ARYL and pyridyl amide pesticides and compositions thereof

Abstract

Described are compounds for controlling aphids. Also described are methods of using the compound to control aphids.

Description

Atty. Docket No: 049648 / 623228 ARYL AND PYRIDYL AMIDE PESTICIDES AND COMPOSITIONS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 551,748, filed February 09, 2024, which is incorporated herein by reference. GOVERNMENT INTEREST

[0002] This invention was made with government support under Grant No(s). 2020-67013- 31858 and 2023-67013-39895, awarded by the U. S. Department of Agriculture's National Institute of Food and Agriculture. The government has certain rights in the invention. FIELD

[0003] The subject matter described herein is directed to aphid insecticidal compounds, particularly those based on aryl and pyridyl amides. BACKGROUND

[0004] Aphids are insects which feed on plant sap and can be vectors of plant viruses, causing destruction to cultivated plants. In particular, the Green Peach Aphid, Myzus persicae, is an aphid that infests hundreds of agricultural crops worldwide and is responsible for over one billion dollars worth of economic losses. Compositions that repel insects, particularly aphids, are widely used to protect crops.

[0005] Neonicotinoids are a class of insecticides which have been widely used in crop protection. Thiamethoxam is a neonicotinoid insecticide commonly used for aphid control. However, crop destruction remains a significant challenge as aphids breed rapidly and have developed resistance to nearly all commercialized insecticides. To prevent pathogen transmission, the rate of toxicity of an insecticide is relevant as non-persistent viruses are transmitted within 10 minutes of an aphid landing. There is a need for insecticides with new chemical scaffolds and novel modes of action, ideally with high rates of toxicity to control aphid populations. The subject matter disclosed herein addresses the need for improved insecticides. SUMMARY

[0006] Described are methods of controlling aphids, the methods comprising contacting an object or locus with a composition comprising a compound of Formula A or Formula I and a carrier, wherein the compound of Formular A and Formula I comprises: 1 LEGAL02 / 45405426v1Formula A Formula I wherein X is N or CH; R1is selected from the group consisting of fluoro, chloro, bromo, iodo, C1-C6alkyl, and C1-C6haloalkyl; each R3is independently selected from the group consisting of halogen, C1-C6haloalkyl, and C1-C6haloalkoxy, R2is haloalkyl or haloalkoxy, and n is 1, 2, or 3. In some embodiments, the described compounds have increased toxicity to aphids relative to toxicity to other insects. In some embodiments, the described compounds have increased toxicity to aphids relative to toxicity to natural enemies of aphids and / or pollinators.

[0007] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I.

[0008] In certain embodiments, each R3is independently selected from the group consisting of −Cl, −CF3, − CF2CF3, −OCF3, and −OCF2CF3.

[0009] In certain embodiments, R2is selected from the group consisting of −CF3, −CF2CF3, −OCF3, and −OCF2CF3.

[0010] In certain embodiments, the compound of Formula I is

[0011] In certain embodiments, the composition is a dust, a granular formulation, a liquid solution, a vaporized mist, an aerosol, or an emulsion.

[0012] In certain embodiments, the object or locus comprises a plant, a plant part, or an environment of a plant or plant part. The plant can be, but is not limited to, a crop plant, vegetable plant, a fruit plant, or ornamental plant. The crop plant can be, but is not limited to, a food crop plant, a feed crop plant, a fiber crop plant, and oil crop plant, an ornamental crop plant, or an industrial crop plant.

[0013] In certain embodiments, controlling aphids comprises: reducing an aphid population,2 LEGAL02 / 45405426v1preventing an aphid infestation, reducing an aphid infestation, or reducing or preventing transmission of a disease carried by aphids. In certain embodiments, controlling aphids comprises controlling a behavior (e.g., probing and / or feeding behavior) of aphids.

[0014] In certain embodiments, the subject matter described herein is directed to methods of preventing an aphid infestation on a plant, the methods comprising contacting the plant or an environment of the plant with a composition containing a compound of Formula A or Formula I and a carrier.

[0015] In certain embodiments, the subject matter described herein is directed to methods of killing aphids on a plant, the methods comprising contacting a plant infested with aphids or an environment of the plant infested with aphids with a composition containing a compound of Formula A or Formula I and a carrier.

[0016] In certain embodiments, the subject matter described herein is directed to methods of reduce transmission of persistent or non-persistent plant viruses to plants by aphids. In certain embodiments, the subject matter described herein is directed to methods of reduce horizontal transmission of persistent or non-persistent plant viruses to plants by aphids. In certain embodiments, the subject matter described herein is directed to methods of reducing infection of plants by persistent or non-persistent plant viruses transmitted to the plants by aphids. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1. Graphs illustrating toxicity curves with aphid mortality at 10 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, and 24 hours after exposure to leaf cores dipped in Compound 1 and UFL001 Compound 2.

[0018] FIG.2. Graphs illustrating aphid mortality at 4 hours and 24 hours after exposure to a whole pepper plant sprayed with Compound 1 or Compound 2 as compared to a control plant.

[0019] FIG. 3. Dissection and neurophysiological recordings of the M. persicae central nervous system. (A) Image of the dissected M. persicae brain with labelled regions. (B) Diagrammatic figure of the aphid CNS and ventral nerve cord, which was drawn into a glass electrode to measure nerve activity that was threshold discriminated and converted to a spike rate in Hz. (C) Concentration-response curves of N-arylamides on the aphid ventral nerve cord. Symbols are means + SEM and sigmoidal curves are fit to a four-parameter logistic equation.

[0020] FIG. 4. Concentration-response curves of N-arylamides treated leaf disks with 0.1% Tween 80. Aphid toxicity of each compound is shown at 4 h (A), 6 h (B), and 24 h (C). Also shown in (C) is the 24 h toxicity of thiamethoxan (Txm) for comparison. In all cases, data points represent the means of replicated (n = 3) percent toxicities at each concentration + SEM3 LEGAL02 / 45405426v1and curves show the fit to a four-parameter logistic equation with the bottom and top variables fixed to 0 and 100%, respectively.

[0021] FIG. 5. Enhancement of water solubility and particle size of 29-SL and 30-SL nano- micelles.5 mg of 29 (A) and 30 (B) solubility in water (right) and after solubilization into SL (left vial). Particle size distribution of 29-SL (C) and 30-SL (D) dispersed in water. The % Passing (left green) indicates the cumulative distribution of particles detected within the range of 0.1 and 10,000 nm. The % Channel (right blue) indicates percentage of a specific particle size detected.

[0022] FIG.6. Changes to aphid probing behaviors after foliar treatment with 29 and 30. (A) A representative control EPG recording, where an aphid will initiate a probe (P with bracket), remove its mouthparts from the leaf (R), then initiate additional probes. (B) Representative EPG recording of an aphid placed on a leaf after foliar application of 29 showing inability to probe. C-H) Probing and feeding behaviors as determined by EPG analysis over 4 h for apterous green peach aphids infested on adaxial surface of a cotton leaf, including (C) % of aphids that probed, (D) time to first probe, (E) total number of probes, (F) time to potential drop, (G) % initial new probes with potential drop (pd) after 1 h, and (H) number of new probes after 1 h. In all plots, bars represent mean percentage of feeding behaviors and error bars represent standard error. Bars not labeled by the same letter represent statistical significance as determined by one-way ANOVA followed by Tukey’s multiple comparisons test or Welch's ANOVA (due to unequal SDs) with Dunnett's T3 multiple comparison test.

[0023] FIG.7. Assessment of antifeedant capabilities of N-arylamide foliar treatment. Feeding behaviors as determined by EPG analysis over 4 h for apterous green peach aphids infested on adaxial surface of a cotton leaf. In each plot, bars represent mean percentage of feeding behaviors and error bars represent standard error. Bars not labeled by the same letter represent statistical significance as determined by one-way ANOVA followed by Tukey’s multiple comparisons test or Welch's ANOVA (due to unequal SDs) with Dunnett's T3 multiple comparison test. DETAILED DESCRIPTION

[0024] Described herein are compounds, compositions, and methods that provide desired aphid insecticide activity. The compositions comprise aryl and pyridyl amides of Formula A or Formula I. The compounds demonstrate excellent aphid insecticide activity. In some embodiments, the compounds demonstrate excellent insecticidal activity against Myzus persicae (Green Peach Aphid).4 LEGAL02 / 45405426v1

[0025] In some embodiments, the described aryl and pyridyl compounds of Formula A or Formula I exhibit relatively aphid-specific toxicity. In some embodiments, the described aryl and pyridyl compounds have increased toxicity to aphids relative to toxicity to other insects. In some embodiments, the described compounds have increased toxicity to aphids relative to toxicity to natural enemies of aphids and / or pollinators. In some embodiments, the described aryl and pyridyl compounds have increased toxicity to aphids relative to toxicity to certain beneficial insects, such as bees. Less than 10% mortality was observed for honeybees treated with a topical dose of 100 µg / bee of compounds 1 and 2 after 24 hours. In certain embodiments, the compounds and compositions described herein are more potent than leading commercial aphid insecticides. Furthermore, the methods and compositions disclosed herein have a rapid rate of toxicity, even at low concentrations.

[0026] The presently disclosed subject matter will now be described more fully. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. I. Definitions

[0027] As used in the present specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0028] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, −C(O)NH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy5 LEGAL02 / 45405426v1line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0029] The prefix “Cu-Cv” indicates that the following group has from u to v carbon atoms. For example, “C1-C6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0030] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 50%. In certain other embodiments, the term “about” includes the indicated amount ± 20%. In certain other embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. In certain other embodiments, the term “about” includes the indicated amount ± 0.5% and in certain other embodiments, 0.1%. Such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0031] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C20alkyl), 1 to 12 carbon atoms (i.e., C1-C12alkyl), 1 to 8 carbon atoms (i.e., C1-C8alkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl), 1 to 4 carbon atoms (i.e., C1-C4alkyl), or 1 to 3 carbon atoms (i.e., C1-C3alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., −(CH2)3CH3), sec-butyl (i.e., −CH(CH3)CH2CH3), isobutyl (i.e., −CH2CH(CH3)2) and tert-butyl (i.e., −C(CH3)3); and “propyl” includes n-propyl (i.e., −(CH2)2CH3) and isopropyl (i.e., −CH(CH3)2).

[0032] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group, or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups6 LEGAL02 / 45405426v1are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0033] “Alkoxy” refers to the group “alkyl−O−”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy and 1,2-dimethylbutoxy.

[0034] “Amido” refers to both a “C-amido” group which refers to the group −C(O)NRyRzand an “N-amido” group which refers to the group −NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0035] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-C20aryl), 6 to 12 carbon ring atoms (i.e., C6-C12aryl), or 6 to 10 carbon ring atoms (i.e., C6-C10aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

[0036] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[0037] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0038] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen.

[0039] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is7 LEGAL02 / 45405426v1through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, −NRy−, −O−, −S−, −S(O)−, −S(O)2−, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., −CH2OCH3, −CH(CH3)OCH3, −CH2CH2OCH3, −CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., −CH2SCH3, −CH(CH3)SCH3, −CH2CH2SCH3, −CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., −CH2S(O)2CH3, −CH(CH3)S(O)2CH3, −CH2CH2S(O)2CH3, −CH2CH2S(O)2CH2CH2OCH3, etc.) and amines (e.g., −CH2NRyCH3, −CH(CH3)NRyCH3, −CH2CH2NRyCH3, −CH2CH2NRyCH2CH2NRyCH3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0040] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0041] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, amidino, aryl, aralkyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, −NHNH2, =NNH2, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, −S(O)OH, −S(O)2OH, sulfonamido, thiol, thioxo, N-oxide or −Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0042] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, −NRgRh,8 LEGAL02 / 45405426v1−NRgC(=O)Rh, −NRgC(=O)NRgRh, −NRgC(=O)ORh, −NRgS(=O)1−2Rh, −C(=O)Rg, −C(=O)ORg, −OC(=O)ORg, −OC(=O)Rg, −C(=O)NRgRh, −OC(=O)NRgRh, −ORg, −SRg, −S(=O)Rg, −S(=O)2Rg, −OS(=O)1−2Rg, −S(=O)1-2ORg, −NRgS(=O)1-2NRgRh, =NSO2Rg, =NORg, −S(=O)1-2NRgRh, −SF5, −SCF3or −OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with −C(=O)Rg, −C(=O)ORg, −C(=O)NRgRh, −CH2SO2Rg, or −CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of Rgand Rhand Riare taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0043] The compounds of the invention, or their agrochemically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic, optically pure, and enantiomerically / diastereomerically enriched forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0044] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable9 LEGAL02 / 45405426v1mirror images of one another.

[0045] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0046] Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0047] As used herein, the term “non-toxic” is intended to convey a composition that, while highly effective in killing and / or repelling targeted insect pests, is safe to use around humans, particularly small children, and pets.

[0048] Additional definitions may also be provided below as appropriate. II. Compounds

[0049] In certain embodiments, the subject matter described herein is directed to aryl and pyridyl amide compounds of Formula A:(Formula A) wherein, X is N or CH; R1is selected from the group consisting of halogen, C1-C6alkyl, and C1-C6haloalkyl; each R3is independently selected from the group consisting of halogen, C1-C6haloalkyl, and C1-C6haloalkoxy; and n is 1, 2, or 3.

[0050] Provided are compounds of Formula A, wherein R1is C1-C6haloalkyl. In certain embodiments, R1is −F, −Cl, −Br, −CH3, −CH2Cl, −CH2F, −CHF2, −CF3, −CH2CH3, −CF2CF3, or −CF2CF2CF3. In certain embodiments, R1is −CF2CF3or −CF2CF2CF3. In certain embodiments, R1is −CF2CF3. In certain embodiments, R1is −CF2CF2CF3. In certain embodiments, R1is −F. In certain embodiments, R1is −Cl. In certain embodiments, R1is −Br. In certain embodiments, R1is −CH3. In certain embodiments, R1is −CH2Cl. In certain embodiments, R1is −CH2F. In certain embodiments, R1is −CHF2. In certain embodiments, R1is −CF3. In certain embodiments, R1is −CH2CH3.

[0051] Provided are compounds of Formula A, wherein each R3is independently selected from10 LEGAL02 / 45405426v1the group consisting of −Cl, −CF3, − CF2CF3, and −OCF3.

[0052] Provided are compounds of Formula A, wherein X is N.

[0053] Provided are compounds of Formula A, wherein X is CH.

[0054] In certain embodiments, provided are compounds of Formula A, wherein n is 1. In certain embodiments, n is 1 and R3is C1-C6haloalkyl or C1-C6haloalkoxy. In certain embodiments, n is 1 and R3is −CF3, −OCF3, or −CF2CF3. In certain embodiments, n is 1, R3is −CF3, −OCF3, or −CF2CF3, and X is N. In certain embodiments, n is 1, R3is −CF3, −OCF3, or −CF2CF3, and X is CH.

[0055] In certain embodiments, provided are compounds of Formula A having a structure of Formula I. In certain embodiments, provided are compounds of Formula A having a structure as provided in any of the compounds of Table 1.

[0056] In certain embodiments, n is 2. In certain embodiments, n is 2 and each R3is chlorine. In certain embodiments, n is 2, each R3is chlorine, and X is N.

[0057] In certain embodiments, n is 3. In certain embodiments, n is 3 and two R3are chlorine. In certain embodiments, n is 3 and one R3is −CF3. In certain embodiments, n is 3, two R3are chlorine, and one R3is −CF3. In certain embodiments, n is 3, two R3are chlorine, one R3is −CF3, and X is CH.

[0058] In certain embodiments, compound of Formula A iscompound 29 compound 30.

[0059] In certain embodiments, the subject matter described herein is directed to aryl and pyridyl amide compounds of Formula I:(Formula I) wherein, X is N or CH; R1 is selected from the group consisting of fluoro, chloro, bromo, iodo, C1-C6 alkyl, and C1-C6haloalkyl; and11 LEGAL02 / 45405426v1R2is haloalkyl or haloalkoxy.

[0060] In certain embodiments X is N, and the compound of Formula I is a N-pyridyl amide. In other embodiments X is CH and the compound of Formula I is an N-aryl amide.

[0061] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I.

[0062] In certain embodiments, R1is selected from the group consisting of: −CH3,−CH2Cl, −CHCl2, −CCl3, −CH2F, −CHF2, and −CF3.

[0063] In certain embodiments, R1is −CH3or −CH2Cl.

[0064] In certain embodiments, R2is selected from the group consisting of: −CF3, −CF2CF3, −OCF3, and −OCF2CF3.

[0065] In certain embodiments, R2is −CF3or −OCF3.

[0066] In certain embodiments, X is CH.

[0067] In certain embodiments, X is N.

[0068] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I; and R2is −CF3.

[0069] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I; and R2is −CF2CF3.

[0070] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3,12 LEGAL02 / 45405426v1−CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I; and R2is −OCF3.

[0071] In certain embodiments, R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I; and R2is −OCF2CF3.

[0072] In certain embodiments, the compound of Formula I is selected from the group consisting of: Table 1. Compounds of Formula I13 LEGAL02 / 45405426v1

[0073] In certain embodiments, the compound of Formula I is O N H CF3(compound 1).

[0074] In certain embodiments, the compound of Formula I is14 LEGAL02 / 45405426v1(compound 2).

[0075] In certain embodiments, the compound of Formula A is(compound 29).

[0076] In certain embodiments, the compound of Formula A is(compound 30). III. Compositions

[0077] Any of the described compounds of Formula A or Formula I can be provided in a composition or formulation. Any of the described compounds of Formula A or Formula I can be combined with: one or more excipients, one or more agrochemically active compounds, one or more biocontrol agents, and combinations thereof.

[0078] An excipient is any ingredient that is intentionally added to the formulation but is not itself expected to exert an effect on plant growth or health. Excipients may act to (a) aid in manufacture, (b) protect, support, or enhance stability, plant delivery, or bioavailability, (c) assist in product identification, and / or (d) enhance any other attribute of the overall safety, effectiveness, or delivery or the composition during storage or use. In some embodiments, an excipient is added to the compound of Formula A or Formula I to decrease evaporation, improve wetting ability, and / or reduce droplet drift. An excipient may or may not be an inert substance. In some embodiments, the excipient is an agriculturally acceptable excipient. An excipient can be, but is not limited to, a carrier, botanical solubilizer (e.g., rubusoside), an adjuvant, a solubilizing agent, a suspending agent, a diluent, an oxygen scavenger, an antioxidant, a food material, an anti-contaminant agent, or combinations thereof. Excipients include, but are not limited to: absorption enhancers, adhesives, anti-foaming agents, anti- oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, dextran, dextrose, diluents, disintegrants, dispersants, dust control agents, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening15 LEGAL02 / 45405426v1agents, tonicity agents, vehicles, water-repelling agents, and wetting agents. Excipients also include, cellulose, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, polysaccharides, starch, milk sugar, and high molecular weight polyethylene glycols, and the like. A carrier can be, but is not limited to, a solvent or dispersion medium containing, for example, water, saline, phosphate buffered saline, gel, solvent, solubilizer, alcohol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), silicon, waxes, petroleum jelly, vegetable oil, sugar, gelatin, amylose, talc, surfactants, and suitable mixtures thereof. A carrier may also contain adjuvants or additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. In some embodiments, the carrier is an agriculturally acceptable carrier. Agriculturally acceptable refers to those properties and / or substances which are acceptable for use in agriculture.

[0079] An agrochemically active compound is a substance that may be used for treating a seed, a plant, plant part, or the environment of the seed or plant or plant part. Agrochemically active compounds include, but are not limited to, fungicides, bactericides, insecticides, acaricides, nematicides, molluscicides, safeners, plant growth regulators, and plant nutrients.

[0080] A biocontrol agent is a biological organism or component thereof, that reduces the incidence or severity of diseases or damage caused by plant pathogens or insects. A biocontrol agent can be, but is not limited, to microorganisms or modified organisms.

[0081] The described compounds of Formula A or Formula I can be provided (formulated) as a liquid, a dispersion, a colloidal dispersion, a solution, a suspension, a colloidal suspension, an emulsion, a foam, a slurry, a lyophilized (freeze-dried) cake or powder, a spray-dried powder, a pellet, a biologically pure pellet, a coated pellet, a powder, a flowable powder, or a granule. A liquid formulation or composition may contain one or more of: a buffer, salt, sorbitol, and / or glycerol. The endophyte combination may be formulated as a heterogeneous mixture or a homogeneous mixture. Powders, pellets, and granules may be formulated using encapsulation technologies known in the art.

[0082] The described compounds of Formula A or Formula I can be provided (formulated) as a heterogeneous mixture or a homogeneous mixture. They may be prepared from concentrates, such as emulsifiable concentrates and wettable powders. In addition to the active agents, the compositions can also comprise various inert ingredients, depending upon the form taken by the composition.

[0083] If prepared from an emulsifiable concentrate, the composition may contain a surfactant such as, for example, a mixture of a polyethylene oxide with a blend of oil soluble non-ionic and anionic sulfonates. The surfactant normally comprises between about 1 and 15% by weight16 LEGAL02 / 45405426v1of the emulsifiable concentrate.

[0084] Wettable powders can also be used to make the aphid insecticide compositions. Compositions so made may be applied to the area to be protected as emulsions in water or other liquid diluents. Typical among the carriers employed in wettable powders are walnut flour, cane sugar, fuller's earth, attapulgite clays, kaolin clays, silicas, and other highly absorbent, readily wetted carriers. The wettable powders themselves generally are prepared to contain about 5 to 80% by weight of the active component, depending on the absorbency of the carrier. A wettable powder usually also contains a small amount of a surfactant.

[0085] In some embodiments, a composition comprising a compound of Formula A or Formula I further comprises a botanical solubilizer. The botanical solubilizer can be, but is not limited to, rubusoside. In some embodiments, a composition comprising any one of compounds 1-30 further comprises a botanical solubilizer. In some embodiments, a composition comprising any one of compounds 1-30 further comprises rubusoside.

[0086] In some embodiments, a composition comprising a compound of Formula A or Formula I further comprises a surfactant. The botanical solubilizer can be, but is not limited to, Tween- 80. In some embodiments, a composition comprising any one of compounds 1-30 further comprises a surfactant. In some embodiments, a composition comprising any one of compounds 1-30 further comprises Tween-80.

[0087] Granular aphid insecticide compositions, wherein the active component is carried on relatively coarse particles as the carrier, are also useful in controlling insect pests. Dry dusts, in which the active component is admixed with finely divided solids such as talc, attapulgite clay, kieselguhr, and other organic and inorganic solids, which act as carriers for the active component, may be used. These finely divided solids usually have an average particle size of less than about 50 microns.

[0088] Pressurized sprays such as aerosols, in which the active component is present in solution or in a finely divided form, may also be used.

[0089] In some embodiments, the concentration of the active agent(s) in any of the aphid insecticide compositions may vary in the range from about 0.00001% to about 10% by weight, depending on the formulation. A very broad latitude in the type of repellent composition and the concentration of the active agent(s) within the aforesaid range is possible.

[0090] In certain embodiments, the subject matter disclosed herein is directed to a compound of Formula A or Formula I in admixture with a carrier.

[0091] In certain embodiments, the compositions disclosed herein comprise about 0.01- 99.99%, 1-99%, 5-95%, 10-90%, 20-80%, 30-70%, 40-60%, or 50% of a compound of17 LEGAL02 / 45405426v1Formula A or Formula I. IV. Methods of Controlling Aphids

[0092] In some embodiments, the compounds of Formula A or Formula I disclosed herein are higher toxicity to aphids relative to other insects. In certain embodiments, the aphid insecticides of Formula A or Formula I control insects of the Aphididae family. In certain embodiments, the aphid insecticides of Formula A or Formula I control aphids of the Myzus, Aphis, Grylloprociphilus, Brevicornyne, Cinara, Macrosiphum, Melaphis, Mindarus, Nasonovia, Acyrthosiphon, Pemphigus, Diuraphis, Sipha, Toxoptera, or Hormaphis genus. In certain embodiments, the aphid insecticides of Formula A or Formula I control Myzus persicae (green peach aphid).

[0093] The locus from which aphid pests are to be controlled is contacted with a toxic amount of the compound of Formula I. In certain embodiments, the locus is a plant, plant part, or an environment of a plant. The plant can be, but is not limited to, a crop plant, a fruit plant, a vegetable plant, or an ornamental plant. A toxic amount of the compound of Formula A or Formula I can vary somewhat, depending on the nature of the locus, including the type of surface, from which the insects are to be controlled. In certain embodiments, the compounds of Formula A or Formula I are toxic to aphids at between about 0.1 to 100 ng / cm2. As is well known in the art, the degree of effectiveness of the aphid insecticide may vary with the formulation and the method of application.

[0094] In certain embodiments, the subject matter described herein is directed to a method of controlling aphids, comprising contacting an object or locus with a composition comprising a compound of Formula A or Formula I and a carrier.

[0095] Contacting the object or locus comprises applying the composition to a plant or plant part or an environment of the plant. The “environment of a plant or plant part (e.g., plant leaf or plant flower)” includes the area surrounding or adjacent to the plant or plant part, including but not limited to the soil, and the air. The environment of a plant or plant part is intended to include within or near the area where plant is grown. The environment of a plant or plant part may be in proximity, touching, adjacent to, or in the same field or growing area as the plant or plant part. The compositions described herein may be applied to the environment of the plant or plant part as a foliar application, as a granular application, as a soil application, or as an encapsulated application.

[0096] The application may comprise, but is not limited, to pouring, spraying, or otherwise depositing the composition on a plant, plant part, or an environment of the plant. Any method18 LEGAL02 / 45405426v1known in the art for applying insecticide compounds may be used to apply the composition comprising a compound of Formula I.

[0097] The aphid insecticide compounds disclosed herein may be formulated into any suitable composition to dispense a suitable amount of the aphid insecticide compound into an environmental area in which it is desired to control aphids. In certain embodiments, the composition is a dust, a granular formulation, a liquid solution, a vaporized mist, an aerosol, or an emulsion.

[0098] In certain embodiments, a compound of Formula A or Formula I is provided in an aphid insecticide medium in which a compound of Formula A or Formula I can be dispersed. Non- limiting examples of suitable media include alcohols such as ethanol, glycerin, and polyethylene glycol; ketones such as acetone; ethers such as tetrahydrofuran and dioxane; aliphatic hydrocarbons or petroleum distillates such as gasoline, naphtha, mineral spirits, tar, hexane, kerosene, toluene, xylene, limonene, turpentine, paraffin, and petroleum benzene; esters such as ethyl acetate; and essential oils such as pine oil or citronella oil.

[0099] In certain embodiments, vaporization of the aphid insecticide may be assisted by thermal volatilization. Thermal volatilization may proceed by flame, ionizing radiation, oven, sunlight, electrical pulse, laser, gas heating element, or electric-powered heating element, such as induction heating, chemical reaction, microwave irradiation, ultrasound, or a mixture thereof.

[0100] This suitable amount for aphid toxicity would typically range from about 0.1 to about 100 ng / cm2of the object, locus or environmental area in which aphid control is to be sought. In certain embodiments, a compound of Formula A or Formula I is applied to the object or locus at a concentration of about 0.1-100 ng / cm2, about 0.1-50 ng / cm2, about 0.1-10 ng / cm2, about 0.5-10 ng / cm2, about 1-10 ng / cm2, or about 1-5 ng / cm2.

[0101] In certain embodiments, the lethal concentration for 50% (LC50) of aphids after exposure to a compound of Formula A or Formula I for a period of time is less than 500 ng / mL, less than 400 ng / mL, less than 300 ng / mL, less than 200 ng / mL, less than 100 ng / mL, less than 50 ng / mL, less than 40 ng / mL, less than 30 ng / mL, less than 20 ng / mL, less than 15 ng / mL, less than 14 ng / mL, less than 13 ng / mL, less than 12 ng / mL, less than 11 ng / mL, less than 10 ng / mL, less than 9 ng / mL, less than 8 ng / mL, less than 7 ng / mL, less than 6 ng / mL, less than 5 ng / mL, less than 4 ng / mL, less than 3 ng / mL, less than 2 ng / mL, less than 1 ng / mL, less than 0.5 ng / mL, less than 0.4 ng / mL, less than 0.3 ng / mL, or less than less than 0.2 ng / mL. In certain embodiments the period of time of exposure for 50% toxicity is less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 30 minutes, less than about19 LEGAL02 / 45405426v145 minutes, less than about 60 minutes, less than about 90 minutes, less than about 2 hours, less than about 3 hours, less than about 4 hours, less than about 5 hours, less than about 6 hours, less than about 7 hours, less than about 8 hours, less than about 12 hours, less than about 16 hours, less than about 18 hours, less than about 24 hours, less than about 2 days, or less than about 3 days.

[0102] In certain embodiments, the described methods comprise applying a compound of Formular A or Formula I, to a plant, plant part, or environment of a plant at a concentration of about 0.1-100 ng / cm2, about 0.1-50 ng / cm2, about 0.1-10 ng / cm2, about 0.5-10 ng / cm2, about 1-10 ng / cm2, or about 1-5 ng / cm2. In certain embodiments, the described methods comprises applying a composition comprising a compound or Formula A or Formula I to a plant, plant part, or environment of a plant such that the compound of Formula A or Formula I is at a concentration on the plant, plant part, or environment of a plant of about 0.1-100 ng / cm2, about 0.1-50 ng / cm2, about 0.1-10 ng / cm2, about 0.5-10 ng / cm2, about 1-10 ng / cm2, or about 1-5 ng / cm2.

[0103] As used herein, “controlling aphids” refers to mitigating, reducing, or eliminating a population of aphids. In certain embodiments, controlling aphids comprises: killing aphids, reducing an aphid population, preventing an aphid infestation, reducing an aphid infestation, or reducing or preventing transmission of disease carried by aphids. In certain embodiments, controlling aphids comprises controlling a behavior (e.g., probing and / or feeding behavior) of aphids. In some embodiments, controlling aphids includes reducing transmission of a plant virus to the plant by an aphid. In certain embodiments, a composition comprising a compound of Formula A or Formula I and a carrier is used to prevent an aphid infestation on a crop. In certain embodiments, a composition comprising a compound of Formula A or Formula I and a carrier is used to kill aphids on a crop which is infested with aphids. V. Methods of Preparing Compounds and Agrochemically Acceptable Salts Thereof

[0104] The present compounds of Formula A or Formula I can be prepared using analogous synthetic routes disclosed in M. Tsikolia et al. (2013) Pestic. Biochem. Physiol.107, 138-147 and M. Tsikolia et al. (2018) Pestic. Biochem. Physiol.151, 40-46. General Procedures for the Preparation of the Compounds

[0105] Method A. Triethylamine (2 equiv) was added to a solution of amine (1 equiv) in dichloromethane (5 mL / mmol) at 0 ˚C followed by the addition of anhydride (1.1 equiv) and 4-dimethylaminopyridine (0.2 equiv). The solution was warmed to room temperature and20 LEGAL02 / 45405426v1stirred for 16 hours. The reaction was quenched with NaHCO3 (aq), and the mixture was extracted with dichloromethane. The organic layers were collected, washed with brine, dried with magnesium sulfate, filtered, concentrated in vacuo, and purified on a silica gel column.

[0106] Method B. Under N2, nBuLi (2.5M, 0.99 equiv) was added to a mixture of amine (2 equiv) in tetrahydrofuran (5 mL / mmol) at −78 °C. The mixture was warmed to 0 °C, stirred for one hour, and then cooled to −78 °C. Ester (1 equiv) was then added dropwise, the solution was warmed to room temperature, and stirred for 16 h. The reaction was quenched with NH4Cl(aq), the solvent was removed through rotary evaporation, and the mixture was extracted with dichloromethane. The organic layers were collected, washed with brine, dried with magnesium sulfate, filtered, concentrated in vacuo, and purified on a silica gel column.

[0107] Compounds can be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database). DTT refers to dithiothreitol. DHAA refers to dehydroascorbic acid.

[0108] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G .M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0109] Compounds may be prepared singly or as compound libraries comprising at least 2, for example about 5 to about 1,000 compounds, or about 10 to about 100 compounds. Libraries of compounds of Formula A or Formula I may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel syntheses using either solution phase or solid phase chemistry,21 LEGAL02 / 45405426v1by procedures known to those skilled in the art. Thus, according to a further aspect, there is provided a compound library comprising at least 2 compounds, or agrochemically acceptable salts thereof.

[0110] Compositions comprising two or more compounds can be prepared simply by contacting one with the other.

[0111] The General Procedures and Examples provide exemplary methods for preparing compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the Schemes, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0112] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES Example 1: Leaf Dip Aphid Toxicity Bioassay

[0113] A leaf dip toxicity bioassay was performed by taking 10 cm leaf cores from cotton plant leaves and dipping the leaf cores in solutions containing Compound 1or Compound 2. The leaf cores were allowed to dry for 1 hour, then 10 adult M. persicae apterae were placed on each leaf core. Three replications of 10 leaf cores were tested for each aphid insecticide (n = 300). Mortality assessments were performed after 10 minutes, 30 minutes, 60 minutes, 4 hours, 6 hours, and 24 hours (FIG.1). The M. persicae LC50values of Compound 1 and Compound 2 over a time course of 24 hours are provided in Table 2 including a 95% confidence interval (CI). Table 2.22 LEGAL02 / 45405426v1

[0114] The 24 h toxicity of Compound 1 and Compound 2 is approximately 10-fold greater than thiamethoxam, one of the most commonly used neonicotinoid insecticides for aphid control. In the same assay, an LC50value of 10 ng / mL was obtained for thiamethoxam at 24 hours. Example 2: Whole Plant Aphid Toxicity Bioassay

[0115] To mimic methods of field application, whole pepper plants were sprayed with 9 mL of a 50 ng / mL solution of Compound 1 or Compound 2 and allowed to dry for 12 hours. The plants had 390 cm2of leaf area to equal 1.15 ng / cm2of leaf area sprayed on to the plant. Then, 50 adult persicae aphids were placed on the plant and mortality was quantified at 4 h and 24 h post infestation as shown in FIG. 2. A total of 3 replicates were performed and bars represent mean (n=3) percent mortality and error bars represent SEM. Bars not labeled by the same letter within the same time point represent statistical significance. A significant increase in mortality was observed after 4 h, with over 40% mortality for Compound 1 and over 90% mortality for Compound 2 as compared to an untreated control where no mortality was observed. After 24 h, mortality increased to approximately 75% for Compound 1 and 95% for Compound 2, indicating Compound 1 and Compound 2 are effective insecticides for aphids with a fast rate of toxicity.23 LEGAL02 / 45405426v1

[0116] Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Example 3: Preparation of N-(2,6-dichloro-4-(trifluoromethyl)phenyl)-2,2,3,3,3- pentafluoropropanamide (30)

[0117] Prepared using General Procedure Method A from triethylamine (0.24 mL, 1.74 mmol), 2,6-dichloro-4-(trifluoromethyl)aniline (0.189 mg, 0.96 mmol), dichloromethane (4.35 mL), pentafluoropropionic anhydride (0.19 mL, 0.956 mmol), and 4-Dimethylaminopyridine (21.3 mg, 0.17 mmol). Automated flash chromatography yielded the product as a white solid (194.7 mg, 62% yield).1H NMR (500 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.66 (s, 2H).13C NMR (126 MHz, Chloroform-d) δ 156.10 (t, J = 26.9 Hz), 134.69, 132.68, 132.33 (q, J = 34.4 Hz), 125.66 (q, J = 3.7 Hz), 122.16 (q, J = 285.5, 273.3, 272.3 Hz), 116.75 (tt, J = 285.6, 34.4, 33.8 Hz), 106.89 (tq, J = 266.6, 39.5 Hz). Example 4. Synthesis of 29 and 30

[0118] The N-arylamides N-(2,6-dichloropyridin-4-yl)-2,2,3,3,4,4-heptafluorobutanamide (compound 29) and N-(2,6-dichloro-trifluoromethyl)phenyl)-2,2,3,3,-pentafluoropropanamide (compound 30) were synthesized and purified according to previously published methods.

[0119] A laboratory colony of M. persicae was derived from a single apterous aphid collected in Florida in 2006. The colony was reared on pepper plants at a temperature range of 24-20°C(D:N) and a photoperiod of 16:8 h (D:N). All host plants were grown at 25∘C and 50% RH inan E-36L1 growth chamber (Percival Scientific Inc., Perry, Iowa) with a photoperiod of 14:10 (L: D). The plants were cultivated in 10 cm-diameter plastic pots filled with commercial Potting Mix soil (Miracle-Gro Lawn Products Inc, Marysville, Ohio, USA) and Osmocote 14- 14-14 (Scotts-Sierra Horticultural Products Company, Marysville, Ohio, USA) fertilizer. Example 5. Aphid toxicity analysis of 29 and 30.

[0120] A. Generation of Soluble Liquid for compounds 29 and 30. The solubilizer used for this study was rubusoside that was isolated from Rubus suavissimus S. Lee (Rosaceae). The purity of rubusoside was determined to be above 98% by HPLC–UV. Appropriate amounts of the24 LEGAL02 / 45405426v1solubilizer (rubusoside) and 29 or 30 were weighed and mixed at the ratio of 100:2 weight / weight (29) or 100:1 weight / weight (30). Ethanol was added to the mixture at volume by weight ratio of 100:5 and the continuum was vortexed vigorously to dissolve and create a clear ethanol solution. This ethanol solution was passed through 0.45 µM nylon filters to eliminate impure particles that may be present in the solution. The ethanol solution was allowed to stand at the room temperature for 60 min for stability observation. The ethanol in the solution was then evaporated under reduced pressure, heated at 50 °C, and agitated in a RAPIDVAP system (Labconco). Once the solvent was evaporated, deionized water was added to reconstitute the solid residue to an aqueous solution of 29 or 30. This became the Soluble Liquid of 29 (29-SL) or 30 (30-SL). The particle size of 29-SL and 30-SL in water was measured by a dynamic light-scattering (DLS) apparatus (Microtrac Nanotrac 250 ULTRA) at 25 °C. Each sample was run 3 times at a 90° scattering angle with durations of 100 s. Particle size per run was averaged over the particle size distribution. Particle size for each sample was averaged over the 3 runs.

[0121] B. Toxicity Bioassays. For all toxicity assays, aphid condition (live or dead) was assessed by prodding them with a fine-tipped camel-hair paint brush. In this study, dead aphids were defined by a lack of coordinated movement after 10 s. Moribund aphids were defined as those showing a lack of movement when manually prodded. Moribund aphids were considered dead aphids. Live aphids were defined as those that showed coordinated walking. Knockdown of aphids was defined as individual aphids with signs of intoxication, such as general hyperexcitation, inability to right themselves, or lack of ambulatory behavior, within 4 h postexposure.

[0122] C. Topical Spray Assay. Aphid toxicity was first tested using a topical assay via spray bottles.29 and 30 were dissolved in acetone at a concentration of 200 ng / mL and placed into 15 mL falcon tubes with a modified spray nozzle. For each replication (×3), 10 adult green peach aphid apterae were placed in sterile plastic petri dishes on Whatman 90 mm (#1) filter paper. These groups consisted of a total of 30 aphids for each group with 29 or 30 tested at 200 ng / mL and control aphids exposed to acetone only. The groups were misted with approximately 1 mL and immediately transferred to another sterile petri dish on dry Whatman 90 mm (#1) filter paper. Knockdown of aphids in each treatment group was assessed 2 min post-exposure and percent knockdown was calculated.

[0123] D. Contact Filter Paper Toxicity Assay. Contact toxicity was performed via a modified filter paper assay where the compounds were dissolved in ethanol at concentrations of 10 ng / mL, 30 ng / mL, 100 ng / mL, 200 ng / mL, 600 ng / mL, and 1000 ng / mL. A total of 1 mL of25 LEGAL02 / 45405426v1these respective concentrations were pipetted onto Whatman 90 mm (#1) filter papers in glass petri dishes and were left to dry for 30 min. Control papers with acetone only were prepared. The dry filter papers were then transferred to sterile plastic petri dishes. Average toxicity was determined across 3 replicates with each replicate containing 20 adult apterous aphids per concentration per compound for a total of 60 individual aphids per concentration. Insects were monitored and mortality recorded at 10 min, 30 min, 1 h, 4 h, and 6 h after placement on the filter paper. Percent mortality then calculated.

[0124] E. Contact Leaf Disk Toxicity Assay. In addition to filter paper contact assays, we aimed to define the toxicity of 29 and 30 via foliar application of compounds onto leaf disks via a leaf dip toxicity assay. Cotton leaves were collected from the top of 4–6-week-old plants where new growth was abundant, grown at 25 °C and 50% relative humidity with a photoperiod of 14:10 (Light:Dark). Leaves were cored with a no.149 arch punch to create disks of 11.34 cm2. Each experiment consisted of two treatments: a concentration of N-arylamide (10 ng / mL, 30 ng / mL, 100 ng / mL, 200 ng / mL, 600 ng / mL, and 1000 ng / mL) dissolved in diH2O and 0.1% Tween-80 solution and a control of diH2O and 0.1% Tween-80 solution. Each concentration had 2 disks per treatment and was replicated a minimum of three times (n = 60 aphids per concentration per compound).

[0125] Leaf disks were dipped individually in a treatment solution or control solution of 1 mL for 10 sec. Cores were allowed to dry in a fume hood for approximately 1 h and then were placed into sterile Petri dishes (VWR polystyrene disposable, 200×15mm) on moistened Whatman 90 mm (#1) filter paper. Ten adult apterous aphids were placed on each core in Petri dishes, covered, and placed in a growth chamber. Insects were monitored and mortality recorded at 10 min, 30 min, 1 h, 4 h, 6 h, and 24 h after placement on leaf cores.

[0126] F. Systemic Toxicity Assay. Aphid mortality after exposure to plants treated with N- arylamides mixed with SL solubilizer was measured through a clip-cage bioassay. A 5 mg aliquot of 29-SL or 30-SL mixture was pipetted on the adaxial side of a single leaf at the bottom of the 4-6-week-old plant and manually spread across the leaf surface with a paint brush. The paint brush was cleaned with 90% ethanol between each plant to ensure the 5 mg aliquot painted onto the leaf remained consistent. Plants were left at room temperature to dry for 2 h and returned to the E-36L1 environmental chamber chamber (Percival Scientific Inc.) to incubate for 24 h. Each experiment consisted of two treatments: an untreated upper leaf from a 29-SL or 30-SL treated plant and an SL-only control. Five adult apterae were placed into a clip cage with a single leaf, covered to prevent aphid escape, and placed in the environmental growth chamber. Aphid mortality was recorded and then averaged across a total of 3 clip cages26 LEGAL02 / 45405426v1(5 aphids per disk) per replicate at 0.5-, 1-, 12-, and 24-h after aphid infestation on the untreated upper leaves. Final toxicity was determined across 3 replications to yield a total of 45 individual aphids per time point.

[0127] G. CNS Electrophysiological Recordings. Extracellular central nervous system (CNS) recordings of neuronal firing frequencies were conducted with M. persicae based on methods previously described for diptera (Chen R et al. “Functional interactions between potassium- chloride cotransporter (KCC) and inward rectifier potassium (Kir) channels in the insect central nervous system.” Pesticide biochemistry and physiology 2023, 192:105389; and Swale DR et al. “Electrophysiological Recording of The Central Nervous System Activity of Third-Instar Drosophila Melanogaster.” Journal of visualized experiments : JoVE 2018, (141): Video- Audio Media), lepidoptera (McComic SE et al. “Characterization of Toxicological and Neurophysiological Effects of Natural Product Based Chromenes to Fall Armyworm, Spodoptera frugiperda.” Journal of economic entomology 2021, 114 (6):2485-2492; and McComic SE et al. “Reduced neuronal sensitivity and susceptibility of the fall armyworm, Spodoptera frugiperda, to pyrethroids in the absence of known knockdown mutations.” Pesticide biochemistry and physiology 2020, 169:104652), and aphids (Nguyen DT et al. “Spontaneous electrical activity recorded from the aphid central nervous system.” Invertebrate neuroscience : IN 2012, 12(2):139-146). Apterous adults of M. persicae were placed in 200 µL of neurophysiological saline containing: 6 mM MgSO4, 2 mM CaCl2, 13 mM KCl, 19 mM MgCl2, 2 mM Na-citrate, 12 mM KH2PO4, 425 mM sucrose, 10 mM HEPES, and 5.9 mM Tris, at pH 6.4. The aphid was gently teased apart to expose the ventral nerve cord (VNC) by removing the viscera (FIG.3A). The VNC is posteriorly connected to the thoracic ganglia mass (TGM), which is located ventrally from the salivary glands. Glass pipette electrodes were pulled from borosilicate capillary tubes using a P-1000 Flaming / Brown micropipette puller (Sutter Instrument). The VNC was drawn into a suction electrode (FIG.3B). Electrical activity was recorded from the VNC and was subjected to amplitude discrimination and converted to a frequency in Hertz (Hz) using LabChart8 Pro (ADInstruments). Noise was eliminated using a Hum Bug (A-M Systems). Baseline firing frequencies were established for 5 min before adding any test compounds. The VNC preparation was then directly exposed to test compounds 29 and 30 in an additional 200 µL application of neurophysiological saline. The concentrations tested were 0.1 ng / mL, 1 ng / mL, 3 ng / mL 10 ng / mL, 30 ng / mL, 100 ng / mL, and 300 ng / mL. The incubation totaled 400 µL at all times during recordings. The final concentration of the vehicle solvent was 0.1% or less.27 LEGAL02 / 45405426v1

[0128] H. Electrical Penetration Graph Recordings. Methods for electrical penetration graph (EPG) analysis of aphid probing and feeding behaviors followed previously described methods (O’Hara FM et al. “Catalyzing systemic movement of inward rectifier potassium channel inhibitors for antifeedant activity against the cotton aphid, Aphis gossypii (Glover).: Pest Manag Sci 2023, 79:194-205; Li Z et al. “Chemical inhibition of Kir channels reduces salivary secretions and phloem feeding of the cotton aphid, Aphis gossypii (Glover).” Pest Manag Sci 2019; and O’Hara FM et al. “Profile of Commercialized Aphicides to Survivorship and Feeding Behavior to the Cotton Aphid, Aphis gossypii.” Pesticide biochemistry and physiology 2022, 186:105174). Apterous adult aphids were removed from colony maintenance cotton plants and immediately used in EPG studies. A 3 cm length of 18-μm gold wire (EPG Systems) was attached to the aphid dorsum with water-based silver glue and the reference electrode placed in the soil. Four aphids were tested simultaneously, with two aphids per test plant and all EPG experiments were performed in a Faraday cage. Signals were recorded with a Giga8 DC amplifier (EPG Systems) and an A / D conversion rate of 100 Hz. The analog signals were digitized utilizing the Giga-8d integrated analog digital (AD) converter and then displayed and evaluated using Stylet Analysis software (EPG Systems).

[0129] Signals from the EPG recordings were identified and classified according to the established nomenclature of EPG variables where waveforms from EPG recordings were categorized as waveforms A-G and potential drop (pd) as previously described (O’Hara FM et al.2023; Li Z et al.2019; O’Hara FM et al.2022; Lee ST et al. “The impact of thiamethoxam on the feeding and behavior of 2 soybean herbivore feeding guilds.” Journal of economic entomology 2023, 116(5):1621-1635; Davis JA et al. “The Importance of an Invasive Aphid Species in Vectoring a Persistently Transmitted Potato Virus: Aphis glycines Is a Vector of Potato leafroll virus.” Plant Disease 2008, 92:1515-1523; Alvarez A et al. “Comparative analysis of Solanum stoloniferum responses to probing by the green peach aphid Myzus persicae and the potato aphid Macrosiphum euphorbiae.” Insect science 2013, 20(2):207-227; Miao J et al. “Sub-lethal effects of four neonicotinoid seed treatments on the demography and feeding behaviour of the wheat aphid Sitobion avenae.” Pest Manag Sci 2014, 70(1):55-59; Tjallingii W. “Electronic recording of penetration behaviour by aphids.” Entomologia experimentalis et applicata 1978, 24(3):721-730; and Walker GP et al. “Principles and applications of electronic monitoring and other techniques in the study of homopteran feeding behavior.” In International Congress of Entomology 1992: Beijing, China), 2000; Entomological Society of America). Initial stylet contact with the leaf epidermis is referred to as waveform A, whilst initial salivation within the epidermis and mesophyll is known as28 LEGAL02 / 45405426v1waveform B. The intercellular apoplastic movement of stylets through the plant tissues is known as waveform C and intracellular punctures that occur within any living cell when aphids take sap samples were labelled as pd. Aphid sieve element feeding behaviors (waveform E) exist in two distinct subphases; sieve-element secretion of watery saliva (E1) and the passive ingestion of phloem sap (E2) (Prado E et al. “Aphid activities during sieve element punctures.” Entomologia experimentalis et applicata 1994, 72(2):157-165). Subphase E2 is always preceded by E1, which would indicate that the secretion of saliva in sieve elements (E1) is required for passive phloem ingestion (E2). Lastly, Waveform F indicates the derailed stylet mechanics in all tissues whilst waveform G indicates the active intake of xylem sap. In total, following probing and feeding behaviors were scored: (a) the proportion of aphids that successfully probed, (b) the proportion of aphids that initiated an additional probe (with potential drop) after 1 h, (c) the time taken for that aphid to first initiate a probe, (d) the time taken for that aphid to first initiate a probe that also contained a potential drop, (e) the time taken from that first probe to initiate a potential drop, (f) the proportion of aphids that successfully reached phloem, (g) the time required for an aphid to successfully reach phloem, and (h) the proportion of aphids that reached xylem.

[0130] Foliar application of 29 and 30 followed our previously described procedures and recordings were performed across a 4 h continuous window with a total of eight replicates consisting of 32 aphids per replicate. To test the antifeedant activity of 29 and 30 after foliar treatment, 500 µL of compound plus 0.1% Tween-80 at a concentration of 1000 ng / mL was applied to the adaxial side of the leaf and left to dry for 1 h prior to EPG analyses.

[0131] I. Data Analyses. For contact and leaf dip toxicity assays, concentration-response curves (CRC) were generated by nonlinear regression with a four-parameter logistic equation (variable slope) using GraphPad Prism 9 (GraphPad Software). For topical, contact, and leaf dip toxicity assays, time-response curves were generated through testing of 6 time points and the time required to induce 50% mortality (LT50) for both compounds were determined through a log transformation of the time points followed by the same four-parameter logistic nonlinear regression model using GraphPad Prism 9. For the systemic toxicity assay data, arcsine square root transformation was performed for all the percentage mortalities, followed by a one-way ANOVA with Tukey’s multiple comparisons test.

[0132] For CNS recordings, mean firing frequencies were calculated and used to construct a CRC for each test compound to determine an EC50value. These values were calculated using non-linear regression in GraphPad Prism 9 software as described above, expressed and normalized to the background control firing rate, with the bottom variable fixed to 100%.29 LEGAL02 / 45405426v1

[0133] All behavior datasets and the percentage of aphids probing, xylem and phloem feeding were tested for normality using the Kolmogorov-Smirnov test using Prism 9. All percentages of aphid probing and feeding behaviors went through an Arcsine square root transformation, followed by an Ordinary one-way ANOVA with Tukey’s multiple comparisons test. The probing and feeding behaviors were initially analyzed with the Brown- Forsythe test to assess whether standard deviations (SDs) were significantly different. Datasets with unequal SDs were analyzed with Welch’s ANOVA followed by Dunnett’s T3 multiple comparisons whereas data sets with equal SDs were analyzed with an ordinary one-way ANOVA followed by Tukey’s multiple comparisons test. Analyses were all performed in GraphPad Prism 9. Results

[0134] 1. 29 and 30 induced rapid knockdown and high toxicity to M. persicae via contact exposure through spray and filter paper. Exposure to 29 and 30 led to signs of intoxication reminiscent of neural poisoning with twitching appendages, uncoordinated movements, and general hyperexcitation. Exposure to 29 and 30 led to rapid knockdown of aphids after topical spray at 200 ng / mL, with 29 showing mean knockdown of 66.7 + 3.3% in 1.5 min and to 80 + 5.8% knockdown at 1.5 min after exposure to 30. No recovery was observed at 200 ng / mL and all knocked down aphids were dead at 1 h. In addition to knockdown, both compounds were found to be highly toxic.29 and 30 led to contact toxicity LC50values of 10 ng / mL [95% CI: 7–14; Hillslope: 0.44; r2: 0.95] and 76 ng / mL [95% CI: 49–118; Hillslope: 0.46; r2: 0.89] after 1 h of exposure, respectively (Table 3). The 1 h mortality data was supported by the LT50value of 53 min [95% CI: 45–62; Hillslope: 1.21; r2: 0.97] of 29 at a concentration of 10 ng / mL (Table 4). The lowest observed LC50in filter paper assays (0.19 ng / mL [95% CI: 0.21–0.37; Hillslope: 0.76; r2: 0.98], Table 3) was after 6 h of contact exposure with 29. Increased concentrations of 29 to 30 ng / mL and 100 ng / mL decreased LT50values to 28 min [95% CI: 22–35; Hillslope: 0.98; r2: 0.97] and 16 min [95% CI: 12–21; Hillslope: 0.95; r2: 0.95], respectively (Table 4). The lowest LT50value of 29 in filter paper toxicity assays were observed at 1000 ng / mL with a value of 7 min [95% CI: 5–10; Hillslope: 1.23; r2: 0.95] (Table 4), but interestingly similar LT50values were observed at 200 ng / mL and 600 ng / mL. Lastly, 30 was most toxic at 6 h post exposure with an LC50value of 4 ng / mL [95% CI: 1–7; Hillslope: 0.82; r2: 0.96] (Table 3).30 LEGAL02 / 45405426v1Table 3. Toxicity of N-arylamide compounds after adult apterous M. persicae contact exposure.Table 4. Toxicity of N-arylamide compounds spray application to adult apterous M. persicae.

[0135] 2. Toxicity of 29 and 30 with leaf dip assays is dependent on addition of Tween-80.29 and 30 were highly toxic via direct contact exposure through spray and tarsal contact via filter paper assays, which justified toxicological analyses after treatment of living leaf material . Surprisingly, no mortality was observed after aphid infestation of 29- or 30-treated leaf disks at concentrations 100-fold higher than the LC50for filter paper assays. To mitigate the potential sequestration of 29 and 30 in the waxy layers of the leaf, we included Tween-80, which is a31 LEGAL02 / 45405426v1nonionic surfactant and emulsifier, to test if this detergent increased bioavailability of 29 and 30 after leaf treatments. Indeed, 29 and 30 toxicities were increased after incorporation of 0.1% Tween-80 into the treatment solution with LC50values of 33 ng / mL [95% CI: 22–55; Hillslope: 1.28; r2: 0.93], and 52 ng / mL [95% CI: 32–88; Hillslope: 0.71; r2: 0.91] at 4 h for 29 and 30, respectively (FIG. 4A). After 6 h of exposure, 29 and 30 toxicities were observed with LC50values of 31 ng / mL [95% CI: 25–39; Hillslope: 1.29; r2: 0.96], and 38 ng / mL [95% CI: 27–52; Hillslope: 0.82; r2: 0.93] for 29 and 30, respectively (FIG.4B). The highest toxicity from leaf disk assays was found to be 24 h post-exposure with LC50values of 20 ng / mL [95% CI: 17– 24; Hillslope: 1.54; r2: 0.97] and 27 ng / mL [95% CI: 19–38; Hillslope: 1.11; r2: 0.97] for 29 and 30, respectively (FIG.4C). Importantly, the LC50value of 29 and 30 was not significantly different when compared to thiamethoxam, a neonicotinoid commercialized for aphid control, which had an LC50value of 11 ng / cm2[95% CI: 5-19; Hillslope: 1.3; r2: 0.98] (FIG.4C, open circles).

[0136] Contact toxicity was assessed through leaf dip bioassays and data indicate compounds 29 and 30 are toxic with 4-h LC50values of 44.7 ng / mL [95% CI: 28.51–71.86; Hillslope: 0.94; r2: 0.87] and 54.1 ng / mL [95% CI: 29.44–100.5; Hillslope: 0.70; r2: 0.84], respectively.

[0137] In addition to determining LC50values, we assessed the time required to induce 50% knockdown (KT50) as this metric is relevant to inhibition of non-persistent viruses. A 4.7-fold increase in KT50values occurred at 200 ng / mL of 29 at a time of 42 min [95% CI: 31–56; Hillslope: 1.02; r2: 0.90] when compared to the contact filter paper assay (Table 4 and Table 5). Exposure to 30 ng / mL of 29 and 30 led to LT50values of 227 min [95% CI: 160–335; Hillslope: 0.58; r2: 0.88] and 199 mm [95% CI: 124–349; Hillslope: 0.47; r2: 0.82], respectively (Table 5). Table 5. Toxicity of N-arylamide compounds foliar application to adult apterous M. persicae.32 LEGAL02 / 45405426v1

[0138] 3. SL technology increased water solubility of 29 and 30.29 and 30 are poorly soluble in water by themselves and thus difficult to disperse as a uniform treatment solution. When each was processed with the botanical solubilizer rubusoside, a water solution containing a supersaturated amount of 29 or 30 was created, referred as 29-SL or 30-SL. 29-SL or 30-SL contained 5 mg / mL of 29 or 30 in the presence of rubusoside and after incorporation, 29-SL appeared clear and transparent (FIG.5A) whereas 30-SL appeared hazy and translucent with a hint of extra small particle suspension (FIG.5B). The clear and transparent 29-SL liquid was found to contain particle sizes ranging from 6.39 nm to 15.19 nm with an average diameter of 9.1 ± 0.26 nm. It was monodispersed with only one peak (FIG.5C). The hazy and translucent 30-SL liquid was found to contain particle sizes ranging from 204.4 nm to 972.0 nm with an average diameter of 427.0 ± 56.56 nm that was monodispersed with only one peak (FIG.5D). 29-SL water solution was physically stable (i.e., no sign of precipitation) for at least seven days whereas 30-SL water solution remained physically stable for 24 h before showing precipitation. Vortexing the solution restored the clarity of 29-SL and 30-SL and returned the mixture to a complete solution.

[0139] 4. SL facilitated translocation of 29 and 30 from lower to upper leaves. Toxicity data from contact assays with filter paper or leaf dips suggests that 29 and 30 induce mortality at nanogram concentrations within 24 h of exposure (Table 4). This led us to hypothesize whether the solubilizer could translocate N-arylamide compounds to untreated upper leaves to induce aphid mortality within 24 h of infestation. Percent mortality from 29- or 30-SL treated plants was not significantly different than the control for 30-mm post-infestation and 30-SL was not different from control at 1 h post exposure, whereas 30-SL resulted in a significant (P < 0.05) increase in aphid mortality at 1-h post infestation (Table 6). Mortality was significantly (P < 0.05) increased for 29-SL and 30-SL treated plants 12- and 24-h post infestation when compared to control groups with approximately 70% and 90% mortality for each compound, respectively (Table 6). Table 6. Translocation toxicityaof 29-SL and 30-SL to M. persicae.33 LEGAL02 / 45405426v1aMeans + SEM not labeled by the same uppercase letter within the same time point represents statistical significance at P < 0.05 by one-way ANOVA with Dunnett’s multiple comparisons test.

[0140] 5. 29 and 30 increased firing rates of central descending neurons of M. persicae. Extracellular recordings were performed on M. persicae descending neurons (FIG. 3A-B) to determine the influence of 29 and 30 to neural firing rates. Compounds 29 and 30 were equipotent to M. persicae central neurons with both compounds eliciting a significant (P < 0.05) increase in firing rates at 30 nM and maximal firing rates at 100 nM (FIG. 3C). The concentration to elicit 50% maximal excitation (EC50) for 29 and 30 was found to be 13 nM [95% CI: 6-35; Hillslope: 0.80; r2: 0.91] and 16 nM [95% CI: 9-53; Hillslope: 0.92; r2: 0.89], which are not significantly different (P > 0.05) from each other (FIG. 3C). Nerve death was observed at concentrations of 1 µM and above.

[0141] 6. 29 and 30 treatments on leaf material altered probing behavior of M. persicae. Specific behaviors, such as probing and feeding, are directly correlated to acquisition and horizontal transmission of plant viruses and thus, we aimed to define how 29 and 30 alter probing and feeding behaviors of M. persicae via EPG. Aphids placed on untreated (control) plants displayed typical probing and feeding behavior patterns with clear probing events followed by C waveforms, E1 waveforms (salivation into phloem sieve-elements), E2 waveforms (phloem ingestion), and G waveforms (intake of xylem elements) (FIG. 6A). Representative EPG analysis of aphids placed on 29 or 30 treated leaves displayed altered probing behavior as shown in FIG. 6B. Foliar application of 29 and 30 did not reduce the proportion of aphids that initiated a probe on cotton leaves (FIG.6C), but foliar exposure to 30 led to a statistically significant (P < 0.01) increase of 4.2-fold in the time required to initiate the first probe compared to control aphids (FIG.6D). Exposure to 29 and 30 significantly (P < 0.05) reduced the total number of probes initiated compared to the control by 4.8-fold and 4- fold, respectively (FIG. 6E). Furthermore, there was a 3.1- and 3.4-fold increase in the time taken from that first probe to the initiation of pd compared to the control for 29 and 30, respectively (FIG.6F). Interestingly, there was also a 7.2-fold and a 2.5- fold reduction in the proportion of aphids that initiated a new probe with potential drop on leaves treated with 29 and 30 when compared to the control, which was statistically significant (P <0.05; FIG.6G). Furthermore, there was a 9-fold and 6-fold reduction in the total number of probes with potential drops that an aphid would initiate after 1 h exposure to 29 and 30 when compared to the control, which were statistically significant (P < 0.01) reductions (FIG.6H).34 LEGAL02 / 45405426v1

[0142] 7. Foliar applications of 29 and 30 reduced phloem feeding by M. persicae. Due to the observed disruption of aphid probing behavior, we tested if 29 and 30 altered aphid vascular bundle feeding behavior, which is relevant for plant nutrient loss and horizontal transmission of persistent pathogens. Foliar application of 29 and 30 did not significantly reduce the proportion of aphids that reached xylem tissue (FIG.7A), but aphids probing on plants treated with 29 and 30 reached phloem (E1 waveform) 2.4-fold and 1.5-fold less than control aphids, which was a statistically significant (P < 0.05) reduction (FIG.7B). Furthermore, only 32.3 ± 12.4% and 59.38 ± 4.84% were able to successfully ingest phloem for 29 and 30, respectively, which is a statistically significant (P <0.05) reduction when compared to the control aphids (74.17 ± 7.50%; FIG.7C). Interestingly, of the small proportion of aphids that did reach phloem after foliar treatment of 29 and 30 did not differ in the time required to reach phloem when compared to control aphids (FIG.7D). Discussion

[0143] Effective control of aphids has been challenged by the global distribution of resistance to commercialized aphicides as well as and reduced insecticide registrations and approvals. Of additional concern is the continued spread of aphid-vectored plant viruses that occurs during distinct feeding events, such as probing for non-persistent viruses or phloem feeding for persistent viruses.

[0144] Contact exposure to 29 and 30 through misting of aphids infested on pepper plants induced rapid knockdown at 200 ng / cm2with 29 leading to 100% knockdown at 3 min post exposure and tarsal contact toxicity via filter paper resulted in a 10 min LC50value of approximately 200 ng / cm2for 29 and 30 (Table 3). Toxicity increased to commercial rates at 6 h post exposure with LC50values of 0.29 ng / cm2and 4 ng / cm2for 29 and 30, respectively (Table 3). The rapid knockdown and high toxicity at 10 min indicated these compounds could satisfy the requirements for reducing aphid populations while simultaneously reducing virus transmission via knockdown prior to probing.

[0145] Addition of a nonionic surfactant increase bioavailability and biological activity of 29 and 30 to aphids on treated leaves. Inclusion of 0.1% Tween-80, which is a nonionic surfactant used to disperse hydrophobic particles in aqueous solutions, into the chemical solution led to high toxicity of 29 and 30 via leaf dip bioassays with 24 h mortality nearly equal to thiamethoxam (FIG. 4C). The dramatic increase in toxicity after inclusion of Tween-80 indicates the use of surfactants with 29 and 30, and likely other compounds with highly fluorinated sidechains and / or with high LogP values, is beneficial to biological activity. For instance, Triton X-100 and pentaethylene glycol monododecyl ether (C12E5) are two additional35 LEGAL02 / 45405426v1polyether nonionic surfactants that have been shown to have the excellent wetting properties on fruit tree, wheat, and rice leaves that provides the premise to test the efficacy of these surfactants with 29 and 30.

[0146] 29 and 30 are nonpolar molecules with low water solubility that restricts the potential for movement of N-arylamides throughout plant vascular bundles without the addition of enhancers to facilitate plant systemic movement.

[0147] Rubusoside, a naturally occurring terpene glycoside present in Chinese sweet leaf tea leaves (Rubus suavissimus), can be used to increase water solubility of lipophilic compounds facilitate translocation through plants. Rubusoside enhances the water solubility of multiple structurally-distinct drugs, is stable for multiple days after solubilization, and is on the Generally Recognized as Safe (GRAS) list. By using rubusoside, 29 and 30 could be dispersed in water to a 5 mg / mL concentration, which facilitated translocation throughout the plant via vascular bundles (Table 6).

[0148] Aphid mediated transmission of plant viruses occurs during distinct feeding events, such as probing for non-persistent viruses or phloem feeding for persistent viruses. Nonpersistent plant viruses tend to be stylet-borne with no latent period, where they can be acquired and transmitted within seconds to minutes of aphid mouthparts penetrating the leaf epidermis (probing). Nonpersistent pathogen acquisition and transmission occurs during the sampling of cell contents in the plant mesophyll tissue and thus, transmission of non-persistent viruses will occur between 4-6 minutes of aphid landing on the plant. Sap sampling by the aphid can be visualized via EPG recordings as a reduction in voltage, referred to as a potential drop (pd), that is due to the difference between cells and the extracellular space. Although there was no change in the percentage of aphids that initiated a probe, time to first probe for aphids exposed to 29 was increased by approximately three-fold when compared control aphids (FIG. 6). Interestingly, there was a significant reduction in aphids that were able to remove their mouthparts and initiate a new probe (with pd) after 1 h of exposure to either N-arylamide (FIG. 6A-B) that corresponded to significant reduction in the total number of probes initiated after 1 h of 29 and 30 exposures (FIG.6G). One concern for inhibition of feeding prior to knockdown is the potential for increased plant-to-plant movement and increased prevalence of non- persistent plant viruses that has been documented with pyrethroids. However, we do not anticipate this being a concern for 29 and 30 due to the near elimination of additional probes after the initial probe (FIG. 6) and because of the rapid knockdown / toxicity at higher concentrations.36 LEGAL02 / 45405426v1

[0149] Plant viruses that are persistently circulative or persistently propagative are typically located within the plant vascular bundles, with virus acquisition and transmission within hours to days of aphid landing due to the latent period of the viruses. These persistent circulative viruses are acquired during phloem sap ingestion of an infected plant and are transmitted when infected insects release saliva into a healthy plant sieve element. 29 and 30 significantly reduced the ability of aphids to reach phloem (FIG. 7B-C), thus reducing the likelihood of persistent pathogen transmission.

[0150] Extracellular recordings of aphid CNS show significant influences to firing rates at nanomolar concentrations (FIG.3) that indicate 29 and 30 modulate a neurological target.29 and 30 as neurotoxins in aphids is supported by the signs of intoxication (e.g., twitching, uncoordinated movements, etc), rapid knockdown, acute mortality, and rapid inhibition of probing and feeding behaviors.

[0151] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practicing the subject matter described herein. The present disclosure is in no way limited to just the methods and materials described.

[0152] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs, and are consistent with: Singleton et al (1994) Dictionary of Microbiology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., Garland Publishing, New York.

[0153] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of” and / or “consisting essentially of” embodiments.

[0154] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of the range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these small ranges which may independently be included in the smaller rangers is also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0155] Many modifications and other embodiments set forth herein will come to mind to one skilled in the art to which this subject matter pertains having the benefit of the teachings37 LEGAL02 / 45405426v1presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.38 LEGAL02 / 45405426v1

Claims

CLAIMS:

1. A method of controlling aphids, the method comprising contacting an object or locus with a composition comprising a compound of Formula A and a carrier, wherein the compound of Formula A comprises(Formula A) wherein X is N or CH; R1is selected from the group consisting of halogen, C1-C6alkyl, and C1-C6haloalkyl; and each R3is independently selected from the group consisting of halogen, C1-C6haloalkyl and C1-C6haloalkoxy; and n is 1, 2, or 3.

2. The method of claim 1, wherein R1is selected from the group consisting of: −F, −Cl, −Br, −I, −CH3, −CH2CH3, −CH2F, −CHF2, −CF3, −CF2CF3, −CHFCF3, −CF2CHF2, −CH2CF3, −CHFCHF2, −CF2CH2F, −CF2CH3, −CHFCH2F, −CH2CHF2, −CHFCH3, −CH2CH2F, −CH2Cl, −CHCl2, −CCl3, −CCl2CCl3, −CHClCCl3, −CCl2CHCl2, −CH2CCl3, −CHClCHCl2, −CCl2CH2Cl, −CCl2CH3, −CHClCH2Cl, −CH2CHCl2, −CHClCH3, −CH2CH2Cl, −CH2I, −CHI2, −CI3, −CI2CI3, −CHICI3, −CI2CHI2, −CH2CI3, −CHICHI2, −CI2CH2I, −CI2CH3, −CHICH2I, −CH2CHI2, −CHICH3, and −CH2CH2I.

3. The method of claim 1, wherein −R1is −F, −Cl, or −Br.

4. The method of claim 1, wherein −R1is −CH3or −CH2CH3.

5. The method of claim 1, wherein R1is −CF2CF3, −CF2CF2CF3, −CH2Cl, −CH2F, −CHF2, or −CF3.

6. The method of any one of claims 1-5, each R3is independently selected from the group consisting of −Cl, −CF3, −CF2CF3, and −OCF3.

7. The method of any one of claims 1-6, wherein n is 1 and R3is C1-C6haloalkyl or C1-C6haloalkoxy.39 LEGAL02 / 45405426v18. The method of claim 7, wherein −R3is −CF3, −OCF3, or −CF2CF3.

9. The method of claim 8, wherein X is N.

10. The method of claim 8, wherein X is CH.

11. The method of claim 1, wherein the compound of Formula A has the structure of formula I(Formula I) wherein, X is N or CH; R1is selected from the group consisting of fluoro, chloro, bromo, iodo, C1-C6alkyl, and C1-C6haloalkyl; and R2is haloalkyl or haloalkoxy.

12. The method of claim 11, wherein the compound of Formula I is selected from the group consisting of:40 LEGAL02 / 45405426v1,13. The method of claim 12, wherein the compound of Formula I is14. The method of any one of claims 1-6, wherein n is 2.41 LEGAL02 / 45405426v115. The method of claim 14, wherein each R3is Cl.

16. The method of claim 15, wherein X is N.

17. The method of any one of claims 1-6, wherein n is 3.

18. The method of claim 17, wherein at least two R3are Cl.

19. The method of claim 17, wherein two R3are Cl and one R3is −CF3.

20. The method of claim 18 or 19, wherein X is CH.

21. The method of claim 1, wherein the compound of Formula A is22. The method of any one of claims 1-21, wherein the composition further comprises an excipient.

23. The method of any one of claims 1-22, wherein the composition further comprises a surfactant, optionally wherein the surfactant is Tween-80.

24. The method of any one of claims 1-23, wherein the composition further comprises a botanical solubilizer, optionally wherein the botanical solubilizer is rubusoside.

25. The method of any one of claims 1-24, wherein the composition is a dust, a granular formulation, a liquid solution, a vaporized mist, an aerosol, or an emulsion.

26. The method of any one of claims 1-25, wherein the object or locus comprises a plant, a plant part, or an environment of a plant.

27. The method of claim 26, wherein plant is a crop plant, vegetable plant, a fruit plant, or ornamental plant.

28. The method of claim 27, wherein the crop plant comprises: a food crop plant, a feed crop plant, a fiber crop plant, and oil crop plant, an ornamental crop plant, or an industrial crop plant.42 LEGAL02 / 45405426v129. The method of any one of claims 1-28, wherein contacting the object or locus comprises: applying the composition to a plant or plant part or an environment of the plant.

30. The method of any one of claims 1-29, wherein the compound of Formula A is applied to the object or locus at a concentration of about 0.1-100 ng / cm2, about 0.1-50 ng / cm2, about 0.1-10 ng / cm2, about 0.5-10 ng / cm2, about 1-10 ng / cm2, or about 1-5 ng / cm2.

31. The method of any one of claims 1-30, wherein a lethal concentration for 50% (LC50) of the aphids after exposure to the compound of Formula A is less than 500 ng / mL, less than 400 ng / mL, less than 300 ng / mL, less than 200 ng / mL, less than 100 ng / mL, less than 50 ng / mL, less than 40 ng / mL, less than 30 ng / mL, less than 20 ng / mL, less than 15 ng / mL, less than 14 ng / mL, less than 13 ng / mL, less than 12 ng / mL, less than 11 ng / mL, less than 10 ng / mL, less than 9 ng / mL, less than 8 ng / mL, less than 7 ng / mL, less than 6 ng / mL, less than 5 ng / mL, less than 4 ng / mL, less than 3 ng / mL, less than 2 ng / mL, less than 1 ng / mL, less than 0.5 ng / mL, less than 0.4 ng / mL, less than 0.3 ng / mL, or less than less than 0.2 ng / mL.

32. The method of claim 31, wherein a lethal concentration for 50% (LC50) of the aphids after exposure to the compound of Formula A is measured in less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 30 minutes, less than about 45 minutes, less than about 60 minutes, less than about 90 minutes, less than about 2 hours, less than about 3 hours, less than about 4 hours, less than about 5 hours, less than about 6 hours, less than about 7 hours, less than about 8 hours, less than about 12 hours, less than about 16 hours, less than about 18 hours, less than about 24 hours, less than about 2 days, or less than about 3 days.

33. The method of any one of claims 1-32, wherein controlling aphids comprises: killing aphids, reducing an aphid population, preventing an aphid infestation, reducing an aphid infestation, reducing or preventing transmission of disease carried by aphids, or altering probing behavior of aphids, altering feeding behavior of aphids, reducing transmission of viruses to plant by aphids.43 LEGAL02 / 45405426v1

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