Adenosine triphosphate biphosphatase inhibitors

Abstract

Disclosed herein are adenosine triphosphate biphosphatase inhibitors # imgabs0 # of formula (I). Also disclosed herein are methods of using the disclosed inhibitors, including methods for protecting crops from pest attack. In one aspect, the adenosine triphosphate biphosphatase inhibitors may be used to enhance the activity of insecticides to protect crops from pathogens and to support crop yield.

Description

Technical Field

[0001] The present disclosure relates to inhibitors of apyrase and methods of using the same, particularly methods of using the same in treating crops susceptible to pathogens. Background Art

[0002] Crops around the world are infected by various pathogens. Pathogens such as insects, mites, nematodes, bacteria, weeds, and fungi have developed a series of mechanisms to survive under pesticides, such as sequestering, exporting, or detoxifying pesticides. The present inventors have discovered molecules and methods for enhancing the efficacy of pesticides by blocking certain resistance mechanisms. Summary of the Invention

[0003] Disclosed herein are molecules and methods for supporting crop viability and yield, for example, by protecting crops from pests. In one embodiment, disclosed herein is a method for inhibiting apyrase, the method comprising contacting apyrase with a compound of the following formula:

[0004] wherein Ar 1 is selected from aryl and heteroaryl;

[0005] R 1 is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, aralkyl, and C 1-3 haloalkyl;

[0006] R 2 is selected from alkyl, aryl, and heteroaryl.

[0007] In additional embodiments, the apyrase inhibitors as described herein are used in combination with one or more pesticides to treat crops at risk.

[0008] The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description. Detailed Description

[0009] I. Terms

[0010] The following explanations of terms and methods are provided to better describe the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" are meant to include one or more. Unless the context clearly dictates otherwise, the term "or" means a single one of the alternative elements or a combination of two or more elements. As used herein, "comprising" means "including". Thus, "comprising A or B" means "including A, B, or A and B", without excluding additional elements. All references (including patents and patent applications) cited herein are hereby incorporated by reference in their entirety, unless otherwise indicated.

[0011] Unless otherwise indicated, all numerical values expressing quantities of ingredients, molecular weights, percentages, temperatures, times, etc. used in the specification or claims are to be understood as being modified by the term "about". Accordingly, unless otherwise implied or stated explicitly, the numerical parameters shown are approximations that may depend on the desired characteristics sought and / or the detection limits under standard test conditions / methods. When distinguishing embodiments directly and explicitly from the prior art being discussed, the embodiment numerical values are not approximations unless the word "about" is explicitly recited.

[0012] Unless otherwise defined, 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 belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, suitable methods and materials are described below. These materials, methods, and examples are illustrative only and not intended to be limiting.

[0013] "Applying" means any suitable mode of application for controlling a fungal pathogen, including treating an existing crop, seeds, soil, or a combination thereof.

[0014] "Controlling" with respect to a fungal pathogen means blocking, inhibiting, and / or eradicating the fungal pathogen and / or preventing the fungal pathogen from damaging a crop. In one embodiment, controlling means reducing one or more fungi to an undetectable level, or reducing or inhibiting the fungi to an acceptable level determined by one of ordinary skill in the art (e.g., a crop grower). The determination of an acceptable level of fungal reduction is based on many factors, including the crop, the pathogen, the severity of the pathogen, use restrictions, economic thresholds, and other factors known to one of ordinary skill in the art.

[0015] As used herein, the terms "booster" and "synergist" refer to one or more compounds that enhance the effectiveness of pesticides as disclosed herein. Without being bound by theory, the booster compounds of the present invention disclosed herein can act by blocking one or more pathways of pathogens such as fungal pathogens such as by detoxifying, sequestering, or transporting pesticides away from toxicity. In certain embodiments, the compounds of the present invention inhibit the enzymatic activity of adenosine triphosphate diphosphatase, which results in the enhancement, potentiation, or synergism of the action of pesticides (such as acaricides, antimicrobials, fungicides, herbicides, insecticides, molluscicides, and / or nematicides). For example, when a booster or synergist is used in combination with a fungicide, the combination of the booster and the fungicide enhances the fungicidal effect of the fungicide and / or renders fungi resistant to the fungicide sensitive to the fungicide due to the activity of the booster. Most commonly, these boosters or synergists do not themselves inhibit the fungus itself and do not have a harmful effect on living organisms that are (or may be) infected with the fungus.

[0016] As used herein, the term "inoculation" refers to a method for applying or administering an effective amount of the disclosed compound or its formulation to a target area of a field and / or a plant. The inoculation method can be, but is not limited to, aerosol spraying, pressure spraying, direct watering, and dipping. The target area of the plant can include, but is not limited to, the leaves, roots, stems, buds, flowers, fruits, seeds, and bulbs of the plant, including bulbs, corms, rhizomes, tubers, taproots, and rootstocks. Inoculation can include methods in which one area of the plant (e.g., the root zone or the leaf surface) is treated and another area of the plant is protected (e.g., inoculating the leaf surface when the disclosed compound is applied to the root zone, or inoculating new growth when the disclosed compound is applied to the leaf surface).

[0017] As used herein, the terms "wettable granules", "water-dispersible granules", and "dispersible granules" refer to solid particle formulations prepared by a granulation process, which optionally contain fine particles or aggregates of polymer-associated active ingredients, wetting agents, and / or dispersants, and optionally inert fillers. Wettable granules can be stored as a formulation and can be provided to the market and / or the end user without further processing. In some embodiments, they can be placed in a water-soluble bag for ease of use by the end user. In actual applications, wettable granules are prepared for application by the end user. The wettable granules are mixed with water in the end user's spray tank to an appropriate dilution for a specific application. The dilution may vary depending on factors such as the crop, the fungal pathogen, the specific time of year, the geographical location, local regulations, and the intensity of the infection. After being appropriately diluted, the solution can be applied by spraying.

[0018] As used herein, the terms "wettable powder", "water-dispersible powder", and "dispersible powder" refer to solid powder formulations that contain an active ingredient or its aggregates optionally associated with a polymer, and one or more of an optional dispersant, wetting agent, and inert filler. Wettable powders can be stored as a formulation and can be provided to the market and / or end user without further processing. In some embodiments, they can be placed in a water-soluble bag for ease of use by the end user. In actual use, 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 an appropriate dilution for a particular application. The dilution may vary depending on factors such as the crop, target pathogen, particular time of year, geographical location, local regulations, and intensity of infection or pathogen load. After being appropriately diluted, the solution can be applied by spraying.

[0019] As used herein, the term "high-solid liquid suspension" refers to a liquid formulation that contains fine particles of an active ingredient or fine polymer particles associated with the active ingredient or its aggregates, a wetting agent and / or dispersant, an antifreeze, an optional anti-settling agent or thickener, an optional preservative, and water or oil as a carrier. High-solid liquid suspensions can be stored as a formulation and can be provided to the market and / or end user without further processing. In actual use, high-solid liquid suspensions are prepared for application by the end user. The high-solid liquid suspension is mixed with water in the end user's spray tank to an appropriate dilution for a particular application. The dilution may vary depending on factors such as the crop, target pathogen, particular time of year, geographical location, local regulations, and intensity of infection or pathogen load. After being appropriately diluted, the suspension can be applied by spraying.

[0020] As used herein, the term "botanically acceptable" means that a composition, diluent, excipient, and / or carrier is generally suitable for use with any part of a plant (including but not limited to seeds, seedlings, plant cells, plants, or flowers) during any part of the plant life cycle. The composition can be prepared according to procedures, methods, and formulations known to those skilled in the agricultural arts. In accordance with the teachings of the present disclosure, those skilled in the agricultural and / or chemical arts can readily prepare the desired composition. Most commonly, the compounds of the present invention can be formulated for storage and / or application in the form of an aqueous or non-aqueous suspension or emulsion, either pure or prepared from a concentrated formulation of the composition. Alternatively, the compounds of the present invention can be formulated for use in an aerosol generating device for application to agricultural products stored in a sealed chamber - a method of application known as atomization. Water-soluble, water-suspendable, or emulsifiable formulations containing the compounds disclosed herein can also be converted or formulated into solids (e.g., wettable powders), which are then diluted into the final formulation. In certain formulations, the compositions of the present disclosure can also be provided in a growth medium such as an in vitro medium for culturing plants or other types of cells, a laboratory plant growth medium, soil, or for spraying on seeds, seedlings, roots, stems, stalks, leaves, flowers, or the entire plant.

[0021] The compounds herein can include all stereoisomers, including E and Z isomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and their tautomers.

[0022] Non-limiting examples of optional substituents include a hydroxyl group, a mercapto group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a formyl group, an imine group, an alkyl group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, a haloalkynyl group, an alkoxy group, an aryl group, an aryloxy group, an aralkyl group, an aralkyloxy group, a heterocycloalkyl group, a heteroaryl group, a cycloalkyl group, an acyl group, an acyloxy group, a carbamate group, an amide group, a urea group, an epoxy group, and an ester group.

[0023] "Alkyl" means an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon. Non-limiting examples of alkyl groups include straight-chain, branched-chain, and cyclic alkyl and alkylene groups. An alkyl group can be, for example, a substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C18 , 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 group. In some cases, alkyl refers to a group having from one to about ten carbon atoms or from one to six carbon atoms, wherein the sp 3 hybridized carbon of the alkyl residue is connected to the rest of the molecule by a single bond. Whenever it appears in this text, numerical ranges such as "C 1-6 alkyl" mean 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, but this definition also covers the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is C 1-10 alkyl, C1-9 alkyl, C 1-8 alkyl, C 1-7 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl or C1 alkyl.

[0024] Examples of 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-dimethyl-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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc.

[0025] Non-limiting examples of straight-chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0026] Branched-chain alkyl groups include any straight-chain alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched-chain alkyl groups include isopropyl, isobutyl, sec-butyl and tert-butyl.

[0027] Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with, for example, oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl is optionally substituted with oxo group, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. Non-limiting examples of the substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl and 3-carboxypropyl.

[0028] "Alkenyl" means an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon double bonds. One or more olefins of the alkenyl group can be, for example, E, Z, cis, trans, terminal or exomethylene. The alkenyl 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 groups. Non-limiting examples of alkenyl and alkenylene groups include vinyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl; 2-chloroethenyl, 4-hydroxybut-1-en-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl and 7-hydroxy-7-methyloct-3,5-dien-2-yl.

[0029] Whenever it appears herein, numerical ranges such as "C 2-6 alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" for which no numerical range is specified. In some embodiments, the alkenyl is C 2-10 alkenyl, C 2-9 alkenyl, C 2-8 alkenyl, C 2-7 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl or C2 alkenyl. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with, for example, an oxo group, a halogen, an amino group, a nitrile, a nitro group, a hydroxyl group, a haloalkyl group, an alkoxy group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, etc. In some embodiments, the alkenyl is optionally substituted with an oxo group, a halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl is optionally substituted with an oxo group, a halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted with a halogen.

[0030] "Alkynyl" means a straight-chain or branched-chain hydrocarbon which is optionally substituted. The triple bond of the alkynyl group can be internal or terminal. The alkynyl or alkynylene 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 groups. 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.

[0031] Whenever it appears herein, numerical ranges such as "C 2-6 alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl is C 2-10 alkynyl, C2-9 Alkynyl, C 2-8 Alkynyl, C 2-7 Alkynyl, C 2-6 Alkynyl, C 2-5 Alkynyl, C 2-4 Alkynyl, C 2-3 Alkynyl or C2 alkynyl. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted by, for example, oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted by oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl is optionally substituted by oxo group, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkynyl is optionally substituted by halogen.

[0032] The haloalkyl group can be any alkyl group substituted by any number of halogen atoms such as fluorine, chlorine, bromine and iodine atoms. The haloalkenyl group can be any alkenyl group substituted by any number of halogen atoms. The haloalkynyl group can be any alkynyl group substituted by any number of halogen atoms.

[0033] The alkoxy group can be an oxygen atom substituted by, for example, any alkyl, alkenyl or alkynyl group. Ether or ether group includes alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and isobutoxy.

[0034] 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 heterocyclic-C(O)-, wherein alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclic are as described herein. By way of example, acyl groups include acetyl and benzoyl groups.

[0035] "Alkoxy" refers to the group of the formula -OR a wherein R a is an alkyl group as defined. Unless otherwise specifically stated in the specification, the alkoxy group can be optionally substituted by, for example, oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted by oxo group, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkoxy is optionally substituted by oxo group, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkoxy is optionally substituted by halogen.

[0036] "Aminoalkyl" refers to an alkyl group as defined above that is substituted by one or more amines. In some embodiments, the alkyl is substituted by one amine. In some embodiments, the alkyl is substituted by one, two or three amines. Hydroxyalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0037] "Aryl" refers to a group derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded 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 groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracenylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, asym-indacene, sym-indacene, indane, indene, naphthalene, phenalene, phenanthrene, heptalene, pyrene and triphenylene. In some embodiments, the aryl is phenyl. Unless otherwise specifically stated in the specification, the aryl can be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen.

[0038] "Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged or spiro ring systems. Representative cycloalkyls include, but are not limited to, those having three to fifteen carbon atoms (C3-C 15 cycloalkyl), three to ten carbon atoms (C3-C 10cycloalkyl having three to eight carbon atoms (C3-C8 cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl) or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Cycloalkyl groups also include fused, bridged and spiro bicyclic and higher fused, bridged and spiro systems. The cycloalkyl group can be substituted with any number of straight-chain, branched-chain 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, cyclopent-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctyl, 2,5-dimethylcyclopent-1-yl, 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]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octyl and bicyclo[3.3.3]undecyl.

[0039] Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0040] Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, 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]heptyl.

[0041] Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, the cycloalkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with halogen.

[0042] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0043] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogens. In some embodiments, the alkyl group is substituted with one, two, or three halogens. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halogens. Haloalkyls include, 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.

[0044] "Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0045] "Heteroalkyl" refers to an alkyl group in which one or more of the skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C 1-6Heteroalkyl, wherein 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 combinations thereof, and wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specifically stated in the specification, the heteroalkyl is optionally substituted with, for example, oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxy groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, the heteroalkyl is optionally substituted with oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted with oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogens.

[0046] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. In some embodiments, the alkyl is substituted with one hydroxy group. In some embodiments, the alkyl is substituted with one, two, or three hydroxy groups. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0047] "Heterocyclic group" refers to a stable 3- to 24-membered heterocycle. The heterocycle can be any ring containing ring atoms that are not carbon, such as N, O, S, P, Si, B, or any other heteroatom. The heterocycle can be substituted with any number of substituents such as alkyl groups and halogen atoms. The 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.

[0048] Non-limiting examples of heterocycles include: heterocyclic units having a monocyclic ring containing one or more heteroatoms, non-limiting examples of which include bisaziridinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinone, oxazolidinone, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-one, 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, where one ring is a heterocycle, non-limiting examples of which include hexahydro-1H-pyrrolizinyl, 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-cyclooct[ b]pyrrolyl.

[0049] "Heterocycloalkyl" means a stable 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically stated in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; and the nitrogen atoms can be optionally quaternized.

[0050] Representative heterocycloalkyls include, but are not limited to, those having two to fifteen carbon atoms (C2-C 15 heterocycloalkyl), two to ten carbon atoms (C2-C 10heterocycloalkyl having from two to eight carbon atoms (C2-C8 heterocycloalkyl), having from two to six carbon atoms (C2-C6 heterocycloalkyl), having from two to five carbon atoms (C2-C5 heterocycloalkyl), or having from two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thieno[1,3]dithiolanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiolanyl, 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 heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, the heterocycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0051] "Heteroaryl" refers to a 5- to 14-membered ring system group containing a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring system. And the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; 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 but are not limited to azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indazinyl, 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., thiophenyl / thienyl). Unless otherwise specifically stated in the specification, the heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0052] II. Compounds

[0053] In one embodiment, the insecticidal activity enhancers disclosed herein include those having formula (I)

[0054] wherein Ar 1 is selected from aryl and heteroaryl;

[0055] R 1 is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, aralkyl and C 1-3 haloalkyl;

[0056] R 2 is selected from alkyl, aryl and heteroaryl; provided that the compound does not have the following formula

[0057]

[0058] Regarding formula (I), the bond representing the carbon-nitrogen double bond can be cis or trans, and the compound can be an E or Z isomer. Thus, in one embodiment of the compound according to formula (I), a compound of formula (Ia) is provided

[0059] wherein Ar 1 is selected from aryl and heteroaryl;

[0060] R 1 is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, aralkyl and C 1-3 haloalkyl;

[0061] R 2 is selected from alkyl, aryl and heteroaryl; provided that the compound does not have the following formula

[0062]

[0063] In another embodiment, the compound of formula (I) has the formula (Ib)

[0064] wherein Ar 1 is selected from aryl and heteroaryl;

[0065] R 1 is selected from hydrogen, C 3-6 cycloalkyl, C 1-6 alkyl, aralkyl and C 1-3 haloalkyl;

[0066] R 2 is selected from alkyl, aryl and heteroaryl.

[0067] In certain embodiments, the compounds of formula (I), (Ia) and (Ib) have the following formula

[0068] wherein each occurrence of X is independently selected from R a , R b , R substituted by one or more identical or different R b , -OR substituted by one or more identical or different R a , or R b or R d , or -OR substituted by one or more identical or different R a , or

[0069] -(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,

[0070] -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 ,

[0071] -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 ,

[0072] -O-(CHR a ) m -C(O)NH-(CHR a ) m -R b , -S-(CHRa ) m -C(O)NH-(CHR a ) m -R b 、-NH-(CH2) m -R b 、

[0073] -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 ;

[0074] or two X substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, which can optionally contain one or more additional heteroatoms, the same or different, and can optionally be substituted by one or more R b groups;

[0075] Each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl;

[0076] R b is independently selected from the following groups: =O, -OR d 、C 1-3 haloalkoxy, -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)2ORd 、 -S(O)NR c R c 、

[0077] -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 、

[0078] -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 、

[0079] -[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 -[NRa C(NR a )] n NR c R c ;

[0080] Each R c is independently R a , or alternatively, two Rs c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, which heterocycloalkyl or heteroaryl may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more Rs b groups;

[0081] Each R d is independently hydrogen or C 1-6 alkyl;

[0082] Each m is independently an integer from 1 to 3; and

[0083] Each n is independently an integer from 0 to 3.

[0084] In certain embodiments, the compounds of formulas (I), (Ia) and (Ib) have an X selected from C 1-6 alkyl, -OR a , -S(O)2NR c R c and halogen.

[0085] In certain embodiments disclosed herein, including the compounds of formulas (I), (Ia), (Ib) and (II), Ar 1 is an optionally substituted aryl, such as an optionally substituted phenyl. In certain examples of such compounds, X is -OR b or R d substituted by one or more Rs a . In one such embodiment, where Ar 1 is phenyl, n is 2 and X is -OR a , where each R a is selected from C 1-6 alkyl. In a particular embodiment, the inhibitor compound has the formula (IIa)

[0086]

[0087] 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 1is hydrogen and R 2 is selected from hydrogen and methyl, such as where R 1 and R 2 is hydrogen.

[0088] In certain embodiments described herein, including embodiments of formulas (I), (Ia), and (Ib), Ar 1 is heteroaryl, such as where Ar 1 is monocyclic heteroaryl or bicyclic heteroaryl.

[0089] In certain embodiments of formulas (I), (Ia), and (Ib), Ar 1 is monocyclic heteroaryl, such as where Ar 1 is optionally substituted pyridinyl. In one embodiment, the compounds of formulas (I), (Ia), and (Ib) have formula (III)

[0090] wherein X is independently selected, each occurrence, from R a , R b substituted with one or more identical or different R b substituted R a substituted with one or more identical or different R b or R d substituted -OR a , or

[0091] -(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、

[0092] -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 、

[0093] -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 、

[0094] -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 、

[0095] -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 ;

[0096] Or two X substituents, together with the atoms to which they are attached, form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, which aryl, cycloalkyl, heterocycloalkyl or heteroaryl group may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more R b groups;

[0097] Each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16Arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl, and 6- to 16-membered heteroarylalkyl;

[0098] R b is independently a group selected from: =O, -OR d , C 1-3 haloalkoxy, -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 ,

[0099] -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 ,

[0100] -OC(O)NR c R c , -OC(NH)NR c R c , -OC(NR a )NR c R c , -[NHC(O)] n Rd ,-[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 ; each R c is independently R a , or alternatively two Rs c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, which heterocycloalkyl or heteroaryl may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more Rs b groups;

[0101] Each R d is independently hydrogen or C 1-6 alkyl;

[0102] Each m is independently an integer from 1 to 3; and

[0103] Each n is independently an integer from 0 to 3.

[0104] In one embodiment, the compounds of formulas (I), (Ia), (Ib) and (III) have formula (IIIa)

[0105]

[0106] In another embodiment of formulas (I), (Ia) and (Ib), wherein Ar 1 is monocyclic heteroaryl, the compound has formula (IV)

[0107]

[0108] In one embodiment of formulas (I), (Ia) and (Ib), wherein Ar 1is a bicyclic heteroaryl, and the compound has the formula (V)

[0109]

[0110] In another embodiment of formulas (I), (Ia), and (Ib), wherein Ar 1 is a bicyclic heteroaryl, the compound has the formula

[0111]

[0112] 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 optionally substituted phenyl, such as in the compounds of formula (VII)

[0113]

[0114] wherein Y is independently selected from R a 、R b 、R b substituted by one or more identical or different R a 、R b or R d substituted -OR a , or

[0115] -(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、

[0116] -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 ,

[0117] , -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 ,

[0118] , -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 ,

[0119] , -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 ;

[0120] Alternatively, two Y substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, which may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more alkyl, cycloalkyl and R b group substituents;

[0121] Each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl;

[0122] R b is independently selected from the following groups: =O, -OR d , C 1-3 haloalkoxy, -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 ,

[0123] -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 ,

[0124] -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 ; each R c is independently R a , or alternatively two Rs c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, which heterocycloalkyl or heteroaryl can optionally contain one or more additional heteroatoms, the same or different, and can optionally be substituted by one or more Rs b groups;

[0125] Each R d is independently hydrogen or C 1-6 alkyl;

[0126] Each m is independently an integer from 1 to 3; and

[0127] Each n is independently an integer from 0 to 3.

[0128] In further embodiments of formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V) and (VI), the compounds disclosed herein include those of formula (VIII).

[0129]

[0130] Specific examples of adenosine triphosphate diphosphatase inhibitors for enhancing the activity of agricultural or horticultural insecticides as described herein, according to the present disclosure and formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and / or (VIII), are shown in Table 1 below:

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] III. Method for Preparing Compounds

[0156] 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 those skilled in the art upon consideration of the present disclosure. For example, such compounds can be prepared by the condensation of acylhydrazines with aldehydes or ketones. In one embodiment, the compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and / or (VIII) are prepared according to Scheme (I) shown below:

[0157]

[0158] wherein Ar 1 , R 1 and R 2 are selected from those described in Part II above. Continuing with reference to Scheme (I), suitable conditions can be determined by those skilled in the art and can include, but are not limited to, weakly acidic conditions. Exemplary conditions suitable for preparing the compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and / or (VIII) of the present invention are described in G Vantomme, S Jiang & J-M 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 acylhydrazines can be prepared, for example, from esters of formula Ar 1 CO2R (wherein R is an alkyl group) as known to those skilled in the art. Ketones and aldehydes suitable for condensation with acylhydrazines can also be prepared as known to those skilled in the art.

[0159] IV. Target Crops and Their Pathogens

[0160] The present disclosure provides formulations and methods for treating crop pathogens. In one embodiment, one or more compounds disclosed herein, such as compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII), are applied in combination with agricultural or horticultural pesticides such as acaricides, antimicrobials, fungicides, herbicides, insecticides, molluscicides, and / or nematicides. As is known to those of ordinary skill in the agricultural art, treatable crops include crops infected by various pathogens, including but not limited to bacteria, viruses, fungal pathogens, mites, nematodes, molluscs, weeds, or other pests. By way of example, such agricultural and horticultural crops that can be treated according to the present disclosure include plants, whether genetically modified or not, including their harvested products, such as: grains; vegetables; root crops; potatoes; trees such as fruit trees, e.g., banana trees, tea trees, coffee trees, or cocoa trees; grasses; turfgrasses; or cotton.

[0161] Roux and colleagues described the compound:

[0162] (referred to herein as "Roux Compound 15") as enhancing the ability of certain fungicides to inhibit the growth of different phytopathogenic fungi (Molecular Plant Pathology, 2017, 18(7), 1012–1023; and WO 2016 / 123191). The compounds of the present invention surprisingly enhance the ability of a variety of pesticides against a variety of pathogens, including fungal pathogens. In addition, examples of the compounds disclosed herein exhibit enhancer activity superior to that of Roux Compound 15.

[0163] The agricultural or horticultural enhancer disclosed herein can be applied to every part of the plant, such as leaves, stems, patterns, flowers, flower buds, fruits, seeds, seedlings, roots, tubers, taproots, buds, or cuttings. The agricultural or horticultural enhancer according to the present disclosure can also be applied to improved varieties / varieties, cultivars, and mutants, hybrids, and genetically modified embodiments of these plants.

[0164] The agricultural or horticultural treatments described herein can be used for seed treatment, foliar application, soil application, or water application to control various diseases occurring in agricultural or horticultural crops, including flowers, turf, and forage.

[0165] The compounds of the present invention can be used to enhance the action of antimicrobials. For example, the compounds of the present invention can be used in combination with antimicrobials to combat bacterial and viral infections.

[0166] The compounds of the present invention can be used to enhance the action of herbicides. For example, the compounds of the present invention can be used in combination with one or more herbicides to control weeds or other unwanted vegetation.

[0167] The compounds of the present invention can be used to enhance the action of insecticides. For example, the compounds of the present invention can be used in combination with one or more insecticides to control insect pests.

[0168] The compounds of the present invention can be used to enhance the action of acaricides or miticides. For example, the compounds of the present invention can be used in combination with one or more acaricides to control mites.

[0169] The compounds of the present invention can be used to enhance the action of molluscicides. For example, the compounds of the present invention can be used in combination with one or more molluscicides to prevent slugs or snails from interfering with crops.

[0170] The compounds of the present invention can be used to enhance the action of nematicides. For example, the compounds of the present invention can be used in combination with one or more nematicides to prevent nematodes from interfering with crops.

[0171] The compounds of the present invention are particularly useful for enhancing the action of fungicides against plant fungal pathogens. Examples of pathogens 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.

[0172] Botrytis cinerea is an airborne plant pathogen with a necrotrophic lifestyle that attacks more than 200 crop hosts worldwide. It mainly attacks dicotyledonous plant species (including important protein, oil, fiber, and horticultural crops, grapes, and strawberries), and Botrytis also causes secondary soft rot of fruits and vegetables during storage, transportation, and in the market. Many types of fungicides cannot control Botrytis cinerea due to its genetic plasticity.

[0173] The genus Colletotrichum includes approximately 600 species that attack more than 3,200 monocotyledonous and dicotyledonous plant species. Colletotrichum graminicola mainly infects maize (Zea mays) and causes losses of approximately $1 billion per year in the United States alone (Connell et al., 2012).

[0174] Banana Fusarium wilt, caused by the soil-borne fungus Fusarium oxysporum f.sp. cubense, is a major threat to banana production worldwide. Currently, there is no fungicide available to effectively control the disease after the plant is infected (Peng J et al., 2014).

[0175] The ascomycete Sclerotinia sclerotiorum is known to attack more than 400 host species and is considered one of the most prolific plant pathogens. Most of the infected crop species are dicotyledons, as well as some agriculturally important monocotyledons. Some important crops infected by Sclerotinia include legumes (soybeans), most vegetables, stone fruits, and tobacco.

[0176] The ascomycete Verticillium dahliae is a soil-borne fungal plant pathogen that causes vascular wilt in a wide range of dicotyledonous host species. Verticillium dahliae can cause severe yield and quality losses in cotton and other important crops such as vegetables, fibers, fruits, nut trees, forest trees, and ornamental plants.

[0177] The ascomycete fungus Septoria tritici blotch (anamorph: Septoria tritici) is one of the most important foliar diseases of wheat leaves and occurs wherever wheat is grown. Yield losses caused by this disease range from 25% to 50%, and are particularly high in Europe, the Mediterranean region, and East Africa. Infection by Septoria tritici is initiated by airborne ascospores produced on crop residues from the previous season. Primary infection usually occurs after emergence in spring or autumn. The characteristic of the mature disease is the appearance of necrotic spots on the leaves and stems of infected plants.

[0178] The basidiomycete fungus Sphacelotheca reiliana systemically infects maize (Zea mays), causing head smut. The yield losses caused by the disease are variable and directly depend on the incidence of the disease. The fungus overwinters in the form of diploid teliospores in crop debris or soil. The flower structure transforms into a sorus containing a large amount of powdery teliospores, similar to the mature gall of common smut.

[0179] Examples of crops treated with the compounds and compositions disclosed by the present invention and plant diseases (pathogens) controlled include, but are not limited to:

[0180] Beet: Cercospora leaf spot (Cercospora beticola), black root rot (Aphanomyces cochlioides), root rot (Thanatephorus cucumeris), leaf rot (Thanatephorus cucumeris), etc.

[0181] 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.

[0182] Cucumber: Powdery mildew (Sphaerotheca fuliginea), downy mildew (Pseudoperonospora cubensis), gummy stem blight (Mycosp haerella melonis), fusarium wilt (Fusarium oxysporum), sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum orbiculare), angular leaf spot (Cladosporium cucumerinum), brown spot (Corynespora cassiicola), damping-off (Pythium debaryanum, Rhizoctonia solani Kuhn), Phomopsis root rot of cucumber (Phomopsis sp.), bacterial leaf spot (Pseudomonas syringae pv. Lechrymans), etc.

[0183] Tomato: Gray mold (Botrytis cinerea), leaf mold (Cladosporium fulvum), late blight (Phytophthora infestans), Verticillium wilt (Verticillium albo-atrum, Verticillium dahliae), powdery mildew (Oidium neolycopersici), early blight (Alternaria solani), leaf mold (Pseudocercospora fuligena), etc.

[0184] Eggplant: Gray mold (Botrytis cinerea), black rot (Corynespora melongenae), powdery mildew (Erysiphe cichoracearum), leaf mold (Mycovellosiella nattrassii), sclerotinia rot (Sclerotinia sclerotiorum), Verticillium wilt (Verticillium dahliae), brown spot (Phomopsis vexans), etc.

[0185] Strawberry: 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), Verticillium wilt (Verticillium dahliae), etc.

[0186] Onion: Neck rot (Botrytis allii), gray mold (Botrytis cinerea), leaf blight (Botrytis squamosa), downy mildew (Peronospora destructor), Phytophthora porn disease (Phytophthora porn), etc.

[0187] Cabbage: Clubroot (Plasmodiophora brassicae), soft rot (Erwinia carotovora), black rot (Xanthomonas campestris pv. campestris), bacterial black spot (Pseudomonas syringae pv. Maculicola, P. s. pv. alisalensis), downy mildew (Peronospora parasitica), sclerotinia rot (Sclerotinia sclerotiorum), black spot (Alternaria brassicicola), gray mold (Botrytis cinerea), etc.

[0188] Common bean: Sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum lindemuthianum), angular leaf spot (Phaeoisariopsis griseola), etc.

[0189] Apple: Powdery mildew (Podosphaera leucotricha), scab (Venturia inaequalis), brown rot (Monilinia mali), black spot (Mycosphaerella pomi), canker (Valsa mali), alternaria leaf spot (Alternaria mali), rust (Gymnosporangium yamadae), ring rot (Botryosphaeria berengeriana), anthracnose (Glomerella cingulata, Colletotrichum acutatum), leaf rot (Diplocarpon mali), fly speck (Zygophiala jamaicensis), sooty blotch (Gloeodes pomigena), violet root rot (Helicobasidium mompa), gray mold (Botrytis cinerea), etc.

[0190] Japanese apricot: Scab (Cladosporium carpophilum), gray mold (Botrytis cinerea), brown rot (Monilinia mumecola), etc.

[0191] Persimmon: Powdery mildew (Phyllactinia kakicola), anthracnose (Gloeosporium kaki), angular leaf spot (Cercospora kaki), etc.

[0192] Peach: Brown rot (Monilinia fructicola), scab (Cladosporium carpophilum), Phomopsis rot (Phomopsis sp.), bacterial leaf spot (Xanthomonas campestris pv. pruni), etc.

[0193] Almond: Brown rot (Monilinia taxa), Spot disease (Stigminacarpophila), Scab (Cladosporium carpophilum), Red leaf spot (Polystigma rubrum), Alternaria leaf spot (Alternaria alternata), Anthracnose (Colletotrichum gloeospoides), etc.

[0194] Yellow peach: Brown rot (Monilinia fructicola), Anthracnose (Colletotrichum acutatum), Black spot (Alternaria sp.), Sclerotinia of young fruit (Monilinia kusanoi), etc.

[0195] Grape: Gray mold (Botrytis cinerea), Powdery mildew (Uncinula necator), Black 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.

[0196] Pear: Scab (Venturia nashicola), Rust (Gymnosporangium asiaticum), Black spot (Alternaria kikuchiana), Ring rot (Botryosphaeria berengeriana), Powdery mildew (Phyllactinia mali), Spruce canker (Phomopsis fukushii), Brown spot (Stemphylium vesicarium), Anthracnose (Glomerella cingulata), etc.

[0197] Tea: Target spot (Pestalotiopsis longiseta, Pestalotiopsis theae), Anthracnose (Colletotrichum theae-sinensis), Net blight (Exobasidium reticulatum), etc.

[0198] Citrus fruits: Alternaria alternata (black spot, Elsinoe fawcettii), blue mold (Penicillium italicum), common green mold (Penicillium digitatum), gray mold (Botrytis cinerea), melanose (Diaporthe citri), citrus canker (Xanthomonas campestris pv. Citri), powdery mildew (Oidium sp.), etc.

[0199] Wheat: powdery mildew (Blumeria graminis f. sp. tritici), red mold (Gibberella zeae), brown rust (Puccinia recondita), brown snow mold (Pythium iwayamai), powdery snow mold (Monographella nivalis), eyespot (Pseudocercosporella herpotrichoides), leaf scorch (Septoria tritici), glume blotch (Leptosphaeria nodorum), patchy snow blight (Typhula incarnata), sclerotial snow blight (Myriosclerotinia borealis), damping-off (Gaeumannomyces graminis), ergot (Claviceps purpurea), bunt (Tilletia caries), loose smut (Ustilago nuda), etc.

[0200] Barley: leaf spot (Pyrenophora graminea), net blotch (Pyrenophora teres), leaf spot (Rhynchosporium secalis), loose smut (Ustilago tritici, Ustilago nuda), etc.

[0201] Rice: Blast (Pyricularia oryzae), Sheath rot (Rhizoctonia solani), Bakanae disease (Gibberella fujikuroi), Brown spot (Cochliobolus miyabeanus), Damping-off (Pythium graminicola), Bacterial leaf blight (Xanthomonas oryzae), Bacterial seedling blight (Burkholderia plantarii), Brown stripe (Acidovorax avenae), Bacterial grain rot (Burkholderia glumae), Cercospora leaf spot (Cercospora oryzae), False smut (Ustilaginoidea virens), Rice brown spot (Alternaria, Curvularia intermedia), Discoloration of rice grains (Alternaria padwickii), Powdering of rice grains (Epicoccum purpurascens), etc.

[0202] Tobacco: Sclerotinia rot (Sclerotinia sclerotiorum), Powdery mildew (Erysiphe cichoracearum), Phytophthora rot (Phytophthora nicotianae), etc.

[0203] Tulip: Botrytis blight (Botrytis cinerea), etc.

[0204] Sunflower: Downy mildew (Plasmopara halstedii), Sclerotinia rot (Sclerotinia sclerotiorum), etc.

[0205] Evergreen grass: Sclerotinia snow blight (Sclerotinia borealis), Giant leaf spot (Rhizoctonia solani), Brown spot (Rhizoctonia solani), Dollar spot (Sclerotinia homoeocarpa), Blast (Pyricularia sp.), Pythium blight (Pythium aphanidermatum), Anthracnose (Colletotrichum graminicola), etc.

[0206] Orchard grass: Powdery mildew (Erysiphe graminis), etc.

[0207] Soybeans: purple spot (Cercospora kikuchii), downy mildew (Peronospora manshurica), Phytophthora rot (Phytophthora sojae), rust (Phakopsora pachyrhizi), sclerotinia rot (Sclerotinia sclerotiorum), anthracnose (Colletotrichum truncatum), gray mold (Botrytis cinerea), citrus scab (Elsinoe glycines), black rot (Diaporthe phaseolorum var. sojae), etc.

[0208] Potatoes: Phytophthora rot (Phytophthora infestans), early blight (Alternaria solani), scurf (Rhizoctonia solani), Verticillium wilt (Verticillium albo - atrum, Verticillium dahliae, Verticillium nigrescens, etc.).

[0209] Bananas: Panama disease (Fusarium oxysporum), banana leaf spot (Mycosphaerella fijiensis, Mycosphaerella musicola), etc.

[0210] Rapeseed: sclerotinia rot (Sclerotinia sclerotiorum), root rot (Phoma lingam), black leaf spot (Alternaria brassicae), etc.

[0211] Coffee: rust (Hemileia vastatrix), anthracnose (Colletotrichum coffeanum), leaf spot (Cercospora coffeicola), etc.

[0212] Sugarcane: brown rust (Puccinia melanocephala), etc.

[0213] Maize: banded leaf spot (Gloeocercospora sorghi), rust (Puccinia sorghi), southern rust (Puccinia polysora), smut (Ustilago maydis), brown spot (Cochliobolus heterostrophus), northern leaf blight (Setosphaeria turcica), etc.

[0214] Cotton: Seedling blight (Pythium sp.), rust (Phakopsora gossypii), sour rot (Mycosphaerella areola), anthracnose (Glomerella gossypii), etc.

[0215] V. Insecticides

[0216] The compounds disclosed in the present invention (including the compounds according to formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII)) can be used to enhance the effects of various agrochemicals, including fungicides, antivirals, bactericides, herbicides, insect / acaricides, molluscicides, nematicides, soil insecticides, plant protectants, synergists, fertilizers and soil conditioners.

[0217] In one embodiment, the compounds disclosed in the present invention can be used to enhance the fungicidal effects of various fungicides. The fungicides used in combination with the enhancers disclosed herein are well known to those skilled in the art and include, but are not limited to, those listed by category in Table 2:

[0218]

[0219]

[0220]

[0221]

[0222]

[0223] Fungicides are more generally catalogued by the Fungicide Resistance Action Committee (FRAC) in the FRAC Coding Table 2022 and reproduced in Appendix 1, the full text of which is incorporated herein by reference.

[0224] In one embodiment, the enhancer compounds disclosed herein are used in combination with one or more compounds from the families or groups listed in Table 2, Appendix 1, or both. In certain embodiments, the enhancer disclosed herein is used in combination with one or more fungicides listed in Column 1 of Table 2. By way of example, such use of enhancer compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and / or (VIII) in combination with fungicides can include application at the same or different times. In one embodiment, the enhancer compound is applied before the fungicide. In one embodiment, the enhancer compound is applied after the fungicide.

[0225] In certain embodiments, the disclosed enhancer is used in combination with a fungicide selected from one or more of the following: benzimidazole, dicarboximide, phenylpyrrole, anilinopyrimidine, hydroxyaniline, formamide, phenylamide, phosphonate, cinnamic acid, oxysterol binding protein inhibitor (OSBPI), triazole carboxamide, cymoxanil, carbamate, benzamide, demethylation inhibiting piperazine, demethylation inhibiting pyrimidine, demethylation inhibiting azole (including imidazole and triazole, such as cyproconazole, difenoconazole, myclobutanil, flutriafol, cyflufenamid, metconazole, ipconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole), morpholine, cyflufenamid, metrafenone, picoxystrobin, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbon, phthalimide, guanidine, polyoxin, fluazinam, and thiazolidine.

[0226] Particular fungicides enhanced according to the methods herein by the use of a combination of an apyrase inhibitor and an enhancer are copper (such as copper octanoate, copper hydroxide, etc.), myclobutanil, propiconazole, tebuconazole, epoxiconazole, difenoconazole, triticonazole, and prothioconazole.

[0227] In one embodiment, treatment with a combination of a selected fungicide and an enhancer according to the present disclosure provides synergistic fungicidal activity against phytopathogenic fungi.

[0228] In one embodiment, the present disclosure provides compositions and methods for treating plants or plant seeds infected with or at risk of being infected with a fungal pathogen. In one embodiment, the compositions of the present disclosure comprise a formulation of a fungicide, an enhancer, and a botanically acceptable carrier. In another embodiment, the fungicide and the enhancer are applied in separate compositions. In additional embodiments, an agricultural or horticultural fungicide is used in combination with other compounds other than the adenosine triphosphate diphosphatase inhibitors disclosed in the present invention. Like the adenosine triphosphate diphosphatase inhibitors, such other compounds can be applied in the same or separate compositions as the fungicide. Examples of other components include known carriers for formulation. Additional examples thereof include conventionally known herbicides, insecticides / acaricides, nematicides, soil insecticides, plant protectants, synergists, fertilizers, soil conditioners, and animal feeds. In one embodiment, the inclusion of such other components produces a synergistic effect on crop growth.

[0229] In one embodiment, the compounds disclosed in the present invention (including the compounds according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII)) are used to enhance the action of herbicides. Exemplary herbicides used in combination with the compounds of the present invention are known to those skilled in the art and include, but are not limited to, those described in Appendix 2. By way of example, suitable herbicides used in combination with the compounds of the present invention include acetyl-CoA synthase inhibitors, acetolactate synthase inhibitors, microtubule assembly inhibitors, microtubule organizing inhibitors, auxin mimics, photosynthesis inhibitors, deoxy-D-xylulose phosphate synthase inhibitors, enolpyruvate shikimate phosphate synthase inhibitors, phytoene desaturase inhibitors, glutamine synthetase inhibitors, dihydropteroate synthase inhibitors, protoporphyrinogen oxidase inhibitors, cellulose synthase inhibitors, uncouplers, hydroxyphenylpyruvate dioxygenase inhibitors, fatty acid thioesterase inhibitors, serine-threonine protein phosphatase inhibitors, solanesyl diphosphate synthase inhibitors, very long chain fatty acid synthesis inhibitors, homogentisate solanesyltransferase inhibitors, lycopene cyclase inhibitors,

[0230] In one embodiment, the compounds disclosed in the present invention (including the compounds according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII)) are used to enhance the action of insecticides. Exemplary insecticides used in combination with the compounds of the present invention are known to those skilled in the art and include, but are not limited to, those described in Appendix 3.

[0231] VI. Formulation

[0232] The present disclosure provides specific adenosine triphosphate diphosphatase inhibitors (including compounds of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII)) to enhance the efficacy of pesticides in effectively restricting the growth of phytopathogenic species. In certain non-limiting embodiments, the adenosine triphosphate diphosphatase inhibitor can be provided in an amount of from about 0.01 to about 80% weight / weight in the final composition, or from about 25% to about 55% in the final composition, such as from about 30% to about 50%, from about 35% to about 45%, such as 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% weight / weight. In one embodiment, the adenosine triphosphate diphosphatase inhibitor is provided in liquid form in an amount of from about 0.01 to about 50% in the final diluted composition, such as from about 15% to about 50%, from about 20% to about 45%, from about 25% to about 40%, such as 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% volume / volume. Those skilled in the art will recognize that formulations of pesticides, adenosine triphosphate diphosphatase inhibitors, or combinations thereof can be provided in the form of concentrates that can be diluted prior to use, or can be provided in a diluted form ready for treatment.

[0233] The enhancer, pesticide, and combinations thereof are not particularly limited by the dosage form. Examples of dosage forms include wettable powders, emulsions, emulsifiable concentrates, oil-dispersible liquids, powders, granules, water-soluble agents, suspensions, granular wettable powders, and tablets. The method for preparing the formulation is not particularly limited, and conventional known methods can be employed according to the dosage form. Several formulation examples are described below. The formulation recipes shown below are only examples and can be modified within the scope not departing from the essence of the present disclosure. For example, additional active and inert components can be added to the following formulations.

[0234] Unless otherwise specified, "parts" means "parts by mass".

[0235] Formulation Example 1: Wettable Powder

[0236] Forty parts of the enhancer disclosed herein, 53 parts of diatomaceous earth, 4 parts of ethoxylated higher alcohol sulfate ester combined with a suitable solid carrier such as magnesium sulfate, and 3 parts of alkyl naphthalene sulfonate are mixed evenly and then finely ground to obtain a wettable powder containing 40 parts by mass of the enhancer.

[0237] Formulation Example 2: Emulsifiable Concentrate

[0238] Three parts of the enhancer disclosed herein, 60 parts of mixed petroleum distillates, 27 parts of dimethyl lactamide, and 10 parts of triphenyl vinyl phenol polyoxyethylene ether are mixed and dissolved to obtain an emulsifiable concentrate containing 3% by mass of the enhancer.

[0239] Formulation Example 3: Granules

[0240] Five parts of the enhancer 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 mixed evenly and then finely ground, and then fluidized bed granulation is carried out to make the median particle size 0.2 to 2.0 mm, thus obtaining granules containing 5% by mass of the enhancer disclosed herein based on dry weight.

[0241] Formulation Example 4: Granules

[0242] Five parts of the enhancer disclosed herein, 73 parts of clay, 20 parts of bentonite, 1 part of sodium dioctyl sulfosuccinate, and 1 part of potassium phosphate are mixed and then ground, and then water is added thereto, and then the mixture is kneaded. Then, extrusion granulation is carried out, and the obtained product is dried to obtain granules containing 5% by mass of the enhancer based on dry weight.

[0243] Formulation Example 5: Suspension

[0244] Ten parts of the enhancer disclosed herein, 4 parts of polyoxyethylene alkyl ether, 2 parts of 3 kDa polycarboxylate sodium as a dispersant, 10 parts of glycerol, 0.2 part of xanthan gum, 0.1 part of biocide as a stabilizer, 0.1 part of silicone antifoam emulsion, and 73.6 parts of water are mixed and then wet ground to a particle size of 3 microns or less to obtain a suspension containing 10% by mass of the enhancer.

[0245] Formulation Example 6: Oil Dispersible Concentrate

[0246] Forty parts of the enhancer disclosed herein, 5 parts of Atlox 4914, 5 parts of organically modified bentonite, and 50 parts of methylated rapeseed oil as a carrier are mixed evenly and then wet ground to a median particle size of 3 microns or less to obtain an oil dispersible concentrate containing 40% by mass of the enhancer.

[0247] Those skilled in the art will recognize that various compositions are used commercially at different concentrations and formulations. For example, fungicides are commonly formulated commercially as liquids at concentrations of 10-40%. In one embodiment, due to the enhanced efficacy when the fungicide is combined with the enhancer disclosed herein, the enhancer disclosed in the present invention allows for the use of lower amounts of a given fungicide.

[0248] VII. Methods for Evaluating Enhancer Activity

[0249] The compounds disclosed in the present invention exhibit activity against a variety of pathogens. Their activity is partially evaluated according to the following assays:

[0250] Method 1: In Vitro Adenosine Triphosphate Diphosphohydrolase Assay:

[0251] An in vitro assay is used to evaluate adenosine triphosphate diphosphohydrolase inhibitors that can be used as insecticidal activity enhancers. The method of Windsor, Bio Techniques 33:1024-1030 (November 2002) is used as follows:

[0252] Screening of Adenosine Triphosphate Diphosphohydrolase Inhibitors—

[0253] A 96-well plate is used for this assay: (Greiner bio-one: REF-655901—96 wells, PS, F-bottom, transparent, non-binding)

[0254] Buffers:

[0255] Reaction buffer: 60 mM Hepes; 3 mM MgCl2, 3 mM CaCl2 and 3 mM ATP (pH 6.5)

[0256] Development buffer A: 2% aqueous ammonium molybdate

[0257] Development buffer B: Aqueous solution of 11% ascorbic acid in 37.5% TCA

[0258] Stop buffer C: 2% aqueous acetic acid in 2% sodium citrate

[0259] · Add 100 μl of reaction buffer to each well.

[0260] · Add 10 μl of DMSO (control) or inhibitor / one compound or multiple compounds such as N1915 or vanadate to each well. (Use an inhibitor concentration of 1 mM; 2 mM vanadate, 1 mM N1915)

[0261] · Add 10 μl of apyrase (concentration based on optimization - dilute the 1 U / μl 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)

[0262] · Incubate the plate at room temperature for 1 hour

[0263] · Mix developing buffer A and B in a 1:1.5 ratio (before use).

[0264] · Add 50 μl of the A:B mixture to each well (incubate for 2 minutes)

[0265] · Add 50 μl of C to each well

[0266] · Measure / read the absorbance of the plate at 630 nm

[0267] The inhibition data for the above apyrase assay of the selected compounds are provided in Table 3:

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274] Refer to Table 3 and report the percent inhibition of apyrase as the rounded average of the results of two assays. Blank cells indicate that the observed inhibition was < 10% or that the difference between replicate assays was large. In some examples, no inhibition was observed due to the lack of solubility of the compound under the assay conditions rather than a lack of apyrase inhibitory activity. Roux compound 15 inhibits approximately 60% of apyrase in this assay.

[0275] Method 2: In vitro evaluation of combined activity

[0276] Evaluate the combinations of selected compounds with fungicides against a range of commercially important phytopathogenic fungi.

[0277] The testing is carried out as follows. The fungicide is combined with a suitable dose of the test compound and applied to the fungal phytopathogen at a rate slightly below that at which it provides any control. If control of the pathogen is observed, the test compound is recorded as active.

[0278] More specifically, the test is conducted as follows. For each combination of fungicide, pathogen, and test compound, the following wells are used. Well 1 contains the fungal pathogen growing on agar and a fungicide at a rate just below that which provides any control of the pathogen. Well 2 is the same as Well 1, except that the test compound is added at rate 1. Well 3 is the same as Well 2, except that the test compound is added at rate 2, where rate 2 is higher than rate 1. Finally, as a benchmark, Well 4 is the same as Well 1, except that it contains a higher rate of fungicide that provides partial control of the pathogen. Each of Wells 1 to 4 is run twice, giving a total of 8 wells for each combination of fungicide, pathogen, and test compound. For each well, after an appropriate incubation period, the percent control of the pathogen by the fungicide is visually evaluated. The test compound is scored as inactive, active, or highly active.

[0279] The following fungicides are used in this assay: azoxystrobin, fluxapyroxad, and prothioconazole-desthio. The following fungal pathogens are used in this assay. The first is a strain of Septoria tritici that is less sensitive to strobilurin fungicides; the second is a strain of Septoria tritici that is less sensitive to SDHI fungicides (i.e., fungicides that inhibit succinate dehydrogenase); the third is Microdochium nivale. In this assay, Roux Compound 15 did not show activity. In contrast, Compound I-4 of the present invention, which only inhibits 24% adenosine triphosphate pyrophosphatase activity in Method 1, is highly effective in the combined assay, showing significant activity against all three fungal pathogens in combination with each of the three fungicides.

[0280] The combination of Compound I-223, which only inhibits 10% adenosine triphosphate pyrophosphatase activity in Method 1, and fluxapyroxad shows significant activity against Microdochium nivale, and the combination with prothioconazole-desthio shows significant activity against Septoria tritici that is less sensitive to strobilurin fungicides.

[0281] The combination of Compound I-214, which inhibits 55% in Method 1, and fluxapyroxad shows significant activity against Microdochium nivale, and the combination with prothioconazole-desthio shows significant activity against Septoria tritici that is less sensitive to strobilurin fungicides and Septoria tritici that is less sensitive to SDHI fungicides.

[0282] The combination of Compound I-9, which inhibits 19% in Method 1, and azoxystrobin shows significant activity against Microdochium nivale, and the combination with prothioconazole-desthio shows significant activity against Septoria tritici that is less sensitive to SDHI fungicides.

[0283] In Method 1, the combination of Compound I-215 and fluxapyroxad, which inhibits 46%, showed significant activity against Microdochium nivale.

[0284] Surprisingly, the exemplary compounds (including those that showed less activity than Roux Compound 15 in the in vitro inhibition assay of Method 1 above) showed significant activity in the combination assay in which Roux Compound 15 showed zero activity.

[0285] Method 3: Greenhouse crop testing

[0286] In this method, the ability of exemplary compounds to control Septoria tritici on wheat, Botrytis cinerea on tomato, Phakopsora pachyrhizi on soybean, and Puccinia recondita on wheat in combination with one of four fungicides (Amistar, Imtrex, Proline, or Balaya) was evaluated in a controlled greenhouse environment. In these studies, soybean cultivar Siverka, tomato (Money maker), and wheat plants (JB Diego) were used. Seeds were sown to a depth of 1 - 2 cm in 9 cm diameter pots using Petersfield potting compost (75% medium grade peat, 12% screened sterilized loam, 3% medium grade vermiculite, 10% coarse sand (5 mm screened, lime free), 1.5 kg PG mixture / m3, lime to pH 5.5 - 6.0, and wetting agent (Vitax Ultra wet 200 ml / m3)) and germinated / grown under 16 - hour day / 8 - hour night light regime at 23°C. Plants were treated two to three weeks after sowing when they were at the BBCH 11 growth stage (when the first pair of true leaves (single leaves) had unfolded). Using a tracked sprayer, plants were treated with a mixture of commercial fungicide and the test compound using a water volume of 200 L / ha. Twenty - four hours after treatment, plants were inoculated with the appropriate fungus (pathogen). The fungal pathogens used were Botrytis cinerea (gray mold on tomato plants), Septoria tritici (septoria leaf spot on wheat plants), Puccinia triticina (brown rust on wheat plants), and Phakopsora pachyrhizi (Asian soybean rust on soybean plants). Each combination of fungicide, pathogen, and test compound was used with four replicates. After disease symptoms had fully developed between seven and twenty days (depending on the pathogen), the percent disease control of each plant was evaluated. Appropriate controls were used for all experiments, including "inoculation checks" where plants were inoculated with the specific pathogen of the plant to evaluate disease levels. Additionally, each commercial fungicide was tested separately as part of each treatment, which served as a benchmark for evaluating the experimental compounds. The combination of exemplary compounds with the fungicides showed enhanced disease control compared to the disease control observed with the fungicides alone. That is, the compounds of the present invention, although not fungicidal per se, enhanced the activity of the fungicides.

[0287] In these studies, the fungicides were applied at the following rates

[0288] Amistar Imtrex Proline Balaya Septoria tritici 0.1 L / ha 0.02 L / ha 0.0075 L / ha 0.0015 L / ha Botrytis cinerea 0.03 L / ha 0.005 L / ha 0.00075 L / ha 0.0015 L / ha Phakopsora pachyrhizi 0.02 L / ha 0.05 L / ha 0.15 L / ha 0.03 L / ha Puccinia horiana 0.03 L / ha 0.35 L / ha 0.125 L / ha 0.2 L / ha

[0289] In this method, the combination of Amistar or Balaya with Compound I-214 applied at 20 ppm provides significantly superior control of Septoria tritici compared to Amistar or Balaya alone or compared to the combination of Roux Compound 15 applied at 30 ppm. The combination of Imtrex or Proline with Compound I-214 at 20 ppm provides similar control of Septoria tritici compared to the combination of Imtrex or Proline with Roux Compound 15 applied at 15 and 30 ppm and provides control superior to Imtrex or Proline alone. The combination of Imtrex and Balaya with Compound I-214 applied at 20 ppm provides significantly superior control of Botrytis cinerea compared to Imtrex or Balaya alone or compared to the combination of Roux Compound 15 applied at 30 ppm. The activity of Imtrex against Puccinia recondita and the activities of Amistar, Proline, and Balaya against Phakopsora pachyrhizi are significantly enhanced by the addition of 20 ppm of Compound I-214.

[0290] The combination of Proline and Balaya shows significantly superior results in controlling Septoria tritici after the addition of Compound I-223 applied at 20 ppm compared to Proline or Balaya alone or compared to the combination of Roux Compound 15 applied at 30 ppm.

[0291] The combination of Amistar with Compound I-4 shows a level of control of Botrytis cinerea comparable to the combination with Roux Compound 15 at the same ratio. In both cases, the control is significantly higher than Amistar used alone. In contrast, the combination of Amistar with Compound I-4 at 15 ppm provides a much higher level of control of Botrytis cinerea compared to the combination of Amistar with Roux Compound 15 at this same lower ratio. Again, the control is significantly higher than Amistar used alone. The combination of Proline with Compound I-4 at 30 ppm provides a level of control of Botrytis cinerea similar to the combination with Roux Compound 15 at the same ratio. In both cases, the activity is significantly higher than Proline used alone. The combination of Imtrex with Compound I-4 at 30 ppm provides control of Botrytis cinerea far superior to Imtrex alone or to the combination with Roux Compound 15 at the same ratio. Finally, the combination of Balaya with Compound I-4 at 15 ppm has significantly higher activity against Botrytis cinerea compared to Balaya alone or compared to the combination with Roux Compound 15 at the same ratio. In fact, the combination of Balaya with Roux Compound 15 at 15 ppm does not have higher activity against Botrytis cinerea compared to Balaya alone.

[0292] 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 regarded as limiting the scope of the invention. On the contrary, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

[0293] Appendix 1

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Appendix 2

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319] Appendix 3

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

Claims

1. A method for inhibiting apyrase, the method comprising contacting the apyrase with a compound of the following formula: wherein Ar 1 is selected from aryl and heteroaryl; R 1 is selected from 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 the compound does not have the following formula 2. The method according to claim 1, wherein the compound has the following formula wherein X is independently selected, each occurrence, from R a , R b , R b substituted by one or more identical or different R a , -OR b or R d substituted by one or more identical or different R 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 ; or two X substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, which may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more R b groups; each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl; R b is independently selected from the following groups: =O, -OR d , C 1-3 haloalkoxy, -OCF2H, -OCH2F, -OCF3, =S, -SRd 、 -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 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 ; Each R c Independently for R a , or alternatively, two R c Together with the nitrogen atom to which they are bound, they form a 5- to 8-membered heterocycloalkyl or heteroaryl group, which may optionally contain one or more identical or different additional heteroatoms and may optionally be replaced by one or more identical or different R b Group substitution; Each R d are independently hydrogen or C 1-6 alkyl; Each m is independently an integer from 1 to 3; and Each n is independently an integer from 0 to 3.

3. The method of claim 2, wherein X is selected from C 1-6 Alkyl, -OR a 、-S(O)2NR c R c and halogens.

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

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

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

7. The method of claim 1, wherein the compound has the formula Where X is independently selected at each occurrence from R a , R b , by one or more identical or different R b Replaced by R a , by one or more identical or different R b or R d Substituted-OR a ,or -(CH2) m -R b 、-(CHRa ) 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 ; or two X substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl, which can optionally contain one or more additional heteroatoms, the same or different, and can optionally be substituted by one or more R b groups; each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl; R b is independently selected from the following groups: =O, -OR d , C 1-3 haloalkoxy, -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 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 ; Each R c Independently for R a , or alternatively two R c Together with the nitrogen atom to which they are bound, they form a 5- to 8-membered heterocycloalkyl or heteroaryl group, which may optionally contain one or more identical or different additional heteroatoms and may optionally be replaced by one or more identical or different R b Group substitution; Each R d are independently hydrogen or C 1-6 alkyl; Each m is independently an integer from 1 to 3; and Each n is independently an integer from 0 to 3.

8. The method according to claim 1, wherein the compound has the following formula 9. The method according to claim 1, wherein the compound has the following formula 10. The method according to claim 1, wherein the compound has the following formula 11. The method according to claim 1, wherein the compound has the following formula 12. The method according to claim 1, wherein the compound has the following formula 13. The method according to any one of claims 1 to 12, wherein R 2 is hydrogen.

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

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

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

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

18. The method according to claim 1, wherein the compound has the following formula wherein Y is independently selected, each time it appears, from R a 、R b 、R b substituted by one or more identical or different R a 、-OR b substituted by one or more identical or different R d or R 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-CRa (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 ; Alternatively, two Y substituents together with the atoms to which they are attached form a 5- to 8-membered aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, which can optionally contain one or more additional heteroatoms, the same or different, and can optionally be substituted by one or more alkyl, cycloalkyl and R b groups; Each R a is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 6-16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 8-membered heterocycloalkyl, 4- to 11-membered heterocycloalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl; R b is independently selected from the group consisting of: =O, -OR d , C 1-3 haloalkoxy, -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 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 ; Each R c is independently R a , or alternatively two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocycloalkyl or heteroaryl, which heterocycloalkyl or heteroaryl may optionally contain one or more additional heteroatoms, the same or different, and may optionally be substituted by one or more R b groups; Each R d is independently hydrogen or C 1-6 alkyl; Each m is independently an integer from 1 to 3; and Each n is independently an integer from 0 to 3.

19. The method according to claim 1, wherein the compound has the formula 20. The method according to claim 19, wherein Ar 1is an optionally substituted phenyl group.

21. The method according to claim 1, wherein the compound is selected from (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)nicotinic hydrazide; (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'-pentylidene benzohydrazide; (E)-N'-(1-(pyridin-3-yl)ethylidene)benzo[d][1,3]dioxole-5-carboxylic hydrazide; (E)-N'-(1-(3,4-dimethylphenyl)ethylidene)-1-naphthoyl hydrazide; (E)-2-fluoro-N'-(1-(pyridin-4-yl)ethylidene)benzohydrazide; (E)-N'-(1-(6-methoxynaphthalen-2-yl)ethylidene)benzo[d][1,3]dioxole-5-carboxylic hydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic hydrazide; (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-5-carboxylic hydrazide; (E)-N'-(1-(naphthalen-1-yl)ethylidene)hexane hydrazide; (Z)-2-(2-benzoylhydrazono)propanoic acid; (E)-2-methyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; (E)-N'-butylidene benzohydrazide; (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'-(hept-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'-(Prop-2-ylidene)-1-naphthoylhydrazide; (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-naphthoylhydrazide; (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)propanohydrazide; (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-carboxohydrazide; (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-naphthalenecarboxohydrazide; (E)-N'-(1-(pyridin-2-yl)ethylidene)-1-naphthalenecarboxohydrazide; (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-carboxylic hydrazide; (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-carboxylic hydrazide; (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)isobutyrylhydrazide; N'-Cyclohexylbenzohydrazide; (E)-N'-(1-Phenylethylidene)propionylhydrazide; (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'-(hept-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)acetylhydrazide; (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)picolylhydrazide; (Z)-N'-(1-(4-fluorophenyl)ethylidene)benzohydrazide; (E)-N'-(2-chlorobenzylidene)-2-naphthoylhydrazide; 4-methyl-N'-(4-methylcyclohexylidene)benzohydrazide; (E)-3-cyclopropyl-N'-(1-(naphthalen-2-yl)ethylidene)-1H-pyrazole-5-carboxylic hydrazide; (E)-N'-octylidene benzohydrazide; (E)-N'-(naphthalen-1-ylmethylene)acetylhydrazide; (E)-2-(2-benzoylhydrazono)propanoic acid; (E)-N'-benzylidene-4-methylbenzohydrazide; (E)-4-chloro-N'-ethylidene benzohydrazide; (E)-N'-(1-phenylethylidene)acetylhydrazide; (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-carboxylic hydrazide; (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-carboxylic hydrazide; (E)-2-Methyl-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (Z)-3,4-Dimethyl-N'-(1-(pyridin-2-yl)ethylidene)benzohydrazide; N'-(diphenylmethylene)isobutyryl hydrazide; 4-Amino-N'-cyclopentylidene benzohydrazide; (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-carboxylic hydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)nicotinic hydrazide; (E)-N'-(1-(4-aminophenyl)ethylidene)benzohydrazide; (E)-4,6-Dimethyl-N'-(1-phenylethylidene)pyrimidine-2-carboxylic hydrazide; (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)propanamide; (E)-N'-(1-(4-chlorophenyl)ethylidene)benzohydrazide; (E)-4-(tert-butyl)-N'-(1-(p-tolyl)ethylidene)benzohydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)cyclohexanecarboxylic hydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)cyclopropanecarboxylic hydrazide; (E)-N'-(1-(naphthalen-2-yl)ethylidene)-3-phenylpropanohydrazide; N'-subcyclopentyl-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-phenylacetylhydrazide; (Z)-3-fluoro-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; (E)-2-(1-(naphthalen-2-yl)ethylidene)hydrazine-1-carboxylic acid methyl ester; (E)-N'-benzylidene benzohydrazide; (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-carboxylic hydrazide; (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)acetylhydrazide; (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)nicotinic hydrazide; (Z)-N'-(1-(naphthalen-2-yl)ethylidene)picolyl hydrazide; (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-carboxylic hydrazide; (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-carboxylic hydrazide; (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-carboxylic hydrazide; (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-carboxylic hydrazide; (E)-N'-(1-(2,3-dihydro-1H-inden-5-yl)ethylidene)-3-methylbenzohydrazide; (E)-4-Methyl-N'-(1-(naphthalen-2-yl)ethylidene)pyrimidine-2-carboxylic hydrazide; (E)-5-Methyl-N'-(1-(naphthalen-2-yl)ethylidene)nicotinic hydrazide; (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)isonicotinic hydrazide; (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-carboxylic hydrazide; (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.

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

23. The method according to claim 22, the method further comprising treating the crop with an insecticide.

24. The method according to claim 23, wherein the insecticide is selected from acaricides, fungicides, herbicides, insecticides, molluscicides, nematicides, or combinations thereof.

25. The method according to claim 24, wherein the insecticide comprises a fungicide.

26. The method according to claim 22, the method further comprising treating the crop with a fungicide selected from: benzimidazoles, dicarboximides, phenylpyrroles, anilinopyrimidines, hydroxyanilines, formamides, phenylamides, phosphonates, cinnamic acids, oxysterol binding protein inhibitors (OSBPIs), triazole carboxamides, cymoxanil, carbamates, benzamides, demethylation inhibiting piperazines, demethylation inhibiting pyrimidines, demethylation inhibiting azoles including imidazoles and triazoles such as cyproconazole, difenoconazole, fenbuconazole, flutriafol, cyflufenamid, metconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, morpholines, cyflufenamid, benzovindiflupyr, fenpyrazamine, strobilurins, copper ammonium complexes, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamates, aromatic hydrocarbons, phthalimides, guanidines, polyoxins, fluazinam, thiazolanes, or combinations thereof.

27. A composition, the composition comprising a compound of the following formula wherein Ar 1 is selected from aryl and heteroaryl; R 1 is selected from hydrogen, C 3-6 cycloalkyl, C 1-6Alkyl, aralkyl, and C 1-3 haloalkyl; R 2 selected from alkyl, aryl, and heteroaryl; provided that the compound does not have the following formula and a botanically acceptable carrier.

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

29. The composition according to claim 27, wherein the composition is a suspension preparation.

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

31. The composition according to claim 30, wherein the composition further comprises sodium polycarboxylate.

32. The composition according to claim 31, wherein the composition further comprises a biocide.

33. The composition according to claim 31, wherein the composition further comprises an organosilicon defoaming emulsion.

34. The composition according to claim 27, wherein the composition is a wettable powder.

35. The composition according to claim 27, wherein the composition is an emulsifiable concentrate.

36. The composition according to claim 35, wherein the composition further comprises triphenylvinylphenol polyoxyethylene ether.

37. The composition according to claim 27, wherein the composition is an oil-dispersible concentrate.

38. An insecticide composition, the insecticide composition comprising an insecticide; a compound of the following formula wherein Ar 1 is selected from aryl and heteroaryl; R 1 is selected from 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 the compound does not have the following formula and a botanically acceptable carrier.

39. The insecticide composition according to claim 38, wherein the insecticide comprises a miticide, a fungicide, a herbicide, an insecticide, a molluscicide, a nematicide, or a combination thereof.

40. A fungicidal composition, the fungicidal composition comprising a fungicide; a compound of the following formula wherein Ar 1 is selected from aryl and heteroaryl; R 1 is selected from 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 the compound does not have the following formula and a botanically acceptable carrier.

41. The composition according to claim 40, wherein the fungicide is selected from benzimidazole, imide, phenylpyrrole, anilinopyrimidine, hydroxyaniline, formamide, phenylamide, phosphonate, cinnamic acid, oxysterol binding protein inhibitor, triazole carboxamide, cymoxanil, carbamate, benzamide, demethylation inhibiting piperazine, demethylation inhibiting pyrimidine, including imidazole and triazole, cyproconazole, difenoconazole, myclobutanil, flutriafol, cyflufenamid, metconazole, prothioconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, demethylation inhibiting triazole such as penconazole, morpholine, cyflufenamid, metrafenone, picoxystrobin, copper ammonium complex, copper hydroxide, copper oxide, copper oxychloride, copper sulfate, sulfur, lime sulfur, ethylene bisdithiocarbamate, aromatic hydrocarbon, phthalimide, guanidine, polyoxin, fluazinam, thiazolidine or a combination thereof.

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