Crystalline forms of oxathiazolidine urea compounds having pesticidal activity

Abstract

Disclosed herein are crystalline forms of (Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl-1H-1,2,4-triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (Z1), processes for making them and use in agrochemical preparations.

Description

CRYSTALLINE FORMS OF OXATHIAZOLIDINE UREA COMPOUNDS HAVING PESTICIDAL ACTIVITY BACKGROUND

[0001] This disclosure relates to crystalline forms of (Z)-1-(2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl-1H-1,2,4-triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (Z1), processes for preparing crystalline forms of Z1, and their uses in agrochemical preparations, compositions and formulations.

[0002] (Z)-1-(2-Fluoro-4-(1-(4-(trifluoromethoxy)phenyl-1H-1,2,4-triazol-3-yl)phenyl)-3-(3- (5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (Z1) is an oxothiazolidine urea exhibiting insecticidal activity. Z1 can be used for the prevention, control, or elimination of pest infestations and pest-borne diseases in variety of crops including corn, soybean, vegetables, cereals and the like.

[0003] Z1, which has a molecular formula of C29H21F7N6O4S, is represented by the chemical structure below: N F3CO N3.

[0004] Z1 can be prepared by the processes disclosed in WO 2021011722A.

[0005] It is advantageous to improve the storage stability of Z1. Z1 can be used in many agrochemical applications including foliar, soil, furrow and seed coating / dressing. As such, development of various formulations that suit such applications is necessary. Improving the formulation stability of Z1 is also highly desirable. Surprisingly, novel crystalline forms of Z1, providing both storage stability and formulation stability, have been discovered. Any solvates, salts, isotopes and tautomeric forms of crystallineforms of Z1 is also within the scope of this disclosure. In one embodiment, the crystalline form of Formula Z1 is a solvate. In some of these instances, the crystalline form of Formula Z1 is a hydrate. SUMMARY

[0006] Disclosed herein are crystalline forms of Z1 having X-ray diffraction patterns substantially as shown in Figures 2, 6, 9, 10, 11 and 12. One aspect of crystalline forms disclosed herein is a crystalline form A of Z1 having an X-ray diffraction pattern substantially as shown in Figure 2, and / or having an IR spectrum substantially as shown in Figure 3 and / or Raman spectrum substantially as shown in Figure 4. Another aspect of the crystalline forms disclosed herein is a crystalline form B of Z1 having an X-ray diffraction pattern having X-ray diffraction pattern substantially as shown in Figure 6 and / or IR spectrum substantially as shown in Figure 7 and / or Raman spectrum substantially as shown in Figure 8. Embodiments of disclosed crystalline forms of Z1 also include crystalline forms of solvates, hydrates, salts, isotopes and tautomers. Crystalline forms of Z1 can be present as a free base, agrochemically- acceptable salt (that is, customary salts often used in the agricultural industry) or a solvate thereof.

[0007] Additionally, processes to make and use crystalline forms of Z1 are provided. BRIEF DESCRIPTION OF DRAWINGS

[0008] FIGURE 1 is an X-ray diffractogram (XRD) of amorphous Z1 as prepared by the processes disclosed in WO 2021011722A using Cu-Kα radiation at 25 ℃;

[0009] FIGURE 2 is an X-ray diffractogram (XRD) of crystalline form A of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0010] FIGURE 3 is an Infra-Red (IR) spectrum of crystalline form A of Z1;

[0011] FIGURE 4 is a Raman spectrum of crystalline form A of Z1;

[0012] FIGURE 5 is a Differential Scanning Calorimetry (DSC) profile of crystalline form A of Z1;

[0013] FIGURE 6 is an X-ray diffractogram (XRD) of crystalline form B of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0014] FIGURE 7 is an Infra-Red (IR) spectrum of crystalline form B of Z1;

[0015] FIGURE 8 is a Raman spectrum of crystalline form B of Z1;

[0016] FIGURE 9 is an X-ray diffractogram (XRD) of crystalline form C of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0017] FIGURE 10 is an X-ray diffractogram (XRD) of crystalline form D of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0018] FIGURE 11 is an X-ray diffractogram (XRD) of crystalline form E of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0019] FIGURE 12 is an X-ray diffractogram (XRD) of crystalline form F of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0020] FIGURE 13 is an X-ray diffractogram (XRD) of a 1:1 mixture of Z1-amorphous and Z1-Form A used for competitive slurry experiments recorded using Cu-Kα radiation at 25 ℃; and

[0021] FIGURE 14 is an X-ray diffractogram (XRD) of the resulting solid isolated following the competitive slurry experiments from a 1:1 mixture of Z1-amorphous and Z1-Form A recorded using Cu-Kα radiation at 25 ℃. DETAILED DESCRIPTION

[0022] The term “crystalline” refers to a solid-state form where the molecules are arranged to form a crystal lattice comprising distinguishable unit cells. A certain crystalline form can be identified by the specific diffraction peaks when subjected to X-ray radiation. A crystalline form can also be identified by exhibiting an endothermic melting peak profile with a characteristic sharp peak using differential scanning calorimetry (DSC).

[0023] In some embodiments, the crystalline form of Z1 is a crystalline form of a solvate of Z1. Throughout the disclosure, in a solvate of Z1 or an acceptable salt thereof, the ratio of solvent molecules to the compound of Z1 or an acceptable salt thereof may be, but is not limited to, 1:2, 1:1, or 2:1.

[0024] In some embodiments, the crystalline form of Z1 is a crystalline form of a hydrate of Z1. Throughout the disclosure, in a hydrate of Z1 or an acceptable salt or solvate thereof, the ratio of water molecules to the compound of Z1 or an acceptable salt or solvate thereof may be, but is not limited to, 1:2 (hemi-hydrate), 1: 1 (monohydrate), 2: 1 (dihydrate).

[0025] As used herein, the term “isotope” refers to a variant of an element that has the same number of protons but a different number of neutrons, resulting in a different atomic mass.Isotopes of a given element may be stable or radioactive, and may be naturally occurring or artificially produced. In certain embodiments, the present invention includes or encompasses isotopically labeled compounds wherein one or more atoms (e.g., hydrogen, carbon, nitrogen, oxygen, sulfur, or halogens) are replaced with their corresponding stable or radioactive isotopes (e.g., deuterium, tritium, ¹³C, ¹⁵N, ¹⁸O, ³⁵S, ¹²⁵I). Isotopic substitution may be employed for, inter alia, analytical tracking, mechanistic studies, metabolic stability, or therapeutic modification.

[0026] Throughout the disclosure, reference to the compound of Z1 or compounds of Z1 is also includes acceptable salts, solvates, or hydrates thereof, unless otherwise indicated herein or clearly contradicted by context.

[0027] Throughout the disclosure, reference to compounds of the present disclosure also includes all regioisomers, structural isomers, geometrical isomers, rotational isomers, tautomers, and stereoisomers, for example diastereomers, enantiomers, and mixtures thereof.

[0028] The compounds of the disclosure may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage e.g., restriction resulting from the presence of a ring or a double bond. Accordingly, any cis / trans and E / Z isomers are expressly included in the present disclosure.

[0029] The compounds of the disclosure may also be present in multiple tautomeric forms. Where one or more tautomeric forms exist, the disclosure expressly includes all such tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented.

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

[0031] All percentages are given herein in weight percentages unless otherwise indicated.

[0032] Reference is made to the accompanying figures, in which,

[0033] FIGURE 1 is an X-ray diffractogram (XRD) of amorphous Z1 as prepared by the processes disclosed in WO 2021011722A using Cu-Kα radiation at 25 ℃;

[0034] FIGURE 2 is an X-ray diffractogram (XRD) of crystalline form A of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0035] FIGURE 3 is an Infra-Red (IR) spectrum of crystalline form A of Z1;

[0036] FIGURE 4 is a Raman spectrum of crystalline form A of Z1;

[0037] FIGURE 5 is a Differential Scanning Calorimetry (DSC) profile of crystalline form A of Z1;

[0038] FIGURE 6 is an X-ray diffractogram (XRD) of crystalline form B of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0039] FIGURE 7 is an Infra-Red (IR) spectrum of crystalline form B of Z1;

[0040] FIGURE 8 is a Raman spectrum of crystalline form B of Z1;

[0041] FIGURE 9 is an X-ray diffractogram (XRD) of crystalline form C of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0042] FIGURE 10 is an X-ray diffractogram (XRD) of crystalline form D of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0043] FIGURE 11 is an X-ray diffractogram (XRD) of crystalline form E of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0044] FIGURE 12 is an X-ray diffractogram (XRD) of crystalline form F of Z1 recorded using Cu-Kα radiation at 25 ℃;

[0045] FIGURE 13 is an X-ray diffractogram (XRD) of a 1:1 mixture of Z1-amorphous and Z1-Form A used for competitive slurry experiments recorded using Cu-Kα radiation at 25 ℃;

[0046] FIGURE 14 is an X-ray diffractogram (XRD) of the resulting solid isolated following the competitive slurry experiments from a 1:1 mixture of Z1-amorphous and Z1-Form A recorded using Cu-Kα radiation at 25.

[0047] Z1 has a molecular formula of C29H21F7N6O4S. The chemical structure of Z1 is represented below.N F3CO NN OS OCF3

[0048] Z1 is an urea

[0049] Amorphous Z1 has been prepared by the processes disclosed in WO 2021011722 and crystalline forms of Z1 disclosed herein are prepared by the processes disclosed throughout this specification.

[0050] Z1 can be used in various agrochemical applications such as foliar, soil, furrow and seed. Specific formulations need to be prepared for specific applications, which requires improving the compatibility of Z1 with various formulation ingredients. Additionally, it is advantageous to improve the storage stability and processability of Z1 to suit these formulations.

[0051] Surprisingly, it was found that certain crystalline forms address the concerns related to storage stability, processability and compatibility of Z1. One aspect of the present disclosure is the discovery that certain crystalline forms of Z1 possess desirable properties in comparison with the amorphous form. Several such crystalline forms are included in the present disclosure. For example, as exemplified herein, the crystalline forms of Z1 comprising certain specific X-ray diffraction patterns found to improve storage stability, processability and formulation compatibility.

[0052] Crystalline forms disclosed herein can be prepared using a number of different solvents and solvent mixtures from solvent classes such as alcohols, ketones, esters, ethers, hydrocarbons, aprotic polar solvents, and water. For example, crystalline form A can be prepared using a number of different solvents and solvent mixtures such as methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, tetrahydrofuran, acetonitrile, toluene, xylenes, hexanes, heptanes, cyclohexane, methylcyclohexane, dichloromethane, and water and mixtures thereof.

[0053] The crystalline form A exhibits an X-ray powder diffractogram (X-RPD) recorded using Cu-Kα radiation at 25 ℃ substantially as shown in Figure 2. The crystalline form A can be characterized by its infrared (IR) spectrum showing the characteristic functional groupvibration peaks at wavenumbers (cm-1, +0.2%) of one or more of 1740, 1661, 1624, 1505, 1470, 1408, 1353, 1326, 1265, 1155, 1067, 1035, 985, 956, 930, 895, 755, 737, 664, 638, 532, preferably, the IR spectrumas shown in Figure 3. The crystalline form A can also be characterized by its Raman spectrum showing the characteristic functional group vibration peaks at wavenumbers (cm-1, +0.2%) of one or more of 1744, 1668, 1626, 1539, 1519, 1502, 1483, 1451, 1437, 1411, 1357, 1326, 1309, 1286, 1270, 1234, 1169, 1124, 1094, 1000, 847, 833, 813, 795, 668, 645, 629, 482, 460, 404, 289, 271, preferably, the Raman spectrum substantially as shown in Figure 4.

[0054] Crystalline form A of Z1 typically has a melting point in the range from 170 to 200 °C, in particular in the range from 180 to 195 °C, and especially in the range from 185 to 195 °C. It is noted that melting points of the crystalline forms disclosed herein can vary depending on impurities present within the sample and the conditions being used to generate the DSC curves.

[0055] In one specific aspect, the crystalline form A can also be characterized by its melting point. Accordingly, also provided herein is a crystalline form A of Z1 exhibiting a differential scanning calorimetry (DSC) profile having an endothermic peak at 190.6 ℃ preferably with a melting enthalpy in the range of 30-76 J / g (Joules per gram) as shown in Figure 5.

[0056] In one aspect, disclosed herein are various crystalline forms of Z1. In another aspect, the crystalline form is crystalline form A of Z1. In one aspect, the crystalline form A comprises at least three of the following reflexes in any combination as 2Ɵ + 0.20 in an X-ray powder diffractogram (X-RPD) recorded using Cu-Kα radiation at 25 ℃: 2Ɵ + 0.20 2Ɵ + 0.20 2Ɵ + 2Ɵ +

[0057] In another aspect, disclosed herein is a crystalline form A of Z1 comprising at least two of the following reflexes in any combination:

[0058] 2Ɵ + 0.20 2Ɵ + 0.20 4.95 19.64

[0059] In one aspect, disclosed herein are various crystalline forms of Z1. In another aspect, the crystalline form is crystalline form A of Z1. In one aspect, the crystalline form A comprises at least three of the following reflexes in any combination as 2Ɵ + 0.20 in an X-ray powder diffractogram (X-RPD) recorded using Cu-Kα radiation at 25 ℃: 2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value

[0060] In another aspect, disclosed herein is a crystalline form A of Z1 comprising at least two of the following reflexes in any combination: 2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value9.89 8.93 21.83 4.07 15.45 5.73 22.83 3.89characteristic peaks at wavenumbers (cm-1, + 0.20%) 1740, 1661, 1624, 1505, 1470, 1408, 1353, 1326, 1265, 1155, 1067, 1035, 985, 956, 930, 895, 755, 737, 664, 638, 532. In a further embodiment, the crystalline form A of Z1 has an IR spectrum substantially as shown in Figure 3.

[0062] In another aspect, the crystalline form A of Z1 has a Raman spectrum exhibiting characteristic peaks at wavenumbers (cm-1, + 0.20%) 1744, 1668, 1626, 1539, 1519, 1502, 1483, 1451, 1437, 1411, 1357, 1326, 1309, 1286, 1270, 1234, 1169, 1124, 1094, 1000, 847, 833, 813, 795, 668, 645, 629, 482, 460, 404, 289, 271. In a further embodiment, the crystalline form A of Z1 has a Raman spectrum substantially as shown in Figure 4.

[0063] In one aspect, the crystalline forms disclosed herein can be prepared by dissolving Z1 in a solvent system. The solvent system may comprise one or more solvents. Z1 may be in an amorphous or crystalline form. The dissolved Z1 is then precipitated into one of the crystalline forms of Z1. In particular aspects, the precipitated crystalline form is crystalline form A of Z1. The precipitated crystalline form is then isolated either by removing the solvent / solvent mixture or by adding another less soluble solvent. The solvents can be removed by evaporation, distillation, decanting or filtration. Alternatively, crystalline forms of Z1 can be precipitated and separated out directly from the reaction mixture by judicious selection of reaction conditions, process parameters, reagents and solvents. For example, crystalline form A of Z1 can be isolated by conducting the reaction process illustrated in Scheme 3. In one embodiment, the crystalline forms of Z1 can be isolated by conducting the reaction process shown in Scheme 3, wherein the intermediate Y1a is synthesized in situ, and carried through to the next step without isolation. In another aspect, the crystalline forms of Z1 can be isolated by conducting the reaction process shown in Scheme 3, wherein the reaction process encompasses isolation of Y1a via crystallization processes. Once the reaction is completed, the precipitated material can beisolated by removing the solvents by either filtration or distillation. A less soluble solvent can be added to the reaction medium to facilitate the precipitation of solid material. The solid material / filter cake can be washed with an appropriate solvent to generate crystalline form A from the synthetic medium. In some aspects, an aqueous workup is used after the reaction is completed and before the crystallization is conducted.

[0064] The crystalline forms can be precipitated by concentrating the solution and / or cooling the solution and / or adding a less soluble solvent. In particular aspects, the crystallization is achieved by adding a seed crystal of Z1. The seed crystal of Z1 can be prepared by using the processes disclosed herein.

[0065] In some aspects, the amorphous form of Z1 or any other solid / crystalline form of Z1 is added to or prepared in a solvent matrix. In these instances, Z1 may not be completely dissolved in the solvent matrix. In some instances, Z1 is partially dissolved or exists as a suspension in the solvent matrix. Crystalline forms of Z1 are isolated by any of the known- techniques in the art in crystalline forms. In some instances, a seed crystal of Z1 is added to the solvent matrix. In other instances, a less soluble solvent can be added to the solvent matrix which accelerates the separation of a crystalline form from the solvent matrix. In certain instances, the solvent matrix comprises solvent selected from the group consisting of alcohols, ketones, esters, ethers, hydrocarbons, aprotic polar solvents, and water. Specific examples of such solvents are methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, tetrahydrofuran, acetonitrile, toluene, xylenes, hexanes, heptanes, cyclohexane, methylcyclohexane, dichloromethane, and water. A crystalline seed is a small quantity of a crystalline material used to induce or facilitate the formation of a specific polymorphic form of a compound during crystallization.The crystalline forms of Z1 prepared according to the methods disclosed herein can be formulated into useful formulations suitable for various agrochemical applications such as foliar applications, soil applications, furrow applications and seed applications. A composition comprising a crystalline form of Z1 can be formulated as a suspension concentrate (SC), an oil-based suspension concentrate (OD), a soluble concentrate (SL), water soluble granules (SG), a dispersible concentrate (DC), an emulsifiable concentrate (EC), flowable suspension (FS) suitable for seed treatment applications, an emulsion seed dressing, a suspension seed dressing, a seed coating, granules (GR), microgranules (MG), a suspoemulsion (SE), or water dispersible granules (WG).

[0066] In some aspects, the compositions comprising a crystal form of Z1 comprise the crystal form in amount less than 80% by weight, less than 70% by weight, less than 60% by weight or less than 50% weight. In some aspects, the composition comprises the crystal form in about 50% by weight. In particular aspects, the composition comprises the crystalline form in about 20-30% by weight. In some aspects, the composition comprises the crystalline form in about 20-25% by weight. Generally, the rest of the composition comprises water and adjuvants and other ingredients. In specific preferred aspects, the crystalline form is crystalline form A of Z1.

[0067] The crystalline forms of Z1 disclosed herein offer several advantages over the amorphous form of Z1. For example, the crystalline form A of Z1 provides several benefits such as storage stability, formulation stability and processability. Previously, Z1 has been isolated in an amorphous oily foam. This physical state is not amenable to conventional formulation technologies. For example, the amorphous Z1 cannot be milled by conventional means to create an SC formulation.

[0068] Accordingly, crystalline forms of Z1 can be used for various agrochemical applications in the form of foliar applications, soil applications, in-furrow applications and seed applications. Disclosed herein is also a method of controlling, eliminating, preventing or reducing a pest infestation using a composition comprising a crystalline form of Z1. Such a method comprises using a composition comprising a crystalline form of Z1 in or near a locus of the pest infestation. The term "locus" means a habitat, breeding ground, plant, seed, soil, material, or environment, in which a pest is growing, may grow, or may traverse. For example, a locus includes but is not limited to, areas where crops, trees, fruits, cereals, fodder species, vines, turf, and / or ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored); in and around materials of construction used in buildings (such as impregnated wood); and the soil around buildings.

[0069] In some aspects, the pest is selected from Phyla Arthropoda, Mollusca, Nematoda, pathogenic fungi, and pathogenic bacteria. In certain aspects, the pest is selected from Phyla Arthropoda, Mollusca and Nematoda.

[0070] In some aspects, the pest is selected from the group consisting of ants, aphids, bed bugs, beetles, bristletails, caterpillars, cockroaches, crickets, earwigs, fleas, flies, grasshoppers, grubs, leafhoppers, lice, locusts, maggots, mites, nematodes, planthoppers, psyllids, sawflies,scales, silverfish, slugs, snails, spiders, springtails, stink bugs, symphylans, termites, thrips, ticks, wasps, whiteflies, and wireworms. In some embodiments of this aspect, said pest is selected from the group consisting of Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Euschistus spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Nilaparvata spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp., and Unaspis spp.

[0071] A particularly preferred pest group to control is sap–feeding pests. Sap–feeding pests, in general, have piercing and / or sucking mouthparts and feed on the sap and inner plant tissues of plants. Examples of sap–feeding pests of particular concern to agriculture include, but are not limited to, aphids, leafhoppers, moths, scales, thrips, psyllids, mealybugs, stinkbugs, and whiteflies. Specific examples of Orders that have sap–feeding pests of concern in agriculture include but are not limited to, Anoplura and Hemiptera. Specific examples of Hemiptera that are of concern in agriculture include, but are not limited to, Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp., Euschistus spp., Lygus spp., Macrosiphum spp., Nezara spp., and Rhopalosiphum spp. Another particularly preferred pest group to control is chewing pests. Chewing pests, in general, have mouthparts that allow them to chew on the plant tissue including roots, stems, leaves, buds, and reproductive tissues (including, but not limited to flowers, fruit, and seeds). Examples of chewing pests of particular concern to agriculture include, but are not limited to, caterpillars, beetles, grasshoppers, and locusts. Specific examples of Orders that have chewing pests of concern in agriculture include but are not limited to, Coleoptera and Lepidoptera. Specific examples of Coleoptera that are of concern in agriculture include, but are not limited to, Anthonomus spp., Cerotoma spp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorus spp., Sitophilus spp. [ADD LEPS]

[0072] A non–exhaustive list of particular Lepidopteran species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposinaniponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Corcyra cephalonica, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diaphania nitidalis, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Estigmene acrea, Eupoecilia ambiguella, Euxoa auxiliaris, Galleria mellonella, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Manduca sexta, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Phyllonorycter blancardella, Pieris rapae, Plathypena scabra, Platynota idaeusalis, Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tinea pellionella, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzea pyrina.

[0073] In some aspects, disclosed herein is an insecticidal composition comprising a crystalline form of Z1. In some instances, the insecticidal composition comprises the crystalline form A of Z1. In some other instances, the insecticidal composition comprises at least one of the crystalline forms of Z1 disclosed herein. In some instances, the insecticidal composition comprises the crystalline form B of Z1. In some aspects, the insecticidal composition comprises at least one auxiliary in addition to crystalline forms of A and B. Such auxiliaries are known in the art for example, surfactants, liquid diluents, wetting agents, dispersants, thickening agents, anti-freezing agents, biocides and any other formulation ingredients.

[0074] The present disclosure also provides processes for preparing compositions for controlling, preventing, eliminating or reducing a pest infestation using the crystalline forms ofZ1. In some instances, the crystalline form is crystalline form A. In some other instances, it is crystalline Form B. The techniques for forming the compositions, for example, the aforementioned formulations, are known to a person of skill in the art.

[0075] The present disclosure provides a method for controlling, preventing, reducing or eliminating a pest infestation in plants, comprising applying a composition comprising a crystalline form, in particular crystalline form A of Z1, to the plants, plant parts, surroundings of the plants, or plant propagation materials a pesticidally-effective amount of the crystalline form A of Z1. In some instances, the method comprises applying a composition comprising any of the crystalline forms of Z1 disclosed herein. The phrase "pesticidally-effective amount" means the amount of a pesticide needed to achieve an observable effect on a pest, for example, the effects of necrosis, death, retardation, prevention, removal, destruction, or otherwise diminishing the occurrence and / or activity of a pest in a locus. This effect may come about when pest populations are repulsed from a locus, pests are incapacitated in, or around, a locus, and / or pests are exterminated in, or around, a locus. Of course, a combination of these effects can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent, and most preferably more than 99 percent, In general, a pesticidally-effective amount, for agricultural purposes, is from about 0.0001 grams per hectare to about 5000 grams per hectare, preferably from about 0.0001 grams per hectare to about 500 grams per hectare, and it is even more preferably from about 0.0001 grams per hectare to about 50 grams per hectare. A preferred plant propagation material is a seed.

[0076] “Surroundings” as used herein, refers to the place where the plants are growing, the place where on which the plant propagation materials are sown or will be sown.

[0077] The crystalline forms of Z1 according to the disclosure herein can be used in combination with one or more other active compound, such as insecticides, fungicides, acaricides, nematicides, plant growth regulating agents, biological agents, herbicides and fertilizers. The preferred crystalline form is the crystalline form A. A preferred combination is at least one of a fungicide and a nematicide. The terms “active compound” and “active ingredient” are used interchangeably throughout this disclosure.

[0078] Such active compounds can be selected from the group consisting of abamectin, acephate, acequinocyl, acetamiprid, acrinathrin, acynonapyr, afidopyropen, alanycarb, aldicarb, allethrin, alpha-cypermethrin, aminopyralid, amitraz, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azocyclotin, azoxystrobin, bendiocarb, benfuracarb, bensultap, benzoximate, benzpyrimoxan, beta-cyfluthrin, beta-cypermethrin, bifenazate, bifenthrin, bioallethrin, bioresmethrin, bistrifluron, broflanilide, bromopropylate, buprofezin, butocarboxim, butoxycarboxim, cadusafos, carbaryl, carbofuran, carbosulfan, carboxin, cartap hydrochloride, chinomethionat, chlorantraniliprole, chlordane, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clofentezine, clopyralid, cloquintocet, clothianidin, copper hydroxide, coumaphos, cyanophos, cyantraniliprole, cyclaniliprole, cyclobutrifluram, cycloprothrin, cycloxaprid, cyenopyrafen, cyflumetofen, cyfluthrin, cyhalothrin, cyhexatin, cymoxanil, cypermethrin, cyphenothrin, cyproflanilide, cyromazine, d-cis-trans-allethrin, DDVP, deltamethrin, demeton-S-methyl, diafenthiuron, diazinon, dichlorvos, dicofol, dicrotophos, difenoconazole, diflovidazin, diflubenzuron, dimethoate, dimethylvinphos, dimpropyridaz, dinotefuran, disulfoton, DNOC, d- trans-allethrin, emamectin, emamectin benzoate, empenthrin, endosulfan, EPN, esfenvalerate, ethaboxam, ethiofencarb, ethion, ethiprole, ethoprophos, etofenprox, famoxadone, famphur, fenamiphos, fenazaquin, fenbuconazole, fenbutatin oxide, fenitrothion, fenmezoditiaz, fenobucarb, fenoxycarb, fenpropathrin, fenpyroximate, fenthion, fenvalerate, fipronil, flazasulfuron, flonicamid, florasulam, fluacrypyrim, fluazaindolizine, flubendiamide, flucycloxuron, flucythrinate, fludioxonil, fluensulfone, flufenoxuron, flumethrin, flumioxazin, fluopyram, fluoxapiprolin, fluoxastrobin, flupyradifurone, flupyrimin, fluroxypyr, fluxametamide, fluxapyroxad, formetanate, fosthiazate, furathiocarb, gamma-cyhalothrin, glyphosate, halauxifen, halfenprox, halofenozide, heptenophos, hexaflumuron, hexythiazox, hydramethylnon, hydroprene, imazamox, imazapyr, imicyafos, imidacloprid, imiprothrin, indazapyroxamet, indoxacarb, inpyrfluxam, ipconazole, isocycloseram, isofenphos, isoflucypram, isoprocarb, isoxathion, kadethrin, kinoprene, lambda-cyhalothrin, lepimectin, lufenuron, malathion, mancozeb, MCPA, mecarbam, mefenoxam, metaflumizone, metalaxyl, metconazole, methamidophos, methenamine, methidathion, methiocarb, methomyl, methoprene, methoxychlor, methoxyfenozide, metolcarb, metsulfuron, mevinphos, milbemectin, monocrotophos, myclobutanil, naled, nicosulfuron, nitrapyrin, novaluron, noviflumuron, omethoate, oxamyl, oxathiapiprolin, oxazosulfyl, oxydemeton-methyl, parathion, parathion- methyl, penflufen, penthiopyrad, permethrin, phenothrin, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, picarbutrazox, picloram, picoxystrobin, pinoxaden, pirimicarb,pirimiphos-methyl, prallethrin, profenofos, propargite, propetamphos, propiconazole, propoxur, propyzamide, prothioconazole, prothiofos, pydiflumetofen, pyflubumide, pymetrozine, pyraclofos, pyraclostrobin, pyrethrum, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyriproxyfen, pyroxasulfone, quinalphos, resmethrin, rimsulfuron, rotenone, sedaxane, silafluofen, spidoxamat, spinetoram, spinosad, spirobudifen, spirodiclofen, spiromesifen, spiropidion, spirotetramat, sulfluramid, sulfotep, sulfoxaflor, tau-fluvalinate, tebuconazole, tebufenozide, tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, terbufos, tetrachlorvinphos, tetradifon, tetramethrin, tetraniliprole, theta-cypermethrin, thiabendazole, thiamethoxam, thiocyclam, thiodicarb, thiofanox, thiometon, thiosultap-sodium, thiram, tiorantraniliprole, tioxazafen, tolfenpyrad, tralkoxydim, tralomethrin, transfluthrin, triazamate, triazophos, trichlorfon, triclopyr, trifloxystrobin, triflumezopyrim, triflumuron, trimethacarb, vamidothion, XMC, xylylcarb, zeta-cypermethrin, and 2,4-D. For the avoidance of doubt each of these pesticides is an active ingredient.

[0079] In one aspect of the mixture compositions disclosed herein, the following is group of preferred mixing partners which can be mixed with crystalline forms of Z1 to expand the use of pesticidal compositions and perform multiple agrochemical functions: one or more active ingredients selected from the group consisting of abamectin, acetamiprid, benzpyrimoxan, bifenthrin, chlorantraniliprole, chlorfenapyr, cyantraniliprole, cyclobutrifluram, ethaboxam, fipronil, flonicamid, flupyradifurone, flupyrimin, fluopyram, fluxametamide, imidacloprid, indoxacarb, inpyrfluxam, ipconazole, isocycloseram, lambda-cyhalothrin, metalaxyl, mefenoxam, methoxyfenozide, oxathiapiprolin, picoxystrobin, pymetrozine, pyriproxyfen, spinetoram, spinosad, spirotetramat, sulfoxaflor, thiamethoxam, and triflumezopyrim.

[0080] In some aspects, the pesticidal compositions comprising crystalline forms of Z1 comprise at least one fungicide selected from the group consisting of azoxystrobin, carboxin, cyanoacetamide oxime, copper hydroxide, cyclobutrifluram, difenoconazole, dithiocarbamate, ethaboxam, fenpicoxamid, florylpicoxamid, fludioxonil, fluopyram, fluoxapiprolin, fluoxastrobin, fluxapyroxad, inpyrfluxam, isoflucypram, ipconazole, mefenoxam, metalaxyl, metarylpicoxamid, methylorubrum populi strain NLS0089, methylorubrum populi strain TS601, metconazole, myclobutanil, oxathiapiprolin, penflufen, picarbutrazox, picoxystrobin, propiconazole, prothioconazole, pydiflumetofen, pyraclostrobin, sedaxane, tebuconazole, thiabendazole, thiram, trifloxystrobin and Vismax (Flg22-Bt peptide) . In some aspects, thepesticidal compositions comprise crystalline form A of Z1 and at least one of the fungicides selected from the above list. And in some aspects, the pesticidal compositions comprise crystalline form B of Z1 and at least one of the fungicides selected from the above list.

[0081] In some aspects, the pesticidal compositions comprising crystalline forms of Z1 comprise at least one nematicide selected from the group consisting of abamectin, Bacillus amyloliquefaciens Strain PTE-4838, Bacillus amyloliquefaciens Strain MBI 600, Bacillus pumilus strain BU F-33, cyclobutrifluram, fluazaindolizine, fluensulfone, oxamyl and tioxazafen. In some aspects, the pesticidal compositions comprise crystalline form A of Z1 and at least one of the nematicides selected from the above list. And in some aspects, the pesticidal compositions comprise crystalline form B of Z1 and at least one of the nematicides selected from the above list.

[0082] The entire disclosure of WO2024102705A1 (Molecules having pesticidal utility and intermediates and processes related thereto) which describes the compound of formula Z1 and other active mixtures, is hereby incorporated by reference in its entirety for all purposes. Accordingly, the present disclosure encompasses agrochemical compositions comprising the disclosed polymorph in combination with one or more additional active agents, regardless of the presence or absence of synergistic, additive, or independent therapeutic effects.

[0083] The polymorph described herein may be formulated in fixed-dose combinations, co- packaged, co-administered, or otherwise delivered with one or more known active agents, including, but not limited to, those described in WO2024102705A1]. Such combinations are considered within the scope of the present disclosure.

[0084] In a particular aspect, disclosed herein is a crystalline form of (Z)-1-(2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl-1H-1,2,4-triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (Z1), acceptable salts, solvates, hydrates, isotopes or tautomers thereof. As used herein, a ‘crystalline form’ refers to a solid- state form characterized by a defined crystal lattice structure, as evidenced by distinctive X-ray diffraction (XRD) peaks and a sharp melting endotherm on DSC curves.

[0085] In certain aspects of the compositions disclosed herein, the weight ratio of crystalline forms of Z1 to the additional active ingredient is selected from the group consisting of 1:125, 1:100, 1:75, 1:50, 1:25, 1:10 and 1:1. In certain other aspects, crystalline forms of Z1 to theadditional active ingredient is selected from the group consisting of 125:1; 100:1; 75:1, 50:1, 25:1, 15:1, 10:1 and 1:1. A skilled artisan may select the values from the above lists, and may create an appropriate range. For example, in certain aspects of the compositions and methods provided herein, the weight ratio of crystalline forms of Z1 to the additional active ingredient is from about 1:125 to about 125:1. In some specific instances, the weight ratio of crystalline forms of Z1 to the additional active ingredient is between 1:100 to 100:1. And in some specific aspects, the weight ratio of crystalline forms of Z1 to the additional active ingredient is 1:25 to 25:1. In some embodiments, the weight ratio of crystalline forms of Z1 to the additional active ingredient is selected from the group consisting of ratios 1:90 to 90:1; 1:80 to 80:1; 1:70 to 70:1; 1:60 to 60:1; 1:50 to 50:1; 1:40 to 40:1: 1:30 to 30:1; 1:20 to 20:1; and 1:10 to 10:1. In some embodiments, the weight ratio of crystalline forms of Z1 to the additional active ingredient is selected from the group consisting of ratios 1:90 to 90:1; 1:80 to 80:1; 1:70 to 70:1; 1:60 to 60:1; 1:50 to 50:1; 1:40 to 40:1: 1:30 to 30:1; 1:20 to 20:1; and 1:10 to 10:1. In some other embodiments, the weight ratio of crystalline forms of Z1 to the additional active ingredient is selected from the group consisting of 1:1; 1:2; 1:3; 1:4;1:5; 1:6; 1:7; 1:8 and 1:9. In some other embodiments, the weight ratio of crystalline forms of Z1 to the additional active ingredient is selected from the group consisting of 1:1; 1:2; 1:3; 1:4;1:5; 1:6; 1:7; 1:8 and 1:9.

[0086] In some aspects, discloses herein a processes to make crystalline forms of Z1. In some particular aspects, disclosed herein are processes to make crystalline form A of Z1. In some other aspects, disclosed herein is a process, where crystalline form A is used as an intermediate. For example, disclosed herein is a process of making a solvent-based formulation, such as an EC formulation, which comprises the step of dissolving crystalline form A in an appropriate solvent.

[0087] The crystalline forms of Z1 are described below by the following examples. They are provided for illustrative purposes only.

[0088] A particular embodiment of a crystalline form of Z1 is crystalline form A. Additionally, this disclosure provides other crystalline forms of Z1 of agrochemical interest. There are illustrated below:

[0089] Crystalline form B2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value 0.20 0.20 7 1 9 82Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value 020 020 2 5 7 1 1

[0091] Crystalline form D 2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value 2 5 5

[0092] Crystalline form E 2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value 8 5 9 9

[0093] Crystalline form F 2Ɵ + 0.20 d-value 2Ɵ + 0.20 d-value 2Ɵ + d-value 2Ɵ + d-value 0.20 0.20 1 2 6 2 5, peaks at wavenumbers (cm-1, + 0.20%) 3307, 1724, 1672, 1618, 1541, 1516, 1501, 1485, 1450, 1418, 1364, 1303, 1251, 1216, 1153, 1060, 1040, 1016, 982, 954, 878, 851, 820, 773, 752, 733, 662, 593, 565, 525, 498. In a further embodiment, the crystalline form B of Z1 has an IR spectrum comprising peaks at wavelengths essentially the same as shown in Figure 7.

[0095] In another aspect, the crystalline form B of Z1 has a Raman spectrum exhibiting characteristic peaks at wavenumbers (cm-1, + 0.20%) 1729, 1672, 1625, 1567, 1518, 1490, 1453, 1395, 1387, 1306, 1231, 1176, 1134, 1087, 991, 842, 824, 672, 635, 501, 143. In a further embodiment, the crystalline form B of Z1 has a Raman spectrum comprising peaks at wavelengths essentially the same as shown in Figure 8.

[0096] In some embodiments, the crystalline forms of Z1 can be present in certain particle sizes. For example, in some aspects, the particle size can be smaller than or equal to 15 µM. In other examples, the particle size can be smaller than or equal to 10 µM. In other examples. the particle size can be smaller than or equal to 8 µM. In some examples, the particle size can be smaller than or equal to 6 µM. In some other examples, the particle size can be smaller than or equal to 5 µM. In some examples, the particle size can be smaller than or equal to 4 µM. In other examples, the particle size can be smaller than or equal to 3 µM. In other examples, the particle size can be smaller than or equal to 1 µM. In some other examples, the particle size can be smaller than or equal to 1 µM and greater than or equal to 0.5 µM.

[0097] In light of the above, the following details are additionally provided:d1. A crystalline form of (Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl-1H-1,2,4-triazol-3- yl)phenyl)-3-(3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2- ylidene)urea (Z1), and acceptable salts, solvates, hydrates, isotopes or tautomers thereof. d2. A crystalline form of (Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl-1H-1,2,4-triazol-3- yl)phenyl)-3-(3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2- ylidene)urea (Z1) selected from the group consisting of: a. Crystalline form A having the X-ray powder diffractogram substantially as shown in Figure 2; b. Crystalline form B having the X-ray powder diffractogram substantially as shown in Figure 6; c. Crystalline form C having the X-ray powder diffractogram substantially as shown in Figure 9; d. Crystalline form D having the X-ray powder diffractogram substantially as shown in Figure 10; e. Crystalline form E having the X-ray powder diffractogram substantially as shown in Figure 11; and f. Crystalline form F having the X-ray powder diffractogram substantially as shown in Figure 12. d3. The crystalline form of Z1 according to d1-d2, comprising at least two of the following reflexes in any combination: 2Ɵ + 2Ɵ + 2Ɵ + 2Ɵ +13.94 18.99 22.18 14.16 19.64 22.48 d4. The crystalline form of Z1 according to d1 – d3, comprising at least three of the following reflexes in any combination: 2Ɵ + 0.20 2Ɵ + 0.20 495 1964d5. The crystalline form of Z1 according to any of the d1-d4, having a melting point of 185 ℃ - 195 ℃. d6. The crystalline form of Z1 according to any of the d1-d5, which is crystalline form A having an X-ray diffraction pattern substantially as shown in Figure 2 and / or having an IR spectrum substantially as shown in Figure 3 and / or having a Raman spectrum substantially as shown in Figure 4 and / or having a DSC curve substantially as shown in Figure 5 and / or having a melting point of 185 ℃ - 195 ℃. d7. The crystalline form of Z1 according to d1, which is crystalline form B having an X-ray diffraction pattern substantially as shown in Figure 6 and / or having an IR spectrum substantially as shown in Figure 7 and / or having a Raman spectrum substantially as shown in Figure 8. d8. Crystalline form C having the X-ray powder diffractogram substantially as shown in Figure 9. d9. Crystalline form D having the X-ray powder diffractogram substantially as shown in Figure 10.d10. Crystalline form E having the X-ray powder diffractogram substantially as shown in Figure 11. d11. Crystalline form F having the X-ray powder diffractogram substantially as shown in Figure 12. d12. A process for preparing the crystalline form of Z1 according to any of the d1 – d11, comprising the steps of: i) preparing a solvent matrix comprising one or more solvents and Z1; ii) transforming Z1 into a crystalline form of Z1; and iii) isolating the crystalline form of Z1. d13. The process according to d12, wherein the solid Z1 used in step i) is amorphous form of Z1 or a crystalline form of Z1. d14. The process according to any of the d12 – d13, wherein the solvent matrix comprises a solvent selected from alcohols, ketones, esters, ethers, hydrocarbons, aprotic polar solvents, and water. d15. The process according to any of the d12 – d14, wherein the solvent matrix comprises one or more solvents selected from the group consisting of methanol, ethanol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, toluene, xylenes, dichloromethane, and water. d16. The process according to any of the d12 - d15, wherein step ii) comprises a) concentrating the solution and / or b) cooling and / or c) adding a less soluble solvent and / or d) adding crystalline seed of Z1. d17. The process according to any of the d12 - d15, wherein the process is for preparation of the crystalline form A of Z1, comprising the steps of: i) preparing a solvent matrix comprising solid Z1 and one or more solvents, wherein the solvents are selected from the group consisting of toluene, xylenes, isopropyl alcohol, dichloromethane, ethyl acetate, methyl ethyl ketone, anisole, heptane, methanol, acetonitrile, and water; ii) transforming Z1 into the crystalline form A of Z1; and iii) isolating the crystalline form A of Z1.d18. A process for preparation of crystalline form A of Z1, comprising the steps of: a) conducting the reaction process illustrated in Scheme 3 to obtain Z1; and b) isolating the crystalline form A from reaction medium. d19. A pesticidal composition comprising the crystalline form A of Z1 according to d1-d6 and at least one auxiliary. d20. The composition according to any of the d1 - d6, wherein the composition is formulated as a suspension concentrate (SC), an oil-based suspension concentrate (OD), a soluble concentrate (SC), flowable suspension (FS), water soluble granules (SG), a dispersible concentrate (DC), an emulsifiable concentrate (EC), an emulsion seed dressing, a suspension seed dressing, a seed coating, granules (GR), microgranules (MG), a suspoemulsion (SE), or water dispersible granules (WG). d21. The composition according to any of the d19 – d20, wherein the composition comprises crystalline form A of Z1 in an amount less than 40% by weight. d23. A method of control of a pest infestation comprising the step of using the composition according to any of the d19 – d21 in or near a locus of the pest infestation. d24. The method according to d23, wherein the pest is selected from Phyla Arthropoda, Mollusca and Nematoda. d25. The method according to any of the d23 – d24 for the control of a pest infestation in alfalfa, almonds, apples, barley, beans, canola, corn, cotton, crucifers, flowers, fodder species (Rye Grass, Sudan Grass, Tall Fescue, Kentucky Blue Grass, and Clover), fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugarbeets, sunflowers, tobacco, tomatoes, and wheat. d26. A method of controlling a pest infestation of a non-human animal selected from the group consisting of livestock, farm animals, domesticated animals, and fish comprising the step of application of the composition according to any of the d19 – d20 to the locus of the pest infestation and / or to medium that the pest inhabits. Formulations

[0098] A pesticide is many times not suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide may be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water- soluble liquids, water-dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions.

[0099] Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, water-dispersible granules, liquids usually known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water-dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 5% to about 90% by weight. The carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phenols.

[0100] Suspension concentrate (SC) technology has been applied to the formulation of many solid crystalline pesticides since the early 1970s. Pesticide particles may be suspended in an oil phase (referred to as oil dispersions), but it is much more usual for suspension concentrates to be dispersions in a water phase. (Mulqueen P. Recent advances in agrochemical formulation. Adv Colloid Interface Sci.2003 Dec 1; 106:83-107. and Knowles, D. A., “Chemistry and Technology of Agrochemical Formulations.” (1998) 47-49; and see for example, US patent 4,071,617.) In general, SC pesticidal formulations are formulations that have generally insoluble solid active ingredients suspended in water with the aid of dispersants and wetting agents. They may have additional ingredients such as one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners, in order to make better products for use in agriculture and other uses, and for in a variety of environments (such as, field, laboratory, and different climate conditions).Such ingredients are known in the art and used in a variety of combinations and amounts in an SC formulation. For example, see WO 2000 / 008931; WO 2009 / 007344; WO 2014 / 047934; WO 2017 / 125010; WO 2017 / 202684; WO 2019 / 072602; WO2019076744; WO 2019 / 123186; WO 2019 / 197634; and WO 2021 / 127126. The method of the preparation of suspension concentrate formulations is known in the art and can be produced by known methods familiar to those skilled in the art.

[0101] Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter (g / L) of liquid dissolved in a carrier that is either a water-miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and non-ionic surfactants.

[0102] Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer. The pesticide in suspension might be microencapsulated in plastic polymer.

[0103] Oil dispersions (OD) comprise suspensions of organic solvent-insoluble pesticides finely dispersed in a mixture of organic solvent and emulsifiers at a concentration in the range from about 2% to about 50% by weight. One or more pesticide might be dissolved in the organic solvent. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils. Suitable emulsifiers for oil dispersions are selected from conventional anionic and non-ionic surfactants. Thickeners or gelling agents are added in the formulation of oil dispersionsto modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets.

[0104] Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier, which has been pre-formed to the appropriate particle size, in the range of from about 0.5 millimeters (mm) to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and molecule, and then crushing and drying to obtain the desired granular particle size. Another form of granules is a water-emulsifiable granule (EG). It is a formulation consisting of granules to be applied as a conventional oil-in-water emulsion of the active ingredient(s), either solubilized or diluted in an organic solvent, after disintegration and dissolution in water. Water-emulsifiable granules comprise one or several active ingredient(s), either solubilized or diluted in a suitable organic solvent that is (are) absorbed in a water-soluble polymeric shell or some other type of soluble or insoluble matrix.

[0105] Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. Dusts may be applied as a seed dressing or as a foliage application with a dust blower machine.

[0106] It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.

[0107] Pesticides can also be applied in the form of an aerosol composition. In such compositions, the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.

[0108] Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait, they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. Baits may be used in pest harborages.

[0109] Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity ofthe fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest's respiratory system or being absorbed through the pest's cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings, or in special chambers.

[0110] Pesticides may be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering, the chemistry of the polymer or by changing factors in the processing, microcapsules may be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product. The microcapsules might be formulated as suspension concentrates or water dispersible granules.

[0111] Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution; oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.

[0112] Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one molecule which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilic surface-active agent, (2) at least one non-ionic hydrophilic surface-active agent, and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers.

[0113] In one embodiment, the present disclosure provides a water-dispersible granule (WG) formulation comprising a crystalline form of a compound of Formula Z1. The WG formulation comprises: (a) from about 5% to about 80% by weight of the crystalline compound of Formula Z1; (b) from about 5% to about 30% by weight of one or more dispersing agents; (c) from about 1% to about 20% by weight of one or more wetting agents; and (d) from about 5% to about 70% by weight of one or more water-soluble or water-dispersible fillers. The formulation is produced by a low-moisture granulation process, such as extrusion granulation or high-shear mixing,followed by drying to yield free-flowing, dust-free granules that readily disperse in water with minimal agitation. The crystalline form of the compound of Formula Z retains its physical integrity within the granules, providing improved handling, storage stability, and bioavailability upon dispersion. The WG formulation is particularly suitable for agricultural or industrial applications where rapid wetting, uniform dispersion, and minimized dusting are desirable. Other formulation components

[0114] Generally, when any one or more of crystalline forms of Z1 is used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.

[0115] A wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate, sodium dioctyl sulfosuccinate, alkyl phenol ethoxylates, and aliphatic alcohol ethoxylates.

[0100] A dispersing agent is a substance that adsorbs onto the surface of particles, helps to preserve the state of dispersion of the particles, and prevents them from reaggregating. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates, and water-dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium-naphthalene-sulfonate-formaldehyde-condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensates and EO-PO (ethylene oxide-propylene oxide) block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of very high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic 'backbones' and a large number of ethylene oxide chains forming the 'teeth' of a 'comb' surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces.

[0101] Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates, sodium naphthalene sulfonate formaldehyde condensates, tristritylphenol- ethoxylate-phosphate-esters, aliphatic alcohol ethoxylates, alkyl ethoxylates, EO-PO block copolymers, and graft copolymers.

[0102] An emulsifying agent is a substance that stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent, the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain an alkylphenol or an aliphatic alcohol with twelve or more ethylene oxide units and the oil- soluble calcium salt of dodecyl benzenesulfonic acid. A range of hydrophile-lipophilic balance ("HLB") values from about 8 to about 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.

[0103] A solubilizing agent is a surfactant that will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.

[0104] Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement depend generally onthe nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates, linear aliphatic alcohol ethoxylates, and aliphatic amine ethoxylates.

[0105] A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules, and water-dispersible granules.

[0106] Organic solvents are used mainly in the formulation of emulsifiable concentrates, oil- in-water emulsions, suspoemulsions, oil dispersions, and ultra-low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The second main group (and the most common) comprises the aromatic solvents such as xylenes and higher molecular weight fractions of C9and C10aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.

[0107] Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, oil dispersions, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets. Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate and oil dispersion formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides in water-based suspension concentrates have been used as thickening-gelling agents for many years, the types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum, locust bean gum, carrageenan, alginates, methyl cellulose, sodium carboxymethyl cellulose (SCMC), and hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol, and polyethylene oxide. Another good anti-settling agent is xanthan gum.

[0108] Microorganisms can cause spoilage of formulated products. Therefore, preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt, sorbic acid and its sodium or potassium salts, benzoic acid and its sodium salt, p-hydroxybenzoic acid sodium salt, methyl p-hydroxybenzoate, and l,2-benzisothiazolin-3-one (BIT).

[0109] The presence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non- silicones. Silicones are usually aqueous emulsions of dimethyl polysiloxane, while the non- silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-water interface.

[0110] "Green" agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and / or sustainable sources, e.g., plant and animal sources. Specific examples are: vegetable oils, seed oils, and esters thereof. Applications

[0111] Any one or more of crystalline forms of Z1 may be applied to any locus. Particular loci to apply such molecules include loci where alfalfa, almonds, apples, barley, beans, canola, corn, cotton, crucifers, flowers, fodder species (Rye Grass, Sudan Grass, Tall Fescue, Kentucky Blue Grass, and Clover), fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugarbeets, sunflowers, tobacco, tomatoes, wheat (for example, Hard Red Winter Wheat, Soft Red Winter Wheat, White Winter Wheat, Hard Red Spring Wheat, and Durum Spring Wheat), and other valuable crops are growing or the seeds thereof are going to be planted.

[0112] Any one or more of crystalline forms of Z1 may also be applied where plants, such as crops, are growing and where there are low levels (even no actual presence) of pests that can commercially damage such plants. Applying such molecules in such locus is to benefit the plantsbeing grown in such locus. Such benefits, may include, but are not limited to: helping the plant grow a better root system; helping the plant better withstand stressful growing conditions; improving the health of a plant; improving the yield of a plant (e.g. increased biomass and / or increased content of valuable ingredients); improving the vigor of a plant (e.g. improved plant growth and / or greener leaves); improving the quality of a plant (e.g. improved content or composition of certain ingredients); and improving the tolerance to abiotic and / or biotic stress of the plant.

[0113] Any one or more of crystalline forms of Z1 may be applied with ammonium sulfate when growing various plants as this may provide additional benefits.

[0114] Any one or more of crystalline forms of Z1 may be applied on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis (for example, CrylAb, CrylAc, CrylFa, CrylA.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Abl / Cry35Abl), other insecticidal toxins, or those expressing herbicide tolerance, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide tolerance, nutrition- enhancement, or any other beneficial traits.

[0115] Any one or more of crystalline forms of Z1 may be applied to the foliar and / or fruiting portions of plants to control pests. Either such crystalline forms of Z1 will come in direct contact with the pest, or the pest will consume such crystalline forms of Z1 when eating the plant or while extracting sap or other nutrients from the plant.

[0116] Any one or more of crystalline forms of Z1 may also be applied to the soil, and when applied in this manner, root and stem feeding pests may be controlled. The roots may absorb such molecules thereby taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.

[0117] Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying a locus) any one or more of crystalline forms of Z1 to a different portion of the plant. For example, control of foliar-feeding insects may be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.

[0118] Any one or more of crystalline forms of Z1 may be used with baits. Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with, and / or be attracted to the bait. Baits can also be applied to a surface of a building, (horizontal,vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies can come into contact with, and / or be attracted to, the bait.

[0119] Any one or more of crystalline forms of Z1 may be encapsulated inside or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).

[0120] Any one or more of crystalline forms of Z1 may be applied to eggs of pests. Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of such molecules may be desirable to control newly emerged larvae.

[0121] Any one or more of crystalline forms of Z1 may be applied as seed treatments. Seed treatments may be applied to all types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide tolerance, such as "Roundup Ready" seed, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide tolerance, nutrition- enhancement, drought tolerance, or any other beneficial traits, Furthermore, such seed treatments with any one or more of crystalline forms of Z1 may further enhance the ability of a plant to withstand stressful growing conditions better. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, amounts of about 1 gram of such polymorph to about 500 grams per 100,000 seeds are expected to provide good benefits; amounts from about 10 grams to about 100 grams per 100,000 seeds are expected to provide better benefits; and amounts from about 25 grams to about 75 grams per 100,000 seeds are expected to provide even better benefits. Any one or more of crystalline forms of Z1 may be applied with one or more active ingredients in a soil amendment.

[0122] Any one or more of crystalline forms of Z1 may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human-animal keeping. Such molecules may be applied by oral administration in the form of, for example, tablets, capsules, drinks, and granules; by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting; and by parenteral administration in the form of, for example, an injection.

[0123] Any one or more of crystalline forms of Z1 may also be employed advantageously in livestock keeping, for example, cattle, chickens, geese, goats, pigs, sheep, and turkeys. They mayalso be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be flies, fleas, and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.

[0124] Any one or more of crystalline forms of Z1 may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above. Any one or more of crystalline forms of Z1 may also be employed in therapeutic methods for human health care, such methods include, but are not limited to, oral administration in the form of, for example, tablets, capsules, drinks, and granules, and by dermal application.

[0125] Crystalline forms of Z1 may also be applied to invasive pests. Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. Such polymorphs may also be used on such new invasive species to control them in such new environments.

[0126] X-ray diffractograms were obtained using multiple powder diffractometers at 25 ℃ as follows: The PXRD diffractogram in Figure 2 was collected on a Bruker D8 diffractometer using Cu K α radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane. The details of the data collection method are: Angular range: 2 to 42° 2θ, Step size: 0.05° 2θ, Collection time: 0.5 s / step (total collection time: 6.40 min).

[0127] PXRD diffractograms in Figures 9, 10 and 11 were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam. A PIXcel-3D detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Soller slits. Samples were prepared and analyzed in either a metal or Millipore 96 well- plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 – 2 mg) were used as received. The scan modefor the metal plate used the gonio scan axis, whereas a 2θ scan was utilized for the Millipore plate. Data were collected from 2.5 to 32.0° 2θ with a step size of 0.0130° 2θ and collection time of 12.75 s / step (total collection time of 2.07 min).

[0128] PXRD diffractograms in Figures 1, 13, and 14 were collected on a Bruker D2 Phaser using Cu Kα radiation (30 kV, 10 mA) and a θ-θ goniometer. The incident beam passes through a 0.2mm divergence slit. A 1 mm air scatter screen is placed above the sample and the beam stop is removed. The diffracted beam passes through a 3mm air scatter slit, 2.5° Soller slits, and a 0.5 Kβ filter followed by a Lynxeye SSD160 Detector with a PSD opening of 1.5°. Samples were analyzed under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane at 15 RPM. Data were collected from 3 to 40° 2θ with a step size of 0.03° 2θ and collection time of 0.5 s / step (total collection time: 10.6 min). PXRD diffractograms in Figures 6 and 12 were collected on a Bruker D2 Phaser using Cu Kα radiation (30 kV, 10 mA) and a θ-θ goniometer. The incident beam passes through a 0.6 mm divergence slit. The diffracted beam passes through an 8 mm air scatter slit and a Kβ filter followed by a Lynxeye Detector with a PSD opening of 5°. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane at 5 RPM. Data were collected from 3 to 40° 2θ with a step size of 0.012° 2θ and collection time of 0.44 s / step (total collection time: 25 min).

[0129] All IR spectra were obtained using the following acquisition parameters: Infrared spectra of neat materials were acquired with a PerkinElmer Spectrum Two FTIR spectrometer and the standard diamond attenuated total reflectance (ATR) accessory, at a resolution of 4 cm⁻¹. Sixteen scans (47-second acquisition time) were collected for each spectrum. The ATR accessory was equipped with a single-bounce diamond ATR crystal. Signal from the solids was amplified using the “anvil up – anvil down” method: Anvil up: a scan of the wet solids was taken with no pressure on the diamond crystal; Anvil down: a second scan was taken while the anvil applies pressure to the sample. The first scan gets much of its signal from the liquid components because liquids make very good contact with the diamond crystal. The second scan pins solids against the crystal and squeezes out much of the liquid. Subtracting these spectra produces agood approximation of the spectrum of the pure solids without performing a sample cleanup. This method produces a spectrum of all solids if there are more than one.

[0130] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50- position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C / min from 25 °C to 200 °C, 25 °C to 225 °C, 25 °C to 260 °C, 25 °C to 270 °C and 25 °C to 280 °C. A purge of dry nitrogen at 50 mL / min was maintained over the sample.

[0131] TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25- position auto-sampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C / min from ambient temperature to 350 °C. A nitrogen purge at 25 mL / min was maintained over the sample.

[0132] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. AcOH = acetic acid aq. = aqueous Boc = tert-butyloxycarbonyl Boc2O = di-tert-butyl dicarbonate DCM = dichloromethane DMF = dimethylformamide DMSO = dimethyl sulfoxide DSC = differential scanning calorimetry equiv. = equivalent EtOAc = ethyl acetate EtOH = ethanol g = gram h = hours HCl = hydrochloric acidHPLC = high-performance liquid chromatography IPA = isopropanol iPrOAc = isopropyl acetate LCMS = liquid chromatography mass spectrometry M = molar MeCN = acetonitrile MEK = methyl ethyl ketone MeOH = methanol mg = milligrams min = minutes mL = milliliters mmol = millimols mp = melting point MS = mass spectrometry m / z = mass to charge ratio N = normal NaCl = sodium chloride Na2CO3= sodium carbonate NaHCO3 = sodium bicarbonate NMR = nuclear magnetic resonance NaOH = sodium hydroxide Na2SO4= sodium sulfate o / n = overnightPhth = phthalimide RT = room temperature t-BuOH = tert-butanol THF = tetrahydrofuran TLC = thin layer chromatography UV = ultraviolet wt % = weight percent μM = micromolar

[0133] EXAMPLES

[0134] Example 1. Synthesis of 2- fluoro-4-(1-(4-trifluoromethoxy)phenyl)-1H-1,2,4- triazol-3-yl)aniline (X1) F F F NH2NPhth NPhthA jacketed reactor equipped with an overhead stirrer, nitrogen inlet, and temperature probe was charged with 4-amino-3-fluorobenzonitrile (5.81 g, 50.0 mmol) in acetic acid (50.0 mL, 1.0 M), which was heated to 90 °C. Phthalic anhydride (7.41 g, 50.0 mmol) was then added and allowed to continue stirring overnight. After stirring overnight, the thick solution was allowed to cool to room temperature and poured into water (100 mL) and allowed to sit for five minutes. A white solid formed and was collected by filtration and dried in a vacuum oven overnight to produce the desired product as a white solid, 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzonitrile (11.225 g, 42.2 mmol, 84% yield):1H NMR (400 MHz, Chloroform-d) δ 8.00 (dd, J = 5.5, 3.1 Hz, 2H), 7.85 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 – 7.45 (m, 3H);19F NMR (376 MHz, Chloroform-d) δ - 113.51.

[0135] A vial equipped with a magnetic stir bar, reflux condenser, and base scrubber was charged with 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzonitrile (1.5 g, 5.6 mmol), dichloromethane (8.6 mL, 0.16 M), and ethanol (8.6 mL, 0.16 M). The reaction was placed in an ice-water bath and acetyl chloride (8.0 mL, 113 mmol, 20 equiv.) was then added dropwise over 45 minutes via syringe drive. The reaction was allowed to continue overnight and warm to room temperature. Upon full conversion the reaction mixture was diluted with heptanes (20 mL) andsolids were collected by filtration to give an off-white solid that was dried in a vacuum oven overnight, yielding the desired product, ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (1.9 g, 5.4 mmol, 96% yield):1H NMR (400 MHz, CDCl3) δ 8.61 – 8.50 (m, 1H), 8.32 – 8.22 (m, 1H), 8.06 – 7.93 (m, 2H), 7.90 – 7.80 (m, 2H), 7.71 – 7.58 (m, 1H), 5.00 (q, J = 7.0 Hz, 2H), 1.66 (t, J = 7.0 Hz, 3H;19F NMR (376 MHz, Chloroform-d) δ -113.35.

[0136] A jacketed reactor equipped with a stir rod, temperature probe, and nitrogen inlet was charged with ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (3 g, 8.6 mmol) and pyridine (34.4 mL, 0.25 M). The mixture was cooled to 2 °C, and (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride was then added and allowed to stir for 1 hour, heated to 25 °C over 30 minutes, and further allowed to stir for an additional three hours. Triethylorthoformate (2.15 mL, 12.9 mmol, 1.5 equiv.) was then added and the reaction was heated to 100 °C and allowed to continue stirring overnight. The reaction was cooled to room temperature, diluted with water (30 mL), solids were collected by filtration, and washed with additional water to give a light yellow / off-white solid that was dried in a vacuum oven overnight, yielding the desired product, 2-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3- yl)phenyl)isoindoline-1,3-dione (3.88 g, 8.28 mmol, 96% yield):1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.17 – 8.08 (m, 2H), 8.00 (dd, J = 5.5, 3.1 Hz, 2H), 7.89 – 7.75 (m, 4H), 7.49 (t, J = 7.7 Hz, 1H), 7.46 – 7.35 (m, 2H);19F NMR (376 MHz, Chloroform-d) δ -58.00, -117.73.

[0137] A jacketed reactor equipped with a stir rod, temperature probe, and nitrogen inlet was charged with 2-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3- yl)phenyl)isoindoline-1,3-dione (2 g, 4.3 mmol) and ethanol (43 mL, 0.1 M). The reaction was heated to 70 °C, hydrazine hydrate (1.5 mL, 35 wt.% solution, 2.5 equiv.) was then added, and the reaction was allowed to continue for three hours. After full conversion was observed, the reaction was cooled to room temperature, diluted with a potassium carbonate solution (20 wt.%, 20 mL), and extracted with EtOAc (75 mL x 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give the desired product as an off-white solid, 2- fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (X1, 1.6 g, 4.3 mmol, 90% purity, 99% yield):1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 7.89 – 7.69 (m, 4H), 7.47 – 7.33 (m, 2H), 6.85 (t, J = 8.6 Hz, 1H), 3.93 (br, 2H);19F NMR (376 MHz, Chloroform-d) δ -58.02, -135.33; ESIMS m / z 339.1 ([M+H]+).

[0138] Example 2. Synthesis of 2-chloro-N-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y1) NH2NHBoc NH2Scheme 2

[0139] A 5 L reactor was fit with a nitrogen inlet, vacuum port, condenser with collection flask, overhead stir rod, thermocouple, and pump feed tube. The reactor was charged with m- toluidine (433.3 g) and n-heptane (1,621 g). The reactor was sparged with nitrogen for 20 min and brought to an internal temperature of 55 °C. A separate vessel was charged with Boc2O (882.6 g) and n-heptane (214 g). The solution of Boc2O was pumped into the reactor over a period of 180 min. After the addition of Boc2O was complete, the bottle and pump line was rinsed with n-heptane (41 g). After an additional 30 min, the temperature was set to 80 °C. Once the temperature had stabilized, the pressure in the reactor was reduced under vacuum to begin removing solvent via a series of distillation operations. After the bulk solvent was removed, n- heptane (825 g) was added to the reactor and a subsequent distillation operation was conducted to remove t-BuOH. After distillation, the reactor was rapidly cooled to an internal temperature of 35 °C and the solution was diluted to an approximate concentration of 25 w / w% product in n- heptane (1,327 g of additional n-heptane were added). The internal temperature was then adjusted to 2 °C. When the internal temperature reached ~30 °C, the crystallization was seeded (2.5 g product). After the temperature was held at 2 °C for 6 h, the reactor was drained into a vacuum filter. The filtrate was used to rinse the reactor. The wet filter cake was dried under staticvacuum and the collected solid was transferred to drying dishes. The solid was dried in a vacuum oven at 50 °C for 48 h. This afforded tert-butyl-m-tolylcarbamate (725 g of material less the 2.5 g seed weight = 722 g, 86%):1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 2.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.09 (dd, J = 8.0, 2.2 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.49 (s, 1H), 2.31 (s, 3H), 1.51 (s, 9H);13C NMR (126 MHz, CDCl3) δ 152.85, 138.90, 138.30, 128.78, 123.84, 119.18, 115.64, 80.40, 28.38, 21.53; ESIMS m / z 152.0 ([M+H-tBu]+).

[0140] A 1 L reactor was equipped with nitrogen inlet, mechanical stirrer, thermocouple, septa, and sealed under a positive pressure of nitrogen. The vessel was charged with sec-butyl lithium (260 mL, 1.4 M in cyclohexane, 364 mmol, 2.5 equiv). Mechanical stirring was set to 300 RPM. The vessel was cooled to an internal temperature of –28 °C. A solution of the substrate was prepared by charging a 250 mL flask with tert-butyl m-tolylcarbamate (30 g, 144.6 mmol), which was then dissolved into THF (15 mL, 184.5 mmol, 1.275 equiv) and tetramethylethylenediamine (TMEDA, 22 mL 144.6 mmol, 1.0 equiv). The solution of substrate was added dropwise to the reactor over 30 min. The internal temperature was maintained below –20 °C over the course of the addition. After an additional 60 min, DMF (23 mL, 289 mmol, 2 equiv) was added dropwise over 15 min. The internal temperature was maintained below –20 °C over the course of the addition. The reaction was quenched with 150 mL of water and the phases were separated. The organic layer was washed with another 100 mL of water and the phases were separated. The organic phase was distilled under vacuum to remove cyclohexane. Isopropyl alcohol was added and the mixture was distilled to remove residual cyclohexane and afford a solution of tert-butyl (2-formyl-5-methylphenyl)carbamate (~140 mmol) in 150 mL of IPA.

[0141] A 250 mL cylindrical jacketed reactor containing ~140 mmol of tert-butyl (2-formyl- 5-methylphenyl)carbamate in 150 mL of IPA was cooled to ~10 °C. To the reaction was added 2.8 g of solid NaBH4. The reaction mass was then heated to an external set temp of 20 °C. After monitoring by HPLC, the reaction was quenched with 24 mL AcOH and 50 mL water. The reaction mass was stirred for 5 min and then 80 mL toluene were added. To the reaction mass was added more water (20 mL) and the layers were separated. The organic layer was distilled and 60 mL of PhMe was added to afford a solution of tert-butyl (2-(hydroxymethyl)-5- methylphenyl)carbamate (~140 mmol) in 150 mL of toluene.

[0142] A 250 mL jacketed reactor containing tert-butyl (2-(hydroxymethyl)-5- methylphenyl)carbamate (~140 mmol) in toluene (150 mL) was agitated. 120 mL of 45 wt.%KOH solution was added. The reaction was heated at 95 °C overnight. After stirring overnight, the reaction mass was cooled to 75 °C and then slowly cooled to -8 °C. The solids were collected via vacuum filtration and washed with toluene (100-125 mL) to produce the (2-amino- 4-methylphenyl)methanol as an off-white solid (11.4 g, 57% yield over three steps) upon drying overnight in a vacuum oven:1H NMR (500 MHz, DMSO-d6) δ 6.90 (d, J = 7.5 Hz, 1H), 6.43 (d, J = 1.7 Hz, 1H), 6.32 (dd, J = 7.5, 1.7 Hz, 1H), 4.91 (d, J = 4.6 Hz, 1H), 4.81 (s, 2H), 4.33 (d, J = 4.1 Hz, 2H), 2.14 (s, 3H);13C NMR (126 MHz, DMSO-d6) δ 146.77, 137.06, 128.37, 123.13, 117.09, 115.68, 61.55, 21.42; ESIMS m / z ([M-OH]+).

[0143] Methanesulfonic acid (11.83 mL, 182 mmol) was added to (2-amino-4- methylphenyl)methanol (5 g, 36.4 mmol) in trifluoroethanol (65 mL) at 40 °C. The reaction was stirred at 40 °C for 24 hours to afford the methanesulfonic acid salt of 5-methyl-2-((2,2,2- trifluoroethoxy)methyl)aniline.

[0144] The reaction mixture was then cooled to RT and transferred to a 500 mL flask and concentrated on the rotary evaporator. Isopropyl acetate (109 mL) was added, and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (4.09 mL, 51.0 mmol) was then added dropwise followed by the dropwise addition of aq.2 N sodium hydroxide (120 mL, 241 mmol). The reaction was allowed to stir in the ice bath for ~15 minutes. The layers were separated. The organic layer was washed with sat NaHCO3(100 mL). The reaction mixture was concentrated to ~50 wt.% solution and heptane was added to make ~1:4 w / w iPrOAc / Heptane solution at ~5 wt.%. The mixture was seeded at RT, cooled to 0 °C for 2 hours and filtered. The wet cake was washed with heptane to afford the desired product as an off-white solid (8.71 g, 81% yield) upon drying:1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.94 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 4.70 (s, 2H), 4.20 (s, 2H), 3.84 (q, J = 8.6 Hz, 2H), 2.38 (s, 3H);19F NMR (376 MHz, CDCl3) δ -73.57.

[0145] Example 3: Synthesis and isolation of amorphous Z1 N N3Z1

[0146] To X1 (100 mg, 0.30 mmol) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (91 mg, 0.36 mmol) in DCM (1.0 mL) was added pyridine (0.029 mL, 0.36 mmol) and the reaction was stirred at 23 °C for 30 min. Y1a (prepared as in U.S. Patent Application Publication 2014 / 0274688 A1; 94 mg, 0.30 mmol), sodium carbonate (199 mg, 2.37 mmol) and water (1.0 mL) were added sequentially, and the reaction was allowed to continue stirring at RT for 1 hr. The reaction was filtered through a phase separator, rinsing with dichloromethane. The filtrate was concentrated onto silica. Purification via flash chromatography (silica; Ethyl Acetate:Hexanes) yielded Z1 (167 mg, 81%) as an off-white, amorphous foam.

[0147] Example 4: Synthesis and isolation of Z1-Form A N F3CO NOS3Cl S HN thiocyanateHNNN F3CO NN O S

[0148] Example 4a: A round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and reflux condenser was charged with 2-chloro-N-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y1, 1.5 g, 5.1 mmol, 1 equiv), KSCN (0.69 g, 7.1 mmol, 1.4 equiv), K2CO3(35 mg, 0.25 mmol, 0.05 equiv), and EtOAc (7.5 mL, 5 V). The reaction mixture was heated at 60 °C for 19 hr. The reaction mixture was washed with water (10 mL) and 10% NaCl (10 mL). Solvent exchange from EtOAc to MeCN provided 2-imino-3-(5- methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a) as a 35.9 wt.% solution in MeCN (96% yield). The MeCN solution of 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a) was used directly in the final coupling step.

[0149] A flask equipped with a nitrogen inlet and mechanical stir was charged with 2-fluoro- 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (X1, 677 mg, 1 equiv., 2.00 mmol), di(1H-1,2,4-triazol-1-yl)methanone (383 mg, 90% Wt, 1.05 Eq, 2.10 mmol) and acetonitrile (12.0 mL) and the mixture was stirred at 29-30 °C overnight.2-Imino-3-(5-methyl-2- ((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a, 1.95 g, 35.9% Wt, 1.1 Eq, 2.20 mmol) in MeCN was added to the reaction mixture, which was heated at 40 °C overnight.

[0150] After the reaction was complete as judged by HPLC analysis, the reaction mixture was cooled to RT, then 15 mL of water was added and allowed from a crystalline product. The suspension was stirred overnight at RT. After filtration, the cake was washed with 15 mL of MeCN:water (1:2), water (10 mL) and MeOH (3 mL). The cake was dried in oven at 50 °C under vacuum to afford the product, (Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4- triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2- ylidene)urea (Z1-Form A, 1.27 g, 1.86 mmol, 93.0%):1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.47 (t, J = 8.4 Hz, 1H), 7.96 (dd, J = 8.6, 1.8 Hz, 1H), 7.88 (dd, J = 12.0, 1.9 Hz, 1H), 7.86 – 7.73 (m, 2H), 7.49 (d, J = 3.1 Hz, 1H), 7.45 – 7.29 (m, 4H), 7.04 (d, J = 1.8 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 3.95 (d, J = 2.7 Hz, 2H), 3.83 – 3.59 (m, 2H), 2.44 (s, 3H);19F NMR (376 MHz, Chloroform-d) δ 58.02, -73.78, -131.31; PXRD matched that of Form A.

[0151] Example 4b: A reactor was charged with 2-chloro-N-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y1, 10.5 g, 95% purity, 33.8 mmol), KSCN (4.67 g, 50 mmol, 1.4 equiv), K2CO3(233 mg, 2 mmol, 0.05 equiv), and EtOAc (45.3 g). The reaction mixture was heated at 60 °C for 24 h. The reaction mixture was cooled to RT and washed with water (62 g). The layers were separated, and the organic layer was washed with a 10% aqueous solution of NaCl (67 g). Solvent exchange from EtOAc to toluene provided 2-imino-3-(5- methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a) as a 11.6 wt.% solution in toluene (87.8 g, 95% yield). The toluene solution of 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a) was used directly in the final coupling step.

[0152] A separate reactor was charged with toluene (158 g) and 15 wt.% phosgene in toluene (44.4 g, 67.4 mmol). A solution containing 2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4- triazol-3-yl)aniline (X1) in toluene (167 g, 5.46 wt.% solution, 26.9 mmol) was added over ~20 min at RT to the reactor containing the phosgene solution. This mixture was stirred for 60 minutes. Triethylamine (6.8 g, 67 mmol) was added, and the mixture was stirred at RT. Upon complete consumption of starting material, the reactor was heated to 40-45 °C and phosgene / toluene were removed by distillation. The reaction mixture was then cooled to RT and the previously prepared solution of 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y1a) in toluene (87.8 g, 11.6 wt.%) was added over ~10 min at RT. This reaction mixture was stirred for 60 minutes.

[0153] The reaction mixture was quenched with water (100 g) and the mixture was stirred for 2 hours. The mixture was filtered, and the mother liquor phases were separated. The organic layer was washed with an aqueous solution of 1 N HCl (100 g) and the resulting biphasic mixture was filtered. The phases were separated, and the organic layer was concentrated in- vacuo. Methanol (100 g) was added, and the reaction mixture was cooled to 10 °C. The mixture was filtered and washed with methanol (20 g) followed by water (14.6 g). The isolated solid was dried in a vacuum oven (55-60 °C, 100-250 Torr) to afford the title compound (Z1-Form A) as a pale brown solid (14.6 g, 97 wt.% purity, 77% yield): Analytical data matched that from above and PXRD matched that of Form A.

[0154] Example 5. Preparation of crystalline forms of Z1 - Forms B-F

[0155] Example 5a (Preparation of Z1-Form B): Z1-Form A (1 g) was dissolved in acetone (3.5 mL) at higher temperatures. The mixture was cooled to 15 ℃ and heptane (7.5 mL) was added. The resulting solid was filtered, washed and dried at RT followed by drying at 60 ℃ under vacuum. PXRD: 6.5, 24.9, 24.5, 12.3, 20.7, 9.1, 15.3± 0.2 °2θ; DSC: 120.2 &185.63 °C (melting).

[0156] Example 5b (Preparation of Z1-Form C): Z1-Form A (25 mg) was dissolved in 125 uL of a 10% water / THF solution at room temperature. The sample was heated to 50 °C for approx.30 mins, then slowly cooled to 5 °C at 0.1 °C / min and held overnight. The sample was then evaporated at room temperature to produce solids that were filtered and analyzed. PXRD: 22.4, 23.4, 18.0, 6.2, 24.6, 12.4, 13.8, 5.0, 18.7 ± 0.2 °2θ; DSC: 104.6 & 184.7 °C (melting).

[0157] Example 5c (Preparation of Z1-Form D): Z1-Form A (100 mg) was dissolved in chlorobenzene (2 mL) at higher temperatures. The mixture was cooled to 15 ℃ and heptane (10 mL) was added. The resulting solid was filtered, washed and dried at RT followed by drying at 60 ℃ under vacuum. PXRD: 18.3, 7.4, 11.9, 21.12.16.2, ± 0.2 °2θ; DSC: 179.7 &198.03 °C (melting).

[0158] Example 5d (Preparation of Z1-Form E): Z1-Form A (1 g) was dissolved in 1,4- dioxane (2 mL) at higher temperatures. The mixture was cooled to 15 ℃ and heptane (7.5 mL) was added. The resulting solid was filtered, washed and dried at RT followed by drying at 60 ℃ under vacuum. PXRD: 12.7, 5.0, 23.9, 18.9, 17.8, 18.9 ± 0.2 °2θ; DSC: 183.9 °C (melting).

[0159] Example 5e (Preparation of Z1-Form F): Z1-Form A (1 g) was dissolved in anisole (20 mL) at higher temperatures. The mixture was cooled to 15 ℃ and hexane (65 mL) was added. The resulting solid was filtered, washed and dried at RT followed by drying at 60 ℃ under vacuum. PXRD: 5.9, 23.7, 23.6, 19.9, 11.5, 20.6, 15.8, 9.2, 16.4, 23.1, 16.1 ± 0.2 °2θ; DSC: 119.1 & 186.01 °C (melting)

[0160] Example 6. Competitive Slurry Experiments

[0161] Example 6a (Competitive Slurry of Z1-Form A and Z1-amorphous):

[0162] Saturated solutions of Z1 were prepared in MeCN, toluene and MeOH by adding solid Z1-Form A to 1.5 mL of solvent in vials at 25 °C, respectively. The mixtures were filtered to remove any remaining solid. Into the saturated solution were added Z1-Form A (20 mg) and Z1-amorphous (20 mg), then the resulting slurries were left mixing at 25 °C over 3 days, respectively. The suspension mixture was filtered and left to dry at 50 °C before PXRD analysis. The solids isolated from all three solvent systems at 25 °C resulted in Z1-Form A by PXRD. Tentative

[0163] Example 6b (Competitive Slurry of Z1-Form B and Z1-amorphous):

[0164] Saturated solutions of Z1 were prepared in acetonitrile by adding solid Z1-Form A to 1.5 mL of solvent in vials at 25 °C, respectively. The mixtures were filtered to remove any remaining solid. Into the saturated solution were added Z1-Form B (20 mg) and Z1-amorphous (20 mg), then the resulting slurries were left mixing at 25 °C over 3 days, respectively. Thesuspension mixture was filtered and left to dry at 50 °C before PXRD analysis. The solid isolated from MeCN resulted in Z1-Form B by PXRD. Obse TentativeS l t T (°C)rvationsAssi nmentExample 7 (SC preparation of Z1-amorphous and Z1-Form A): The following SC Testing Samples were made using known procedures in the art and readily available components. % w / w in % w / w in Component C iti 1 C iti 2 0 2 % % % % % % % le le

Claims

CLAIMS 1. A crystalline form of (Z)-1-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl-1H-1,2,4-triazol- 3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2- ylidene)urea (Z1), and acceptable salts, solvates, hydrates, isotopes or tautomers thereof.

2. The crystalline form of Z1 according to claim 1, which is crystalline form A having the X-ray powder diffractogram substantially as shown in Figure 2. [00116] 3.The crystalline form of Z1 according to claim 1 or 2, comprising at least two of the following reflexes in any combination, with 2Ɵ values based on Cu Kα radiation (1.5418 Å): 2Ɵ + 2Ɵ + 2Ɵ + 2Ɵ +4. The crystalline form of Z1 according to claims 1 or 3, comprising at least three of the following reflexes in any combination, with 2Ɵ values based on Cu Kα radiation (1.5418 Å): 2Ɵ + 0.20 2Ɵ + 0.2018.24 24.36 18.99 24.88 5. The crystalline for4, having a melting point of 185 ℃ - 195 ℃.

6. The crystalline form of Z1 according to any of the claims 1-5, which is crystalline form A having an X-ray diffraction pattern substantially as shown in Figure 2 and / or having an IR spectrum substantially as shown in Figure 3 and / or having a Raman spectrum substantially as shown in Figure 4 and / or having a DSC curve substantially as shown in Figure 5 and / or having a melting point of 185 ℃ - 195 ℃.

7. A process for preparing the crystalline form of Z1 according to any of the claims 1-6, comprising the steps of: i) preparing a solvent matrix comprising one or more solvents and Z1; ii) transforming Z1 into a crystalline form of Z1; and iii) isolating the crystalline form of Z1.

8. The process according to claim 7, wherein the Z1 used in step i) is amorphous form of Z1 or a crystalline form of Z1.

9. The process according to claims 7-8, wherein the solvent matrix comprises a solvent selected from alcohols, ketones, esters, ethers, hydrocarbons, aprotic polar solvents, and water.

10. The process according to any of the claims 7-9, wherein the solvent matrix comprises one or more solvents selected from the group consisting of methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, tetrahydrofuran, acetonitrile, toluene, xylenes, hexanes, heptanes, cyclohexane, methylcyclohexane, dichloromethane, and water.

11. The process according to any of the claims 8-10, wherein step ii) comprises a) concentrating the solution and / or b) cooling and / or c) adding a less soluble solvent and / or d) adding crystalline seed of Z1.

12. The process according to any of the claims 8-11, wherein the process is for preparation of the crystalline form A of Z1, comprising the steps of:i) preparing a solvent matrix comprising solid Z1 and one or more solvents, wherein the solvents are selected from the group consisting of methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, tetrahydrofuran, acetonitrile, toluene, xylenes, hexanes, heptanes, cyclohexane, methylcyclohexane, dichloromethane, and water.; ii) transforming Z1 into the crystalline form A of Z1; and iii) isolating the crystalline form A of Z1.

13. A process for preparation of crystalline form A of Z1, comprising the steps of: i) conducting the reaction process illustrated in Scheme 3 to obtain Z1; and ii) isolating the crystalline form A from reaction medium.

14. A pesticidal composition comprising the crystalline form A of Z1 according to any of the claims 1-6 and at least one auxiliary.

15. The composition according to claim 14, wherein the composition is formulated as a suspension concentrate (SC), an oil-based suspension concentrate (OD), a soluble concentrate (SC), a flowable suspension (FS), water soluble granules (SG), a dispersible concentrate (DC) and an emulsifiable concentrate (EC), an emulsion seed dressing, a suspension seed dressing, a seed coating, granules (GR), microgranules (MG), a suspoemulsion (SE), or water dispersible granules (WG).

16. The composition according to claims 14 or 15, wherein the composition comprises crystalline form A of Z1 in an amount less than 40% by weight.

17. A method of control of a pest infestation comprising the step of using the composition according to any of the claims 14-16 in or near a locus of the pest infestation.

18. The method according to claim 17, wherein the pest is selected from Phyla Arthropoda, Mollusca and Nematoda.

19. The method according to claims 17-23 for the control of a pest infestation in alfalfa, almonds, apples, barley, beans, canola, corn, cotton, crucifers, flowers, fodder species (fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugarbeets, sunflowers, tobacco, tomatoes, and wheat.

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