —C(O)NR ｃ R ｃ , —C(NH)NR ｃ R ｃ , -C(NR ａ ) NR ｃ R ｃ , —C(NOH)R ａ , -C(NOH)NR ｃ R ｃ , -OC(O)R ｄ , -OC(O)OR ｄ , —OC(O)NR ｃ R ｃ , -OC(NH)NR ｃ R ｃ , -OC(NR ａ ) NR ｃ R ｃ , -[NHC(O)] ｎ R ｄ , -[NR ａ C(O)] ｎ R ｄ , -[NHC(O)] ｎ OR ｄ , -[NR ａ C(O)] ｎ OR ｄ , -[NHC(O)] ｎ NR ｃ R ｃ , -[NR ａ C(O)] ｎ NR ｃ R ｃ , -[NHC(NH)] ｎ NR ｃ R ｃ and -[NR ａ C (NR ａ )] ｎ NR ｃ R ｃ is a group selected from the group consisting of: Each R ｃ are independently R ａ or alternatively, two R ｃ together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclylalkyl or heteroaryl, which may optionally contain one or more of the same or different additional heteroatoms, which may optionally be the same or different R ｂ may be substituted with one or more of the groups; Each R ｄ are independently hydrogen or C １－６ is alkyl; each m is independently an integer from 1 to 3; 2. The method of claim 1, wherein each n is independently an integer from 0 to 3.

19. The compound has the formula 【Chemical 29】 2. The method of claim 1, comprising:

20. Ar １ 20. The method of claim 19, wherein is optionally substituted phenyl.

21. The compound is (E)-N-(2-chlorophenyl)-3-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)benzenesulfonamide; (E)-N-(4-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)phenyl)thiophene-2-sulfonamide; (E)-3-(morpholinosulfonyl)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-3-fluoro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (Z)-N'-(undecan-2-ylidene)benzohydrazide; (E)-5-bromo-N'-(1-(naphthalen-2-yl)ethylidene)nicotinohydrazide; (Z)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-4-(1H-tetrazol-1-yl)benzohydrazide; (E)-N'-pentylidenebenzohydrazide; (E)-N'-(1-(pyridin-3-yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide; (E)-N'-(1-(3,4-dimethylphenyl)ethylidene)-1-naphthohydrazide; (E)-2-fluoro-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-N'-(1-(6-methoxynaphthalen-2-yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carbohydrazide; (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-5-carbohydrazide; (E)-N'-(1-(naphthalen-1-yl)ethylidene)hexanehydrazide; (Z)-2-(2-benzoylhydrazinylidene)propanoic acid; (E)-2-methyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-butylidenebenzohydrazide; (E)-3,4-dimethoxy-N'-(1-(6-methoxynaphthalen-2-yl)ethylidene)benzohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)-1H-benzo[d]imidazole-6-carbohydrazide; (E)-N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)benzohydrazide; (E)-2-(1-(naphthalen-1-yl)ethylidene)hydrazine-1-carboxamide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)hexanehydrazide; (E)-N'-(4-ethylbenzylidene)benzohydrazide; (E)-N'-(2,2-dimethylpropylidene)benzohydrazide; (E)-2,4-dichloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3,4-dimethoxy-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-3-nitrobenzohydrazide; 2-fluoro-N'-(heptan-4-ylidene)benzohydrazide; (E)-3-chloro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (Z)-N'-(1-cyclopropylethylidene)-3-methylbenzohydrazide; (E)-N'-(4-methylbenzylidene)benzohydrazide; N'-(4-(tert-butyl)cyclohexylidene)benzohydrazide; (E)-N'-(1-(2,4-dimethylphenyl)ethylidene)-3,4-dimethylbenzohydrazide; N'-(propan-2-ylidene)-1-naphthohydrazide; (E)-4-methyl-N'-(1-phenylethylidene)benzohydrazide; (E)-3-nitro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-methyl-4-nitro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(2-chlorophenyl)ethylidene)-1-naphthohydrazide; (E)-3-Bromo-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-Methoxy-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-4-methyl-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-2,5-dichloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-2,3-dichloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-4-(2-(1-(2,4-dimethylphenyl)ethylidene)hydrazine-1-carbonyl)benzamide; (E)-3-Bromo-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-2-hydroxy-2-methyl-N'-(naphthalen-2-ylmethylene)propanehydrazide; (E)-3-methyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-chloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-Methoxy-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-4-fluoro-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-4-hydroxy-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-3-Methoxy-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-5-chloro-2-methoxy-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-2-fluoro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-nitro-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-N'-(1-(pyridin-2-yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide; (E)-4-nitro-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-2-Methoxy-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (Z)-2-methoxy-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-2-Methoxy-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-4-(dimethylamino)-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(pyridin-3-yl)ethylidene)-1-naphthohydrazide; (E)-N'-(1-(pyridin-2-yl)ethylidene)-1-naphthohydrazide; (E)-N'-(1-(4-fluorophenyl)ethylidene)-1-naphthohydrazide; (E)-N'-(1-(pyridin-4-yl)ethylidene)-1-naphthohydrazide; (E)-N'-(1-(pyridin-3-yl)ethylidene)-2-naphthohydrazide; (E)-N'-(1-(pyridin-4-yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide; (E)-4-chloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-3-chloro-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-2-fluoro-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-3-Bromo-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-4-Bromo-1-methyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-3-carbohydrazide; (E)-3,4,5-trimethoxy-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-4-Methoxy-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-2-nitrobenzohydrazide; (E)-4-(dimethylamino)-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-4-(dimethylamino)-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-2-fluoro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-phenylethylidene)isobutyrohydrazide; N'-cyclohexylidene benzohydrazide; (E)-N'-(1-phenylethylidene)propionohydrazide; (Z)-N'-(phenyl(pyridin-2-yl)methylene)benzohydrazide; (E)-2-methyl-N'-(2-methylpropylidene)benzohydrazide; (E)-N'-butylidene-2-methylbenzohydrazide; (E)-2-chloro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-2-hydroxy-N'-(naphthalen-1-ylmethylene)acetohydrazide; (E)-2-methyl-N'-(1-(naphthalen-2-yl)ethylidene)furan-3-carbohydrazide; (E)-N'-(1-(2-fluorophenyl)ethylidene)benzohydrazide; (E)-N'-(1-(6-methoxynaphthalen-2-yl)ethylidene)-2,4-dimethylbenzohydrazide; 4-fluoro-N'-(heptan-4-ylidene)benzohydrazide; (E)-N'-(1-(pyridin-2-yl)ethylidene)benzo[d][1,3]dioxole-5-carbohydrazide; (E)-3,5-dimethoxy-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(6-methoxynaphthalen-2-yl)ethylidene)-2-(1H-pyrrol-1-yl)benzohydrazide; (E)-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-4-(((4-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(3,3,5-trimethylcyclohexylidene)benzohydrazide; (E)-N'-(1-(1-(difluoromethoxy)naphthalen-2-yl)ethylidene)-2,4-dimethylbenzohydrazide; (E)-4-(diethylamino)-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-3-nitro-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-N'-(3-methylcyclohexylidene)benzohydrazide; (E)-4-hydroxy-N'-(1-phenylethylidene)benzohydrazide; (E)-N'-(1-(3,4-dichlorophenyl)ethylidene)-1-naphthohydrazide; (Z)-N'-(1-cyclopropylethylidene)benzohydrazide; (E)-3-methyl-N'-(1-phenylpropylidene)benzohydrazide; (E)-3-methyl-N'-(1-phenylpentylidene)benzohydrazide; (Z)-N'-(1-phenylethylidene)acetohydrazide; (E)-N'-(phenyl(pyridin-4-yl)methylene)benzohydrazide; (E)-4-fluoro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)isonicotinohydrazide; (Z)-4-fluoro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (Z)-N'-(1-(4-chlorophenyl)ethylidene)benzohydrazide; (Z)-N'-(1-(2-chlorophenyl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)picolinohydrazide; (Z)-N'-(1-(4-fluorophenyl)ethylidene)benzohydrazide; (E)-N'-(2-chlorobenzylidene)-2-naphthohydrazide; 4-methyl-N'-(4-methylcyclohexylidene)benzohydrazide; (E)-3-cyclopropyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-5-carbohydrazide; (E)-N'-octylidenebenzohydrazide; (E)-N'-(naphthalen-1-ylmethylene)acetohydrazide; (E)-2-(2-benzoylhydrazinylidene)propanoic acid; (E)-N'-benzylidene-4-methylbenzohydrazide; (E)-4-chloro-N'-ethylidenebenzohydrazide; (E)-N'-(1-phenylethylidene)acetohydrazide; (E)-N'-(3-methylbenzylidene)benzohydrazide; (E)-3-methyl-N'-(4-methylpentan-2-ylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-[1,1'-biphenyl]-4-carbohydrazide; (Z)-N'-(1-phenylbutylidene)benzohydrazide; (Z)-3-methyl-N'-(1-phenylpentylidene)benzohydrazide; N'-cyclohexylidene-3-methylbenzohydrazide; (E)-N'-(1-phenylethylidene)benzohydrazide; N'-cyclopentylidene-2-methylbenzohydrazide; (E)-3-Bromo-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(naphthalen-2-ylmethylene)benzohydrazide; (E)-3-methyl-N'-(naphthalen-2-ylmethylene)benzohydrazide; (E)-3-methyl-N'-(2-methylbenzylidene)benzohydrazide; (E)-4-fluoro-N'-(1-phenylethylidene)benzohydrazide; (E)-4-chloro-N'-(1-phenylethylidene)benzohydrazide; (E)-4-chloro-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (E)-4-chloro-N'-(1-(4-chlorophenyl)ethylidene)benzohydrazide; (E)-2-chloro-4-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)pyrazine-2-carbohydrazide; (E)-2-methyl-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (Z)-3,4-dimethyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; N'-(diphenylmethylene)isobutyrohydrazide; 4-amino-N'-cyclopentylidenebenzohydrazide; (E)-4-(tert-butyl)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (E)-3-methyl-N'-(3-methylbenzylidene)benzohydrazide; (E)-2,5-dimethyl-N'-(1-(naphthalen-2-yl)ethylidene)furan-3-carbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)nicotinohydrazide; (E)-N'-(1-(4-aminophenyl)ethylidene)benzohydrazide; (E)-4,6-dimethyl-N'-(1-phenylethylidene)pyrimidine-2-carbohydrazide; (E)-3-fluoro-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-N'-(2-methylpropylidene)benzohydrazide; (E)-N'-(1-(3,4-dimethylphenyl)ethylidene)-3,4-dimethylbenzohydrazide; (E)-3-methyl-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-2-methyl-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-N'-(4-cyanobenzylidene)-3-methylbenzohydrazide; (E)-N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)-3-methylbenzohydrazide; (E)-3-methyl-N'-(1-phenylbutylidene)benzohydrazide; (E)-N-(4-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)phenyl)propionamide; (E)-N'-(1-(4-chlorophenyl)ethylidene)benzohydrazide; (E)-4-(tert-butyl)-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)cyclohexanecarbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)cyclopropanecarbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-3-phenylpropanehydrazide; N'-cyclopentylidene-3-methylbenzohydrazide; (E)-4-chloro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-3,4-dimethyl-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-N'-(4-bromobenzylidene)-3-methylbenzohydrazide; (E)-N'-(naphthalen-2-ylmethylene)-2-phenylacetohydrazide; (Z)-3-fluoro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carboxylate methyl; (E)-N'-benzylidenebenzohydrazide; (E)-N'-(4-methylpent-3-en-2-ylidene)benzohydrazide; 5-(naphthalen-2-yl)-4H-pyrazol-3-ol; (E)-2-methyl-N'-(3-methylbutan-2-ylidene)benzohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)furan-2-carbohydrazide; (E)-4-(tert-butyl)-N'-(1-(4-ethylphenyl)ethylidene)benzohydrazide; (E)-2-chloro-N'-(1-phenylethylidene)benzohydrazide; (E)-2-chloro-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-3,4-dichloro-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-2-(thiophen-2-yl)acetohydrazide; (Z)-3-cyclopropyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-5-carbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)thiophene-2-carbohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)nicotinohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)picolinohydrazide; (E)-N'-ethylidene-2-methylbenzohydrazide; (Z)-3,4,5-trimethoxy-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-4-methyl-N'-(3-methylbutylidene)benzohydrazide; (E)-N'-(1-cyclopropylethylidene)-3-methylbenzohydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)-3-phenylpropanehydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)hexanehydrazide; (E)-4-Bromo-N'-(butan-2-ylidene)benzohydrazide; (Z)-4-(dimethylamino)-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-3,4-dimethyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-(3,3-dimethylbutan-2-ylidene)-4-methylbenzohydrazide; (E)-4-(tert-butyl)-N'-(1-(pyridin-3-yl)ethylidene)benzohydrazide; (E)-3-fluoro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-3-methyl-N'-(1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylidene)benzohydrazide; (E)-6-methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyridazine-4-carbohydrazide; (E)-3,4-dimethyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-4-methyl-N'-(1-(naphthalen-2-yl)ethylidene)thiophene-2-carbohydrazide; (E)-N-(4-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)phenyl)methanesulfonamide; (E)-3-(dimethylamino)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-3-(trifluoromethyl)benzohydrazide; (E)-6-methyl-N'-(1-(naphthalen-2-yl)ethylidene)picolinohydrazide; (E)-5-methyl-N'-(1-(naphthalen-2-yl)ethylidene)thiophene-2-carbohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N-(3-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)phenyl)methanesulfonamide; (E)-3-methyl-N'-(1-(quinolin-3-yl)ethylidene)benzohydrazide; (E)-5-methyl-N'-(1-(naphthalen-2-yl)ethylidene)thiophene-3-carbohydrazide; (E)-N'-(1-(3,4-dimethylphenyl)ethylidene)-3-methylbenzohydrazide; (E)-3-ethyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-2-methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyrimidine-4-carbohydrazide; (E)-3-(hydroxymethyl)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-N,N-dimethyl-3-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)benzenesulfonamide; (E)-N-methyl-3-(2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carbonyl)benzenesulfonamide; (E)-6-methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyrimidine-4-carbohydrazide; (E)-N'-(1-(2,3-dihydro-1H-inden-5-yl)ethylidene)-3-methylbenzohydrazide; (E)-4-methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyrimidine-2-carbohydrazide; (E)-5-methyl-N'-(1-(naphthalen-2-yl)ethylidene)nicotinohydrazide; (E)-4-methyl-N'-(1-(naphthalen-2-yl)ethylidene)picolinohydrazide; (E)-N'-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-3-methylbenzohydrazide; (E)-2-methyl-N'-(1-(naphthalen-2-yl)ethylidene)isonicotinohydrazide; (E)-3-methyl-N'-(1-(quinolin-2-yl)ethylidene)benzohydrazide; (E)-N'-(1-(isoquinolin-3-yl)ethylidene)-3-methylbenzohydrazide; (E)-3-methyl-N'-(1-phenylethylidene)benzohydrazide; (E)-6-methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyrazine-2-carbohydrazide; (E)-3-(methylsulfonyl)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and (E)-N'-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylidene)-3-methylbenzohydrazide The method of claim 1 , wherein the compound is selected from the group consisting of:

22. 22. The method of any one of claims 1 to 21, wherein contacting the apyrase comprises treating a crop with the compound.

23. 23. The method of claim 22, further comprising treating the crop with a pesticide.

24. 24. The method of claim 23, wherein the pesticide is selected from an acaricide, a fungicide, a herbicide, an insecticide, a molluscicide, a nematicide, or a combination thereof.

25. 25. The method of claim 24, wherein the pesticide comprises a fungicide.

26. Crops can be treated with cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, morpholine, cyflufenamid, metrafenone, pyriophenone, strobilurin, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbons, phthalimide, guanidine, polyoxin, furazinam 23. The method of claim 22, further comprising treating with a fungicide selected from benzimidazoles, including imidazoles and triazoles such as thiazolidines, dicarboximides, phenylpyrroles, anilinopyrimidines, hydroxyanilides, carboxamides, phenylamides, phosphonates, cinnamic acids, oxysterol binding protein inhibitors (OSBPIs), triazole carboxamides, cymoxanil, carbamates, benzamides, demethylation inhibiting piperazines, demethylation inhibiting pyrimidines, demethylation inhibiting azoles, or combinations thereof.

27. formula 【Chemistry 30】 wherein Ar １ is selected from aryl and heteroaryl; R １ is hydrogen, C ３－６ Cycloalkyl, C １ - ６ Alkyl, aralkyl, and C １ - ３ haloalkyl; R ２ is selected from alkyl, aryl, and heteroaryl; provided that said compound has the formula 【Chemical 31】 and The composition is free of a botanically acceptable carrier.

28. 28. The composition of claim 27, wherein the composition comprises from about 1 to about 80 weight percent of the compound.

29. 28. The composition of claim 27, wherein the composition is a suspension formulation.

30. 30. The composition of claim 29, wherein the composition comprises from about 1 to about 50 weight percent of the compound.

31. 31. The composition of claim 30, further comprising a sodium polycarboxylate.

32. 32. The composition of claim 31 further comprising a biocide.

33. 32. The composition of claim 31, further comprising an organosilicon antifoam emulsion.

34. 28. The composition of claim 27, wherein the composition is a wettable powder.

35. 28. The composition of claim 27, wherein the composition is an emulsion.

36. 36. The composition of claim 35, further comprising a tristyrylphenol ethoxylate.

37. 28. The composition of claim 27, wherein the composition is an oil-dispersible concentrate.

38. 1. An insecticidal composition comprising: Pesticides and; formula 【Chemical 32】 wherein Ar １ is selected from aryl and heteroaryl; R １ is hydrogen, C ３－６ Cycloalkyl, C1- ６ Alkyl, aralkyl, and C １ - ３ haloalkyl; R ２ is selected from alkyl, aryl, and heteroaryl; provided that said compound has the formula 【Chemical 33】 and The insecticidal composition is free of a botanically acceptable carrier.

39. 39. The pesticidal composition of claim 38, wherein the pesticide comprises an acaricide, a fungicide, a herbicide, an insecticide, a molluscicide, a nematicide, or a combination thereof.

40. 1. A disinfecting composition comprising: a disinfectant; formula 【Chemical 34】 wherein Ar １ is selected from aryl and heteroaryl; R １ is hydrogen, C ３－６ Cycloalkyl, C １ - ６ Alkyl, aralkyl, and C １ - ３ haloalkyl; R ２ is selected from alkyl, aryl, and heteroaryl; provided that said compound has the formula 【Chemistry 35】 and The fungicidal composition is free of a botanically acceptable carrier.

41. Fungicides include imidazoles and triazoles, cyproconazole, difenoconazole, fenbuconazole, flutriafol, mefentrifluconazole, metconazole, ipconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, morpholine, cyflufenamid, metrafenone, pyriophenone, strobilurins, copper ammonium complexes, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbons, 41. The composition of claim 40, wherein the compound is selected from the group consisting of phthalimides, guanidines, polyoxins, furadinams, benzimidazoles including thiazolidines, dicarboximides, phenylpyrroles, anilinopyrimidines, hydroxyanilides, carboxamides, phenylamides, phosphonates, cinnamic acids, oxysterol binding protein inhibitors, triazole carboxamides, cymoxanil, carbamates, benzamides, demethylation inhibiting piperazines, demethylation inhibiting pyrimidines, demethylation inhibiting azoles, or combinations thereof.

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